Combination therapy comprising AOH1996 and BCL-2 inhibitor

Abstract

Provided herein are, inter alia, methods and compositions for the treatment of leukemia. The methods include administering to a subject AOH1996 or a combination of AOH1996 and a Bcl-2 inhibitor. Administration of a combined synergistic amount of the AOH1996 and the Bcl-2 inhibitor results in a surprisingly increased anti-leukemia efficacy.

Description

PATENTAttorney Docket No.: 048440-209001 WOClient Ref. No. TEC 24-041COMBINATION THERAPY COMPRISING AOH1996 AND BCL-2 INHIBITORCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 714,658, filed October 31, 2024, which is hereby incorporated by reference in its entirety and for all purposes.BACKGROUND

[0002] Acute myeloid leukemia (AML) is a frequently fatal bone marrow stem cell cancer. AML can typically be characterized by unbridled proliferation of malignant marrow stem cells with associated infection, anemia, and bleeding. Leukemic stem cells are heterogeneous cells capable of self-renewal, proliferation and differentiation. Leukemic stem cells can initiate the process of carcinogenesis, can confer drug resistance, cause cancer relapse, and additionally display phenotypic and epigenetic plasticity. In view of similarities between leukemic stem cells and hematopoietic stem cells, current treatment approaches are limited. Further, despite an increased understanding of AML biology, treatment approaches and novel therapies critical to AML management are needed.

[0003] The methods and compositions provided herein, inter alia, address this need and solve other problems in the art.BRIEF SUMMARY

[0004] In an aspect is provided a method of treating leukemia in a subject in need thereof, the method including administering to the subject an effective amount of AOH1996 and venetoclax.

[0005] In another aspect is provided a method of treating leukemia in a subject in need thereof, the method including administering to the subject an effective amount of AOH1996 and a Bcl-2 inhibitor.

[0006] In an aspect is provided a method of treating leukemia in a subject in need thereof, the method including administering to the subject an effective amount of AOH1996.

[0007] In an aspect is provided a method of inhibiting proliferation of a leukemic stem cell (LSC), the method including contacting the LSC with an effective amount of AOH1996 and venetoclax.

[0008] In another aspect is provided a method of inhibiting proliferation of a leukemic stem cell (LSC), the method including contacting the LSC with an effective amount of AOH1996 and a Bcl-2 inhibitor.

[0009] In another aspect is provided a method of inhibiting proliferation of a leukemic stem cell (LSC), the method including contacting the LSC with an effective amount of AOH1996.

[0010] In an aspect is provided a pharmaceutical composition including AOH1996, venetoclax and a pharmaceutically acceptable excipient.

[0011] In an aspect is provided a pharmaceutical composition including AOH1996, a Bcl-2 inhibitor and a pharmaceutically acceptable excipient.

[0012] In another aspect is provided a kit including AOH1996 and venetoclax.

[0013] In another aspect is provided a kit including AOH1996 and a Bcl-2 inhibitor.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG.s 1A-1L. Impact of AOH1996 (AOH) on leukemic stem cells and leukemogenesis via inhibition of mitofusion and mitochondrial metabolism. FIG. 1A. Effects of AOH (1 pM) on proliferation and apoptosis of LSC-enriched AML blasts. CD34+CD38- cells were isolated from primary MNCs (n = 4) or AML blasts (n = 4). Top, cell proliferation levels. Bottom, apoptosis levels. FIG. IB. Effects of AOH on colony formation of LSC-enriched AML blasts. CD34+CD38- AML blasts (top) or MNCs (bottom) (2 x 105cells / mL, n = 3) were treated with DMSO control (CON) or indicated doses of AOH for 24 hours, then plated in methylcellulose. After 14 days, colonies were imaged using a light microscope and counted. Data are shown as mean±SE, with triplicate determinations. Colony numbers are presented in a bar graph. FIG. 1C. Unsupervised hierarchical clustering of significantly different (adj. p <0.05) metabolites from primary CD34+ AML blasts treated with AOH (0.5 pM), DMSO or Non-treat controls for 24 hours. Metabolite changes were displayed as a heat map. FIG.s 1D-1F Primary CD34+CD38- AML blasts were treated with VEH or AOH (1 pM) for 24 hours. FIG. ID. Effects of AOH on FAO (measured by3H-palmitate levels, top) and OXPHOS (indicated by OCR levels, bottom). FIG. IE. Transmission electron microscopy (TEM) imaging of mitochondria. Enlarged images are shown. Scale bar, 1 pm. FIG. IF. Quantification of mitochondrial length (n=30). Asterisks indicate statistically significant differences based on unpaired t-test analysis. FIG.s 1G-1J AOH effects on mitochondrial PCNA'sinteraction with 0PA1 and its impact on OPA1 stability in CD34+CD38- AML blasts treated with VEH or AOH (1 pM) for 24 hours. FIG. 1G. CD34+CD38- AML blasts were treated with AOH on dose dependent. Immunoblot analysis of mitofusion-regulated and mitochondrial metabolism- regulated proteins. FIG. 1H. Mitochondrial fractions from control or AOH (1 pM) treated cells were immunoprecipitated with anti-PCNA and immunoblotted with anti-OPAl antibodies. Input loading controls are shown. FIG. II. Cells were treated with cycloheximide (CHX, 10 pM) for indicated times in the presence of DMSO control or AOH (1 pM), and lysates were immunoblotted with anti- OPAl antibodies. FIG. 1J. CD34+CD38- AML blasts were treated with DMSO control or AOH (1 pM) for 24 hours. Left, lysates were immunoprecipitated with anti-OPAl and immunoblotted with anti-MARCH5 antibodies. Input loading controls are shown. Right, ubiquitination assay with lysates immunoprecipitated with anti-OPAl and immunoblotted with anti-Ub antibodies. FIG.s 1K-1L. Antileukemic activities of AOH in vivo. Human primary AML blasts (1.0 x 106) were injected intravenously into Esl(ko) SCID mice. After 7 days, mice were treated with vehicle control or AOH (100 mg / kg, BID, oral gavage, 3 weeks). FIG. IK. Leukemia burden, measured by the percentage of human CD45+ cells (left) and spleen size (right). FIG. IL. Left, effects of AOH treatment in vivo on FAO / OXPHOS in human CD45+ cells isolated from treated mice. FAO (top) and OXPHOS (bottom, indicated by OCR) levels were measured. Right, top, Kaplan-Meier survival curve of primary transplanted leukemic mice treated with CON (n = 10) and AOH -treated mice (n = 10). Median survival (MS): 35 days (CON), 50 days (AOH). Right, bottom, Kaplan-Meier survival curve of secondary transplanted leukemic mice treated with CON (n = 10) and AOH-treated mice (n = 10). MS: 30 days (CON), 42 days (AOH). Statistical significance determined by Log-rank (Mantel-Cox) test (p < 0.0001).

[0015] FIG.s 1M-1S. Effects of AOH1996 (AOH) on proliferation and apoptosis of AML cell lines and primary AML blasts. FIG.s 1M-1N. Effect of AOH on AML cell viability. AML cell lines Kasumi-1, U937, THP-1, Molml3, HL-60, KG-la, and MV4-11 FIG. IM. and primary AML blasts FIG. IN. (105cells) were incubated with various doses of AOH for 24 hours. Cell viability was assessed using the WST-1 proliferation assay. IC50 values: Kasumi-1, 1.732 pM; U937, 0.717 pM; THP-1, 9.096 pM; Molml3, 1.439 pM; HL-60, 2.33 pM; KG-1A, 0.91 pM; MV-4-11, 1.7637 pM; AML1 160, 14.58 pM; AML1222, 12.37 pM; AML2240, 6.434 pM. FIG.s 1O-1P. Effect of AOH on proliferation and apoptosis. AML cell lines Kasumi-1, U937, THP-1, Molml3, HL-60, KG-la, and MV4-11 (105cells) were treated with 1 pM AOH for 24 hours. FIG. IO. Cell proliferation wasmeasured by WST-1 assay. FIG. IP. Apoptosis levels were assessed using annexin V staining and flow cytometry. FIG. IQ. DNA fragmentation and PARP cleavage were analyzed by Western blot. Data are presented as mean ± SE from two independent experiments with triplicate determinations. Statistically significant differences are indicated by asterisks based on unpaired t-test analysis. FIG. 1R. Effect of AOH (1 pM) on apoptosis of LSC-enriched AML blasts. CD34+CD38- cells isolated from primary MNCs (n = 4) or AML blasts (n = 4) were treated with AOH. Top panel shows DNA fragmentation; bottom panel shows PARP cleavage levels. FIG. IS. Effect of AOH on colony formation of LSC-enriched AML blasts. CD34+CD38- AML blasts (left) or MNCs (right) (2 * 105cells / mL, n = 3) were treated with DMSO (control) or indicated doses of AOH for 24 hours, then plated in methylcellulose. After 14 days, colonies were imaged and counted using a light microscope. Representative colony images are shown.

[0016] FIG.s 2A-2I. Synergistic effects of AOH and VEN in vitro and in vivo. FIG. 2A. Synergistic effect of AOH and VEN on LSC-enriched AML blasts. Two primary CD34+CD38- AML blasts (1 x 105cells / mL, n = 3) were treated with indicated concentration of AOH and VEN. Levels of cell proliferation were evaluated and synergy score of the drug combination was calculated. Maximum (max) synergy score: 26.32 (AML1) and 22.98 (AML2). FIG.s 2B-2D. Synergistic effects of AOH and VEN on FAO / OXPHOS levels and mitochondrial fusion of LSC- enriched AML blasts. Primary CD34+CD38- AML blasts (n = 4) were treated with DMSO (CON), AOH (1 pM), VEN (20 nM), or combination of AOH and VEN for 24 hours. FIG. 2B. FAO levels. FIG. 2C. OXPHOS levels (indicated by OCR). FIG. 2D. Mitochondria length. Left, represented TEM images. Right, quantification of mitochondria length (n=30). FIG. 2E. Primary CD34+CD38- AML blasts (n=4) were treated with DMSO (CON), VEN (20 nM), AOH (1 pM), or combination of AOH and VEN for 24 hours. Top, DNA fragmentation. Bottom, PARP cleavage. FIG.s 2F-2G. Synergistic effects of AOH and VEN on MllPTD / WT / Flt3ITD / ITDAML mouse model. FIG. 2F.Experimental design for AOH and VEN combined treatment. IxlO6MllPTD / WT / Flt3ITD / ITDBM MNCs were intravenously injected into normal Ceslc(ko) B6 WT recipients. The transplanted mice were then randomly divided into 4 groups (n = 10 / group) and treated with either vehicle (CON), AOH (100 mg / kg, BID, PO, 21 days), VEN (100 mg / kg, daily, PO, 21 days) or AOH / VEN at the same doses of single agents. On day 21, 106BM MNCs cells from each treatment group were harvested for secondary transplant. FIG. 2G. Left, Kaplan-Meier survival curve of primary transplanted leukemic mice treated with CON (MS 34 days), VEN (MS 34 days), AOH (MS 43.5 days), orAOH / VEN (MS 54 days). Right, Kaplan-Meier survival curve of secondary transplanted leukemic mice treated with CON (MS 28 days), VEN (MS 32.5 days), AOH (MS 41 days), or AOH / VEN (MS 49.5 days). FIG. 2H-2L Synergistic effects of AOH and VEN on FLT3-WT PDX AML model. FIG. 2H. Experimental design for AOH and VEN combined treatment. hCD45+ BM FLT3-WT AML cells (IxlO6cells / mouse) were transplanted into Esl(ko) SCID mice to generate a cohort of AML bearing PDX mice. The transplanted mice were then randomly divided into 4 groups (n = 10 / group) and treated with either vehicle (CON), AOH (100 mg / kg, BID, PO, 21 days), VEN (100 mg / kg, daily, PO, 21 days) or AOH / VEN at the same doses of single agents. On day 21, 106BM MNCs cells from each treatment group were harvested for secondary transplant. FIG. 21. Left, Kaplan-Meier survival curve of primary transplanted leukemic mice treated with CON [median survival (MS) 41 days], VEN (MS 48 days), AOH (MS 55 days), or AOH / VEN (MS 75.5 days). Right, Kaplan-Meier survival curve of secondary transplanted leukemic mice treated with CON (MS 40 days), VEN (MS 51 days), AOH (MS 60 days), or AOH / VEN (MS 76 days).

[0017] FIG.s 2J-2L. Effects of AOH1996 (AOH) on the metabolic profile of leukemic stem cells (LSCs). FIG. 2J. Unsupervised hierarchical clustering reveals significant changes in metabolite abundances in primary CD34+ AML blasts treated with DMSO control (VEH) or AOH (0.5 pM) for 24 hours (n=4 per group), analyzed through untargeted metabolomics. FIG. 2K. Differential abundance of metabolites (Tukey p <0.05) in primary CD34+ AML blasts treated with AOH (0.5 pM) compared to DMSO or Non-treat controls or DMSO vs Non-treat for 24 hours (n=4 per group), measured using semi-targeted metabolomics assay. FIG. 2L. Glycolysis (indicated by ECAR) was measured by Seahorse assay in primary CD34+CD38- AML blasts treated with DMSO control (CON) or AOH (1 pM) for 24 hours.

[0018] FIG.s 3A-3D. Effects of AOH1996 (AOH) on mitochondrial PCNA binding with OPA1. FIG. 3A. HL-60 cells were treated with either DMSO or various concentrations of AOH for 24 hours. Cell lysates were then immunoblotted with the indicated antibodies. FIG. 3B. and FIG. 3C. Effects of AOH on mitochondrial PCNA-OPA1 binding. FIG. 3B. Left, co-crystal structure of the ZRANB3 APIM motif peptide bound to PCNA superimposed onto the PCNA co-complex. Right, the AOH1996-1LE compound within the APIM-motif binding pocket potentially blocks OPA1 peptide binding. FIG. 3C. The AOH1996-1LE compound binds to PCNA, causing steric clashes with residues V1282 and Lysl280. This binding modifies the APIM motif binding pocket,potentially disrupting interaction with the 0PA1 peptide. Conformational changes in the interdomain-connector loop (Glnl25-Ilel28) and the loop formed by Ala231-Pro234 may further impair binding between OPA1 and PCNA. FIG. 3D. Effects of AOH on OPA1 expression in mitochondria. Primary CD34+CD38- AML blasts were treated with either DMSO or AOH (1 pM) for 24 hours. Cells were stained with anti-TOM20 and anti-OPAl antibodies, and images were captured using a confocal microscope. Scale bar, 10 pm.

[0019] FIG.s 4A-4B. Synergistic effect of AOH1996 (AOH) and venetoclax (VEN) in vivo. IxlO6MllpTD / WT / Flt3ITD / ITDBM MNCs were intravenously injected into normal Ceslc(ko) B6 WT recipients. The transplanted mice were then randomly divided into 4 groups (n = 10 / group) and treated with either vehicle (CON), AOH (100 mg / kg, BID, PO, 21 days), VEN (100 mg / kg, daily, PO, 21 days) or AOH / VEN at the same doses of single agents. On day 21, 106BM MNCs cells from each treatment group were harvested for secondary transplant. FIG. 4A. Left, WBC (xlO3) in the bone marrow (BM) of primary transplant mice. Right, representative image of the spleen. FIG. 4B. WBC (xlO3) in the peripheral blood (PB) of secondary transplant mice.

[0020] FIG.s 5A-5C. Superior efficacy of AOH 1996 (AOH) / venetoclax (VEN) / azacitidine (AZA) triple combination in targeting LSCs and suppressing leukemogenesis relative to VEN / AZA double combination. FIG.5A. Synergistic effect of the triple combination relative to the double combination of VEN / AZA. FIG. 5B. In vivo, FLT3-WT PDX AML mice were treated with AOH alone, AOH / VEN, VEN / AZA, or AOH / VEN / AZA. FIG. 5C. Triplet therapy significantly extended survival compared to both doublet (AOH / VEN / AZA: 160 vs. AOH / VEN: 83.5, p=0.0002; vs.VEN / AZA: 87.5, p=0.0083) (left panel). In a 2nd transplantation, mice receiving BM from triplet- treated donors also showed significantly prolonged survival versus both doublet groups (AOH / VEN / AZA: 120 days vs. AOH / VEN: 69 days, p<0.0001; vs. VEN / AZA: 71 days, p<0.0001) (right panel).DETAILED DESCRIPTION

[0021] While various embodiments and aspects of the present invention are shown and described herein, it will be obvious to those skilled in the art that such embodiments and aspects are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that variousalternatives to the embodiments of the invention described herein may be employed in practicing the invention.

[0022] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, without limitation, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.

[0023] The following definitions are included for the purpose of understanding the present subject matter and for constructing the appended patent claims. Abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0024] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. See, e.g., Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of this disclosure. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.

[0025] Throughout the description and claims of this specification the word “comprise” and other forms of the word, such as “comprising” and “comprises,” means including but not limited to, and is not intended to exclude, for example, other components.

[0026] As used herein, the terms "includes" or “including” are used to indicate that the list of elements or steps that follow is not exhaustive. This means that additional elements or steps may be present in the invention, even if they are not explicitly mentioned. The terms "includes" or “including” are synonymous with "comprising" and are considered open-ended, allowing for the inclusion of other unrecited elements or steps.

[0027] As used herein, the terms “consists” or "consisting of' are used as closed-ended terms that exclude any element, step, or ingredient not specifically mentioned after the term. Use of the terms“consists” or "consisting of means that the recited feature is limited to only those components and does not allow for the inclusion of any additional elements.

[0028] The term “about” refers to any minimal alteration in the concentration or amount of an agent that does not change the efficacy of the agent in preparation of a formulation and in treatment of a disease or disorder. The term “about” with respect to concentration range of the agents (e.g., therapeutic / active agents) of the current disclosure also refers to any variation of a stated amount or range which would be an effective amount or range. In embodiments, the term "about" means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about means the specified value.

[0029] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it is understood that the particular value forms another aspect. It is further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. It is also understood that throughout the application, data are provided in a number of different formats and that this data represent endpoints and starting points and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0030] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0031] A "cell" as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the artincluding, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaryotic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. The term “cell” as used herein also refers to individual cells, cell lines, or cultures derived from such cells. A “culture” refers to a composition comprising isolated cells of the same or a different type. In embodiments, the cell is in vivo (e.g. within a subject, a patient). In embodiments, the cell is in situ. In embodiments, the cell is in vitro. In embodiments, a cell (e.g. LSC, leukemia cell) may be derived from a subject. For example, in embodiments, the cell may be in or derived from a biological sample obtained from the subject. In embodiments, the cell is a cancer cell. In embodiments, the cancer cell is a leukemia cell. In embodiments, the cell is a leukemic stem cell (LSC).

[0032] “Leukemic stem cell” or “LSC” is used in accordance with its plain ordinary meaning in the art and refers to a malignant stem cell capable of differentiating into a hematopoietic cancer cell (e.g. leukemia cell). In embodiments, an LSC is capable of self-renewal, thereby allowing proliferation of the LSC. In embodiments, a LSC remains as an undifferentiated hematopoietic blast. In embodiments, the LSC differentiates into a leukemia cell.

[0033] The term “isolated”, when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified. In embodiments, when referring to a cell, the term “isolated” means that the cell is separated from the organism from which it is originally derived. In embodiments, when referring to a cancer cell, the term “isolated” means that the cell is isolated from non-cancer cells (e.g. healthy cells). In embodiments, when applied to a leukemia cell, the term “isolated” means that the leukemia cell is isolated from other leukocytes (e.g. healthy or non-cancer leukocytes).

