Bruton's tyrosine kinase inhibitors and methods of use thereof

Abstract

The present disclosure is directed to the use of the compound of formula (III) in the treatment of DLBCL. [Formula 1] TIFF2024526241000015.tif30128

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 216,796, entitled “Inhibitors Of Bruton's Tyrosine Kinase And Methods Of Their Use,” filed June 30, 2021, which is incorporated by reference in its entirety.

[0002] FIELD OF THEINVENTION The present disclosure is directed to the use of small molecule tyrosine kinase inhibitors for the treatment of Diffuse Large B-Cell Lymphoma (DLBCL). [Background technology]

[0003] Malignancies, particularly DLBCL, continue to plague patients. DLBCL is the most common type of aggressive non-Hodgkin's lymphoma (NHL) in the United States. Activated B-Cell Diffuse Large B-Cell Lymphoma (ABC-DLBCL) accounts for approximately 30% of all DLBCL diagnoses. Although the majority of patients with DLBCL respond to initial treatment, approximately one-third of patients have refractory disease or experience relapse after standard therapy. B Cell Receptor (BCR) signaling is a key proliferation and survival pathway in various B-cell malignancies, including DLBCL. There remains a need for alternative and effective cancer therapies. Human Bruton's Tyrosine Kinase ("BTK") is a protein of approximately 76 kDa that belongs to the Tec family of non-receptor tyrosine kinases. Tec kinases form the second large family of cytoplasmic tyrosine kinases in mammalian cells, consisting of BTK plus four other members: the homologous kinases TEC, ITK, TXK / RLK, and BMX. Tec kinases are evolutionarily conserved throughout vertebrates. They are related to, but structurally distinct from, the larger Src and Syk kinase families. Tec family proteins are abundantly expressed in hematopoietic tissues and play important roles in the proliferation and differentiation of mammalian blood and endothelial cells. Based on BTK expression from IHC studies described in the art, Btk inhibition has the potential to modulate biology associated with B cells, macrophages, mast cells, osteoclasts, and platelet microparticles. Corneth,OB,et al.Curr.Top.Microbiol.Immunol.BTK Signaling in B Cell Differentiation and Autoimmunity.2015 Sept.5. Summary of the Invention

[0004] 1. A method of treating DLBCL in a subject, comprising: (a) detecting a gene encoding any one of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, CD10, BCL6, MUM1, MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, PRDM1 in a sample from the patient; , VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, HNF1B, or any combination thereof; and (b) determining the expression level or alteration of one or more biomarker genes selected from:

[0005] [ka] and administering to a patient a biomarker gene expression level in a normal patient. In some embodiments, the modification is a base substitution, an insertion, a deletion, a DNA rearrangement, a translocation, a copy number change, or a combination thereof.

[0006] Also provided is a method of treating activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) in a subject, comprising: (a) detecting in a sample from the patient, CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, CD10, BCL6, MUM1, MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GHL15, GHL16, GHL17, GHL18, GHL19, GHL20, GHL21, GHL22, GHL23, GHL24, GHL25, GHL26, GHL27, GHL28, GHL29, GHL30, GHL31, GHL32, GHL33, GHL34, GHL35, GHL36, GHL37, GHL38, GHL39, GHL40, GHL41, GHL42, GHL43, GHL44, GHL45, GHL46, GHL47, GHL48, GHL49, GHL50, GHL51, GHL52, GHL53, GHL54, GHL55, GHL56, GHL57, GHL58, GHL59, GHL60, GHL61, GHL62, GHL63, GHL64, GHL65, GHL66, GHL67, GHL68, GHL69 ... (b) determining the expression level or alteration of one or more biomarker genes selected from RHPR, CD58, PRDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, HNF1B, or any combination thereof; and (b) if the expression of the one or more biomarker genes is increased relative to a control or reference level or if an alteration in the one or more biomarker genes is present, administering a therapeutically effective amount of a compound of formula (III):

[0007] [ka] and administering to a patient a biomarker gene expression level in a normal patient. In some embodiments, the modification is a base substitution, an insertion, a deletion, a DNA rearrangement, a translocation, a copy number change, or a combination thereof.

[0008] Also provided is a method of treating non-germinal center B-cell Diffuse Large B-cell Lymphoma (non-GCB-DLBCL) in a subject, comprising: (a) detecting in a sample from the patient, CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, CD10, BCL6, MUM1, MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, P (b) determining the expression level or alteration of one or more biomarker genes selected from RDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, HNF1B, or any combination thereof; and (b) if the expression of the one or more biomarker genes is increased relative to a control or reference level or if an alteration in the one or more biomarker genes is present, administering a therapeutically effective amount of a compound of formula (III):

[0009] [ka] and administering to a patient a biomarker gene expression level in a normal patient. In some embodiments, the modification is a base substitution, an insertion, a deletion, a DNA rearrangement, a translocation, a copy number change, or a combination thereof.

[0010] Also provided is a method of treating germinal center B-cell Diffuse Large B-cell Lymphoma (GCB-DLBCL) in a subject, comprising: (a) detecting CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, CD10, BCL6, MUM1, MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, P in a sample from the patient; (b) determining the expression level or alteration of one or more biomarker genes selected from RDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, HNF1B, or any combination thereof; and (b) if the expression of the one or more biomarker genes is increased relative to a control or reference level or if an alteration in the one or more biomarker genes is present, administering a therapeutically effective amount of a compound of formula (III):

[0011] [ka] and administering to a patient a biomarker gene expression level in a normal patient. In some embodiments, the modification is a base substitution, an insertion, a deletion, a DNA rearrangement, a translocation, a copy number change, or a combination thereof.

[0012] In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 140 mg to about 560 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 140 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 280 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 560 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is administered once a day. In some embodiments, the therapeutically effective amount of the compound of formula (III) is administered twice a day. In some embodiments, the therapeutically effective amount of the compound of formula (III) is administered three times a day. In some embodiments, the compound of formula (III) is administered orally.

[0013] Some embodiments further comprise administering 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide). Some embodiments further comprise administering cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The present disclosure may be more fully understood by reference to the following description, including the following glossary and concluding examples. It is also understood that certain features of the compositions and methods of the present disclosure, which are described herein in the context of separate embodiments for clarity, may be provided in combination in a single embodiment. Conversely, various features of the compositions and methods of the present disclosure, which are described in the context of a single embodiment for brevity, may be provided separately or in any subcombination. In general, those skilled in the art will understand that the terms used herein, and in particular in the appended claims (e.g., the body of the appended claims), are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including but not limited to", the term "having" should be interpreted as "having at least", the term "includes" should be interpreted as "includes but is not limited to", etc.). Moreover, where a specific number is intended in an introduced claim recitation, such intent will be expressly recited in the claim, and in the absence of such recitation, one of ordinary skill in the art will understand that no such intent exists. For example, as an aid to understanding, the claims at the following appended claims may include the introductory phrases "at least one" and "one or more" to introduce the claim recitations.However, the use of such phrases should not be construed as suggesting that a claim statement introduced by the indefinite article "a" or "an" limits any particular claim containing such an introduced claim statement to an embodiment containing only one such statement, even when the same claim includes the introductory phrase "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should be construed to mean "at least one" or "one or more"). The same applies when a definite article is used to introduce a claim statement. In addition, those skilled in the art will recognize that even if a specific number of introduced claim statements is explicitly recited, such a statement should be construed to mean at least the recited number (e.g., the bare statement "two statements" without other modifiers means at least two statements, or two or more statements). Furthermore, in instances where notation similar to "at least one of A, B, and C, etc." is used, such syntax is generally intended in the sense that one of ordinary skill in the art would understand such notation (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, systems having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In instances where notation similar to "at least one of A, B, or C, etc." is used, such syntax is generally intended in the sense that one of ordinary skill in the art would understand such notation (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, systems having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). Those skilled in the art will further appreciate that virtually all disjunctive words and / or phrases presenting two or more alternative terms, whether in the specification, claims, or drawings, should be understood to contemplate the possibility of including one of the terms, either of the terms, or both terms.For example, the phrase "A or B" is understood to include the possibilities of "A" or "B" or "A and B."

[0015] In addition, when features or aspects of the disclosure are described in terms of a Markush group, one of skill in the art will recognize that the disclosure is also thereby described in terms of any individual members or subgroups of members of the Markush group.

[0016] As will be appreciated by those of skill in the art, for all purposes, e.g., in terms of providing a written description, all ranges disclosed herein also encompass all possible subranges and combinations of those subranges. Any recited range can be readily recognized as fully descriptive and allowing for the same range to be broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third, and upper third, etc. Also, as will be appreciated by those of skill in the art, all phrases such as "up to" and "at least" refer to ranges that are inclusive of the recited numbers and that can then be broken down into subranges, as discussed above. Finally, as will be appreciated by those of skill in the art, a range includes each individual member. Thus, for example, a group having 1-3 cells refers to a group having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to a group having 1, 2, 3, 4, or 5 cells, etc.

[0017] Various of the above-disclosed and other features and functions, or alternatives thereof, may be combined into many other different systems or applications in which various presently unforeseen or unanticipated alternatives, modifications, variations, or improvements thereon may be made by those skilled in the art, each of which is also intended to be encompassed by the disclosed aspects.

[0018] As used herein, the term "about," when immediately preceding a numerical value, means a range of plus or minus 10% of that value, unless the context of this disclosure indicates otherwise or is inconsistent with the interpretation below; for example, "about 50" means 45 to 55, "about 25,000" means 22,500 to 27,500, etc.

[0019] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or State government or the appropriate agency of a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, and more specifically, in humans.

[0020] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, or (2) salts formed when an acidic proton present in either parent compound is replaced with a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinated with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Further salts include, by way of example only, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc., if the compound contains a basic functional group, such as sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.

[0021] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier that is administered with the compounds of the present disclosure. "Pharmaceutically acceptable excipient" refers to a non-toxic, biologically tolerable, and otherwise biologically suitable substance for administration to a subject, such as an inert substance that is added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a drug and is compatible with the drug. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0022] A "subject" includes a human. The terms "human," "patient," and "subject" are used interchangeably herein.

[0023] "Treating" or "treatment" of any disease or disorder, in one aspect, refers to ameliorating the disease or disorder (i.e., arresting or reducing the onset of the disease or at least one of its clinical symptoms). In another aspect, "treating" or "treatment" refers to ameliorating at least one physical parameter that may not be discernible by the subject. In yet another aspect, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing discernible symptoms) or physiologically (e.g., stabilizing physical parameters) or both. In yet another aspect, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

[0024] "Compounds of the disclosure" and equivalent expressions are meant to include compounds of formula (III) as described herein, including, where the context permits, pharma- ceutically acceptable salts and solvates thereof, such as hydrates and polymorphs. Similarly, references to intermediates, whether or not they are themselves claimed, are meant to include their salts and solvates, where the context permits.

[0025] As used herein, the term "isotopic variant" refers to a compound that contains an unnatural proportion of isotopes at one or more of the atoms that constitute such compound. For example, an "isotopic variant" of a compound may be radiolabeled, i.e., contain one or more non-radioactive isotopes, such as deuterium ( 2 H or D), carbon 13 ( 13 C), or nitrogen-15 ( 15 In such isotopically substituted compounds, the subsequent atom, if present, may vary, so that, for example, any hydrogen may be replaced with 2 H / D, any carbon may be 13 C or any nitrogen may be 15 It will be understood that the atom may be N, and the presence or location of such an atom may be determined within the skill of the art. Similarly, the present disclosure may include the preparation of isotopic variants with radioisotopes, for example, where the resulting compounds may be used in drug and / or substrate tissue distribution studies. Radiolabeled compounds of the present disclosure may be used in diagnostic methods such as single photon emission computed tomography (SPECT). The radioisotope tritium, i.e. 3 H and carbon 14, i.e. 14 C are particularly useful due to their ease of incorporation and ready means of detection. Additionally, positron emitting isotopes, e.g. 11 C. 18 F, 15 O, and 13 N-substituted compounds can be prepared and are useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy.

[0026] All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0027] It is also understood that compounds that have the same molecular formula but differ in the nature or sequence of bonds of their atoms or the arrangement of their atoms in space are referred to as "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers," e.g., diastereomers, enantiomers, and atropisomers.

[0028] Stereoisomers that are not mirror images of each other are termed "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S ordering rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light and are designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0029] "Atropisomer" refers to a stereoisomer that arises due to hindered rotation about a single bond.

[0030] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, differing in the replacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the shifting of pi electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are similarly formed by treatment with acid or base.

[0031] Tautomeric forms may be relevant in achieving optimal chemical reactivity and biological activity of a compound of interest.

[0032] Compounds of the present disclosure may possess one or more asymmetric centers and therefore such compounds may be produced as individual (R) or (S) stereoisomers or as mixtures thereof.

[0033] Unless otherwise indicated, the description or naming of a particular compound in the present specification and claims is intended to include both its individual enantiomers and mixtures, racemic or otherwise. Within this disclosure, any open valency appearing on a carbon, oxygen, or nitrogen atom in any structure described herein indicates the presence of a hydrogen atom. When a chiral center is present in a structure and no specific stereochemistry is shown for that center, both enantiomers, either separately or as mixtures, are encompassed by the structure. Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0034] The present disclosure relates to a compound of formula (III):

[0035] [ka] or a pharma- ceutically acceptable salt, hydrate, polymorph, or solvate thereof. The compound of formula (III) is also known as N-((1R,2S)-2-acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide.

[0036] The present disclosure relates to methods of using the compounds described herein to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated by Bruton's tyrosine kinase. These methods are achieved by administering to the subject a compound of the present disclosure in an amount sufficient to inhibit Bruton's tyrosine kinase. In a further aspect, a method is provided herein for inhibiting Bruton's tyrosine kinase in a subject in need of treatment, by administering to the subject a composition comprising a therapeutically effective amount of a compound of formula (III).

[0037] Some aspects of the present disclosure are directed to a method of treating a subject suffering from a malignant tumor by administering to the subject a therapeutically effective amount of a composition comprising a compound of formula (III). In some aspects, the malignant tumor is DLBCL. In some aspects, the malignant tumor is ABC-DLBCL, GCB-DLBCL, or non-germinal center B-cell diffuse large B-cell lymphoma (non-GCB-DLBCL). When used for the treatment of DLBCL, the compound of formula (III) can be administered as a single agent. Alternatively, when used for the treatment of DLBCL, the compound of formula (III) can be administered in combination with other agents known to be useful in the treatment of DLBCL. When used for the treatment of ABC-DLBCL, GCB-DLBCL, or non-GCB-DLBCL, the compound of formula (III) can be administered as a single agent. Alternatively, when used for the treatment of ABC-DLBCL, germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL), or non-germinal center B-cell diffuse large B-cell lymphoma (non-GCB-DLBCL), the compounds of formula (III) may be administered in combination with other agents known to be useful in the treatment of DLBCL.

[0038] Another aspect of the present disclosure is directed to a method of treating a subject suffering from DLBCL by administering to the subject a therapeutically effective amount of a composition containing a compound of formula (III). In yet other aspects, the compounds of the present disclosure may be used to treat ABC-DLBCL, GCB-DLBCL, or non-GCB-DLBCL.

[0039] DLBCL is the most common type of aggressive non-Hodgkin's lymphoma (NHL) in the United States. The clinical course of patients with DLBCL is highly heterogeneous. The majority of patients with DLBCL respond to initial treatment, but about one-third of patients have refractory disease or experience relapse after standard therapy. DLBCL is a clinically and biologically heterogeneous disease, which can be demonstrated by several clinical and molecularly defined prognostic models.

[0040] Early effective treatment of DLBCL is an important factor that affects the survival of DLBCL patients. Selection of treatment regimens to which DLBCL is resistant may delay the onset of effective treatment of cancer, leading to cancer growth and metastasis. This may then have a negative effect on the patient's treatment outcome. Tumor-specific characteristics, such as the expression of one or more specific genes and / or encoded proteins, associated with responsiveness to anticancer drugs, such as the compound of formula (III), are useful as prognostic biomarkers to identify potential patients who may respond or fail to treatment with the compound of formula (III) at an earlier stage. As a result, patients suffering from DLBCL who express such biomarkers may be selected for treatment with the compound of formula (III). In addition, the biomarkers may be used to evaluate response to treatment with the compound of formula (III).