[0034] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, ' -carboxy glutamate, and O- phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[0035] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0036] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. A "fusion protein" refers to a chimeric protein encoding two or more separate protein sequences that are recombinantly expressed as a single moiety.

[0037] An amino acid or nucleotide base "position" is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations, fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. Forexample, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0038] The terms "numbered with reference to" or "corresponding to," when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence. An amino acid residue in a protein "corresponds" to a given residue when it occupies the same essential structural position within the protein as the given residue. One skilled in the art will immediately recognize the identity and location of residues corresponding to a specific position in a protein (e.g., Blc-2) in other proteins with different numbering systems. For example, by performing a simple sequence alignment with a protein (e.g., Blc-2) the identity and location of residues corresponding to specific positions of the protein are identified in other protein sequences aligning to the protein. For example, a selected residue in a selected protein corresponds to glutamic acid at position 138 when the selected residue occupies the same essential spatial or other structural relationship as a glutamic acid at position 138. In some embodiments, where a selected protein is aligned for maximum homology with a protein, the position in the aligned selected protein aligning with glutamic acid 138 is the to correspond to glutamic acid 138. Instead of a primary sequence alignment, a three-dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the glutamic acid at position 138, and the overall structures compared. In this case, an amino acid that occupies the same essential position as glutamic acid 138 in the structural model is the to correspond to the glutamic acid 138 residue.

[0039] "Conservatively modified variants" applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, "conservatively modified variants" refers to those nucleic acids that encode identical or essentially identical amino acid sequences. Because of the degeneracy of the genetic code, a number of nucleic acid sequences will encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, atevery position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide is implicit in each described sequence.

[0040] As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the disclosure.

[0041] The following eight groups each contain amino acids that are conservative substitutions for one another:1) Alanine (A), Glycine (G);2) Aspartic acid (D), Glutamic acid (E);3) Asparagine (N), Glutamine (Q);4) Arginine (R), Lysine (K);5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V);6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W);7) Serine (S), Threonine (T); and8) Cysteine (C), Methionine (M)(see, e.g., Creighton, Proteins (1984)).

[0042] The terms "identical" or percent "identity," in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site http: / / www.ncbi.nlm.nih.gov / BLAST / or the like). Such sequences are then said to be "substantially identical." This definition also refers to, or may be applied to, the compliment of a test sequence. The definition also includes sequences that have deletions and / or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps and the like. Preferably, identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50- 100 amino acids or nucleotides in length.

[0043] "Percentage of sequence identity" is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.

[0044] A "comparison window", as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of, e.g., a full length sequence or from 20 to 600, about 50 to about 200, or about 100 to about 150 amino acids or nucleotides in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman (1970) Adv. Appl. Math.2:482c, by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by the search for similarity method of Pearson and Lipman (1988) roc. Nat ’I. Acad. Sei. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Ausubel etal., Current Protocols in Molecular Biology (1995 supplement)).

[0045] An example of an algorithm that is suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nuc. Acids Res. 25:3389-3402, and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http: / / www.ncbi.nlm.nih.gov / ). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment.The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, an expectation (E) or 10, M=5, N=-4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word length of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89: 10915) alignments (B) of 50, expectation (E) of 10, M=5, N=-4, and a comparison of both strands.

[0046] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul (1993) roc. Natl. Acad. Set. USA 90:5873-5787). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.

[0047] An indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross reactive with the antibodies raised against the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, where the two peptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules or their complements hybridize to each other under stringent conditions, as described below. Yet another indication that two nucleic acid sequences are substantially identical is that the same primers can be used to amplify the sequence.

[0048] The term “Bcl-2 protein” or “Bcl-2” as used herein includes any of the recombinant or naturally-occurring forms of Bcl-2 protein, also known as Apoptosis regulator Bcl-2, or variants or homologs thereof that maintain Bcl-2 activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to Bcl-2). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring Bcl-2 protein. In embodiments, the Bcl-2 protein is substantially identical to the protein identified by the UniProt reference number P10415 or a variant or homolog having substantial identity thereto.

[0049] The term “Bcl-XL protein" or “Bcl-XL” as used herein includes any of the recombinant or naturally-occurring forms of Bcl-XL protein, also known as Bcl-2-like protein 1, Apoptosis regulator BcLX or variants or homologs thereof that maintain Bcl-XL activity (e g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to Bcl-XL). Tn someaspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring Bcl-XL protein. In embodiments, the Bcl-XL protein is substantially identical to the protein identified by the UniProt reference number Q07817 or a variant or homolog having substantial identity thereto.

[0050] The term “Blc-W protein" or “Blc-W” as used herein includes any of the recombinant or naturally-occurring forms of Blc-W protein, also known as Bcl-2-like protein 2, Bcl2-L-2, Apoptosis regulator Bcl-W or variants or homologs thereof that maintain Blc-W activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to Blc-W). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring Blc-W protein. In embodiments, the Blc-W protein is substantially identical to the protein identified by the UniProt reference number Q92843 or a variant or homolog having substantial identity thereto.

[0051] The term “Mcl-1 protein" or “Mcl-1” as used herein includes any of the recombinant or naturally-occurring forms of Mcl-1 protein, also known as Induced myeloid leukemia cell differentiation protein Mcl-1, Bcl-2-like protein 3, Bcl2-L-3, Bcl-2-related protein EAT / mcll, mcll / EAT or variants or homologs thereof that maintain Mcl-1 activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to Mcl-1). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring Mcl-1 protein. In embodiments, the Mcl-1 protein is substantially identical to the protein identified by the UniProt reference number Q07820 or a variant or homolog having substantial identity thereto.

[0052] The term “PCNA protein” or “PCNA” as used herein includes any of the recombinant or naturally-occurring forms of proliferating cell nuclear antigen (PCNA) protein, also known as cyclin, or variants or homologs thereof that maintain PCNA activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to PCNA). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200continuous amino acid portion) compared to a naturally occurring PCNA protein. In embodiments, the PCNA protein is substantially identical to the protein identified by the UniProt reference number P12004 or a variant or homolog having substantial identity thereto.

[0053] The term “MARCH5 protein” or “MARCH5” as used herein includes any of the recombinant or naturally-occurring forms of MARCH5 protein, also known as E3 ubiquitin-protein ligase MARCHF5, Membrane-associated RING finger protein 5, or variants or homologs thereof that maintain MARCH5 activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to MARCH5). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring MARCH5 protein. In embodiments, the MARCH5 protein is substantially identical to the protein identified by the UniProt reference number Q9NX47 or a variant or homolog having substantial identity thereto.

[0054] “Patient,” “subject,” “patient in need thereof,” and “subject in need thereof’ are herein used interchangeably and refer to a living organism suffering from or prone to a disease (e.g. leukemia) or condition that can be treated by administration using the methods and compositions provided herein. Thus, in embodiments, “subject” refers to a living organism having leukemia (e.g. AML). Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human. Tissues, cells (e.g. leukemia cells, LSCs) and their progeny of a biological entity obtained in vitro or cultured in vitro are also contemplated.

[0055] The terms “treating”, or “treatment” refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. The term "treating" and conjugations thereof, may include prevention of an injury,pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing.

[0056] As used herein, “treating” or “treatment of’ a condition, disease or disorder or symptoms associated with a condition, disease or disorder refers to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of condition, disorder or disease, stabilization of the state of condition, disorder or disease, prevention of development of condition, disorder or disease, prevention of spread of condition, disorder or disease, delay or slowing of condition, disorder or disease progression, delay or slowing of condition, disorder or disease onset, amelioration or palliation of the condition, disorder or disease state, and remission, whether partial or total. “Treating” can also mean prolonging survival of a subject beyond that expected in the absence of treatment. “Treating” can also mean inhibiting the progression of the condition, disorder or disease, slowing the progression of the condition, disorder or disease temporarily, although in some instances, it involves halting the progression of the condition, disorder or disease permanently. As used herein the terms treatment, treat, or treating refers to a method of reducing the effects of one or more symptoms of a disease or condition characterized by expression of the protease or symptom of the disease or condition characterized by expression of the protease. Thus, in the disclosed method, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease, condition, or symptom of the disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject as compared to a control. Thus, the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition. Further, as used herein, references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level and such terms can include but do not necessarily include complete elimination.

[0057] The terms "prevent," "preventing," or "prevention," and other grammatical equivalents as used herein, include to keep from developing, occur, hinder or avert a disease or conditionsymptoms as well as to decrease the occurrence of symptoms. The prevention may be complete (i.e., no detectable symptoms) or partial, so that fewer symptoms are observed than would likely occur absent treatment. The terms further include a prophylactic benefit. For a disease or condition to be prevented, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[0058] A "control" sample or value refers to a sample that serves as a reference, usually a known reference, for comparison to a test sample. For example, a test sample can be taken from a test condition (e.g. leukemia), e.g., in the presence of a test compound, and compared to samples from known conditions, e.g., in the absence of the test compound (negative control), or in the presence of a known compound (positive control). In embodiments, the test sample is taken from a subject who has leukemia in the presence of a composition (AOH1996, combination of AOH1996 and Bcl-2 inhibitor (e.g. venetoclax)) provided herein including embodiments thereof and compared to a sample from a subject who has leukemia in the absence of a composition (AOH1996, combination of AOH1996 and Bcl-2 inhibitor (e.g. venetoclax)) provided herein including embodiments thereof. In embodiments, the test sample is taken from a subject who has leukemia in the presence of a double combination therapy (e.g. combination of AOH1996 and Bcl-2 inhibitor) provided herein including embodiments thereof and compared to a sample taken from a subject who has leukemia in the presence of a single therapy. In embodiments, the test sample is taken from a subject who has leukemia in the presence of a triple combination therapy (e.g. combination of AOH1996, Bcl-2 inhibitor, chemotherapy (e.g. hypomethylating agent (azacitidine))) provided herein including embodiments thereof and compared to a sample taken from a subject who has leukemia in the presence of a single therapy or a double combination therapy provided herein including embodiments thereof. A control can also represent an average value gathered from a number of tests or results. One of skill in the art will recognize that controls can be designed for assessment of any number of parameters. For example, a control can be devised to compare therapeutic benefit based on pharmacological data ( .g., half-life) or therapeutic measures e.g., comparison of side effects). One of skill in the art will understand which controls are valuable in a given situation and be able to analyze data based on comparisons to control values. Controls are also valuable for determining the significance of data. For example, if values for a given parameter are widely variant in controls, variation in test samples will not be considered as significant.

[0059] “ Control” or “control experiment” may refer to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity of a protein (e.g. a Bcl-2 family protein) in the absence of a composition (e.g. AOH1996 and Bcl-2 inhibitor (venetoclax)) as described herein (including embodiments and examples). In embodiments, a control is the measurement of cell (LSC, leukemia cell) proliferation or apoptosis in the absence of a composition as described herein.

[0060] “Biological sample” or “sample” refer to materials obtained from or derived from a subject or patient. A biological sample includes sections of tissues such as biopsy and autopsy samples, and frozen sections taken for histological purposes. Such samples include bodily fluids such as blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, and the like), sputum, tissue, cultured cells (e.g., primary cultures, explants, and transformed cells) stool, urine, immune cells, hematopoietic cells, fibroblasts, macrophages, T cells, etc. A biological sample is typically obtained from a eukaryotic organism, such as a mammal such as a primate e.g., chimpanzee or human; cow; dog; cat; a rodent, e.g., guinea pig, rat, mouse; rabbit; or a bird; reptile; or fish. In embodiments, the biological sample is obtained from a subject having leukemia. In embodiments, the biological sample is a blood sample or a bone marrow sample. In embodiments, the biological sample includes a hematopoietic stem cell (HSC). In embodiments, the biological sample includes a leukemic stem cell. In embodiments, the biological sample includes a leukemia cell.

[0061] “Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. In some instances, “disease” or “condition” refers to a “cancer”. In embodiments, the cancer is leukemia.

[0062] The term "leukemia" refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic(subleukemic). Exemplary leukemias that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, acute myeloid leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, aleukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0063] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture. In embodiments, contacting refers to allowing a compound provided herein (e.g. AOH1996, Bcl-2 inhibitor (e.g. venetoclax), chemotherapy (e.g. azacitidine)) to interact or physically interact with a cell (e.g. a leukemia cell, a LSC). In some embodiments contacting includes allowing a compound (e g. AOH1996, Bcl-2 inhibitor (e.g. venetoclax), chemotherapy (e.g. azacitidine)) described herein to interact with a protein or enzyme. In embodiments, contacting refers to allowing AOH1996 to interact with a PCNA protein. In embodiments, contacting refers to allowing a Bcl-2 inhibitor to interact with a Blc-2 protein. In embodiments, contacting refers to allowing venetoclax to interact with a Blc-2 protein.

[0064] The terms “phenotype” and “phenotypic” as used herein refer to an organism’s observable characteristics such as onset or progression of disease symptoms, biochemical properties, or physiological properties.

[0065] The word "expression" or "expressed" as used herein in reference to a DNA nucleic acid sequence (e.g., a gene) means the transcriptional and / or translational product of that sequence. The level of expression of a DNA molecule in a cell may be determined on the basis of either the amount of corresponding mRNA that is present within the cell or the amount of protein encoded by that DNA produced by the cell (Sambrook et al., 1989 Molecular Cloning: A Laboratory Manual, 18.1- 18.88). When used in reference to polypeptides, expression includes any step involved in the production of a polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0066] The term "gene" means the segment of DNA involved in producing a protein; it includes regions preceding and following the coding region (leader and trailer) as well as intervening sequences (introns) between individual coding segments (exons). The leader, the trailer as well as the introns include regulatory elements that are necessary during the transcription and the translation of a gene. Further, a "protein gene product" is a protein expressed from a particular gene.

[0067] The term “recombinant” when used with reference, e.g., to a cell, or nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, recombinant cells express genes that are not found within the native (non-recombinant) form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all. Transgenic cells and animals are those that express a heterologous gene or coding sequence, typically as a result of recombinant methods.

[0068] The term “exogenous” refers to a molecule or substance (e.g., a compound, nucleic acid or protein) that originates from outside a given cell or organism. In embodiments, the Bcl-2 inhibitor provided herein including embodiments thereof is exogenous to the subject. In embodiments, the Bcl-2 inhibitor provided herein including embodiments thereof is exogenous to the cell (e.g. LSC, leukemia cell). In embodiments, the chemotherapy (e.g. hypomethylating agent) provided herein including embodiments thereof is exogenous to the subject. In embodiments, the chemotherapy (e.g. hypomethylating agent) provided herein including embodiments thereof is exogenous to the cell(e.g. LSC, leukemia cell). Conversely, the term “endogenous” refers to a molecule or substance that is native to, or originates within, a given cell or organism.

[0069] "Analog," "analogue," or "derivative" is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical agent that is structurally similar to another agent (i.e., a so-called "reference" agent) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of a chiral center of the reference agent. In some embodiments, a derivative may be a conjugate with a pharmaceutically acceptable agent, for example, phosphate or phosphonate.

[0070] As used herein, the term "salt" refers to acid or base salts of the agents used herein. Illustrative but non-limiting examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, and the like) salts, and quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.

[0071] The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolyl sulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginateand the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al.. Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present disclosure. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms. In other cases, the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with buffer prior to use.

[0072] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art.

[0073] An “adjuvant” (from Latin, adiuvare: to aid) is a pharmacological and / or immunological agent that modifies the effect of other agents.

[0074] A “diluent” (also referred to as a filler, dilutant or thinner) is a diluting agent. Certain fluids are too viscous to be pumped easily or too dense to flow from one particular point to the other. This can be problematic, because it might not be economically feasible to transport such fluids in this state. To ease this restricted movement, diluents are added. This decreases the viscosity of the fluids, thereby also decreasing the pumping / transportation costs.

[0075] The terms “administration” or “administering” refer to the act of providing an agent of the current embodiments or pharmaceutical composition including an agent of the current embodiments to the individual in need of treatment. In embodiments, administering means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow- release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole,intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.

[0076] By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of additional therapies. The compound or the composition of the disclosure can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). The preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation).

[0077] As used herein, “sequential administration” includes that the administration of two agents (e.g., the compounds or compositions described herein) occurs separately on the same day or do not occur on a same day (e.g., occurs on consecutive days).

[0078] As used herein, “concurrent administration” includes overlapping in duration at least in part. For example, when two agents (e.g., any of the agents or class of agents described herein that has bioactivity) are administered concurrently, their administration occurs within a certain desired time. The agents’ administration may begin and end on the same day. The administration of one agent can also precede the administration of a second agent by day(s) as long as both agents are taken on the same day at least once. Similarly, the administration of one agent can extend beyond the administration of a second agent as long as both agents are taken on the same day at least once. The bioactive agents / agents do not have to be taken at the same time each day to include concurrent administration.

[0079] As used herein, “intermittent administration” includes the administration of an agent for a period of time (which can be considered a “first period of administration”), followed by a time during which the agent is not taken or is taken at a lower maintenance dose (which can be considered “off-period”) followed by a period during which the agent is administered again (which can be considered a “second period of administration”). Generally, during the second phase of administration, the dosage level of the agent will match that administered during the first period of administration but can be increased or decreased as medically necessary.

[0080] As described above, in embodiments, compositions disclosed herein can be delivered orally, systemically, intravenously, subcutaneously, or intramuscularly. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. The compositions of the present disclosure may additionally include components to provide sustained release and / or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions disclosed herein can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., G o Phann. Res. 12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Phann. Pharmacol. 49:669-674, 1997).

[0081] As used herein, an “effective amount” or “therapeutically effective amount” is that amount sufficient to affect a desired biological effect, such as beneficial results, including clinical results. As such, an “effective amount” depends upon the context in which it is being applied. An effective amount may vary according to factors known in the art, such as the disease state, age, sex, and weight of the individual being treated. Several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. In addition, the compositions / formulations of this disclosure can be administered as frequently as necessary to achieve a therapeutic amount.

[0082] Pharmaceutical compositions may include compositions wherein the therapeutic drug (e.g., agents described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. When administered in methods to treat a disease, such compositions will contain an amount of therapeuticdrug effective to achieve the desired result, e.g., modulating the activity of a target molecule, and / or reducing, eliminating, or slowing the progression of disease symptoms.

[0083] The dosage and frequency (single or multiple doses) administered to a mammal can vary depending upon a variety of factors, for example, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated, kind of concurrent treatment, complications from the disease being treated or other health-related problems. Other therapeutic regimens or agents can be used in conjunction with the methods and agents of this disclosure. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the ability of those skilled in the art.

[0084] For any therapeutic agent described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of therapeutic drug(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.

[0085] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring agent’s effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

[0086] The terms “dose” and “dosage” are used interchangeably herein. A dose refers to the amount of active ingredient given to an individual at each administration. The dose will vary depending on a number of factors, including the range of normal doses for a given therapy, frequency of administration; size and tolerance of the individual; severity of the condition; risk of side effects; and the route of administration. One of skill will recognize that the dose can be modified depending on the above factors or based on therapeutic progress.