[0041] Biomarkers based on gene expression profiling In some cases, Gene Expression Profiling (GEP) has been used to investigate molecular heterogeneity and predict outcomes in DLBCL. GEP can distinguish two prognostic subtypes, GCB-DLBCL and ABC-DLBCL, among which functional differences include the activity of BCR signaling. ABC-DLBCL cells have chronically active BCR signaling, and their survival is highly dependent on it.

[0042] BCR signaling is a key proliferation and survival pathway in various B cell malignancies, including DLBCL. After BCR stimulation, normal and malignant B cells secrete the chemokines CCL3 and CCL4 (MIP-1α and β), which promote B cell interaction with accessory cells such as T helper cells. CCL3 and CCL4 are chemokines of the CC subfamily and are inducible in some hematopoietic cells, especially those involved in adaptive immune responses (macrophages, dendritic cells, and B and T lymphocytes). CCL3 signals through the chemokine receptors CCR1 and CCR5, and CCL4 signals exclusively through CCR5. CCL3 is a key response gene in B cells, which is upregulated by BCR signaling and repressed by Bcl-6. Plasma CCL3 and CCL4 levels are elevated in patients with B cell malignancies such as DLBCL and chronic lymphocytic leukemia (CLL). In DLBCL, SCYA3, the gene encoding CCL3, was highly expressed in ABC subtypes in DLBCL. Unlike GCB cells, ABC-DLBCL cells secreted high levels of CCL3 and CCL4 after BCR induction, which were sensitive to inhibition with BTK inhibitors such as ibrutinib. High serum CCL3 levels (>40 pg / ml) correlated with higher International Prognostic Index (IPI), LDH, and β2-microglobulin in Ann Arbor advanced stage, as did CCL4 (>180 pg / ml). High CCL3 correlated with significantly shorter progression-free and overall survival. Furthermore, a correlation was observed between anti-IgM responsiveness and sensitivity to ibrutinib treatment in ABC-DLBL subtypes compared with GCB subtypes. Furthermore, in most patients, high serum CCL3 and CCL4 levels returned to low levels after ibrutinib therapy. As a result of these findings, CCL3 and CCL4 protein concentrations can be used as biomarkers for BCR pathway activation and prognosis in DLBCL, as well as for the assessment of efficacy of BTK inhibitor therapy.Other biomarkers that can also be used as biomarkers for the assessment of prognosis and efficacy of BTK inhibitor therapy in DLBCL include biomarker genes selected from ACTG2, LOR, GAPT, CCND2, SELL, GENl, and HDAC9. These genes encode the ACTG2, LOR, GAPT, CCND2, SELL, GENl, and HDAC9 proteins, respectively. ACTG2 (actin, gamma 2, smooth muscle, intestine) is a ubiquitously expressed, highly conserved protein involved in cell motility and maintenance of the cytoskeleton. LOR encodes the protein loricrin, a major protein component of the stratum corneum, the outermost layer of the epidermis. GAPT (GRB2-binding adaptor protein, transmembrane) negatively regulates B-cell proliferation after stimulation via the B-cell receptor. CCND2 (cyclin D2) is a regulator of cyclin-dependent kinases and is involved in cell cycle regulation. SELL (selectin L or CD62L) is a cell adhesion molecule found on lymphocytes and is involved in lymphocyte-endothelial cell interactions. GENl (Gen endonuclease homolog 1) encodes an endonuclease that degrades Holliday junctions during homologous recombination and DNA repair. HDAC9 or histone deacetylase 9 is an enzyme involved in transcriptional regulation, cell cycle progression, and developmental events. Elevated expression of ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, is indicative of DLBCL. Elevated expression of ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, is indicative of ABC-DLBCL.

[0043] The methods provided herein relate to the use of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, or HDAC9 expression as predictive biomarkers to identify responder populations, particularly patients who may be sensitive to treatment with a compound of formula (III). The methods provided herein provide clinical advantages for the diagnosis and treatment of DLBCL, including easy access to samples, given that CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, can be reliably quantified in plasma and serum samples, including low-cost analysis, and rapid adjustment (normalization within days) with BCR-targeted therapy. In some aspects, serum levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, can be easily quantified by Enzyme-Linked Immunosorbent Assay (ELISA) or other rapid protein detection methods.

[0044] Thus, in some embodiments, patients exhibiting higher than normal expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof may be sensitive to treatment with a compound of formula (III). In some embodiments, patients exhibiting about the same or lower expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof relative to normal may be resistant to treatment with a compound of formula (III). Thus, measuring the expression levels, gene or protein expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof is particularly useful for identifying patients who may respond to therapy with a compound of formula (III).

[0045] Some embodiments are directed to a method of predicting a positive response of a patient having DLBCL to a compound of formula (III) by assessing the extent to which expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, is decreased following treatment with a compound of formula (III).

[0046] Some embodiments are directed to methods and procedures for determining patient sensitivity to a compound of formula (III). Some embodiments are directed to methods for determining or predicting whether an individual in need of therapy for DLBCL will respond to a treatment prior to administration of the treatment, the treatment comprising administration of a compound of formula (III). In some embodiments, methods are disclosed herein for selecting patients diagnosed with DLBCL for treatment with a compound of formula (III), based on the level of expression of biomarkers CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof. In some embodiments, the method comprises identifying a patient likely to respond to treatment with a compound of formula (III). In some embodiments, the method comprises determining a treatment regimen. Also disclosed herein, in certain aspects, is a method for evaluating treatment of DLBCL in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (III) and determining the patient's responsiveness to the treatment based on the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof. Also disclosed herein, in certain aspects, is a method for evaluating treatment of DLBCL in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (III) and determining the patient's responsiveness to the treatment based on the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, and continuing the treatment when the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof has decreased by a predetermined amount.Also disclosed herein in certain embodiments is a method for treating DLBCL or ABC-DLBCL in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (III), determining the patient's responsiveness to the treatment based on the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, and discontinuing the treatment if the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof has not decreased by a predetermined amount. In some embodiments, a high expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof prior to treatment is predictive of a therapeutic response to treatment with a compound of formula (III). In some embodiments, a decrease in the level of expression (e.g., normalization of expression) of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof following administration of a compound of Formula (III) is predictive of efficacy of the compound of Formula (III) for treating DLBCL or ABC-DLBCL.

[0047] In some embodiments, methods are provided for treating DLBCL or ABC-DLBCL by preselecting a patient exhibiting elevated levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, thereby increasing the likelihood of the patient's response to a compound of formula (III). In some embodiments, methods are provided for treating DLBCL or ABC-DLBCL in a patient in need thereof by assessing whether the patient exhibits elevated levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, thereby increasing the likelihood of the patient's response to a compound of formula (III). In some aspects, methods are provided for treating DLBCL or ABC-DLBCL in a patient in need thereof by assessing whether the patient exhibits changes in the expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, following treatment with a compound of formula (III).

[0048] In some embodiments, the DLBCL is an ABC subtype DLBCL. In some embodiments, the Activated B Cell-like (ABC) subtype of DLBCL is characterized by a CD79B mutation. In some embodiments, the CD79B mutation is a mutation in the Immunoreceptor Tyrosine-based Activation Motif (ITAM) signaling module. In some embodiments, the CD79B mutation is a missense mutation of the first Immunoreceptor Tyrosine-based Activation Motif (ITAM) tyrosine. In some embodiments, the CD79B mutation increases surface BCR expression and attenuates Lyn kinase activity. In some embodiments, the ABC subtype of DLBCL is characterized by a CD79A mutation. In some embodiments, the CD79A mutation is in the Immunoreceptor Tyrosine-based Activation Motif (ITAM) signaling module. In some embodiments, the CD79A mutation is a splice donor site mutation in the ITAM signaling module. In some embodiments, the CD79A mutation deletes the ITAM signaling module. In some embodiments, the ABC subtype of DLBCL is characterized by mutations in MyD88, A20, or a combination thereof. In some embodiments, the MyD88 mutation is the amino acid substitution L265P in the MYD88 Toll / IL-1 Receptor (TIR) ​​domain.

[0049] Some embodiments are directed to a method for treating DLBCL or ABC-DLBCL in a patient in need thereof, comprising: (a) determining the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, in a sample (e.g., a serum sample) from the patient; and (b) administering to the patient a therapeutically effective amount of a compound of formula (III) if the expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof is increased relative to a control or reference level. In some embodiments, the reference level is the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, in a normal patient (e.g., a patient not having DLBCL).

[0050] In some aspects, a method is provided for assessing response to a compound of formula (III) in a patient having DLBCL or ABC-DLBCL, comprising determining the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, in a sample from the patient (e.g., a serum sample) following administration of a therapeutically effective amount of a compound of formula (III), wherein a favorable outcome for treatment with the compound of formula (III) is predicted when the patient sample exhibits a decreased level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, relative to a control or reference level. In some embodiments, a method is provided for assessing response to a compound of formula (III) in a patient with DLBCL or ABC-DLBCL, comprising determining the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, in a sample (e.g., a serum sample) from the patient after administration of a therapeutically effective amount of a compound of formula (III), wherein the patient is characterized as responding to treatment with a compound of formula (III) if the patient sample exhibits a decreased level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, relative to a control or reference level. In some embodiments, the reference level is the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, in a normal patient (e.g., a patient without DLBCL). In some embodiments, the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, following treatment with a compound of Formula (III) is reduced by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% or more following treatment with ibrutinib.In some embodiments, the level of CCL3 expression after treatment is reduced (i.e., normalized) to the level of expression in normal patients after treatment with a compound of Formula (III). In some embodiments, the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof is measured 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, 36 hours, or 48 hours or more after treatment with a compound of Formula (III).

[0051] In some embodiments, an exemplary method for treating DLBCL or ABC-DLBCL in a patient in need thereof includes (a) determining the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, in a sample (e.g., a serum sample) from the patient after administration of a therapeutically effective amount of a compound of formula (III), and (b) modifying, interrupting, or continuing treatment based on the expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, relative to a control or reference level. In some embodiments, the reference level is the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, in a sample (e.g., a serum sample) taken from the patient before administration of a therapeutically effective amount of a compound of formula (III). In some embodiments, the treatment regimen is continued. In some embodiments, the treatment regimen is altered. In some embodiments, the dosage of the compound of Formula (III) is increased. In some embodiments, the dosage of the compound of Formula (III) is decreased. In some embodiments, the dosage of the compound of Formula (III) is not altered. In some embodiments, the frequency of administration of the compound of Formula (III) is increased. In some embodiments, the frequency of administration of the compound of Formula (III) is decreased. In some embodiments, the frequency of administration of the compound of Formula (III) is not altered. In some embodiments, the timing of administration of the compound of Formula (III) is altered (e.g., time of day, or time relative to administration of other therapeutic agents). In some embodiments, the timing of administration of the compound of Formula (III) is not altered. In some embodiments, an additional therapeutic agent is administered. In some embodiments, an additional anti-cancer agent is administered.

[0052] In some aspects, an exemplary method for treating DLBCL or ABC-DLBCL in a patient in need thereof includes: (a) administering a treatment comprising a therapeutically effective amount of a compound of Formula (III); (b) determining the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, in a sample from the patient after administration of the treatment; and (c) discontinuing the treatment if the expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof has not decreased by a predetermined amount relative to the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof before the treatment. In some embodiments, the predetermined amount is one in which the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof is reduced by 3%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% or more following treatment with a compound of Formula (III). In some embodiments, the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof is measured 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, 36 hours, or 48 hours or more after treatment with a compound of Formula (III).

[0053] In some embodiments, a method is provided for predicting a response to a compound of formula (III) in a patient with DLBCL or ABC-DLBCL, comprising determining an expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, in a sample (e.g., a serum sample) from the patient before administration of the compound of formula (III) and comparing it to a control or reference, where a favorable outcome for treatment with the compound of formula (III) is predicted if the patient sample shows a high expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, relative to the control or reference level. In some embodiments, the reference level is the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, in a normal patient (e.g., a patient without DLBCL).

[0054] In some aspects, a method for treating DLBCL or ABC-DLBCL in a selected patient is provided, comprising administering to the selected patient a therapeutically effective amount of a compound of formula (III) in an amount effective to treat DLBCL or ABC-DLBCL, wherein the selected patient has elevated expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof prior to administration of the compound of formula (III), and wherein elevated expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof relative to normal indicates that the selected patient will benefit from continued treatment with the compound of formula (III).

[0055] In some embodiments, a method for identifying a patient likely to be therapeutically responsive to treatment with a compound of formula (III) is provided, comprising: (a) measuring the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, in a sample (e.g., a serum sample) obtained from a patient having DLBCL or ABC-DLBCL or suspected of having DLBCL or ABC-DLBCL; and (b) comparing the levels obtained in step (a) with the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, in a control sample. and comparing the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof measured in step (a) relative to the control sample indicates that the patient will therapeutically respond to treatment with the compound of formula (III), and a non-increased or decreased level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof relative to the control sample indicates that the patient is likely not to respond to or is resistant to treatment with the compound of formula (III).

[0056] Some embodiments include a method for predicting whether a patient will respond therapeutically to a method of treating DLBCL or ABC-DLBCL comprising administering a compound of Formula (III), comprising: (a) measuring the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, in a sample (e.g., a serum sample) obtained from the patient; and (b) comparing the levels obtained in step (a) with the expression level of the CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, in a control sample. and comparing the level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof measured in step (a) to the control sample, wherein an increased level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof measured in step (a) indicates that the patient will therapeutically respond to treatment with the compound of formula (III), and a non-increased or decreased level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof relative to the control sample indicates that the patient may not respond to or may be resistant to treatment with the compound of formula (III).

[0057] In some embodiments, the methods provided herein are performed repeatedly over time, in which a decreased level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, in a patient sample relative to a pre-treatment or reference sample indicates a favorable response of the patient to treatment with the compound of formula (III), and an increased level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, in a patient sample relative to a control sample indicates that the patient may not respond to or may be resistant to treatment with the compound of formula (III). Thus, in some embodiments, a method is provided for monitoring the treatment of a patient having DLBCL or ABC-DLBCL, wherein the DLBCL or ABC-DLBCL is treated by a method comprising administering to the patient a compound of formula (III), alone or in combination with an anti-cancer or tumor agent.

[0058] In some embodiments, the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof is measured 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, 36 hours, or 48 hours or more after treatment with a compound of Formula (III). In some embodiments, the expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, are measured 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, 36 hours, or 48 hours or more after a single dosage of a compound of formula (III). In some embodiments, the expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, are measured 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, 36 hours, or 48 hours or more after multiple administrations of a compound of formula (III). In some embodiments, the expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, are measured 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, 36 hours, or 48 hours or more after multiple administrations of a compound of formula (III) and the final dosage. In some embodiments, the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof is measured 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, 36 hours, or 48 hours or more after administration of the last dosage of a compound of Formula (III) in a treatment regimen.

[0059] In some embodiments, the expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, are monitored over time during the course of a treatment regimen with a compound of formula (III). In some embodiments, the expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, are measured daily, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 2 weeks, every 3 weeks, monthly, or at longer intervals. In some embodiments, the expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, are monitored over time during the course of a treatment regimen with a compound of formula (III), and the expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, are determined after each administration of a compound of formula (III). In some embodiments, the expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, are monitored over time during the course of a treatment regimen with a compound of formula (III), and the expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, are determined after multiple administrations of a compound of formula (III). In some embodiments, the expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, are monitored over time during the course of a treatment regimen with a compound of formula (III), and the expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, are determined after 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more administrations of a compound of formula (III).

[0060] In some embodiments, the expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, are monitored over time during the course of a treatment regimen with a compound of formula (III), and an increase in the expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof indicates that the patient is resistant, or will become resistant, to treatment with a compound of formula (III). In some embodiments, the expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, are monitored over time during the course of a treatment regimen with a compound of formula (III), and if a change in the expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof is detected relative to a reference level, the treatment regimen is altered, continued, or discontinued. In some embodiments, the treatment regimen is discontinued. In some embodiments, the treatment regimen is continued. In some embodiments, the treatment regimen is altered. In some embodiments, the dosage of the compound of formula (III) is increased. In some embodiments, the dosage of the compound of formula (III) is decreased. In some embodiments, the dosage of the compound of formula (III) is not altered. In some embodiments, the frequency of administration of the compound of formula (III) is increased. In some embodiments, the frequency of administration of the compound of formula (III) is decreased. In some embodiments, the frequency of administration of the compound of Formula (III) is not altered. In some embodiments, the timing of administration of the compound of Formula (III) is altered (e.g., time of day, or time relative to administration of other therapeutic agents). In some embodiments, the timing of administration of the compound of Formula (III) is not altered. In some embodiments, an additional therapeutic agent is administered.