[0087] Dosages may be varied depending upon the requirements of the patient and the therapeutic drug being employed. The dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by theexistence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the agent. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered agent effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

[0088] A weight percent of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0089] “Excipient” is used herein to include any other agent that may be contained in or combined with a disclosed agent, in which the excipient is not a therapeutically or biologically active agent / agent. As such, an excipient should be pharmaceutically or biologically acceptable or relevant (for example, an excipient should generally be non-toxic to the individual). “Excipient” includes a single such agent and is also intended to include a plurality of excipients. For the purposes of the present disclosure the term “excipient” and “carrier” are used interchangeably in some embodiments of the present disclosure and said terms are defined herein as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”

[0090] As defined herein, the term “activation”, “activate”, “activating” and the like in reference to a protein refers to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state. The terms reference activation, or activating, sensitizing, or up- regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.

[0091] The terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist.

[0092] As defined herein, the term “inhibition”, “inhibit”, “inhibiting” and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g. decreasing) the activity or function ofthe protein (e.g. PCNA, Bcl-2, etc.) relative to the activity or function of the protein in the absence of the inhibitor. In embodiments inhibition means negatively affecting (e.g. decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments, inhibition refers to reduction of a disease or symptoms of disease. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g. an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g. an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation).

[0093] The terms “inhibitor,” “repressor” or “antagonist” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein (e g. PCNA, Bcl-2, etc.). The antagonist can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10- fold or lower than the expression or activity in the absence of the antagonist.

[0094] The term “inhibiting” also means reducing an effect (disease state, cancer cell proliferation, expression level of a gene / protein / mRNA, function or activity of a gene / protein / mRNA) relative to the state in the absence of a compound or composition of the present disclosure.

[0095] The term "expression" includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post- translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0096] The term “aberrant” as used herein refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity mayrefer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g. by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.

[0097] The term “signaling pathway” as used herein refers to a series of interactions between cellular and optionally extra-cellular components (e.g. proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propagated to other signaling pathway components. For example, binding of a protein with a compound as described herein may reduce signaling activity of the protein, or a downstream signaling event, resulting in changes in cell growth, proliferation, or survival.METHODS OF TREATMENT

[0098] Provided herein, inter alia, are methods for treating leukemia in a subject in need thereof including administering to the subject an effective amount of AOH1996 and venetoclax. Without wishing to be bound by scientific theory, AOH1996 inhibits and / or decreases binding of mitochondrial PCNA to mitofusion-regulating OPA1 protein. In embodiments, OPA1 binding to E3 ligase MARCH5 is increased, subsequently resulting in OPA1 degradation. In embodiments, AOH1996 induces inhibition of OPA1 activity / function decreases fatty acid oxidation (FAO), oxidative phosphorylation (OXPHOS), and induces mitochondrial fission in leukemia stem cells (LSCs). Applicant is the first to demonstrate that the combination of AOH1996 with Bcl-2 inhibitor venetoclax synergistically inhibits FAO / OXPHOS, induces mitochondrial fission, and diminishes LSC activity in leukemia cells. Applicant has further discovered that the combination of AOH1996 and venetoclax increases survival in primary and secondary transplant models of leukemia. Thus, in an aspect is provided a method of treating leukemia in a subject in need thereof, the method including administering to the subject an effective amount of AOH1996 and venetoclax.

[0099] As used herein, AOH1996 refers to the compound having the formula:, or a pharmaceutically acceptable salt thereof. In embodiments,AOH1996 is referred to herein as “AOH”.

[0100] As used herein, venetoclax refers to the compound having the formula:pharmaceutically acceptable salt thereof. The term “venetoclax,” may be referred to as VENCLEXTA®, VENCLYXTO®, GDC-0199, ABT-199, RG-7601, or the like, and refers in the usual and customary sense, to 4-(4-{ [2-(4-Chlorophenyl)-4,4- dimethyl-1 -cyclohexen- 1 -yl]methyl } - 1 -piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl)amino]phenyl]sulfonyl)-2-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (CAS Registry number 1257044-40-8), or a pharmaceutically acceptable salt thereof.

[0101] In embodiments, the effective amount is a combined synergistic amount of the AOH1996 and the venetoclax. A "combined synergistic amount" as used herein refers to the sum of a first amount (e.g., an amount of AOH1996) and a second amount (e g., an amount of venetoclax) that results in a synergistic effect (i.e. an effect greater than an additive effect). Therefore, the terms "synergy", "synergism", "synergistic", "combined synergistic amount", and "synergistic therapeutic effect" which are used herein interchangeably, refer to a measured effect of compounds administered in combination where the measured effect is greater than the sum of the individual effects of each of the compounds administered alone as a single agent.

[0102] In embodiments, a synergistic amount may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1,3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4,5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7,7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9,10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of the amount of the AOH1996 when used separately from the venetoclax. In embodiments, a synergistic amount may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0,3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3,5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6,7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9,10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of the amount of the venetoclax when used separately from the AOH1996.

[0103] The synergistic effect may be an anti-apoptotic Blc-2 protein activity decreasing effect. In embodiments, synergy between the AOH1996 and the venetoclax may result in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9,5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2,7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5,9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84,85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease (e.g., decrease of anti-apoptotic Blc-2 protein activity) than the sum of the decrease of the AOH1996 or the venetoclax when used individually and separately. In embodiments, synergy between the AOH1996and the venetoclax may result in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7,3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0,6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3,8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, or 100% greater decrease of anti-apoptotic Blc-2 protein activity than the sum of the inhibition of the AOH1996 and the venetoclax when used individually and separately.

[0104] The synergistic effect may be a leukemic stem cell (LSC) apoptosis increasing effect. In embodiments, synergy between the AOH1996 and the venetoclax may result in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9,5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2,7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5,9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84,85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase (e.g., increase ofLSC apoptosis) than the sum of the increase of the AOH1996 or the venetoclax when used individually and separately. In embodiments, synergy between the AOH1996 and the venetoclax may result in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8,1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1,4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4,6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7,8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75,76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%greater increase of LSC apoptosis than the sum of the increase of the AOH1996 or the venetoclax when used individually and separately.

[0105] The synergistic effect may be a leukemic stem cell (LSC) proliferation decreasing effect. In embodiments, synergy between the AOH1996 and the venetoclax may result in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1,7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4,9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease (e g., decrease of LSC proliferation) than the sum of the decrease of the AOH1996 or the venetoclax when used individually and separately. In embodiments, synergy between the AOH1996 and the venetoclax may result in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8,1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1,4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4,6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7,8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75,76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease of LSC proliferation than the sum of the inhibition of the AOH1996 and the venetoclax when used individually and separately.

[0106] The synergistic effect may be a leukemia cell apoptosis increasing effect. In embodiments, synergy between the AOH1996 and the venetoclax may result in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9,3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2,5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5,7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8,9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase (e.g., increase of leukemia cell apoptosis) than the sum of the increase of the AOH1996 or the venetoclax when used individually and separately. In embodiments, synergy between the AOH1996 and the venetoclax may result in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4,4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7,6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0,9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase of leukemia cell apoptosis than the sum of the increase of the AOH1996 or the venetoclax when used individually and separately.

[0107] The synergistic effect may be a leukemia cell proliferation decreasing effect. In embodiments, synergy between the AOH1996 and the venetoclax may result in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9,5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2,7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5,9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84,85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in leukemia cell proliferation than the sum of the decrease of the AOH1996 or the venetoclax when used individually and separately. In embodiments, synergy between the AOH1996 and the venetoclax may result in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7,6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater inhibition of leukemia cell proliferation than the sum of the inhibition of the AOH1996 and the venetoclax when used individually and separately.

[0108] The synergistic effect may be a leukemia-treating effect. In embodiments, the synergistic effect is acute myeloid leukemia (AML) (i.e. AML treating synergistic effect), chronic lymphocytic leukemia (CLL) (i.e. CLL treating synergistic effect), chronic myelogenous leukemia (CML) (i.e. CML treating synergistic effect), acute lymphocytic leukemia (ALL) (i.e. ALL treating synergistic effect), or small lymphocytic lymphoma (SLL) (i.e. SLL treating synergistic effect) treating effect. In embodiments, the synergistic effect is AML treating synergistic effect. In embodiments, the synergistic effect is CLL treating synergistic effect). In embodiments, the synergistic effect is CML treating synergistic effect. In embodiments, the synergistic effect is ALL treating synergistic effect In embodiments, the synergistic effect is SLL treating synergistic effect.

[0109] In embodiments, the AOH1996 and the venetoclax are administered simultaneously or sequentially. In embodiments, the AOH1996 and the venetoclax are administered simultaneously. In embodiments, the AOH1996 and the venetoclax are administered sequentially. During the course of treatment, the AOH1996 and the venetoclax may at times be administered sequentially and at other times be administered simultaneously.

[0110] The AOH1996 and the venetoclax may be administered in combination either simultaneously (e.g., as a mixture), separately but simultaneously (e.g., via separate intravenous lines) or sequentially (e.g., one agent is administered first followed by administration of the second agent). Thus, the term combination is used to refer to concomitant, simultaneous or sequential administration of the AOH1996 and the venetoclax.[OHl] In embodiments, where the AOH1996 and the venetoclax are administered sequentially, the AOH1996 is administered at a first time point and the venetoclax is administered at a second time point, wherein the first time point precedes the second time point. Alternatively, in embodiments, where the AOH1996 and the venetoclax are administered sequentially, the venetoclaxis administered at a first time point and the AOH1996 is administered at a second time point, wherein the first time point precedes the second time point.

[0112] The course of treatment is best determined on an individual basis depending on the particular characteristics of the subject and the type of treatment selected. The treatment, such as those disclosed herein, can be administered to the subject on a daily, twice daily, bi-weekly, monthly or any applicable basis that is therapeutically effective. The treatment can be administered alone or in combination with any other treatment disclosed herein or known in the art. The additional treatment can be administered simultaneously with the first treatment, at a different time, or on an entirely different therapeutic schedule (e.g., the first treatment can be daily, while the additional treatment is weekly).

[0113] In instances where the AOH1996 and the venetoclax are administered simultaneously, the AOH1996 and the venetoclax may be administered as a mixture. Thus, in embodiments, the AOH1996 and the venetoclax are admixed prior to administration.

[0114] For the methods provided herein, in embodiments, the methods further include administering an effective amount of a chemotherapy (e.g. hypomethylating agent (e.g. azacitidine)). In embodiments, the effective amount is a combined synergistic amount of the AOH1996, the venetoclax, and the chemotherapy. In embodiments, a combined synergistic amount refers to the sum of a first amount (e.g., an amount of the AOH1996), a second amount (e g., an amount of the venetoclax), and a third amount (e.g., an amount of a chemotherapy) that results in a synergistic effect (i.e. an effect greater than an additive effect).

[0115] In embodiments, a synergistic amount may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1,3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4,5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7,7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9,10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of the amount of the AOH1996 when used separately from the venetoclax and the chemotherapy. In embodiments, a synergistic amount may be about 0.1, 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1,7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4,9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of the amount of the venetoclax when used separately from the AOH1996 and the chemotherapy. In embodiments, a synergistic amount may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8,1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1,4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4,6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7,8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75,76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of the amount of the chemotherapy when used separately from the AOH1996 and the venetoclax.

[0116] In embodiments, the synergistic effect is leukemia cell death. Leukemia cell death can be quantified, for example, by a decrease in the number of leukemia cells or increase in leukemia cell apoptosis. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9,2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2,4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5,6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8,8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in number of leukemia cells than the sum of the decrease when the AOH1996, the venetoclax, and the chemotherapy are used individually and separately. In embodiments, synergybetween the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7,2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0,5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3,7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6,9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in number of leukemia cells than the sum of the decrease when the AOH1996 is used separately and individually from the venetoclax and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7,3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0,6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3,8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, or 100% greater decrease in number of leukemia cells than the sum of the decrease when the venetoclax is used separately and individually from the AOH1996 and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4,2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7,4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0,7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3,9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82,83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in numberof leukemia cells than the sum of the decrease when the chemotherapy is used separately and individually from the AOH1996 and the venetoclax.

[0117] In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about O. l, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2,4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5,6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8,8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in number of leukemia cells than the sum of the decrease when the AOH1996, the venetoclax, and the chemotherapy are used individually and separately. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8,2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1,5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4,7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7,9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in number of leukemia cells than the sum of the decrease when the AOH1996 is used separately and individually from the venetoclax and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7,3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0,6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3,8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in number of leukemia cells than the sum of the decrease when the venetoclax is used separately and individually from the AOH1996 and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4,4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7,6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0,9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in number of leukemia cells than the sum of the decrease when the chemotherapy is used separately and individually from the AOH1996 and the venetoclax.

[0118] In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9,2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2,4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5,6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8,8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in leukemia cell apoptosis than the sum of the increase when the AOH1996, the venetoclax, and the chemotherapy are used individually and separately. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7,2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0,5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3,7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6,9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in leukemia cell apoptosis than the sum of the increase when the AOH1996 is used separately and individually from the venetoclax and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7,3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0,6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3,8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, or 100% greater increase in leukemia cell apoptosis than the sum of the increase when the venetoclax is used separately and individually from the AOH1996 and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5,4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8,6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1,9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in leukemia cell apoptosis than the sum of the increase when the chemotherapy is used separately and individually from the AOH1996 and the venetoclax.

[0119] In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about O. l, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2,4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5,6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8,8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in leukemia cell apoptosis than the sum of the increase when the AOH1996, the venetoclax, and the chemotherapy are used individually and separately. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8,2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1,5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4,7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7,9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in leukemia cell apoptosis than the sum of the increase when the AOH1996 is used separately and individually from the venetoclax and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7,3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0,6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3,8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, or 100% greater increase in leukemia cell apoptosis than the sum of the increase when the venetoclax is used separately and individually from the AOH1996 and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4,4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7,6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0,9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in leukemia cell apoptosis than the sum of the increase when the chemotherapy is used separately and individually from the AOH1996 and the venetoclax.

[0120] In embodiments, the synergistic effect is decreased leukemia cell proliferation. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2,2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5,4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8,6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1,9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in leukemia cell proliferation than the sum of the decrease when the AOH19996, the venetoclax, and the chemotherapy are used individually and separately. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0,3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3,5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6,7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9,10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in leukemia cell proliferation than the sum of the decrease when the AOH1996 is used separately and individually from the venetoclax and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4,8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in leukemia cell proliferation than the sum of the decrease when the venetoclax is used separately and individually from the AOH1996 and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2,2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5,4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8,6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1,9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in leukemia cell proliferation than the sum of the decrease when the chemotherapy is used separately and individually from the AOH1996 and the venetoclax.

[0121] In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2,4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5,6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8,8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in leukemia cell proliferation than the sum of the decrease when the AOH19996, the venetoclax, and the chemotherapy are used individually and separately. In embodiments,synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9,5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2,7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5,9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84,85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in leukemia cell proliferation than the sum of the decrease when the AOH1996 is used separately and individually from the venetoclax and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1,1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4,3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7,5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0,8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99, or 100% greater decrease in leukemia cell proliferation than the sum of the decrease when the venetoclax is used separately and individually from the AOH1996 and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6,1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9,4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2,6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5,8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or100% greater decrease in leukemia cell proliferation than the sum of the decrease when the chemotherapy is used separately and individually from the AOH1996 and the venetoclax.

[0122] In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9,2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2,4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5,6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8,8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in LSC apoptosis than the sum of the increase when the AOH1996, the venetoclax, and the chemotherapy are used individually and separately. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0,3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3,5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6,7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9,10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in LSC apoptosis than the sum of the increase when the AOH1996 is used separately and individually from the venetoclax and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4,8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in LSC apoptosis than the sum of the increase when the venetoclax is used separately and individually from the AOH1996 and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7,2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0,5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3,7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6,9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in LSC apoptosis than the sum of the increase when the chemotherapy is used separately and individually from the AOH1996 and the venetoclax.

[0123] In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2,4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5,6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8,8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in LSC apoptosis than the sum of the increase when the AOH1996, the venetoclax, and the chemotherapy are used individually and separately. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1,3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4,5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7,7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9,10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in LSC apoptosis than the sum of the increase when the AOH1996 is used separately and individually from the venetoclax and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6,1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9,4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2,6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5,8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or100% greater increase in LSC apoptosis than the sum of the increase when the venetoclax is used separately and individually from the AOH1996 and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8,2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1,5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4,7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7,9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in LSC apoptosis than the sum of the increase when the chemotherapy is used separately and individually from the AOH1996 and the venetoclax.

[0124] In embodiments, the synergistic effect is decreased LSC proliferation. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1,7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4,9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in LSC proliferation than the sum of the decrease when the AOH1996, the venetoclax, and the chemotherapy are used individually and separately. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0,3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3,5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6,7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9,10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in LSC proliferation than the sum of the decrease when the AOH1996 is used separately and individually from the venetoclax and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4,8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in LSC proliferation than the sum of the decrease when the venetoclax is used separately and individually from the AOH1996 and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1,7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4,9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in LSC proliferation than the sum of the decrease when the chemotherapy is used separately and individually from the AOH1996 and the venetoclax.

[0125] In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2,4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5,6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8,8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in LSC proliferation than the sum of the decrease when the AOH1996, the venetoclax, and the chemotherapy are used individually and separately. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8,2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1,5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4,7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7,9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in LSC proliferation than the sum of the decrease when the AOH1996 is used separately and individually from the venetoclax and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6,1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9,4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2,6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5,8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or100% greater decrease in LSC proliferation than the sum of the decrease when the venetoclax is used separately and individually from the AOH1996 and the chemotherapy. In embodiments, synergy between the AOH1996, the venetoclax, and the chemotherapy results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9,5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2,7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5,9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84,85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in LSC proliferation than the sum of the decrease when the chemotherapy is used separately and individually from the AOH1996 and the venetoclax.

[0126] In embodiments, the chemotherapy is a hypomethylating agent. The term “hypomethylating agent” or “HMA” refers to a compound that decreases or inhibits DNA methylation. In embodiments, the hypomethylating agent inhibits the function or activity of DNA methyltransferase. In embodiments, the hypomethylating agent is a nucleoside or a ribonucleoside capable of incorporation into DNA. In embodiments, the nucleoside or ribonucleoside is a non- naturally occurring nucleoside or ribonucleoside or an unnatural nucleoside or ribonucleoside. Thus, in embodiments, the hypomethylating agent refers to a nucleoside or ribonucleoside analog, a synthetic nucleoside or ribonucleoside, or a nucleoside or ribonucleoside mimetic which are not found in nature. In embodiments, the hypomethylating agent covalently binds to a DNA methyltransferase, thereby inhibiting DNA synthesis and facilitating cytotoxicity. In embodiments, the hypomethylating agent is exogenous to the cell. For example, in embodiments, thehypomethylating agent does not naturally occur in the cell. Hypomethylating agents are described in further detail in Sato T, Issa JJ, Kropf P. DNA Hypomethylating Drugs in Cancer Therapy. Cold Spring Harb Perspect Med. 2017 May l;7(5):a026948. doi: 10.1101 / cshperspect.a026948. PMID: 28159832; PMCID: PMC5411681., which is incorporated herein in its entirety and for all purposes.

[0127] In embodiments, the hypomethylating agent is azacitidine, decitabine, or guadecitabine. In embodiments, the hypomethylating agent is azacitidine. In embodiments, the hypomethylating agent is decitabine. In embodiments, the hypomethylating agent is guadecitabine.

[0128] The term “azacitidine,” also known as VID AZ A®, AZADINE®, ONUREG®, Ladakamycin, U-18496, CC-486, or the like, refers in the usual and customary sense, to 4-amino-l- P-D-ribofuranosyl-l,3,5-triazin-2(l / / )-one (CAS Registry number 320-67-2), or a pharmaceutically acceptable salt thereof.

[0129] The term “decitabine,” also known as DACOGEN®, DEMYLOCAN®, 5-aza-2'- deoxy cytidine, or the like, refers in the usual and customary sense, to 4-amino-l-((2R,5R)-4- hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-l,3,5-triazin-2(lH)-one (CAS Registry number 2353-33-5), or a pharmaceutically acceptable salt thereof.

[0130] The term “guadecitabine,” or the like, refers in the usual and customary sense, to {[(2R,3S,5R)-5-(4-amino-2-oxo-l,2-dihydro-l,3,5-triazin-l-yl)-2-(hydroxymethyl)oxolan-3- yl]oxy}({[(2R,3S,5R)-5-(2-amino-6-oxo-6,9-dihydro-3H-purin-9-yl)-3-hydroxyoxolan-2- yl]methoxy})phosphinic acid (CAS Registry number 929904-85-8), or a pharmaceutically acceptable salt thereof.

[0131] For the methods provided herein, in embodiments, the AOH1996, the venetoclax, and the chemotherapy are administered simultaneously or sequentially. In embodiments, wherein the chemotherapy is azacitidine, the AOH1996, the venetoclax, and the azacitidine are administered simultaneously or sequentially. In embodiments, the AOH1996, the venetoclax, and the chemotherapy are administered simultaneously. In embodiments, the AOH1996, the venetoclax, and the chemotherapy are administered sequentially. During the course of treatment, the AOH1996, the venetoclax, and the chemotherapy may at times be administered sequentially and at other times be administered simultaneously.

[0132] The AOH1996, the venetoclax, and the chemotherapy may be administered in combination either simultaneously (e.g., as a mixture), separately but simultaneously (e.g., via separate intravenous lines) or sequentially (e.g., one agent is administered first followed by administration of the second agent and third agent; one agent is administered first followed by administration of the second agent followed by administration of the third agent). Thus, the term combination is used to refer to concomitant, simultaneous or sequential administration of the AOH1996, the venetoclax, and the chemotherapy.

[0133] For the methods provided herein, in embodiments, the leukemia is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), or acute lymphocytic leukemia (ALL). In embodiments, the leukemia is CLL. In embodiments, the leukemia is AML. In embodiments, the leukemia is CML.

[0134] For the methods provided herein, in embodiments, the subject has a relapsed leukemia, a Blc-2 inhibitor resistant leukemia, a chemotherapy resistant leukemia, or a combination thereof. In embodiments, the subject has a relapsed leukemia. As used herein, the terms “relapse”, “recurrence”, and the like in reference to cancer refers to detection of cancer after a period of time when the leukemia was not detected following treatment of the leukemia. In embodiments, the relapsed leukemia is found in the same region where it started (e.g. local recurrence). In embodiments, the relapsed leukemia is found in a different region of the body from where it started (e.g. distant recurrence). In embodiments, the relapsed leukemia is found in the lymph nodes near where it started (e.g. regional recurrence). In embodiments, the leukemia is a relapsed leukemia after administering a chemotherapy. In embodiments, the leukemia is a relapsed leukemia after administering a Bcl-2 inhibitor. In embodiments, the relapsed leukemia is chemotherapy resistant. In embodiments, the relapsed cancer is Bcl-2 inhibitor resistant.

[0135] In embodiments, the subject has a Bcl-2 inhibitor resistant leukemia. In embodiments, the subject has a chemotherapy resistant leukemia. As used herein, the terms “resistance” or “resistant” refer to lack of sensitivity or intended response of a cancer cell or cancer to a therapeutic agent (e.g. a Bcl-2 inhibitor, a chemotherapy). For example, resistance to a chemotherapy can refer to loss of the anti -cancer effects (e.g. reduction in tumor volume or tumor volume growth) of the chemotherapy. In embodiments, resistance is resistance to a chemotherapeutic. Thus, a“chemotherapeutic resistant leukemia” is leukemia that lacks sensitivity or the intended response toa chemotherapeutic. Chemotherapeutic resistance may refer to decreased sensitivity of the cancer to a chemotherapy compared to previous sensitivity to the chemotherapy. Thus, chemotherapeutic resistance may occur despite the leukemia previously responding to the chemotherapy. Chemotherapeutic resistance may refer to the ability of leukemic cells to survive and grow despite chemotherapy treatment. Similarly, Bcl-2 inhibitor resistance may refer to decreased sensitivity of the leukemia to a Bcl-2 inhibitor compared to previous sensitivity to the Bcl-2 inhibitor. Thus, the resistance to the Bcl-2 inhibitor may occur despite the leukemia previously responding to the Bcl-2 inhibitor. Bcl-2 inhibitor resistance may refer to the ability of leukemic cells to survive and grow despite treatment with a Bcl-2 inhibitor. In embodiments, the subject has chemotherapy resistance following previous sensitivity (e.g. anti-cancer effects (e.g. reduction in tumor volume or tumor volume growth)) to the chemotherapeutic. In embodiments, the subject has Bcl-2 inhibitor resistance following previous sensitivity (e.g. anti-cancer effects (e.g. reduction in tumor volume or tumor volume growth)) to the Bcl-2 inhibitor. Thus, in embodiments, the subject has a Bcl-2 inhibitor resistant cancer. In embodiments, the Bcl-2 inhibitor cancer is a venetoclax-resistant cancer.

[0136] In embodiments, the subject was previously administered a Bcl-2 inhibitor. In embodiments, the subject was previously administered a BH3 mimetic. In embodiments, the subject was previously administered a chemotherapy.

[0137] Provided herein, inter alia, are methods for treating leukemia in a subject in need thereof including administering to the subject an effective amount of AOH1996 and a Bcl-2 inhibitor. Applicant describes herein that the combination of AOH1996 and Bcl-2 inhibitor exhibits potent anti-leukemic activity both in vivo and in vitro. In embodiments, administering the combination of AOH1996 and Bcl-2 inhibitor shows decreased number of leukemic cells (leukemic burden), increased apoptosis of leukemia cells, and increased survival relative to administration of either agent alone. Thus, in an aspect is provided a method of treating leukemia in a subject in need thereof, the method including administering to the subject an effective amount of AOH1996 and a Bcl-2 inhibitor. For the methods provided herein, in embodiments, the Bcl-2 inhibitor is a Bcl-2 homology 3 (BH3) mimetic compound.

[0138] As used herein, “Bcl-2 inhibitor” refers to a compound that inhibits or decreases the activity or function of one or more of an anti-apoptotic Bcl-2 family member protein (e.g. Bcl-2, Bcl-XL, Blc-W, or Mcl-1). In embodiments, the Bcl-2 inhibitor binds to a Bcl-2 family memberprotein. In embodiments, the Bcl-2 inhibitor binds to an anti-apoptotic Bcl-2 family member protein. In embodiments, the Bcl-2 inhibitor binds to an anti-apoptotic Bcl-2 family member protein, thereby inhibiting or decreasing binding of a pro-apoptotic Bcl-2 family member protein to the anti- apoptotic Bcl-2 family member protein. In embodiments, the Bcl-2 inhibitor increases or upregulates the pro-apoptotic activity of a pro-apoptotic Bcl-2 family member protein. In embodiments, the Bcl- 2 inhibitor binds to the BH1 domain, BH2 domain, BH3 domain, or BH4 domain of an anti- apoptotic Bcl-2 family member. In embodiments, the Bcl-2 inhibitor is a BH1 mimetic, a BH2 mimetic, a BH3 mimetic, a BH4 mimetic, or a combination thereof. In embodiments, the Bcl-2 family inhibitor is a BH3 mimetic.

[0139] As used herein, “BH3 mimetic” or “BH3 mimetic compound” refer to antagonists of anti- apoptotic Bcl-2 family member proteins that function as competitive inhibitors by binding to the hydrophobic pocket of the anti-apoptotic Bcl-2 family protein, thereby inhibiting or displacing binding of a BH3 domain of a pro-apoptotic Bcl-2 family member protein (e.g. a multi-domain or BH3-only pro-apoptotic Bcl-2 protein). In embodiments, a BH3 mimetic compound inhibits or displaces binding of an amphipathic a-helix of a BH3 domain of a pro-apoptotic Bcl-2 family protein (e g. Bax, Bak) to the hydrophobic cleft of the anti-apoptotic Bcl-2 protein. The hydrophobic cleft may be formed, for example, by the BH1-BH3 domains of the anti-apoptotic Bcl- 2 family protein. In embodiments, the anti-apoptotic Bcl-2 family member protein is Bcl-2, Bcl-XL, Blc-W, or Mcl-1. In embodiments, the pro-apoptotic Blc-2 family member protein is BAX, BAK, BIM, PUMA, or NOXA. Thus, binding of a BH3 mimetic to an anti-apoptotic Bcl-2 family member results in release of pro-apoptotic BH3 proteins (e.g. BAX, BAK, BIM, PUMA, NOXA, etc.) from the binding pocket of the anti-apoptotic Bcl-2 family member protein, enabling downstream pro- apoptotic signaling. In embodiments, the BH3 mimetic compound opens pores in the mitochondrial out membrane, thereby facilitating mitochondrial-mediated apoptosis. In embodiments, the BH3 mimetic compound is exogenous to the cell. For example, in embodiments, the BH3 mimetic compound does not naturally occur in the cell.

[0140] In embodiments, the BH3 mimetic compound binds Bcl-2, Bcl-XL, Blc-W, Mcl-1, or a combination thereof. In embodiments, the BH3 mimetic compound binds Bcl-2. In embodiments, the BH3 mimetic compound binds Bcl-XL. In embodiments, the BH3 mimetic compound binds Blc- W. In embodiments, the BH3 mimetic compound binds Mcl-1. In embodiments, the BH3 mimeticcompound is venetoclax, S63845, A1331852, obatoclax, ABT-263, S55746, AMG176, AZD5991, WEHI-539, ABT-737, or a combination thereof. In embodiments, the BH3 mimetic compound is venetoclax. In embodiments, the BH3 mimetic compound is S63845. In embodiments, the BH3 mimetic compound is A1331852. In embodiments, the BH3 mimetic compound is obatoclax. In embodiments, the BH3 mimetic compound is ABT-263. In embodiments, the BH3 mimetic compound is S55746. In embodiments, the BH3 mimetic compound is AMG176. In embodiments, the BH3 mimetic compound is AZD5991. In embodiments, the BH3 mimetic compound is WEHI- 539. In embodiments, the BH3 mimetic compound is ABT-737. BH3 mimetic compounds are described in further detail in Lasica, M.; Anderson, M.A. Review of Venetoclax in CLL, AML and Multiple Myeloma. J. Pers. Med. 2021, 11, 463. https: / / doi.org / 10.3390 / jpml l060463.; Saraswathy, S.D.; Mirunalini, A.; Karthikeyan, K.; Premkumar, K. BH3 Mimetic Peptides: An Effective Strategy to Complement Anticancer Therapy, Current Protein & Peptide Science, 24: 10, pages 853-864, 2023, issn 1389-2037 / 1875-5550, doi 10.2174 / 1389203724666230822100131.; Montero, I; Haq R. Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics. Cancer Discov. 2022 May 2;12(5): 1217-1232. doi: 10.1158 / 2159-8290.CD-21-1334. PMID: 35491624; PMCID: PMC9306285.; and Parry, N., Wheadon, H. & Copland, M. The application of BH3 mimetics in myeloid leukemias. Cell Death Dis 12, 222 (2021). https: / / doi.org / 10.1038 / s41419-021-03500-6., which are incorporated herein in their entirety and for all purposes.

[0141] The term “S63845,” or the like, refers in the usual and customary sense, to (R)-2-((5-(3- chloro-2-methyl-4-(2-(4-methylpiperazin-l-yl)ethoxy)phenyl)-6-(5-fluorofuran-2-yl)thieno[2,3- d]pyrimidin-4-yl)oxy)-3-(2-((l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl)methoxy)phenyl)propanoic acid (CAS Registry number 1799633-27-4), or a pharmaceutically acceptable salt thereof.

[0142] The term “A1331852,” or the like, refers in the usual and customary sense, to 3-[l-(l- adamantylmethyl)-5-methylpyrazol-4-yl]-6-[8-(l,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-l / 7- isoquinolin-2-yl]pyridine-2-carboxylic acid (CAS Registry number 1430844-80-6), or a pharmaceutically acceptable salt thereof.

[0143] The term “obatoclax,” also known as GX15-070, GX 05-070, or the like, refers in the usual and customary sense, to 2-(2-((3,5-Dimethyl-177-pyrrol-2-yl)methylene)-3-methoxy-2 / 7-pyrrol-5- yl)-l / f-indole (CAS Registry number 803712-67-6), or a pharmaceutically acceptable salt thereof.

[0144] The term “ABT-263,” also known as Navitoclax, or the like, refers in the usual and customary sense, to 4-(4-{[2-(4-Chlorophenyl)-5,5-dimethyl-l-cyclohexen-l-yl]methyl}-l- piperazinyl)-N-[(4-{[(2R)-4-(4-morpholinyl)-l-(phenylsulfanyl)-2-butanyl]amino}-3- [(trifluoromethyl)sulfonyl]phenyl)sulfonyl]benzamide (CAS Registry number 923564-51-6), or a pharmaceutically acceptable salt thereof.

[0145] The term “S55746,” also known as BCL201, or the like, refers in the usual and customary sense, to N-(4-hydroxyphenyl)-3-[6-[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydro-lH-isoquinoline- 2-carbonyl]-l,3-benzodioxol-5-yl]-N-phenyl-5, 6, 7, 8-tetrahydroindolizine-l -carboxamide (CAS Registry number 1448584-12-0), or a pharmaceutically acceptable salt thereof.

[0146] The term “AMG176,” also known as tapotoclax, or the like, refers in the usual and customary sense, to (3lR,4S,6'R,7lS,8lE,l TS,12'R)-7-chloro-7'-methoxy-i r,12l-dimethyl-13',13l- dioxospiro[2,3-dihydro-lH-naphthalene-4,22'-20-oxa-13X6-thia-l,14- diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15'-one (CAS Registry number 1883727-34-1), or a pharmaceutically acceptable salt thereof.

[0147] The term “AZD5991,” or the like, refers in the usual and customary sense, to 17-Chloro- 5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22- pentaazaheptacyclo(27.7.1.14,7.011,15.016,21.020,24.030,35)octatriaconta- l(36),4(38),6,l l,14,16,18,20,23,29(37),30(35),31,33-tridecaene-23-carboxylic acid (CAS Registry number 2143061-81-6), or a pharmaceutically acceptable salt thereof.

[0148] The term “WEHI-539,” or the like, refers in the usual and customary sense, to (E)-5-(3-(4-(aminomethyl)phenoxy)propyl)-2-(8-(2-(benzo[d]thi azol -2 -yl)hydrazono)-5, 6,7,8- tetrahydronaphthalen-2-yl)thiazole-4-carboxylic acid (CAS Registry number 1431866-33-9), or a pharmaceutically acceptable salt thereof.

[0149] The term “ABT-737,” or the like, refers in the usual and customary sense, to 4-[4-[(4'- Chloro[l,l'-biphenyl]-2-yl)methyl]-l-piperazinyl]-N-[[4-[[(lR)-3-(dimethylamino)-l- [(phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]benzamide (CAS Registry number 852808-04-9), or a pharmaceutically acceptable salt thereof.

[0150] In embodiments, the effective amount is a combined synergistic amount of the AOH1996 and the Bcl-2 inhibitor.

[0151] In embodiments, a synergistic amount may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1,3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4,5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7,7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9,10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of the amount of the AOH1996 when used separately from the Bcl-2 inhibitor. In embodiments, a synergistic amount may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9,3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2,5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5,7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8,9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of the amount of the Bcl-2 inhibitor when used separately from the AOH1996.

[0152] The synergistic effect may be an anti-apoptotic Blc-2 protein activity decreasing effect. In embodiments, synergy between the AOH1996 and the Bcl-2 inhibitor may result in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1,7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4,9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease (e.g., decrease of anti-apoptotic Blc-2 protein activity) than the sum of the decrease of the AOH1996 or the Bcl-2 inhibitor when used individually and separately. In embodiments, synergy between the AOH1996and the Bcl-2 inhibitor may result in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3,1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6,3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9,6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2,8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69,70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,97, 98, 99, or 100% greater inhibition of anti-apoptotic Blc-2 protein activity than the sum of the inhibition of the AOH1996 and the Bcl-2 inhibitor when used individually and separately.

[0153] The synergistic effect may be a leukemic stem cell (LSC) apoptosis increasing effect. In embodiments, synergy between the AOH1996 and the Bcl-2 inhibitor may result in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1,7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4,9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase (e.g., increase of LSC apoptosis) than the sum of the increase of the AOH1996 or the Bcl-2 inhibitor when used individually and separately. In embodiments, synergy between the AOH1996 and the Bcl-2 inhibitor may result in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8,1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1,4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4,6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7,8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75,76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%greater increase (e.g., increase of LSC apoptosis) than the sum of the increase of the AOH1996 or the Bcl-2 inhibitor when used individually and separately.

[0154] The synergistic effect may be a leukemic stem cell (LSC) proliferation decreasing effect. In embodiments, synergy between the AOH1996 and the Bcl-2 inhibitor may result in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4,2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7,4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0,7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3,9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82,83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease (e g., decrease of LSC proliferation) than the sum of the decrease of the AOH1996 or the Bcl-2 inhibitor when used individually and separately. In embodiments, synergy between the AOH1996 and the Bcl-2 inhibitor may result in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4,8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater inhibition of LSC proliferation than the sum of the inhibition of the AOH1996 and the Bcl-2 inhibitor when used individually and separately.

[0155] The synergistic effect may be a leukemia cell apoptosis increasing effect. In embodiments, synergy between the AOH1996 and the Bcl-2 inhibitor may result in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8,2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1,5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4,7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7,9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase (e.g., increase of leukemia cell apoptosis) than the sum of the increase of the AOH1996 or the Bcl-2 inhibitor when used individually and separately. In embodiments, synergy between the AOH1996 and the Bcl-2 inhibitor may result in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9,4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2,6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5,8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or100% greater increase (e.g., increase of leukemia cell apoptosis) than the sum of the increase of the AOH1996 or the Bcl-2 inhibitor when used individually and separately.

[0156] The synergistic effect may be a leukemia cell proliferation decreasing effect. In embodiments, synergy between the AOH1996 and the Bcl-2 inhibitor may result in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1,7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4,9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease (e.g., decrease of leukemia cell proliferation) than the sum of the decrease of the AOH1996 or the Bcl-2 inhibitor when used individually and separately. In embodiments, synergy between the AOH1996 and the Bcl-2 inhibitor may result in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1,62, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater inhibition of leukemia cell proliferation than the sum of the inhibition of the AOH1996 and the Bel -2 inhibitor when used individually and separately.

[0157] In embodiments, the AOH1996 and the Bcl-2 inhibitor are administered simultaneously or sequentially. In embodiments, the AOH1996 and the Bcl-2 inhibitor are administered simultaneously. In embodiments, the AOH1996 and the Bcl-2 inhibitor are administered sequentially. During the course of treatment, the AOH1996 and the Bcl-2 inhibitor may at times be administered sequentially and at other times be administered simultaneously.

[0158] The AOH1996 and the Bcl-2 inhibitor may be administered in combination either simultaneously (e.g., as a mixture), separately but simultaneously (e.g., via separate intravenous lines) or sequentially (e.g., one agent is administered first followed by administration of the second agent). Thus, the term combination is used to refer to concomitant, simultaneous or sequential administration of the AOH1996 and the Bcl-2 inhibitor.