[0061] In some embodiments, the dosage of the compound of formula (III) is increased if the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof increases over the course of therapy with the compound of formula (III). In some embodiments, the frequency of administration of the compound of formula (III) is increased if the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof increases over the course of therapy. In some embodiments, an additional therapeutic agent is administered if the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof increases over the course of therapy.

[0062] In some embodiments, "high expression levels" of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, in a patient relative to normal means that the patient exhibits a 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, 70-fold, 75-fold, 80-fold, 85-fold, 90-fold, 95-fold, or 100-fold or greater increase in pretien expression levels of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof. In some embodiments, a "high expression level" of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, in a patient relative to normal means that the patient exhibits a 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, 70-fold, 75-fold, 80-fold, 85-fold, 90-fold, 95-fold, or 100-fold or greater increase in expression of a nucleic acid (e.g., mRNA) encoding CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof.

[0063] In some embodiments, the method includes obtaining a sample (e.g., a serum sample) from a patient and measuring the protein expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9 protein, or any combination thereof. In some embodiments, measuring the protein expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof comprises an immunoassay. In some embodiments, measuring the protein expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof comprises an ELISA. In some embodiments, measuring the protein expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof comprises detecting CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9 protein, or any combination thereof with an antibody. In some embodiments, the antibody is labeled. In some embodiments, measuring the protein expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof comprises detecting CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof with a first antibody to form an antibody complex with CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, and then detecting the antibody complex with a second antibody that binds to the first antibody. In some embodiments, the antibody is labeled.

[0064] In some embodiments, the method includes obtaining a sample containing nucleic acid from a patient and measuring the expression level of a nucleic acid encoding CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof. In some embodiments, the method includes isolating or purifying mRNA from the sample. In some embodiments, the method includes amplifying the mRNA transcript, for example, by RT-PCR. In some embodiments, a higher baseline level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof (e.g., as assessed by determining the number of cycles at which fluorescence exceeds a set threshold level ("ct") mRNA expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof) indicates that the cancer is more likely to be sensitive to treatment with a compound of formula (III).

[0065] In some embodiments, the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof in the sample is compared to the level of expression in a reference DLBCL or ABC-DLBCL cell, or a population of DLBCL or ABC-DLBCL cells. In some embodiments, the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof in the sample is compared to the level of expression in a reference DLBCL or ABC-DLBCL cell line. In some embodiments, the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof in the sample is compared to the level of expression in a reference DLBCL cell or a population of DLBCL cells known to be resistant to treatment with a compound of formula (III). In some embodiments, the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof in the sample is compared to the level of expression in a reference DLBCL cell or population of DLBCL cells known to be sensitive to treatment with a compound of formula (III). In some embodiments, the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof in the sample is compared to the level of expression in a reference DLBCL cell line known to be resistant to treatment with a compound of formula (III). In some embodiments, the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof in the sample is compared to the level of expression in a reference DLBCL cell line known to be sensitive to treatment with a compound of formula (III). In some embodiments, the DLBCL cell line is an activated B-cell-like (ABC)-DLBCL cell line. In some embodiments, the DLBCL cell line is a Germinal Center B-cell-like (GCB)-DLBCL cell line.In some embodiments, the DLBCL cell line is OCI-Ly1, OCI-Ly2, OCI-Ly3, OCI-Ly4, OCI-Ly6, OCI-Ly7, OCI-Ly10, OCI-Ly18, OCI-Ly19, U2932, DB, HBL-1, RIVA, or TMD8. In some embodiments, the DLBCL cell line sensitive to treatment with a compound of formula (III) is TMD8, HBL-1, or OCI-Ly10. In some embodiments, the DLBCL cell line resistant to treatment with a compound of formula (III) is OCI-Ly13, DB, or OCI-Ly19.

[0066] Some embodiments are directed to methods in which a subject having DLBCL is treated with a therapeutically effective amount of a compound of formula (III) for more than six months, and after about six months of treatment, the subject is monitored at predetermined time intervals to determine the level of expression of CCL3 and / or CCL4. In some embodiments, the monitoring comprises (a) determining the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, in a sample (e.g., a serum sample) after or during the course of treatment with the compound of formula (III), and (b) modifying or continuing the treatment based on the expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof, relative to a control or reference level. In some embodiments, the reference level is the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, in a sample (e.g., a serum sample) taken from the patient prior to administration of a therapeutically effective amount of a compound of formula (III). In some embodiments, the reference level is the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, in a normal patient (e.g., a patient without DLBCL). In some embodiments, the treatment regimen is continued. In some embodiments, the treatment regimen is altered. In some embodiments, the dosage of the compound of formula (III) is increased. In some embodiments, the dosage of the compound of formula (III) is decreased. In some embodiments, the dosage of the compound of formula (III) is not altered. In some embodiments, the frequency of administration of the compound of formula (III) is increased. In some embodiments, the frequency of administration of the compound of formula (III) is decreased. In some embodiments, the frequency of administration of the compound of Formula (III) is not altered. In some embodiments, the timing of administration of the compound of Formula (III) is altered (e.g., time of day, or time relative to administration of other therapeutic agents). In some embodiments, the timing of administration of the compound of Formula (III) is not altered. In some embodiments, an additional therapeutic agent is administered.In some embodiments, an additional anti-cancer agent is administered.

[0067] In some embodiments, the method further comprises discontinuing treatment with the compound of formula (III) if the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof increases relative to a reference or control over the course of treatment with the compound of formula (III). In some embodiments, the method further comprises continuing treatment with the compound of formula (III) if the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof decreases relative to a reference level. In some embodiments, the reference is the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof in a DLBCL patient. In some embodiments, the reference is the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, in the same patient prior to treatment with a compound of Formula (III).

[0068] In some aspects, an individual is characterized as having DLBCL if the individual exhibits an increased expression level in at least one biomarker selected from CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, relative to a control.

[0069] Also disclosed herein in some aspects is a method of evaluating an individual having DLBCL or ABC-DLBCL for treatment with a compound of formula (III) by determining the expression level of at least one biomarker selected from CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, and administering to the individual a therapeutically effective amount of a compound of formula (III) if there is an increase in the expression level of at least one biomarker selected from CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof.

[0070] Further disclosed herein in some aspects are methods of monitoring disease progression in an individual having DLBCL or ABC-DLBCL by determining the expression level of at least one biomarker selected from CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof, and characterizing the individual as having DLBCL or ABC-DLBCL if the individual shows an increased expression level in at least one biomarker CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof.

[0071] The methods provided herein relate to the use of CD10, BCL6, or MUM1 expression as predictive biomarkers to identify responder populations, particularly patients who may be susceptible to treatment with compounds of formula (III), such as compounds of formula (III). The methods provided herein provide clinical advantages for the diagnosis and treatment of GCB-DLBCL, including easy access to samples, low-cost analysis, and rapid adjustment (normalization within days) with BCR-targeted therapy, given that CD10, BCL6, MUM1, or any combination thereof can be reliably quantified in plasma and serum samples. In some embodiments, serum levels of CD10, BCL6, MUM1, or any combination thereof can be easily quantified by enzyme-linked immunosorbent assay (ELISA) or other rapid protein detection methods. Other methods for detecting CD10, BCL6, MUM1, or any combination thereof can be found in Hans et.Al. (Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray; Neoplasia (2004) 103:275-282), which is incorporated herein in its entirety. Thus, in some embodiments, patients exhibiting higher than normal expression levels of CD10, BCL6, or a combination thereof, and lower than normal expression of MUM1, may be sensitive to treatment with a compound of formula (III). In some embodiments, patients exhibiting about the same or lower expression levels of CD10, BCL, or a combination thereof, and higher than normal expression of MUM1, may be resistant to treatment with a compound of formula (III). Thus, measuring the expression levels, gene or protein expression of CD10, BCL6, MUM1, or a combination thereof is particularly useful for identifying patients who may respond to therapy with a compound of formula (III).