[0159] In embodiments, where the AOH1996 and the Bcl-2 inhibitor are administered sequentially, the AOH1996 is administered at a first time point and the Bcl-2 inhibitor is administered at a second time point, wherein the first time point precedes the second time point. Alternatively, in embodiments, where the AOH1996 and the Bcl-2 inhibitor are administered sequentially, the Bcl-2 inhibitor is administered at a first time point and the AOH1996 is administered at a second time point, wherein the first time point precedes the second time point.

[0160] In instances where the AOH1996 and the Bcl-2 inhibitor are administered simultaneously, the AOH1996 and the Bcl-2 inhibitor may be administered as a mixture. Thus, in embodiments, the AOH1996 and the Bcl-2 inhibitor are admixed prior to administration.

[0161] For the methods provided herein, in embodiments, the methods further include administered an effective amount of a chemotherapy. In embodiments, the effective amount of the AOH1996, the Bcl-2 inhibitor, and the chemotherapy (e.g. hypomethylating agent) is a combinedsynergistic amount of the AOH1996, the Bcl-2 inhibitor, and the chemotherapy. In embodiments, a combined synergistic amount refers to the sum of a first amount (e.g., an amount of AOH1996), a second amount (e.g., an amount of a Bcl-2 inhibitor), and a third amount (e.g., an amount of a chemotherapy) that results in a synergistic effect (i.e. an effect greater than an additive effect).

[0162] In embodiments, a synergistic amount may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1,3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4,5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7,7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9,10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of the amount of the AOH1996 when used separately from the Bcl-2 inhibitor and the chemotherapy. In embodiments, a synergistic amount may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4,2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7,4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0,7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3,9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82,83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of the amount of the Bcl-2 inhibitor when used separately from the AOH1996 and the chemotherapy. In embodiments, a synergistic amount may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4,8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or99% of the amount of the chemotherapy when used separately from the AOH1996 and the Bel -2 inhibitor.

[0163] In embodiments, the synergistic effect is leukemia cell death. Leukemia cell death can be quantified, for example, by a decrease in the number of leukemia cells or increase in leukemia cell apoptosis. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4,8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in number of leukemia cells than the sum of the decrease when the AOH1996, the Bcl-2 inhibitor, and the chemotherapy are used individually and separately. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4,4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7,6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0,9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in number of leukemia cells than the sum of the decrease when the AOH1996 is used separately and individually from the Bcl-2 inhibitor and the chemotherapy. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9,3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2,5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5,7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8,9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in number of leukemia cells than the sum of the decrease when the Bcl-2 inhibitor is used separately and individually from theAOH1996 and the chemotherapy. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3,1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6,3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9,6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2,8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69,70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,97, 98, 99, or 100% greater decrease in number of leukemia cells than the sum of the decrease when the chemotherapy is used separately and individually from the AOH1996 and the Bcl-2 inhibitor.

[0164] In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4,8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in leukemia cell apoptosis than the sum of the increase when the AOH1996, the Bcl-2 inhibitor, and the chemotherapy are used individually and separately. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4,4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7,6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0,9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in leukemia cell apoptosis than the sum of the increase when the AOH1996 is used separately and individually from the Bcl-2 inhibitor and the chemotherapy. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9,3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2,5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5,7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8,9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in leukemia cell apoptosis than the sum of the increase when the Bcl-2 inhibitor is used separately and individually from theAOH1996 and the chemotherapy. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1,1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4,3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7,5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0,8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99, or 100% greater increase in leukemia cell apoptosis than the sum of the increase when the chemotherapy is used separately and individually from the AOH1996 and the Bcl-2 inhibitor.

[0165] In embodiments, the synergistic effect is decreased leukemia cell proliferation. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results inat least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4,4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7,6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0,9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in leukemia cell proliferation than the sum of the decrease when the AOH1996, the Bel -2 inhibitor, and the chemotherapy are used individually and separately. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9,3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2,5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5,7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8,9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in leukemia cell proliferation than the sum of the decrease when the AOH1996 is used separately and individually from the Bcl-2 inhibitor and the chemotherapy. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1,1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4,3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7,5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0,8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99, or 100% greater decrease in leukemia cell proliferation than the sum of the decrease when the Bcl-2 inhibitor is used separately and individually from the AOH1996 and thechemotherapy. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4,8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in leukemia cell proliferation than the sum of the decrease when the chemotherapy is used separately and individually from the AOH1996 and the Bcl-2 inhibitor.

[0166] In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4,8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in LSC apoptosis than the sum of the increase when the AOH1996, theBcl-2 inhibitor, and the chemotherapy are used individually and separately. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1,7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4,9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in LSCapoptosis than the sum of the increase when the AOH1996 is used separately and individually from the Bcl-2 inhibitor and the chemotherapy. In embodiments, synergy between the AOH1996, the Bcl- 2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1,1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4,3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7,5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0,8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99, or 100% greater increase in LSC apoptosis than the sum of the increase when theBcl-2 inhibitor is used separately and individually from the AOH1996 and the chemotherapy. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4,4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7,6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0,9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater increase in LSC apoptosis than the sum of the increase when the chemotherapy is used separately and individually from the AOH1996 and the Bcl-2 inhibitor.

[0167] In embodiments, the synergistic effect is decreased LSC proliferation. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1,7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4,9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in LSC proliferation than the sum of the decrease when the AOH1996, the Bcl-2 inhibitor, and the chemotherapy are used individually and separately. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9,3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2,5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5,7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8,9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in LSC proliferation than the sum of the decrease when the AOH1996 is used separately and individually from the Bcl-2 inhibitor and the chemotherapy. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4,8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in LSC proliferation than the sum of the decrease when the Bcl-2 inhibitor is used separately and individually from the AOH1996 and the chemotherapy. In embodiments, synergy between the AOH1996, the Bcl-2 inhibitor, and the chemotherapy results in at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1,7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4,9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater decrease in LSC proliferation than the sum of the decrease when the chemotherapy is used separately and individually from the AOH1996 and the Bcl-2 inhibitor.

[0168] In embodiments, the chemotherapy is a hypomethylating agent. In embodiments, the hypomethylating agent is azacitidine, decitabine, or guadecitabine. In embodiments, the hypomethylating agent is azacitidine.

[0169] For the methods provided herein, in embodiments, the AOH1996, the Bcl-2 inhibitor, and the chemotherapy are administered simultaneously or sequentially. In embodiments, the AOH1996, the Bcl-2 inhibitor, and the chemotherapy are administered simultaneously. In embodiments, the AOH1996, the Bcl-2 inhibitor, and the chemotherapy are administered sequentially.

[0170] In embodiments, the leukemia is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), or acute lymphocytic leukemia (ALL).

[0171] For the method provided herein, in embodiments, the subject has a relapsed leukemia, a Blc-2 inhibitor resistant leukemia, a chemotherapy resistant leukemia, or a combination thereof. In embodiments, the subject has a Bcl-2 inhibitor resistant leukemia. In embodiments, the subject has a chemotherapy resistant leukemia.

[0172] In embodiments, the subject was previously administered a Bcl-2 inhibitor. In embodiments, the subject was previously administered a chemotherapy.

[0173] Provided herein, inter alia, are methods of treating leukemia in a subject including administering to a subject AOH1996. As described throughout the specification, Applicant has discovered that AOH1996 has potent antileukemic activity both in vivo and in vitro. Applicant has demonstrated herein that, in embodiments, AOH1996 kills LSC and increases the survival rate of animal models of leukemia. Thus, an aspect is provided a method of treating leukemia in a subject in need thereof, the method including administering to the subject an effective amount of AOH1996.

[0174] In embodiments, the method further includes administering to the subject an effective amount of a Bcl-2 inhibitor. In embodiments, the effective amount of the AOH199 and the effectiveamount of Bcl-2 inhibitor is a combined synergistic amount of the AOH1996 and the Bcl-2 inhibitor. In embodiments, the AOH1996 and the Bcl-2 inhibitor are administered simultaneously or sequentially. In embodiments, the AOH1996 and the Bcl-2 inhibitor are administered simultaneously. In embodiments, the AOH1996 and the Bcl-2 inhibitor are administered sequentially.

[0175] For the method provided herein, in embodiments, the Bcl-2 inhibitor is a BH3 mimetic. In embodiments, the BH3 mimetic is venetoclax. Thus, in embodiments, the method further includes administering to the subject an effective amount of venetoclax. In embodiments, the effective amount of the AOH199 and the effective amount of venetoclax is a combined synergistic amount of the AOH1996 and the venetoclax. In embodiments, the AOH1996 and the venetoclax are administered simultaneously or sequentially. In embodiments, the AOH1996 and the venetoclax are administered simultaneously. In embodiments, the AOH1996 and the venetoclax are administered sequentially.

[0176] In embodiments, the method further includes administering to the subject an effective amount of a chemotherapy. In embodiments, the chemotherapy is a hypomethylating agent. In embodiments, the hypomethylating agent is azacitidine. Thus, in embodiments, the method further includes administering to the subject an effective amount of azacitidine.

[0177] In embodiments, the effective amount is a combined synergistic amount of the AOH1996, the Bcl-2 inhibitor, and the chemotherapy. In embodiments, the effective amount is a combined synergistic amount of the AOH1996, the Bcl-2 inhibitor, and the azacitidine. In embodiments, the effective amount is a combined synergistic amount of the AOH1996, the venetoclax, and the chemotherapy. In embodiments, the effective amount is a combined synergistic amount of the AOH1996, the venetoclax, and the azacitidine.

[0178] In embodiments, the AOH1996, the Bcl-2 inhibitor, and the chemotherapy are administered simultaneously or sequentially. In embodiments, the AOH1996, the Bcl-2 inhibitor, and the azacitidine are administered simultaneously or sequentially. In embodiments, the AOH1996, the venetoclax, and the chemotherapy are administered simultaneously or sequentially. In embodiments, the AOH1996, the venetoclax, and the azacitidine are administered simultaneously or sequentially.

[0179] In embodiments, the leukemia is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), or acute lymphocytic leukemia (ALL). In embodiments, the leukemia AML.

[0180] In embodiments, the subject has a relapsed leukemia, a Bcl-2 inhibitor resistant leukemia, a chemotherapeutic resistant cancer, or a combination thereof.

[0181] For the methods provided herein, in embodiments, the AOH1996 may be administered at a dose of about 1 mg / kg to about 200 mg / kg of the agent (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115,116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135,136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155,156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175,176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195,196, 197, 198, 199, or 200 mg / kg). In embodiments, an effective dose of AOH1996 is administered to a subject in need thereof for treating leukemia (e.g. AML).

[0182] The AOH1996 may be administered to a subject in need thereof, at a dose between about 1 mg / kg to about 200 mg / kg of the compound, between about 5 mg / kg to about 200 mg / kg of the compound, between about 10 mg / kg to about 200 mg / kg of the compound, between about 15 mg / kg to about 200 mg / kg of the compound, between about 20 mg / kg to about 200 mg / kg of the compound, between about 25 mg / kg to about 200 mg / kg of the compound, between about 30 mg / kg to about 200 mg / kg of the compound, between about 35 mg / kg to about 200 mg / kg of the compound, between about 40 mg / kg to about 200 mg / kg of the compound, between about 45 mg / kg to about 200 mg / kg of the compound, between about 50 mg / kg to about 200 mg / kg of the compound, between about 55 mg / kg to about 200 mg / kg of the compound, between about 60 mg / kg to about 200 mg / kg of the compound, between about 65 mg / kg to about 200 mg / kg of the compound, between about 70 mg / kg to about 200 mg / kg of the compound, between about 75 mg / kg to about 200 mg / kg of the compound, between about 80 mg / kg to about 200 mg / kg of the compound, between about 85 mg / kg to about 200 mg / kg of the compound, between about 90 mg / kgto about 200 mg / kg of the compound, between about 95 mg / kg to about 200 mg / kg of the compound, between 100 about mg / kg to about 200 mg / kg of the compound, between about 105 mg / kg to about 200 mg / kg of the compound, between about 110 mg / kg to about 200 mg / kg of the compound, between about 115 mg / kg to about 200 mg / kg of the compound, between about 120 mg / kg to about 200 mg / kg of the compound, between about 125 mg / kg to about 200 mg / kg of the compound, between about 130 mg / kg to about 200 mg / kg of the compound, between about 135 mg / kg to about 200 mg / kg of the compound, between about 140 mg / kg to about 200 mg / kg of the compound, between about 145 mg / kg to about 200 mg / kg of the compound, between about 150 mg / kg to about 200 mg / kg of the compound, between about 155 mg / kg to about 200 mg / kg of the compound, between about 160 mg / kg to about 200 mg / kg of the compound, between 165 about mg / kg to about 200 mg / kg of the compound, between about 170 mg / kg to about 200 mg / kg of the compound, between about 175 mg / kg to about 200 mg / kg of the compound, between about 180 mg / kg to about 200 mg / kg of the compound, between about 185 mg / kg to about 200 mg / kg of the compound, between about 190 mg / kg to about 200 mg / kg of the compound, or between 195 about mg / kg to about 200 mg / kg of the compound.

[0183] The AOH1996 may be administered to a subject in need thereof, at a dose between about 1 mg / kg to about 195 mg / kg of the compound, between about 1 mg / kg to about 190 mg / kg of the compound, between about 1 mg / kg to about mg / kg of the compound, between about 1 mg / kg to about 185 mg / kg of the compound, between about 1 mg / kg to about 180 mg / kg of the compound, between about 1 mg / kg to about mg / kg of the compound, between about 1 mg / kg to about 175 mg / kg of the compound, between about 1 mg / kg to about 170 mg / kg of the compound, between about 1 mg / kg to about mg / kg of the compound, between about 1 mg / kg to about 165 mg / kg of the compound, between about 1 mg / kg to about mg / kg of the compound, between about 1 mg / kg to about 160 mg / kg of the compound, between about 1 mg / kg to about 155 mg / kg of the compound, between about 1 mg / kg to about 150 mg / kg of the compound, between about 1 mg / kg to about 145 mg / kg of the compound, between about 1 mg / kg to about 140 mg / kg of the compound, between about 1 mg / kg to about 135 mg / kg of the compound, between about 1 mg / kg to about 130 mg / kg of the compound, between about 1 mg / kg to about 125 mg / kg of the compound, between about 1 mg / kg to about 120 mg / kg of the compound, between about 1 mg / kg to about 115 mg / kg of the compound, between about 1 mg / kg to about 110 mg / kg of the compound, between about 1 mg / kg to about 105 mg / kg of the compound, between about 1 mg / kg to about 110 mg / kg of the compound,between about 1 mg / kg to about 105 mg / kg of the compound, between about 1 mg / kg to about 100 mg / kg of the compound, between about 1 mg / kg to about 95 mg / kg of the compound, between about 1 mg / kg to about 90 mg / kg of the compound, between about 1 mg / kg to about 85 mg / kg of the compound, between about 1 mg / kg to about 80 mg / kg of the compound, between about 1 mg / kg to about 75 mg / kg of the compound, between about 1 mg / kg to about 70 mg / kg of the compound, between about 1 mg / kg to about 65 mg / kg of the compound, between about 1 mg / kg to about 60 mg / kg of the compound, between about 1 mg / kg to about 55 mg / kg of the compound, between about 1 mg / kg to about 50 mg / kg of the compound, between about 1 mg / kg to about 45 mg / kg of the compound, between about 1 mg / kg to about 40 mg / kg of the compound, between about 1 mg / kg to about 35 mg / kg of the compound, between about 1 mg / kg to about mg / kg of the compound, between about 1 mg / kg to about 30 mg / kg of the compound, between about 1 mg / kg to about 25 mg / kg of the compound, between about 1 mg / kg to about 20 mg / kg of the compound, between about 1 mg / kg to about 15 mg / kg of the compound, between about 1 mg / kg to about 10 mg / kg of the compound, or between about 1 mg / kg to about 5 mg / kg of the compound.

[0184] In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 5 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 10 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 15 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 20 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 25 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 30 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 35 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 40 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 45 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 50 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 55 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 60 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 65 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 70 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 75 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 80 mg / kg to about 200mg / kg. In embodiments, the AOH1996 is administered at a dose of about 85 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 90 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 95 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 100 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 105 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 110 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 115 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 120 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 125 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 130 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 135 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 140 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 5 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 150 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 155 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 160 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 165 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 170 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 175 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 180 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 185 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 190 mg / kg to about 200 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 195 mg / kg to about 200 mg / kg.

[0185] In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 195 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 190 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 185 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 180 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 175 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 170 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 165mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 160 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 155 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 150 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 145 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 140 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 135 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 130 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 125 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 120 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 115 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 110 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 105 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 100 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 95 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 90 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 85 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 80 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 75 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 70 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 65 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 60 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 55 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 50 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 45 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 40 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 35 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 30 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 25 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 20 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 15 mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 10mg / kg. In embodiments, the AOH1996 is administered at a dose of about 1 mg / kg to about 5 mg / kg. In embodiments, the AOH1996 is administered with an effective dose of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111,112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131,132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151,152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171,172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191,192, 193, 194, 195, 196, 197, 198, 199, or 200 mg / kg. In embodiments, the AOH1996 may be administered with an effective dose of about 100 mg / kg. In embodiments, the AOH1996 may be administered with an effective dose of 100 mg / kg.

[0186] In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 320 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 340 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 360 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 380 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 400 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 420 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 440 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 460 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 480 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 500 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 520 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 540 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 560 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 580 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 600 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 620 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 640 mg to about 700 mg. Inembodiments, the AOH1996 is administered at a dose of about 660 mg to about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 680 mg to about 700 mg.

[0187] In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 680 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 660 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 640 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 620 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 600 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 580 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 560 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 540 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 520 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 500 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 480 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 460 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 440 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 420 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 400 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 380 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 360 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 340 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg to about 320 mg. In embodiments, the AOH1996 is administered at a dose of about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 560 mg, about 580 mg, about 600 mg, about 620 mg, about 640 mg, about 660 mg, about 680 mg, or about 700 mg. In embodiments, the AOH1996 is administered at a dose of about 600 mg. In embodiments, the AOH1996 is administered at a dose of 600 mg.

[0188] For the method provided herein, in embodiments, the AOH1996 is administered once a day, two times a day, three times a day, or four times a day. In embodiments, the AOH1996 is administered once a day. In embodiments, the AOH1996 is administered two times a day. Inembodiments, the AOH1996 is administered for about 5 to about 50 days. In embodiments, the AOH1996 is administered for about 5 to about 50 days. In embodiments, the AOH1996 is administered for about 10 to about 50 days. In embodiments, the AOH1996 is administered for about 15 to about 50 days. In embodiments, the AOH1996 is administered for about 20 to about 50 days. In embodiments, the AOH1996 is administered for about 25 to about 50 days. In embodiments, the AOH1996 is administered for about 30 to about 50 days. In embodiments, the AOH1996 is administered for about 35 to about 50 days. In embodiments, the AOH1996 is administered for about 40 to about 50 days. In embodiments, the AOH1996 is administered for about 45 to about 50 days.

[0189] In embodiments, the AOH1996 is administered for about 5 to about 45 days. In embodiments, the AOH1996 is administered for about 5 to about 40 days. In embodiments, the AOH1996 is administered for about 5 to about 35 days. In embodiments, the AOH1996 is administered for about 5 to about 30 days. In embodiments, the AOH1996 is administered for about 5 to about 25 days. In embodiments, the AOH1996 is administered for about 5 to about 20 days. In embodiments, the AOH1996 is administered for about 5 to about 15 days. In embodiments, the AOH1996 is administered for about 5 to about 10 days. In embodiments, the AOH1996 is administered for about 7 days. In embodiments, the AOH1996 is administered for 7 days. In embodiments, the AOH1996 is administered for about 21 days. In embodiments, the AOH1996 is administered for 21 days. In embodiments, the AOH1996 is administered for about 28 days. In embodiments, the AOH1996 is administered for 28 days.

[0190] In embodiments, the AOH1996 is administered two times a day for 21 days.

[0191] For the method provided herein, in embodiments, the venetoclax may be administered at a dose of about 1 mg / kg to about 200 mg / kg of the agent (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115,116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135,136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155,156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171 , 172, 173, 174, 175,176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, or 200 mg / kg). In embodiments, an effective dose of venetoclax is administered to a subject in need thereof for treating leukemia (e.g. AML).

[0192] The venetoclax may be administered to a subject in need thereof, at a dose between about 1 mg / kg to about 200 mg / kg of the compound, between about 5 mg / kg to about 200 mg / kg of the compound, between about 10 mg / kg to about 200 mg / kg of the compound, between about 15 mg / kg to about 200 mg / kg of the compound, between about 20 mg / kg to about 200 mg / kg of the compound, between about 25 mg / kg to about 200 mg / kg of the compound, between about 30 mg / kg to about 200 mg / kg of the compound, between about 35 mg / kg to about 200 mg / kg of the compound, between about 40 mg / kg to about 200 mg / kg of the compound, between about 45 mg / kg to about 200 mg / kg of the compound, between about 50 mg / kg to about 200 mg / kg of the compound, between about 55 mg / kg to about 200 mg / kg of the compound, between about 60 mg / kg to about 200 mg / kg of the compound, between about 65 mg / kg to about 200 mg / kg of the compound, between about 70 mg / kg to about 200 mg / kg of the compound, between about 75 mg / kg to about 200 mg / kg of the compound, between about 80 mg / kg to about 200 mg / kg of the compound, between about 85 mg / kg to about 200 mg / kg of the compound, between about 90 mg / kg to about 200 mg / kg of the compound, between about 95 mg / kg to about 200 mg / kg of the compound, between 100 about mg / kg to about 200 mg / kg of the compound, between about 105 mg / kg to about 200 mg / kg of the compound, between about 110 mg / kg to about 200 mg / kg of the compound, between about 115 mg / kg to about 200 mg / kg of the compound, between about 120 mg / kg to about 200 mg / kg of the compound, between about 125 mg / kg to about 200 mg / kg of the compound, between about 130 mg / kg to about 200 mg / kg of the compound, between about 135 mg / kg to about 200 mg / kg of the compound, between about 140 mg / kg to about 200 mg / kg of the compound, between about 145 mg / kg to about 200 mg / kg of the compound, between about 150 mg / kg to about 200 mg / kg of the compound, between about 155 mg / kg to about 200 mg / kg of the compound, between about 160 mg / kg to about 200 mg / kg of the compound, between 165 about mg / kg to about 200 mg / kg of the compound, between about 170 mg / kg to about 200 mg / kg of the compound, between about 175 mg / kg to about 200 mg / kg of the compound, between about 180 mg / kg to about 200 mg / kg of the compound, between about 185 mg / kg to about 200 mg / kg of the compound, between about 190 mg / kg to about 200 mg / kg of the compound, or between 195 about mg / kg to about 200 mg / kg of the compound.

[0193] The venetoclax may be administered to a subject in need thereof, at a dose between about 1 mg / kg to about 195 mg / kg of the compound, between about 1 mg / kg to about 190 mg / kg of the compound, between about 1 mg / kg to about 185 mg / kg of the compound, between about 1 mg / kg to about 180 mg / kg of the compound, between about 1 mg / kg to about 175 mg / kg of the compound, between about 1 mg / kg to about 170 mg / kg of the compound, between about 1 mg / kg to about 165 mg / kg of the compound, between about 1 mg / kg to about 160 mg / kg of the compound, between about 1 mg / kg to about 155 mg / kg of the compound, between about 1 mg / kg to about 150 mg / kg of the compound, between about 1 mg / kg to about 145 mg / kg of the compound, between about 1 mg / kg to about 140 mg / kg of the compound, between about 1 mg / kg to about 135 mg / kg of the compound, between about 1 mg / kg to about 130 mg / kg of the compound, between about 1 mg / kg to about 125 mg / kg of the compound, between about 1 mg / kg to about 120 mg / kg of the compound, between about 1 mg / kg to about 115 mg / kg of the compound, between about 1 mg / kg to about 110 mg / kg of the compound, between about 1 mg / kg to about 105 mg / kg of the compound, between about 1 mg / kg to about 100 mg / kg of the compound, between about 1 mg / kg to about 95 mg / kg of the compound, between about 1 mg / kg to about 90 mg / kg of the compound, between about 1 mg / kg to about 85 mg / kg of the compound, between about 1 mg / kg to about 80 mg / kg of the compound, between about 1 mg / kg to about 75 mg / kg of the compound, between about 1 mg / kg to about 70 mg / kg of the compound, between about 1 mg / kg to about 65 mg / kg of the compound, between about 1 mg / kg to about 60 mg / kg of the compound, between about 1 mg / kg to about 55 mg / kg of the compound, between about 1 mg / kg to about 50 mg / kg of the compound, between about 1 mg / kg to about 45 mg / kg of the compound, between about 1 mg / kg to about 40 mg / kg of the compound, between about 1 mg / kg to about 35 mg / kg of the compound, between about 1 mg / kg to about 30 mg / kg of the compound, between about 1 mg / kg to about 25 mg / kg of the compound, between about 1 mg / kg to about 20 mg / kg of the compound, between about 1 mg / kg to about 15 mg / kg of the compound, between about 1 mg / kg to about 10 mg / kg of the compound, or between about 1 mg / kg to about 5 mg / kg of the compound.

[0194] In embodiments, the venetoclax may be administered at a dose of about 1 mg / kg to about 200 mg / kg. In embodiments, the venetoclax may be administered with an effective dose of about 100 mg / kg. In embodiments, the venetoclax may be administered with an effective dose of 100 mg / kg.

[0195] In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 5 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 10 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 15 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 20 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 25 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 30 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 35 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 40 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 45 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 50 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 55 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 60 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 65 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 70 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 75 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 80 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 85 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 90 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 95 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 100 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 105 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 110 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 115 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 120 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 125 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 130 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 135 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 140 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 145 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 150 mg / kg to about 200mg / kg. In embodiments, the venetoclax is administered at a dose of about 155 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 160 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 165 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 170 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 175 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 180 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 185 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 190 mg / kg to about 200 mg / kg. In embodiments, the venetoclax is administered at a dose of about 195 mg / kg to about 200 mg / kg.

[0196] In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 195 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 190 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 185 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 180 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 175 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 170 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 165 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 160 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 155 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 150 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 145 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 140 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 135 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 130 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 125 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 120 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 115 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 110 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 105 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 100 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 95mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 90 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 85 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 80 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 75 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 70 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 65 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 60 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 55 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 50 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 45 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 40 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 35 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 30 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 25 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 20 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 15 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 10 mg / kg. In embodiments, the venetoclax is administered at a dose of about 1 mg / kg to about 5 mg / kg.In embodiments, the venetoclax is administered at a dose of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 mg.

[0197] In embodiments, the venetoclax is administered at a dose of about 200 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 220 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 240 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 260 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 280 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 300 mg to about 600 mg. Inembodiments, the venetoclax is administered at a dose of about 320 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 340 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 360 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 380 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 400 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 420 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 440 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 460 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 480 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 500 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 520 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 540 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 560 mg to about 600 mg. In embodiments, the venetoclax is administered at a dose of about 580 mg to about 600 mg.

[0198] In embodiments, the venetoclax is administered at a dose of about 200 mg to about 580 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 560 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 540 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 520 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 500 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 480 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 460 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 440 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 420 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 400 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 380 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 360 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 340 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 320 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 300 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 280 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 260 mg. Inembodiments, the venetoclax is administered at a dose of about 200 mg to about 240 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg to about 220 mg. In embodiments, the venetoclax is administered at a dose of about 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, or 600 mg. In embodiments, the venetoclax is administered at a dose of about 400 mg. In embodiments, the venetoclax is administered at a dose of 400 mg.

[0199] For the method provided herein, in embodiments, the venetoclax is administered once a day, two times a day, three times a day, or four times a day. In embodiments, the venetoclax is administered once a day. In embodiments, the venetoclax is administered for about 5 to about 50 days. In embodiments, the venetoclax is administered for about 5 to about 50 days. In embodiments, the venetoclax is administered for about 10 to about 50 days. In embodiments, the venetoclax is administered for about 15 to about 50 days. In embodiments, the venetoclax is administered for about 20 to about 50 days. In embodiments, the venetoclax is administered for about 25 to about 50 days. In embodiments, the venetoclax is administered for about 30 to about 50 days. In embodiments, the venetoclax is administered for about 35 to about 50 days. In embodiments, the venetoclax is administered for about 40 to about 50 days. In embodiments, the venetoclax is administered for about 45 to about 50 days.

[0200] In embodiments, the venetoclax is administered for about 5 to about 45 days. In embodiments, the venetoclax is administered for about 5 to about 40 days. In embodiments, the venetoclax is administered for about 5 to about 35 days. In embodiments, the venetoclax is administered for about 5 to about 30 days. In embodiments, the venetoclax is administered for about 5 to about 25 days. In embodiments, the venetoclax is administered for about 5 to about 20 days. In embodiments, the venetoclax is administered for about 5 to about 15 days. In embodiments, the venetoclax is administered for about 5 to about 10 days. In embodiments, the venetoclax is administered for about 21 days. In embodiments, the venetoclax is administered for 21 days.

[0201] In embodiments, the venetoclax is administered once daily for 21 days.

[0202] For the method provided herein, in embodiments, the AOH1996 is administered at a dose of about 100 mg / kg two times a day for about 21 days. In embodiments, the venetoclax is administered at a dose of about 100 mg / kg once a day for about 21 days. In embodiments, theAOH1996 is administered at a dose of about 100 mg / kg two times a day and the venetoclax is administered at a dose of about 100 mg / kg once a day for about 21 days.

[0203] For the method provided herein, in embodiments, the AOH1996 is administered at a dose of about 600 mg. In embodiments, the AOH1996 is administered at a dose of about 600 mg two times a day. In embodiments, the venetoclax is administered at a dose of about 400 mg. In embodiments, the venetoclax is administered at a dose of about 400 mg once a day. In embodiments, the AOH1996 is administered at a dose of about 600 mg and the venetoclax is administered at a dose of about 400 mg. In embodiments, the AOH1996 is administered at a dose of about 600 mg two times a day and the venetoclax is administered at a dose of about 400 mg once a day. In embodiments, the administration of the AOH1996 is oral administration. In embodiments, the venetoclax administration is oral administration. In embodiments, the administration of the AOH1996 is oral administration and the venetoclax administration is oral administration.

[0204] For the method provided herein, in embodiments, the azacitidine is administered at a dose of about 20 mg to about 360 mg. In embodiments, the azacitidine is administered at a dose of about 40 mg to about 360 mg. In embodiments, the azacitidine is administered at a dose of about 60 mg to about 360 mg. In embodiments, the azacitidine is administered at a dose of about 80 mg to about 360 mg. In embodiments, the azacitidine is administered at a dose of about 100 mg to about 360 mg. In embodiments, the azacitidine is administered at a dose of about 120 mg to about 360 mg. In embodiments, the azacitidine is administered at a dose of about 140 mg to about 360 mg. In embodiments, the azacitidine is administered at a dose of about 160 mg to about 360 mg. In embodiments, the azacitidine is administered at a dose of about 180 mg to about 360 mg. In embodiments, the azacitidine is administered at a dose of about 200 mg to about 360 mg. In embodiments, the azacitidine is administered at a dose of about 220 mg to about 360 mg. In embodiments, the azacitidine is administered at a dose of about 240 mg to about 360 mg. In embodiments, the azacitidine is administered at a dose of about 260 mg to about 360 mg. In embodiments, the azacitidine is administered at a dose of about 280 mg to about 360 mg. In embodiments, the azacitidine is administered at a dose of about 300 mg to about 360 mg. In embodiments, the azacitidine is administered at a dose of about 320 mg to about 360 mg. In embodiments, the azacitidine is administered at a dose of about 340 mg to about 360 mg.

[0205] In embodiments, the azacitidine is administered at a dose of about 20 mg to about 340 mg. In embodiments, the azacitidine is administered at a dose of about 20 mg to about 320 mg. In embodiments, the azacitidine is administered at a dose of about 20 mg to about 300 mg. In embodiments, the azacitidine is administered at a dose of about 20 mg to about 280 mg. In embodiments, the azacitidine is administered at a dose of about 20 mg to about 260 mg. In embodiments, the azacitidine is administered at a dose of about 20 mg to about 240 mg. In embodiments, the azacitidine is administered at a dose of about 20 mg to about 220 mg. In embodiments, the azacitidine is administered at a dose of about 20 mg to about 200 mg. In embodiments, the azacitidine is administered at a dose of about 20 mg to about 180 mg. In embodiments, the azacitidine is administered at a dose of about 20 mg to about 160 mg. In embodiments, the azacitidine is administered at a dose of about 20 mg to about 140 mg. In embodiments, the azacitidine is administered at a dose of about 20 mg to about 120 mg. In embodiments, the azacitidine is administered at a dose of about 20 mg to about 100 mg. In embodiments, the azacitidine is administered at a dose of about 20 mg to about 80 mg. In embodiments, the azacitidine is administered at a dose of about 20 mg to about 60 mg. In embodiments, the azacitidine is administered at a dose of about 20 mg to about 40 mg. In embodiments, the azacitidine is administered at a dose of about 360 mg, about 340 mg, about 320 mg, about 300 mg, about 280 mg, about 260 mg, about 240 mg, about 220 mg, about 200 mg, about 180 mg, about 160 mg, about 140 mg, about 120 mg, about 100 mg, about 80 mg, about 60 mg, about 40 mg, or about 20 mg.

[0206] In embodiments, the azacitidine is administered at a dose of about 20 mg / m2to about 150 mg / m2. In embodiments, the azacitidine is administered at a dose of about 30 mg / m2to about 150 mg / m2. In embodiments, the azacitidine is administered at a dose of about 40 mg / m2to about 150 mg / m2. In embodiments, the azacitidine is administered at a dose of about 50 mg / m2to about 150 mg / m2. In embodiments, the azacitidine is administered at a dose of about 60 mg / m2to about 150 mg / m2. In embodiments, the azacitidine is administered at a dose of about 70 mg / m2to about 150 mg / m2. In embodiments, the azacitidine is administered at a dose of about 80 mg / m2to about 150 mg / m2. In embodiments, the azacitidine is administered at a dose of about 90 mg / m2to about 150 mg / m2. In embodiments, the azacitidine is administered at a dose of about 100 mg / m2to about 150 mg / m2. In embodiments, the azacitidine is administered at a dose of about 110 mg / m2to about 150 mg / m2. In embodiments, the azacitidine is administered at a dose of about 120 mg / m2to about 150mg / m2. In embodiments, the azacitidine is administered at a dose of about 130 mg / m2to about 150 mg / m2. In embodiments, the azacitidine is administered at a dose of about 140 mg / m2to about 150 mg / m2.

[0207] In embodiments, the azacitidine is administered at a dose of about 20 mg / m2to about 140 mg / m2. In embodiments, the azacitidine is administered at a dose of about 20 mg / m2to about 130 mg / m2. In embodiments, the azacitidine is administered at a dose of about 20 mg / m2to about 120 mg / m2. In embodiments, the azacitidine is administered at a dose of about 20 mg / m2to about 110 mg / m2. In embodiments, the azacitidine is administered at a dose of about 20 mg / m2to about 100 mg / m2. In embodiments, the azacitidine is administered at a dose of about 20 mg / m2to about 90 mg / m2. In embodiments, the azacitidine is administered at a dose of about 20 mg / m2to about 80 mg / m2. In embodiments, the azacitidine is administered at a dose of about 20 mg / m2to about 70 mg / m2. In embodiments, the azacitidine is administered at a dose of about 20 mg / m2to about 60 mg / m2. In embodiments, the azacitidine is administered at a dose of about 20 mg / m2to about 50 mg / m2. In embodiments, the azacitidine is administered at a dose of about 20 mg / m2to about 40 mg / m2. In embodiments, the azacitidine is administered at a dose of about 20 mg / m2to about 30 mg / m2. In embodiments, the azacitidine is administered at a dose of about 20 mg / m2, about 30 mg / m2, about 40 mg / m2, about 50 mg / m2, about 60 mg / m2, about 70 mg / m2, about 80 mg / m2, about 90 mg / m2, about 100 mg / m2, about 110 mg / m2, about 120 mg / m2, about 130 mg / m2, about 140 mg / m2, or about 150 mg / m2. In embodiments, the azacitidine is administered at a dose of about 75 mg / m2. In embodiments, the azacitidine is administered at a dose of 75 mg / m2.

[0208] In embodiments, the azacitidine is administered for about 5 days to about 35 days. In embodiments, the azacitidine is administered for about 6 days to about 35 days. In embodiments, the azacitidine is administered for about 7 days to about 35 days. In embodiments, the azacitidine is administered for about 8 days to about 35 days. In embodiments, the azacitidine is administered for about 9 days to about 35 days. In embodiments, the azacitidine is administered for about 10 days to about 35 days. In embodiments, the azacitidine is administered for about 11 days to about 35 days. In embodiments, the azacitidine is administered for about 12 days to about 35 days. In embodiments, the azacitidine is administered for about 13 days to about 35 days. In embodiments, the azacitidine is administered for about 14 days to about 35 days. In embodiments, the azacitidine is administered for about 15 days to about 35 days. In embodiments, the azacitidine is administered forabout 16 days to about 35 days. In embodiments, the azacitidine is administered for about 17 days to about 35 days. In embodiments, the azacitidine is administered for about 18 days to about 35 days. In embodiments, the azacitidine is administered for about 19 days to about 35 days. In embodiments, the azacitidine is administered for about 20 days to about 35 days. In embodiments, the azacitidine is administered for about 21 days to about 35 days. In embodiments, the azacitidine is administered for about 22 days to about 35 days. In embodiments, the azacitidine is administered for about 23 days to about 35 days. In embodiments, the azacitidine is administered for about 24 days to about 35 days. In embodiments, the azacitidine is administered for about 25 days to about 35 days. In embodiments, the azacitidine is administered for about 26 days to about 35 days. In embodiments, the azacitidine is administered for about 27 days to about 35 days. In embodiments, the azacitidine is administered for about 28 days to about 35 days. In embodiments, the azacitidine is administered for about 29 days to about 35 days. In embodiments, the azacitidine is administered for about 30 days to about 35 days. In embodiments, the azacitidine is administered for about 31 days to about 35 days. In embodiments, the azacitidine is administered for about 32 days to about 35 days. In embodiments, the azacitidine is administered for about 33 days to about 35 days. In embodiments, the azacitidine is administered for about 34 days to about 35 days.