[0072] Some embodiments are directed to methods and procedures for determining patient sensitivity to a compound of formula (III). Some embodiments are directed to methods for determining or predicting whether an individual in need of therapy for GCB-DLBCL will respond to a treatment prior to administration of the treatment, the treatment comprising administration of a compound of formula (III). In an embodiment, disclosed herein is a method for selecting a patient diagnosed with diffuse large cell GCB-DLBCL for treatment with a compound of formula (III), based on the level of expression of biomarkers CD10, BCL6, MUM1, or any combination thereof. In some embodiments, the method comprises identifying a patient likely to respond to treatment with a compound of formula (III). In some embodiments, the method comprises determining a treatment regimen. Also disclosed herein in certain aspects is a method for evaluating treatment of GCB-DLBCL in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (III) and determining the patient's responsiveness to treatment based on the level of expression of CD10, BCL6, MUM1, or any combination thereof. In some aspects, a high expression level of CD10, BCL6, or a combination thereof, and a low expression level of MUM1 prior to treatment predicts a therapeutic response to treatment with a compound of formula (III). In some aspects, a method for treating GCB-DLBCL is provided by preselecting a patient exhibiting elevated levels of CD10, BCL6, or a combination thereof, and a low level of MUM1, thereby increasing the likelihood of a response in the patient to a compound of formula (III). In some aspects, methods are provided for treating GCB-DLBCL in a patient in need thereof by assessing whether the patient exhibits elevated levels of CD10, BCL6, or a combination thereof, and low levels of MUM1, thereby increasing the likelihood of response in the patient to a compound of formula (III).Some embodiments are directed to a method for treating GCB-DLBCL in a patient in need thereof, comprising: (a) determining the expression level of CD10, BCL6, MUM1, or any combination thereof in a sample (e.g., a serum sample) from the patient; and (b) administering to the patient a therapeutically effective amount of a compound of formula (III) if expression of CD10, BCL6, or any combination thereof is increased relative to a control or reference level and expression of MUM1 is decreased relative to a control or reference level. In some embodiments, the reference level is the level of expression of CD10, BCL6, MUM1, or any combination thereof in a normal patient (e.g., a patient without DLBCL or GCB-DLBCL).

[0073] In some embodiments, an exemplary method for treating GCB-DLBCL in a patient in need thereof includes: (a) determining the expression level of CD10, BCL6, MUM1, or any combination thereof in a sample (e.g., a serum sample) from the patient after administration of a therapeutically effective amount of a compound of formula (III); and (b) modifying, interrupting, or continuing treatment based on the expression of CD10, BCL6, MUM1, or any combination thereof relative to a control or reference level. In some embodiments, the reference level is the expression level of CD10, BCL6, MUM1, or any combination thereof in a sample (e.g., a serum sample) taken from the patient before administration of a therapeutically effective amount of a compound of formula (III). In some embodiments, the treatment regimen is continued. In some embodiments, the treatment regimen is modified. In some embodiments, the dosage of the compound of formula (III) is increased. In some embodiments, the dosage of the compound of formula (III) is decreased. In some embodiments, the dosage of the compound of formula (III) is not modified. In some embodiments, the frequency of administration of the compound of formula (III) is increased. In some embodiments, the frequency of administration of the compound of Formula (III) is decreased. In some embodiments, the frequency of administration of the compound of Formula (III) is not altered. In some embodiments, the timing of administration of the compound of Formula (III) is altered (e.g., time of day, or time relative to administration of other therapeutic agents). In some embodiments, the timing of administration of the compound of Formula (III) is not altered. In some embodiments, an additional therapeutic agent is administered. In some embodiments, an additional anti-cancer agent is administered.

[0074] In some embodiments, a method is provided for predicting a response to a compound of formula (III) in a patient with GCB-DLBCL, comprising determining an expression level of CD10, BCL6, MUM1, or any combination thereof in a sample (e.g., a serum sample) from the patient before administration of the compound of formula (III) and comparing it to a control or reference, where a favorable outcome is predicted for treatment with the compound of formula (III) if the patient sample shows a high expression level of CD10, BCL6, MUM1, or any combination thereof relative to the control or reference level. In some embodiments, the reference level is the expression level of CD10, BCL6, MUM1, or any combination thereof in a normal patient (e.g., a patient without DLBCL or GCB-BLBCL).

[0075] In some aspects, a method is provided for treating GCB-DLBCL in a selected patient, comprising administering to the selected patient a therapeutically effective amount of a compound of formula (III) in an amount effective to treat GCB-DLBCL, wherein the selected patient has high expression levels of CD10, BCL6, or a combination thereof, and low expression levels of MUM1 prior to administration of the compound of formula (III), and wherein the high expression levels of CD10, BCL6, or a combination thereof, and low levels of MUM1 relative to normal indicate that the selected patient will benefit from continued treatment with the compound of formula (III).

[0076] In some aspects, a method is provided for identifying a patient likely to respond therapeutically to treatment with a compound of formula (III), comprising: (a) measuring the expression level of CD10, BCL6, MUM1, or any combination thereof, in a sample (e.g., a serum sample) obtained from a patient having or suspected of having GCB-DLBCL; and (b) comparing the level obtained in step (a) with the level of expression of CD10, BCL6, MUM1, or any combination thereof in a control sample, wherein an increase in the level of CD10, BCL6, or combination thereof, and a decrease in the level of MUM1 measured in step (a) relative to the control sample indicates that the patient will respond therapeutically to treatment with a compound of formula (III).

[0077] In some embodiments, a method is provided for predicting whether a patient will therapeutically respond to a method of treating GCB-DLBCL comprising administering a compound of formula (III), the method comprising: (a) measuring the expression level of CD10, BCL6, MUM1, or any combination thereof, in a sample (e.g., a serum sample) obtained from the patient; and (b) comparing the level obtained in step (a) with the expression level of CD10, BCL6, MUM1, or any combination thereof in a control sample, wherein an increase in the level of CD10, BCL6, or combination thereof, and a decrease in MUM1 expression measured in step (a) indicates that the patient will therapeutically respond to treatment with a compound of formula (III).

[0078] In some aspects, a "high expression level" of CD10, BCL6, or a combination thereof in a patient relative to normal means that the patient exhibits a 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, 70-fold, 75-fold, 80-fold, 85-fold, 90-fold, 95-fold, or 100-fold or greater increase in protein expression levels of CD10, BCL6, or a combination thereof. In some aspects, a "high expression level" of CD10, BCL6, or a combination thereof in a patient relative to normal means that the patient exhibits a 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, 70-fold, 75-fold, 80-fold, 85-fold, 90-fold, 95-fold, or 100-fold or greater increase in expression of a nucleic acid (e.g., mRNA) encoding CD10, BCL6, MUM1, or any combination thereof. In some aspects, a "low expression level" of MUM1 in a patient relative to normal means that the patient exhibits a 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, 70-fold, 75-fold, 80-fold, 85-fold, 90-fold, 95-fold, or 100-fold or greater decrease in MUM1 protein expression levels. In some aspects, a "low expression level" of MUM1 in a patient relative to normal means that the patient exhibits a 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, 70-fold, 75-fold, 80-fold, 85-fold, 90-fold, 95-fold, or 100-fold or greater decrease in expression of the encoding nucleic acid (e.g., mRNA).

[0079] In some embodiments, the method includes obtaining a sample (e.g., a serum sample) from the patient and measuring the protein expression level of CD10, BCL6, MUM1 protein, or any combination thereof. In some embodiments, measuring the protein expression level of CD10, BCL6, MUM1, or any combination thereof comprises an immunoassay. In some embodiments, measuring the protein expression level of CD10, BCL6, MUM1, or any combination thereof comprises an ELISA. In some embodiments, measuring the protein expression level of CD10, BCL6, MUM1, or any combination thereof comprises detecting the protein level of CD10, BCL6, MUM1, or any combination thereof with an antibody. In some embodiments, the antibody is labeled. In some embodiments, measuring the protein expression level of CD10, BCL6, MUM1, or any combination thereof comprises detecting CD10, BCL6, MUM1, or any combination thereof with a first antibody to form an antibody complex with CD10, BCL6, MUM1, or any combination thereof, and then detecting the antibody complex with a second antibody that binds to the first antibody. In some embodiments, the antibody is labeled.

[0080] In some embodiments, the method includes obtaining a sample containing nucleic acid from a patient and measuring the expression level of a nucleic acid encoding CD10, BCL6, MUM1, or any combination thereof. In some embodiments, the method includes isolating or purifying mRNA from the sample. In some embodiments, the method includes amplifying the mRNA transcript, for example, by RT-PCR. In some embodiments, a higher baseline level of CD10, BCL6, MUM1, or any combination thereof (e.g., as assessed by determining the cycle number at which fluorescence exceeds a set threshold level ("ct") mRNA expression of CD10, BCL6, MUM1, or any combination thereof) indicates that the cancer is more likely to be sensitive to treatment with a compound of formula (III).