[0209] In embodiments, the azacitidine is administered for about 5 days to about 34 days. In embodiments, the azacitidine is administered for about 5 days to about 33 days. In embodiments, the azacitidine is administered for about 5 days to about 32 days. In embodiments, the azacitidine is administered for about 5 days to about 31 days. In embodiments, the azacitidine is administered for about 5 days to about 30 days. In embodiments, the azacitidine is administered for about 5 days to about 29 days. In embodiments, the azacitidine is administered for about 5 days to about 28 days. In embodiments, the azacitidine is administered for about 5 days to about 27 days. In embodiments, the azacitidine is administered for about 5 days to about 26 days. In embodiments, the azacitidine is administered for about 5 days to about 25 days. In embodiments, the azacitidine is administered for about 5 days to about 24 days. In embodiments, the azacitidine is administered for about 5 days to about 23 days. In embodiments, the azacitidine is administered for about 5 days to about 22 days. In embodiments, the azacitidine is administered for about 5 days to about 21 days. In embodiments, the azacitidine is administered for about 5 days to about 20 days. In embodiments, the azacitidine is administered for about 5 days to about 19 days. In embodiments, the azacitidine is administered for about 5 days to about 18 days. In embodiments, the azacitidine is administered for about 5 days toabout 17 days. In embodiments, the azacitidine is administered for about 5 days to about 16 days. In embodiments, the azacitidine is administered for about 5 days to about 15 days. In embodiments, the azacitidine is administered for about 5 days to about 14 days. In embodiments, the azacitidine is administered for about 5 days to about 13 days. In embodiments, the azacitidine is administered for about 5 days to about 12 days. In embodiments, the azacitidine is administered for about 5 days to about 11 days. In embodiments, the azacitidine is administered for about 5 days to about 10 days. In embodiments, the azacitidine is administered for about 5 days to about 9 days. In embodiments, the azacitidine is administered for about 5 days to about 8 days. In embodiments, the azacitidine is administered for about 5 days to about 7 days. In embodiments, the azacitidine is administered for about 5 days to about 6 days. In embodiments, the azacitidine is administered for about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, or about 35 days. In embodiments, the azacitidine is administered for about 7 days. In embodiments, the azacitidine is administered for about 14 days. In embodiments, the azacitidine is administered for about 21 days. In embodiments, the azacitidine is administered for about 28 days.

[0210] For the method provided herein, the AOH1996 is administered at a dose of about 600 mg, the venetoclax is administered at a dose of about 400 mg, and the azacitidine is administered at a dose of about 75 mg / m2. In embodiments, the AOH1996 is administered at a dose of about 600 mg two times a day, the venetoclax is administered at a dose of about 400 mg once a day, and the azacitidine is administered at a dose of about 75 mg / m2once a day. In embodiments, the azacitidine administration is oral administration. In embodiments, the azacitidine administration is intravenous administration.METHODS OF INHIBITING CELL PROLIFERATION

[0211] Provided herein, inter alia, are methods of inhibiting proliferation of a leukemic stem cell, including contacting the leukemic stem cell with an effective amount of AOH1996 and venetoclax. Applicant has described throughout the specification, including in the examples and figures, that the combination of AOH1996 and venetoclax potently inhibits proliferation of leukemic stem cells. Inembodiments, subjects administered a combination of AOH1996 and venetoclax show decreased proliferation of leukemic stem cells and increased survival. Cell proliferation may be measured using any method known to a person skilled in the art, including assessing cell viability by measuring metabolic activity, detecting DNA synthesis, detecting incorporation of nucleotide analogs (e.g. thymidine analogs) in newly synthesized DNA during cell proliferation, flow cytometry, and imaging. Methods for measuring cell proliferation include, but are not limited to, WST-1 cell viability and proliferation assay, CyQUANT© cell proliferation assay, and MTT assay. Thus, in an aspect is provided a method of inhibiting proliferation of a leukemic stem cell (LSC), the method including contacting the LSC with an effective amount of AOH1996 and venetoclax.

[0212] For the methods provided herein, in embodiments, the LSC is contacted with the effective amount of AOH1996 and venetoclax in vivo or in vitro. In embodiments, the LSC is contacted with the effective amount of AOH1996 and venetoclax in vivo. For example, in embodiments, the LSC is in a subject. Thus, in embodiments, the contacting includes administering to the subject the AOH1996 and the venetoclax. In embodiments, the LSC is contacted with the effective amount of AOH1996 and venetoclax in vitro. For example, in embodiments, the LSC is in a culture. Thus, in embodiments, contacting includes culturing the LSC in a culture media including the AOH1996 and venetoclax.

[0213] In embodiments, the effective amount is a combined synergistic amount of the AOH1996 and the venetoclax. In embodiments, the LSC is contacted with the AOH1996 and the venetoclax simultaneously or sequentially. In embodiments, the LSC is contacted with the AOH1996 and the venetoclax simultaneously. In embodiments, the LSC is contacted with the AOH1996 and the venetoclax sequentially.

[0214] In embodiments, the method further includes contacting the LSC with an effective amount of a chemotherapy. In embodiments, the chemotherapy is a hypomethylating agent. In embodiments, the hypomethylating agent is azacitidine, decitabine, or guadecitabine. In embodiments, the hypomethylating agent is azacitidine. Thus, in embodiments, the method further includes contacting the LSC with an effective amount of azacitidine. In embodiments, the effective amount is a combined synergistic amount of the AOH1996, the venetoclax, and the chemotherapy. In embodiments, the effective amount is a combined synergistic amount of the AOH1996, the venetoclax, and the azacitidine.

[0215] In an aspect is provided a method of inhibiting proliferation of a leukemic stem cell (LSC), the method including contacting the LSC with an effective amount of AOH1996. In embodiments, the method further includes contacting the LSC with an effective amount of a Bcl-2 inhibitor. In embodiments, the Bcl-2 inhibitor is a BH3 mimetic. In embodiments, the BH3 mimetic is venetoclax, S63845, A1331852, obatoclax, ABT-263, S55746, AMG176, AZD5991, WEHI-539, ABT-737, or a combination thereof. In embodiments, the BH3 mimetic is venetoclax. Thus, in embodiments, the method further includes contacting the LSC with an effective amount of venetoclax.

[0216] In embodiments, the effective amount of the AOH199 and the effective amount of the Bcl- 2 inhibitor is a combined synergistic amount of the AOH1996 and the Bcl-2 inhibitor. In embodiments, the effective amount of the AOH199 and the effective amount of the venetoclax is a combined synergistic amount of the AOH1996 and the venetoclax.

[0217] In embodiments, the LSC is contacted with the AOH1996 and the Bcl-2 inhibitor simultaneously or sequentially. In embodiments, the LSC is contacted with the AOH1996 and the venetoclax simultaneously or sequentially.

[0218] In embodiments, the method further includes contacting the LSC with an effective amount of a chemotherapy. In embodiments, the chemotherapy is a hypomethylating agent. In embodiments, the hypomethylating agent is azacitidine, decitabine, or guadecitabine. In embodiments, the hypomethylating agent is azacitidine. Thus, in embodiments, the method further includes contacting the LSC with an effective amount of azacitidine.

[0219] For the method provided herein, in embodiments, the effective amount is a combined synergistic amount of the AOH1996, the Bcl-2 inhibitor, and the chemotherapy. In embodiments, the effective amount is a combined synergistic amount of the AOH1996, the venetoclax, and the chemotherapy. In embodiments, the effective amount is a combined synergistic amount of the AOH1996, the venetoclax, and the azacitidine.

[0220] In embodiments, the LSC is contacted with the AOH1996 and the Bcl-2 inhibitor simultaneously or sequentially. In embodiments, the LSC is contacted with the AOH1996 and the venetoclax simultaneously or sequentially. In embodiments, the contacting is in vivo. In embodiments, the contacting is in vitro.

[0221] In another aspect is provided a method of inhibiting proliferation of a leukemic stem cell (LSC), the method including contacting the LSC with an effective amount of AOH1996 and a Bcl-2 inhibitor. In embodiments, the Bcl-2 inhibitor is a BH3 mimetic. In embodiments, the BH3 mimetic is venetoclax, S63845, A1331852, obatoclax, ABT-263, S55746, AMG176, AZD5991, WEHI-539, ABT-737, or a combination thereof.

[0222] For the methods provided herein, in embodiments, the LSC is contacted with the effective amount of AOH1996 and Bcl-2 inhibitor in vivo or in vitro. In embodiments, the LSC is contacted with the effective amount of AOH1996 and Bcl-2 inhibitor in vivo. In embodiments, the LSC is contacted with the effective amount of AOH1996 and Bcl-2 inhibitor in vitro.

[0223] In embodiments, the effective amount is a combined synergistic amount of the AOH1996 and the Bcl-2 inhibitor. In embodiments, the LSC is contacted with the AOH1996 and the Bcl-2 inhibitor simultaneously or sequentially. In embodiments, the LSC is contacted with the AOH1996 and the Bcl-2 inhibitor simultaneously. In embodiments, the LSC is contacted with the AOH1996 and the Bcl-2 inhibitor sequentially.

[0224] In embodiments, the method further includes contacting the LSC with an effective amount of a chemotherapy. In embodiments, the chemotherapy is a hypomethylating agent. In embodiments, the hypomethylating agent is azacitidine, decitabine, or guadecitabine. In embodiments, the hypomethylating agent is azacitidine. Thus, in embodiments, the method further includes contacting the LSC with an effective amount of azacitidine. In embodiments, the effective amount is a combined synergistic amount of the AOH1996, the Bcl-2 inhibitor, and the chemotherapy. In embodiments, the effective amount is a combined synergistic amount of the AOH1996, the Bcl-2 inhibitor, and the azacitidine.PHARMACEUTICAL COMPOSITIONS

[0225] The compositions including AOH1996 and venetoclax as provided herein, including embodiments thereof, are further contemplated as pharmaceutical compositions. Thus, in an aspect a pharmaceutical composition including AOH1996 and venetoclax is provided.

[0226] The provided compositions are, inter alia, suitable for formulation and administration in vitro or in vivo. Suitable carriers and excipients and their formulations are described in Remington: The Science and Practice of Pharmacy, 21st Edition, David B. Troy, ed., Lippicott Williams &Wilkins (2005). By pharmaceutically acceptable carrier is meant a material that is not biologically or otherwise undesirable, i.e., the material is administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with the other components of the pharmaceutical composition in which it is contained. If administered to a subject, the carrier is optionally selected to minimize degradation of the active ingredient and to minimize adverse side effects in the subject.

[0227] Pharmaceutical compositions provided herein include compositions wherein the active ingredient (e.g. compositions described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. When administered in methods to treat leukemia, the compositions described herein will contain an amount of active ingredient (e.g. AOH1996, venetoclax) effective to achieve the desired result, e.g., modulating the activity of a target molecule (e.g. PCNA, OPA1, Bcl-2), and / or reducing, eliminating, or slowing the progression of leukemia symptoms. Determination of a therapeutically effective amount of a compound of the invention is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.

[0228] Provided compositions can include a single agent or more than one agent. The compositions for administration will commonly include an agent as described herein dissolved in a pharmaceutically acceptable carrier, preferably an aqueous carrier. A variety of aqueous carriers can be used, e g., buffered saline and the like. These solutions are sterile and generally free of undesirable matter. These compositions may be sterilized by conventional, well known sterilization techniques. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of active agent in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the subject’s needs.

[0229] In embodiments, the pharmaceutical composition includes a first amount of the AOH1996 and a second amount of the venetoclax, wherein the first amount and the second amount provide a combined synergistic amount.

[0230] In embodiments, the pharmaceutical composition further includes a chemotherapy. In embodiments, the chemotherapy is a hypomethylating agent. In embodiments, the hypomethylating agent is azacitidine, decitabine, or guadecitabine. In embodiments, the hypomethylating agent is azacitidine. Thus, in embodiments, the pharmaceutical composition further includes azacitidine.

[0231] In embodiments, the pharmaceutical composition includes a third amount of the chemotherapy, and wherein the first amount of the AOH1996, said second amount of the venetoclax, and the third amount of the chemotherapy provide a combined synergistic amount. In embodiments, the pharmaceutical composition includes a third amount of the azacidine, and wherein the first amount of the AOH1996, said second amount of the venetoclax, and the third amount of the azacitidine provide a combined synergistic amount.

[0232] The compositions including AOH1996 and Bcl-2 inhibitor as provided herein, including embodiments thereof, are further contemplated as pharmaceutical compositions. Thus, in an aspect a pharmaceutical composition including AOH1996 and Bcl-2 inhibitor is provided. In embodiments, the Bcl-2 inhibitor is a BH3 mimetic. In embodiments, the BH3 mimetic is venetoclax, S63845, A1331852, obatoclax, ABT-263, S55746, AMG176, AZD5991, WEHI-539, ABT-737, or a combination thereof. In embodiments, the BH3 mimetic is venetoclax.

[0233] In embodiments, the pharmaceutical composition includes a first amount of the AOH1996 and a second amount of the Bcl-2 inhibitor, wherein the first amount and the second amount provide a combined synergistic amount.

[0234] In embodiments, the pharmaceutical composition further includes a chemotherapy. In embodiments, the chemotherapy is a hypomethylating agent. In embodiments, the hypomethylating agent is azacitidine, decitabine, or guadecitabine. In embodiments, the hypomethylating agent is azacitidine. Thus, in embodiments, the pharmaceutical composition further includes azacitidine.

[0235] In embodiments, the pharmaceutical composition includes a third amount of the chemotherapy, and wherein the first amount of the AOH1996, said second amount of the Bcl-2 inhibitor, and the third amount of the chemotherapy provide a combined synergistic amount. In embodiments, the pharmaceutical composition includes a third amount of the azacidine, and wherein the first amount of the AOH1996, said second amount of the Bcl-2 inhibitor, and the third amount of the azacitidine provide a combined synergistic amount.PHARMACEUTICAL KITS

[0236] The compositions and methods of use of AOH1996 and venetoclax may be used for therapeutic purposes, for example, treatment of leukemia (e.g. AML, etc.). The compositions provided herein, including embodiments thereof may be packaged in a kit for the treatment of leukemia. Thus, in an aspect is provided a kit including AOH1996 and venetoclax.

[0237] In embodiments, the kit includes a first amount of the AOH1996 and a second amount of the venetoclax, wherein the first amount and the second amount provide a combined synergistic amount.

[0238] In embodiments, the AOH1996 is provided in a first dosage form and the venetoclax is provided in a second dosage form. A “first dosage form” as provided herein refers to a discrete composition of AOH1996 and is separate from other dosage forms (e.g., the second dosage form of the venetoclax). In embodiments, the first dosage form does not include any other active agents. In embodiments, the first dosage form does not include any other therapeutic agent. Likewise, a “second dosage form” as provided herein refers to a discrete composition of the venetoclax and is separate from other dosage forms (e.g., the first dosage form of the AOH1996). In embodiments, the second dosage form does not include any other active agents. In embodiments, the second dosage form does not include any other therapeutic agent.

[0239] In embodiments, the AOH1996 and the venetoclax are provided in a single dosage form. In embodiments, the single dosage form does not include any other active agents other than the AOH1996 and the venetoclax. In embodiments, the single dosage form does not include any other therapeutic agent other than the AOH1996 and the venetoclax.

[0240] In embodiments, the kit further includes a chemotherapy. In embodiments, the chemotherapy is a hypomethylating agent. In embodiments, the hypomethylating agent is azacitidine, decitabine, or guadecitabine. In embodiments, the hypomethylating agent is azacitidine. Thus, in embodiments, the kit further includes azacitidine.

[0241] In embodiments, the kit includes a third amount of the chemotherapy, and wherein the first amount of the AOH1996, the second amount of the venetoclax, and the third amount of the chemotherapy provide a combined synergistic amount. In embodiments, the kit includes a thirdamount of the azaci dine, and wherein the first amount of the AOH1996, the second amount of the venetoclax, and the third amount of the AOH1996 provide a combined synergistic amount.

[0242] In embodiments, the chemotherapy is provided in a third dosage form. A “third dosage form” as provided herein refers to a discrete composition of a chemotherapy (e.g. azacitidine) and is separate from other dosage forms (e g., the first dosage form of the AOH1999, the second dosage form of the venetoclax). In embodiments, the third dosage form does not include any other active agents. In embodiments, the third dosage form does not include any other therapeutic agent.

[0243] In embodiments, the AOH1996, the venetoclax, and the chemotherapy are provided in a single dosage form. In embodiments, the single dosage form does not include any other active agents other than the AOH1996, the venetoclax, and the chemotherapy. In embodiments, the single dosage form does not include any other therapeutic agent other than the AOH1996, the venetoclax, and the chemotherapy.

[0244] In embodiments, the AOH1996, the venetoclax, and the azacitidine are provided in a single dosage form. In embodiments, the single dosage form does not include any other active agents other than the AOH1996, the venetoclax, and the azacitidine. In embodiments, the single dosage form does not include any other therapeutic agent other than the AOH1996, the venetoclax, and the azacitidine.

[0245] The compositions and methods of use of AOH1996 and the Bcl-2 inhibitor provided herein including embodiments thereof may be used for therapeutic purposes, for example, treatment of leukemia (e.g. AML, etc.). Thus, in an aspect is provided a kit including AOH1996 and Bcl-2 inhibitor. In embodiments, the Bcl-2 inhibitor is a BH3 mimetic. In embodiments, the BH3 mimetic is venetoclax, S63845, A1331852, obatoclax, ABT-263, S55746, AMG176, AZD5991, WEHI-539, ABT-737, or a combination thereof. In embodiments, the BH3 mimetic is venetoclax.

[0246] In embodiments, the kit includes a first amount of the AOH1996 and a second amount of the Bcl-2 inhibitor, wherein the first amount and the second amount provide a combined synergistic amount.

[0247] In embodiments, the AOH1996 is provided in a first dosage form and the Bcl-2 inhibitor is provided in a second dosage form.

[0248] In embodiments, the AOH1996 and the Bcl-2 inhibitor are provided in a single dosage form. In embodiments, the single dosage form does not include any other active agents other than the AOH1996 and the Bcl-2 inhibitor. In embodiments, the single dosage form does not include any other therapeutic agent other than the AOH1996 and the Bcl-2 inhibitor.

[0249] In embodiments, the kit further includes a chemotherapy. In embodiments, the chemotherapy is a hypomethylating agent. In embodiments, the hypomethylating agent is azacitidine, decitabine, or guadecitabine. In embodiments, the hypomethylating agent is azacitidine. Thus, in embodiments, the kit further includes azacitidine.

[0250] In embodiments, the kit includes a third amount of the chemotherapy, and wherein the first amount of the AOH1996, the second amount of the Bcl-2 inhibitor, and the third amount of the chemotherapy provide a combined synergistic amount. In embodiments, the kit includes a third amount of the azaci dine, and wherein the first amount of the AOH1996, the second amount of the Bcl-2 inhibitor, and the third amount of the AOH1996 provide a combined synergistic amount.

[0251] In embodiments, the chemotherapy is provided in a third dosage form. In embodiments, the AOH1996, the Bcl-2 inhibitor, and the chemotherapy are provided in a single dosage form. In embodiments, the single dosage form does not include any other active agents other than the AOH1996, the Bcl-2 inhibitor, and the chemotherapy. In embodiments, the single dosage form does not include any other therapeutic agent other than the AOH1996, the Bcl-2 inhibitor, and the chemotherapy.

[0252] In embodiments, the AOH1996, the Bcl-2 inhibitor, and the azacitidine are provided in a single dosage form. In embodiments, the single dosage form does not include any other active agents other than the AOH1996, the Bcl-2 inhibitor, and the azacitidine. In embodiments, the single dosage form does not include any other therapeutic agent other than the AOH1996, the Bcl-2 inhibitor, and the azacitidine.

[0253] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.P EMBODIMENTS

[0254] P Embodiment 1. A method of treating leukemia in a subject in need thereof, the method comprising administering to said subject an effective amount of AOH1996 and venetoclax.

[0255] P Embodiment 2. The method of P Embodiment 1, wherein said effective amount is a combined synergistic amount of said AOH1996 and said venetoclax.

[0256] P Embodiment 3. The method of P Embodiment 1 or 2, wherein said AOH1996 and said venetoclax are administered simultaneously or sequentially.

[0257] P Embodiment 4. The method of any one of P Embodiments 1 to 3, wherein the leukemia is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), or acute lymphocytic leukemia (ALL).

[0258] P Embodiment 5. The method of P Embodiment 4, wherein the leukemia is acute myeloid leukemia (AML).

[0259] P Embodiment 6. A method of treating leukemia in a subject in need thereof, the method comprising administering to said subject an effective amount of AOH1996.

[0260] P Embodiment 7. The method of P Embodiment 6, further comprising administering to said subject an effective amount of venetoclax.

[0261] P Embodiment 8. The method of P Embodiment 7, wherein said effective amount of said AOH199 and said effective amount of venetoclax is a combined synergistic amount of said AOH1996 and said venetoclax.

[0262] P Embodiment 9. The method of P Embodiment 7 or 8, wherein said AOH1996 and said venetoclax are administered simultaneously or sequentially.

[0263] P Embodiment 10. The method of any one of P Embodiments 6 to 9, wherein the leukemia is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), or acute lymphocytic leukemia (ALL).

[0264] P Embodiment 11. The method of P Embodiment 10, wherein the leukemia AML.

[0265] P Embodiment 12. A method of inhibiting proliferation of a leukemic stem cell (LSC), the method comprising contacting said LSC with an effective amount of AOH1996 and venetoclax.

[0266] P Embodiment 13. The method of P Embodiment 12, wherein said effective amount is a combined synergistic amount of said AOH1996 and said venetoclax.

[0267] P Embodiment 14. The method of P Embodiment 12 or 13, wherein said LSC is contacted with said AOH1996 and said venetoclax simultaneously or sequentially.

[0268] P Embodiment 15. A method of inhibiting proliferation of a leukemic stem cell (LSC), the method comprising contacting said LSC with an effective amount of AOH1996.

[0269] P Embodiment 16. The method of P Embodiment 15, further comprising contacting said LSC with an effective amount of venetoclax.

[0270] P Embodiment 17. The method of P Embodiment 16, wherein said effective amount of said AOH199 and said effective amount of venetoclax is a combined synergistic amount of said AOH1996 and said venetoclax.

[0271] P Embodiment 18. The method of P Embodiment 16 or 17, wherein said LSC is contacted with said AOH1996 and said venetoclax simultaneously or sequentially.

[0272] P Embodiment 19. A pharmaceutical composition comprising AOH1996, venetoclax and a pharmaceutically acceptable excipient.

[0273] P Embodiment 20. The pharmaceutical composition of P Embodiment 19, wherein said pharmaceutical composition comprises a first amount of said AOH1996 and a second amount of said venetoclax, wherein said first amount and said second amount provide a combined synergistic amount.

[0274] P Embodiment 21. A kit comprising AOH1996 and venetoclax.

[0275] P Embodiment 22. The kit of P Embodiment 21, wherein said kit comprises a first amount of said AOH1996 and a second amount of said venetoclax, wherein said first amount and said second amount provide a combined synergistic amount.

[0276] P Embodiment 23. The kit of P Embodiment 21 or 22, wherein said AOH1996 is provided in a first dosage form and said venetoclax is provided in a second dosage form.

[0277] P Embodiment 24. The kit of P Embodiment 21 or 22, wherein said AOH1996 and said venetoclax is provided in a single dosage form.EMBODIMENTS

[0278] Embodiment 1. A method of treating leukemia in a subject in need thereof, the method comprising administering to said subject an effective amount of AOH1996 and venetoclax.

[0279] Embodiment 2. The method of Embodiment 1, wherein said AOH1996 and said venetoclax are administered simultaneously or sequentially.

[0280] Embodiment 3. The method of Embodiment 1 or 2, further comprising administering to said subject an effective amount of azacitidine.

[0281] Embodiment 4. The method of Embodiment 3, wherein said AOH1996, said venetoclax, and said azacitidine are administered simultaneously or sequentially.

[0282] Embodiment 5. The method of any one of Embodiments 1 to 4, wherein the leukemia is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), or acute lymphocytic leukemia (ALL).

[0283] Embodiment 6. The method of Embodiment 5, wherein the leukemia is acute myeloid leukemia (AML).

[0284] Embodiment 7. The method of any one of Embodiments 1 to 6, wherein the subject has a relapsed leukemia, a Bcl-2 inhibitor resistant leukemia, a chemotherapeutic resistant cancer, or a combination thereof.

[0285] Embodiment 8. A method of treating leukemia in a subject in need thereof, the method comprising administering to said subject an effective amount of AOH1996.

[0286] Embodiment 9. The method of Embodiment 8, further comprising administering to said subject an effective amount of venetoclax.

[0287] Embodiment 10. The method of Embodiment 9, wherein said AOH1996 and said venetoclax are administered simultaneously or sequentially.

[0288] Embodiment 11. The method of any one of Embodiments 8 to 10, further comprising administering to said subject an effective amount of azacitidine.

[0289] Embodiment 12. The method of Embodiment 11, wherein said AOH1996, said venetoclax, and said azacitidine are administered simultaneously or sequentially.

[0290] Embodiment 13. The method of any one of Embodiments 8 to 12, wherein the leukemia is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), or acute lymphocytic leukemia (ALL).

[0291] Embodiment 14. The method of Embodiment 13, wherein the leukemia AML.

[0292] Embodiment 15. The method of any one of Embodiments 8 to 14, wherein the subject has a relapsed leukemia, a Bcl-2 inhibitor resistant leukemia, a chemotherapeutic resistant cancer, or a combination thereof.

[0293] Embodiment 16. A method of inhibiting proliferation of a leukemic stem cell (LSC), the method comprising contacting said LSC with an effective amount of AOH1996 and venetoclax.

[0294] Embodiment 17. The method of Embodiment 16, wherein said LSC is contacted with said AOH1996 and said venetoclax simultaneously or sequentially.

[0295] Embodiment 18. The method of Embodiment 16 or 17 further comprising contacting said LSC with an effective amount of azacitidine.

[0296] Embodiment 19. The method of Embodiment 18, wherein said LSC is contacted with said AOH1996, said venetoclax, and said azacitidine simultaneously or sequentially.

[0297] Embodiment 20. The method of any one of Embodiments 16 to 19, wherein said contacting is in vivo.

[0298] Embodiment 21. The method of any one of Embodiments 16 to 19, wherein said contacting is in vitro.

[0299] Embodiment 22. A method of inhibiting proliferation of a leukemic stem cell (LSC), the method comprising contacting said LSC with an effective amount of AOH1996.

[0300] Embodiment 23. The method of Embodiment 22, further comprising contacting said LSC with an effective amount of venetoclax.

[0301] Embodiment 24. The method of Embodiment 23, wherein said LSC is contacted with said AOH1996 and said venetoclax simultaneously or sequentially.

[0302] Embodiment 25. The method of any one of Embodiments 22 to 24, further comprising contacting said LSC with an effective amount of azacitidine.

[0303] Embodiment 26. The method of Embodiment 25, wherein said AOH1996, said venetoclax, and said azacitidine are administered simultaneously or sequentially.

[0304] Embodiment 27. The method of any one of Embodiments 22 to 26, wherein said contacting is in vivo.

[0305] Embodiment 28. The method of any one of Embodiments 22 to 26, wherein said contacting is in vitro.

[0306] Embodiment 29. A pharmaceutical composition comprising AOH1996, venetoclax and a pharmaceutically acceptable excipient.

[0307] Embodiment 30. The pharmaceutical composition of Embodiment 29, further comprising azacitidine.

[0308] Embodiment 31. A kit comprising AOH1996 and venetoclax.

[0309] Embodiment 32. The kit of Embodiment 31, wherein said AOH1996 is provided in a first dosage form and said venetoclax is provided in a second dosage form.

[0310] Embodiment 33. The kit of Embodiment 31, wherein said AOH1996 and said venetoclax are provided in a single dosage form.

[0311] Embodiment 34. The kit of any one of Embodiments 31 to 33, wherein said kit further comprises azacitidine.

[0312] Embodiment 35. The kit of Embodiment 34, wherein said azacitidine is provided in a third dosage form.

[0313] Embodiment 36. The kit of Embodiment 34, wherein said AOH1996, said venetoclax, and said azacitidine are provided in a single dosage form.EXAMPLESExample 1: Introduction to Exemplary Studies

[0314] Cytoplasmic proliferating cell nuclear antigen (PCNA) is highly expressed in acute myeloid leukemia (AML) cells and supports the oxidative metabolism and growth of leukemia stem cells (LSCs). AOH1996 (AOH) is an oral compound that targets a cancer associated isoform of PCNA and has demonstrated antileukemic activity in AML models. Applicant demonstrates herewith that AOH significantly inhibited the growth of AML cell lines and primary CD34+CD38- blasts (enriched for LSCs) in vitro, while sparing normal hematopoietic stem cells (HSCs). Applicant further shows that in vivo, AOH extended survival compared to control (50 vs. 35 days) and reduced LSC burden, as demonstrated in secondary transplant models (42 vs. 30 days, control). Mechanistically, AOH disrupted binding of mitochondrial PCNA to mitofusion-regulating OPA1 protein and enhanced OPA1 interaction with its E3 ligase, MARCH5, which led to OPA1 ubiquitination and degradation. This decreased mitochondrial fusion, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS), while inducing mitofission and inhibiting LSC growth.

[0315] Applicant discovered that the combination of AOH with the Bcl-2 inhibitor venetoclax (VEN) further enhanced the antileukemic activity of AOH. As described herewith, the combination therapy significantly reduces mitofusion, FAO, and OXPHOS, and improves survival in both primary and secondary AML transplant models. While VEN is FDA-approved for AML, AOH is in clinical trials for solid tumors.Example 2: AOH1996 Targets Mitochondrial Dynamics and Metabolism in Leukemic Stem Cells via Mitochondrial PCNA Inhibition

[0316] Proliferating cell nuclear antigen (PCNA) is involved in tumor DNA synthesis and repair, and disease progression1,2. In contrast to its nuclear role, cytoplasmic PCNA maintains mitochondrial DNA integrity, regulates mitochondrial dynamics (such as fission and fusion), and mediates cellular stress responses by supporting mitochondrial function under stress conditions3,4. In acute myeloid leukemia (AML), cytoplasmic PCNA is highly expressed, supporting oxidative metabolism and growth, especially in leukemia stem cells (LSCs)5. LSCs reportedly rely on mitochondrial fusion, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS) for survival6. Therefore, targeting cytoplasmic PCNA could disrupt LSC homeostasis, leading to their elimination and potential disease eradication. Building on the previous PCNA inhibitor A0H1160, we developed a leading clinical candidate AOH1996, which is orally administrable andmetabolically stable and showed significant inhibition of tumor growth with minimal toxicity for healthy cells7'9.

[0317] AOH treatment significantly inhibited proliferation, colony formation, and induced apoptosis at 24 hours in a dose-dependent manner in seven representative AML cell lines and primary CD34+CD38- blasts (enriched for LSCs), while sparing normal CD34+CD38- mononuclear cells (MNCs) enriched for hematopoietic stem cells (HSCs) (FIG.s 1A-1B and FIG.s 1M-1S). Untargeted metabolomic analysis of primary CD34+ AML cells treated with AOH (0.5 pM) versus DMSO and Non-treated controls identified 198 and 213 differentially abundant metabolites (Adj. p <0.05) (FIG. 2 J). Using semi-targeted and untargeted metabolomics, AOH treatment led to reduced NAD+, FAD, and ATP levels, indicating decreased OXPHOS. Additionally, most phospholipids, long-chain fatty acids, and acyl carnitines increased, while acetyl carnitine decreased, suggesting upregulated phospholipid synthesis and reduced fatty acid metabolism (FIG. 1C and FIG. 2K)10 11. Utilizing Seahorse and FAO functional assays, it was confirmed that AOH treatment decreased FAO and OXPHOS (lower OCR) but not glycolysis (ECAR) in CD34+CD38- AML blasts (FIG. ID and FIG. 2L). Transmission electron microscope revealed AOH (1 pM) significantly inhibited mitofusion, evidenced by reduced mitochondrial length (FIG.s 1E-1F). AOH treatment for 24 hours also reduced levels of mitofusion-regulated proteins (e.g., OPA1, MFN1) and FAO / OXPHOS- regulated proteins (e.g., BCL-2, CPT1B, NRF2) in HL-60 cells and CD34+CD38- AML blasts (FIG. 1G and FIG. 3A). PCNA contains an AlkB homolog 2 PCNA-interacting motif (APIM), which serves as a binding site for the OPA1 peptide. Treatment with AOH inhibits the interaction between the OPA1 peptide and PCNA via this motif (FIG. 3B-3C). It was confirmed that AOH disrupts mitochondrial PCNA-OPA1 interactions, leading to increased OPA1 binding to its E3 ligase, MARCH5, which enhances ubiquitination and accelerates degradation (FIG.s 1H-1 J and FIG. 3D) These results show that AOH inhibits mitofusion and mitochondrial oxidative metabolisms in LSC-enriched blast subpopulation by inhibiting contribution of cytoplasmic PCNA to mitochondrial oxidative metabolism5.

[0318] In vivo, a significant antileukemic activity of AOH in AML PDXs was shown. Compared to vehicle-treated mice, PDX mice receiving AOH (100 mg / kg, BID, 3 weeks) showed reduced leukemia burden (percentage of hCD45+ and spleen size) and extended median survival (CON: 35 days vs. AOH: 50 days) (FIG.s 1K-1L). Analysis of human CD34+ cells from the bone marrow oftreated mice, showed decreased FAO / OXPHOS levels (FIG. IL, left) The antileukemic effect decreased LSC burden, as evidenced by the longer survival of recipients of BM MNCs from AOH- treated donors compared with recipients of BM MNCs from vehicle-treated donors in subsequent transplants (CON: 30 days vs. AOH: 42 days) (FIG. IL, right bottom). Of note, AOH in combination with a BCL-2 inhibitor, venetoclax (VEN), resulted in a synergistic activity both in vitro and in vivo, as shown by inhibition of FAO / OXPHOS and mitofusion, and increased apoptosis of CD34+CD38- AML blasts (FIG.s 2A-2E). The AOH / VEN combination significantly extended survival in both primary and secondary transplant experiments in murine (MllPTD / WT / Flt3ITD ITD)12models compared to either agent alone. Primary survival (days): CON: 34, VEN: 34, AOH: 43.5, AOH / VEN: 54; secondary survival (days): CON: 28, VEN: 32.5, AOH: 41, AOH / VEN: 49.5 (FIG.s 2F-2G, FIG. 4A-4B). Similar results were seen in PDX AML models (FIG.s 2H-2I).

[0319] In summary, AOH exhibits potent antileukemic activity in AML models by inhibiting mitochondrial PCNA-regulated dynamics and metabolism, and reducing LSC burden. Applicant discovered when AOH is combined with VEN, enhanced antileukemic activity occurs.Example 3: Materials and Methods

[0320] Human samples

[0321] Normal hematopoietic stem cells (HSCs) and acute myeloid leukemia (AML) samples were obtained from healthy donors and patients at City of Hope National Medical Center (COHNMC) under Institutional Review Board-approved protocols (#06229, #03162, #07047, #18067). These protocols follow the guidelines of the Department of Health and Human Services and adhere to the Declaration of Helsinki. Written informed consent was obtained from donors (#06229) and pat...

Claims

WHAT IS CLAIMED IS:

1. A method of treating leukemia in a subject in need thereof, the method comprising administering to said subject an effective amount of AOH1996 and venetoclax.

2. The method of claim 1, wherein said AOH1996 and said venetoclax are administered simultaneously or sequentially.

3. The method of claim 1, further comprising administering to said subject an effective amount of azacitidine.

4. The method of claim 3, wherein said AOH1996, said venetoclax, and said azacitidine are administered simultaneously or sequentially.

5. The method of claim 1, wherein the leukemia is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), or acute lymphocytic leukemia (ALL).

6. The method of claim 5, wherein the leukemia is acute myeloid leukemia (AML).

7. The method of claim 1, wherein the subject has a relapsed leukemia, a Bcl-2 inhibitor resistant leukemia, a chemotherapeutic resistant cancer, or a combination thereof.

8. A method of treating leukemia in a subject in need thereof, the method comprising administering to said subject an effective amount of AOH1996.

9. The method of claim 8, further comprising administering to said subject an effective amount of venetoclax.

10. The method of claim 9, wherein said AOH1996 and said venetoclax are administered simultaneously or sequentially.

11. The method of claim 8, further comprising administering to said subject an effective amount of azacitidine.

12. The method of claim 11, wherein said AOH1996, said venetoclax, and said azacitidine are administered simultaneously or sequentially13. The method of claim 8, wherein the leukemia is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), or acute lymphocytic leukemia (ALL).

14. The method of claim 13, wherein the leukemia AML.

15. The method of claim 8, wherein the subject has a relapsed leukemia, a Bcl-2 inhibitor resistant leukemia, a chemotherapeutic resistant cancer, or a combination thereof.

16. A method of inhibiting proliferation of a leukemic stem cell (LSC), the method comprising contacting said LSC with an effective amount of AOH1996 and venetoclax.

17. The method of claim 16, wherein said LSC is contacted with said AOH1996 and said venetoclax simultaneously or sequentially.

18. The method of claim 16 further comprising contacting said LSC with an effective amount of azacitidine.

19. The method of claim 18, wherein said LSC is contacted with said AOH1996, said venetoclax, and said azacitidine simultaneously or sequentially.

20. The method of claim 16, wherein said contacting is in vivo.

21. The method of claim 16, wherein said contacting is in vitro.

22. A method of inhibiting proliferation of a leukemic stem cell (LSC), the method comprising contacting said LSC with an effective amount of AOH1996.

23. The method of claim 22, further comprising contacting said LSC with an effective amount of venetoclax.

24. The method of claim 23, wherein said LSC is contacted with said AOH1996 and said venetoclax simultaneously or sequentially.

25. The method of claim 22, further comprising contacting said LSC with an effective amount of azacitidine.

26. The method of claim 25, wherein said AOH1996, said venetoclax, and said azacitidine are administered simultaneously or sequentially.

27. The method of claim 22, wherein said contacting is in vivo.

28. The method of claim 22, wherein said contacting is in vitro.

29. A pharmaceutical composition comprising AOH1996, venetoclax and a pharmaceutically acceptable excipient.

30. The pharmaceutical composition of claim 29, further comprising azacitidine.

31. A kit comprising AOH1996 and venetoclax.

32. The kit of claim 31, wherein said AOH1996 is provided in a first dosage form and said venetoclax is provided in a second dosage form.

33. The kit of claim 31, wherein said AOH1996 and said venetoclax are provided in a single dosage form.

34. The kit of claim 31, wherein said kit further comprises azacitidine.

35. The kit of claim 34, wherein said azacitidine is provided in a third dosage form.

36. The kit of claim 34, wherein said AOH1996, said venetoclax, and said azacitidine are provided in a single dosage form.

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