[0081] In some embodiments, the level of expression of CD10, BCL6, MUM1, or any combination thereof in the sample is compared to the level of expression in a reference GCB-DLBCL cell or population of GCB-DLBCL cells. In some embodiments, the level of expression of CD10, BCL6, MUM1, or any combination thereof in the sample is compared to the level of expression in a reference GCB-DLBCL cell line. In some embodiments, the level of expression of CD10, BCL6, MUM1, or any combination thereof in the sample is compared to the level of expression in a reference GCB-DLBCL cell or population of GCB-DLBCL cells known to be resistant to treatment with a compound of formula (III). In some embodiments, the level of expression of CD10, BCL6, MUM1, or any combination thereof in the sample is compared to the level of expression in a reference GCB-DLBCL cell or population of GCB-DLBCL cells known to be sensitive to treatment with a compound of formula (III). In some embodiments, the level of expression of CD10, BCL6, MUM1, or any combination thereof in the sample is compared to the level of expression in a reference DLBCL cell line known to be resistant to treatment with a compound of formula (III). In some embodiments, the level of expression of CD10, BCL6, MUM1, or any combination thereof in the sample is compared to the level of expression in a reference GCB-DLBCL cell line known to be sensitive to treatment with a compound of formula (III). In some embodiments, the GCB-DLBCL or DLBCL cell line is OCI-Lyl, OCI-Ly2, OCI-Ly3, OCI-Ly4, OCI-Ly6, OCI-Ly7, OCI-LylO, OCI-Lyl8, OCI-Lyl9, U2932, DB, HBL-1, RIVA, or TMD8. In some embodiments, the GCB-DLBCL or DLBCL cell line sensitive to treatment with a compound of formula (III) is TMD8, HBL-1, or OCI-Lyl 0. In some embodiments, the GCB-DLBCL or DLBCL cell line resistant to treatment with a compound of formula (III) is OCI-Ly3, DB, or OCI-Lyl 9.

[0082] In some embodiments, the maintenance therapy comprises administration of a daily dosage of a compound of formula (III). Kits and articles of manufacture are also described herein for use in the diagnostic and therapeutic applications described herein. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers, such as vials, tubes, and the like, each of which comprises one of the separate elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from any acceptable material, such as, for example, glass or plastic. In some embodiments, the kits provided herein are for use in determining the level of expression of CD10, BCL6, MUM1, or a combination thereof. In some embodiments, the kits provided herein are for use as a companion diagnostic with a compound of formula (III). In some embodiments, the kits are used to select patients for treatment with a compound of formula (III), to identify subjects as susceptible to a compound of formula (III), and to evaluate treatment with a compound of formula (III). In some embodiments, the kit is used to select patients for treatment with a compound of formula (III), to identify subjects as resistant or likely to become resistant to a compound of formula (III), to monitor the development of resistance to a compound of formula (III), or a combination thereof.

[0083] The kits provided herein contain one or more reagents for detecting the expression of CD10, BCL6, MUM1, or any combination thereof. Exemplary reagents include, but are not limited to, antibodies, buffers, nucleic acids, microarrays, ELISA plates, substrates for enzyme staining, chromagens, or other materials, such as slides, containers, microtiter plates, and, optionally, instructions for carrying out the method. Those skilled in the art will recognize many other possible containers and plates and reagents that can be used to contact various materials.

[0084] In some aspects, an individual is characterized as having GCB-DLBCL if the individual exhibits increased expression levels of at least one biomarker selected from CD10, BCL6, or a combination thereof, and optionally, elevated levels of MUM1 relative to a control.

[0085] Also disclosed in some aspects is a method of evaluating an individual having GCB-DLBCL for treatment with a compound of formula (III) by determining the expression level of at least one biomarker selected from CD10, BCL6, MUM1, or any combination thereof, and administering to the individual a therapeutically effective amount of a compound of formula (III) if there is an increase in the expression level of at least one biomarker selected from CD10, BCL6, or a combination thereof, and optionally a decrease in the expression level of MUM1.

[0086] In some embodiments, subjects are monitored monthly, every two months, every three months, every four months, every five months, every six months, every seven months, every eight months, every nine months, every ten months, every eleven months, or yearly to determine the level of expression of the biomarker genes disclosed herein.

[0087] Genetic modification-based biomarkers In some aspects, the methods disclosed herein are based on detecting the presence or absence of an alteration, such as a base substitution, an insertion, a deletion, a DNA rearrangement, a translocation, a copy number change, or a combination thereof.

[0088] Methods provided herein relate to detecting alterations in MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, PRDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, or HNF1B as predictive biomarkers for identifying responder populations, particularly patients who may be sensitive to treatment with a compound of formula (III). The methods provided herein provide clinical advantages to the diagnosis and treatment of B-cell lymphoma, including easy access to samples, given that alterations to the biomarker genes described herein can be reliably detected.

[0089] In some aspects, a method of treating DLBCL in a subject comprises: (a) determining the presence or absence of an alteration in one or more biomarker genes in the subject, where the biomarker genes are selected from MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, PRDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, or HNF1B; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (III) if an alteration in the one or more biomarker genes is present. In some embodiments, the DLBCL subtype is activated B cell diffuse large B cell lymphoma (ABC-DLBCL), germinal center B cell diffuse large B cell lymphoma (GCB-DLBCL), or non-germinal center B cell diffuse large B cell lymphoma (non-GCB-DLBCL).

[0090] In some embodiments, a method of monitoring whether a subject receiving a compound of Formula (III) for the treatment of DLBCL has developed or is likely to develop resistance to the therapy comprises (a) determining the presence or absence of an alteration in one or more biomarker genes in the subject, wherein the biomarker genes are selected from MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, PRDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, or HNF1B, and determining that if an alteration in the one or more biomarker genes is present, the subject is likely to develop resistance to the therapy. In some embodiments, the DLBCL subtype is activated B cell diffuse large B cell lymphoma (ABC-DLBCL), germinal center B cell diffuse large B cell lymphoma (GCB-DLBCL), or non-germinal center B cell diffuse large B cell lymphoma (non-GCB-DLBCL).

[0091] In some embodiments, a method of predicting a response in a subject receiving a compound of formula (III) for the treatment of DLBCL comprises determining the presence or absence of an alteration in one or more biomarker genes in the subject, wherein the biomarker genes are selected from MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, PRDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, or HNF1B, and determining that if an alteration in the one or more biomarker genes is present, the subject is likely to respond to the therapy. In some embodiments, the DLBCL subtype is activated B cell diffuse large B cell lymphoma (ABC-DLBCL), germinal center B cell diffuse large B cell lymphoma (GCB-DLBCL), or non-germinal center B cell diffuse large B cell lymphoma (non-GCB-DLBCL).

[0092] In some embodiments, a method of optimizing therapy of a subject receiving a compound of Formula (III) for the treatment of diffuse large B-cell lymphoma (DLBCL) is provided, comprising: (a) determining the presence or absence of an alteration in one or more biomarker genes in the subject, wherein the biomarker genes are MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, Further disclosed herein are methods comprising (a) determining whether or not a mutation in one or more biomarker genes is present in the blood, and (b) modifying treatment based on the presence or absence of an alteration in one or more biomarker genes selected from SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, PRDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, or HNF1B. In some embodiments, the DLBCL subtype is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL), or non-germinal center B-cell diffuse large B-cell lymphoma (non-GCB-DLBCL).

[0093] In some aspects, a method of evaluating treatment with a compound of formula (III) in a subject comprises: (a) determining the presence or absence of an alteration in one or more biomarker genes in the subject, the biomarker genes being selected from MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, PRDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, or HNF1B; and (b) modifying, interrupting, or continuing treatment based on the presence or absence of an alteration in the one or more biomarker genes. In some embodiments, the treatment regimen is modified. In some embodiments, the dosage of the compound of Formula (III) is increased. In some embodiments, the dosage of the compound of Formula (III) is decreased. In some embodiments, the dosage of the compound of Formula (III) is not altered. In some embodiments, the frequency of administration of the compound of Formula (III) is increased. In some embodiments, the frequency of administration of the compound of Formula (III) is decreased. In some embodiments, the frequency of administration of the compound of Formula (III) is not altered. In some embodiments, administration of the compound of Formula (III) is discontinued.

[0094] Also provided is a method for selecting a subject having diffuse large B-cell lymphoma (DLBCL) for treatment with a compound of formula (III), comprising: (a) determining the presence or absence of an alteration in one or more biomarker genes in the subject, wherein the biomarker genes are MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, M Disclosed herein are methods comprising: (a) determining whether or not an alteration in one or more biomarker genes is present; and (b) selecting a subject if an alteration in one or more biomarker genes is present; and administering to the subject a therapeutically effective amount of a compound of formula (III). In some embodiments, the DLBCL subtype is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL), or non-germinal center B-cell diffuse large B-cell lymphoma (non-GCB-DLBCL).

[0095] In some aspects, a subject with DLBCL is characterized as resistant or likely to become resistant to therapy with a compound of formula (III) if the subject has an alteration in one or more biomarker genes selected from MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, PRDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, or HNF1B. In some embodiments, the DLBCL subtype is activated B cell diffuse large B cell lymphoma (ABC-DLBCL), germinal center B cell diffuse large B cell lymphoma (GCB-DLBCL), or non-germinal center B cell diffuse large B cell lymphoma (non-GCB-DLBCL).

[0096] In some aspects, the activated B-cell diffuse large B-cell lymphoma subtype of DLBCL (ABC-DLBCL) is characterized by one or more alterations in MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, PRDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, or HNF1B. The alterations can be base substitutions, insertions, deletions, DNA rearrangements, translocations, copy number changes, or combinations thereof.

[0097] In some aspects, the germinal center (GCB) subtype of DLBCL is characterized by one or more alterations in MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, PRDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, or HNF1B. The alterations can be base substitutions, insertions, deletions, DNA rearrangements, translocations, copy number changes, or combinations thereof.

[0098] In some aspects, the non-germinal center (non-GCB) subtype of DLBCL is characterized by one or more alterations in MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, PRDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, or HNF1B. The alterations can be base substitutions, insertions, deletions, DNA rearrangements, translocations, copy number changes, or combinations thereof.

[0099] In some aspects, the sample for use in the method is from any tissue or fluid from a patient. Samples include, but are not limited to, whole blood, isolated bone marrow, bone marrow aspirate, pleural fluid, peritoneal fluid, central spinal fluid, intraperitoneal fluid, pancreatic fluid, cerebrospinal fluid, brain fluid, ascites, pericardial fluid, urine, saliva, bronchial lavage, sweat, tears, ear fluid, sputum, hydrocele fluid, semen, vaginal fluid, milk, amniotic fluid, and secretions of the respiratory, intestinal, or genitourinary tract. In certain aspects, the sample is a serum sample. In certain aspects, the sample is a tumor biopsy sample. In certain aspects, the sample is from a fluid or tissue that is part of or associated with the lymphatic or circulatory system. In some aspects, the sample is a blood sample, and the blood sample is a venous, arterial, peripheral, tissue, or umbilical cord blood sample. In certain embodiments, the sample is a blood cell sample containing one or more Peripheral Blood Mononuclear Cells (PBMCs). In some embodiments, the sample contains one or more Circulating Tumor Cells (CTCs). In some embodiments, the sample contains one or more Disseminated Tumor Cells (DTCs, e.g., DTCs in a bone marrow aspirate sample).

[0100] In some embodiments, the sample is obtained from the subject by any suitable means to obtain the sample using known and routine clinical methods. Procedures for obtaining fluid samples from subjects are well known. For example, procedures for collecting and processing whole blood and lymph are well known and can be used to obtain samples for use in the methods provided. Typically, blood samples are collected by adding an anticoagulant (e.g., EDTA, or citrate and heparin, or CPD (citrate, phosphate, dextrose), or equivalent) to the sample to prevent blood clotting. In some examples, blood samples are collected in collection tubes that contain an amount of EDTA to prevent blood sample clotting.

[0101] In some embodiments, the collection of samples from the subject is performed at regular intervals, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, weekly, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, daily, weekly, bimonthly, quarterly, biennially, or annually. In some embodiments, samples are collected at a predetermined time or regular intervals before, during, or after treatment with anticancer drugs, or between successive treatments. In certain examples, samples are obtained from the subject before treatment with anticancer drugs, and again at regular intervals after treatment.

[0102] In some embodiments, the collection of samples is performed at a predetermined time or at regular intervals relative to treatment with the compound of formula (III). For example, samples are collected from the patient at a predetermined time or at regular intervals before, during, or after treatment with the compound of formula (III), or between successive treatments. In certain examples, samples are obtained from the patient before administration of the compound of formula (III), and then obtained again at regular intervals after treatment with the compound of formula (III). In some embodiments, the patient is administered the compound of formula (III) and one or more additional anti-cancer agents.

[0103] In some embodiments, the sample is obtained 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 14 months, 16 months, 18 months, 20 months, 22 months, 24 months, 26 months, 28 months, 30 months, 32 months, 34 months, or 36 months or more after the first administration of a compound of Formula (III). In some embodiments, the sample is obtained 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 14 months, 16 months, 18 months, 20 months, 22 months, 24 months, 26 months, 28 months, 30 months, 32 months, 34 months, or 36 months or more after the first administration of a compound of Formula (III) to a subject with DLBCL or ABC-DLBCL. In some embodiments, samples are obtained 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more times over the course of treatment with the compound of Formula (III). In some embodiments, the subject is responsive to treatment with the compound of Formula (III) when the compound of Formula (III) is first administered.

[0104] In some embodiments, the sample is obtained 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 14 months, 16 months, 18 months, 20 months, 22 months, 24 months, 26 months, 28 months, 30 months, 32 months, 34 months, or 36 months or more after the first administration of a compound of Formula (III).

[0105] In a preferred embodiment, the compounds of formula (III) can be used to treat DLBCL. In yet other embodiments, the compounds of the present disclosure can be used to treat ABC-DLBCL, GCB-DLBCL, or non-GCB-DLBCL.

[0106] In the method of treatment according to the present disclosure, an effective amount of an agent according to the present disclosure is administered to a subject suffering from or diagnosed with such a disease, disorder, or condition. A "therapeutically effective amount" means an amount or dosage sufficient to generally produce the desired therapeutic benefit in a patient in need of such treatment for a specified disease, disorder, or condition. A therapeutically effective amount or dosage of a compound of the present disclosure can be ascertained by routine methods, such as modeling, dose escalation studies, or clinical trials, and can be ascertained by considering routine factors, such as the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to the drug, and the judgment of the treating physician. Exemplary dosages are from about 0.0001 to about 1,000 mg of compound per kg of subject body weight per day, preferably in the range of about 0.05 to 100 mg / kg / day or about 1 to 35 mg / kg / day, in single or divided dosage units (e.g., twice daily, three times daily, four times daily). For a 70 kg human, illustrative ranges for suitable dosages are from about 0.05 to about 7 g / day or from about 0.2 to about 2.5 g / day.

[0107] In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 0.0001 mg to about 10,000 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 0.0001 mg to about 1,000 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 0.0001 mg to about 100 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 100 mg to about 200 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 100 mg to about 300 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 100 mg to about 400 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 100 mg to about 500 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 100 mg to about 600 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 100 mg to about 700 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 100 mg to about 800 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 100 mg to about 900 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 100 mg to about 1,000 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 140 mg to about 560 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 140 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 280 mg. In some embodiments, the therapeutically effective amount of the compound of formula (III) is about 560 mg.

[0108] In some embodiments, a therapeutically effective amount of a compound of formula (III) is administered once a day. In some embodiments, a therapeutically effective amount of a compound of formula (III) is administered twice a day. In some embodiments, a therapeutically effective amount of a compound of formula (III) is administered three times a day. In some embodiments, a therapeutically effective amount of a compound of formula (III) is administered orally.

[0109] In some embodiments, the maintenance therapy comprises administration of a daily dosage of the compound of formula (III). In some embodiments, the maintenance therapy comprises multiple cycles of administration of the compound of formula (III). In some embodiments, the cycle of administration is 1 month, 2 months, 3 months, 4 months, 6 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months or more. In some embodiments, the cycle of administration comprises administration of a single therapeutic dosage of the compound of formula (III) over the cycle. In some embodiments, the cycle of administration comprises two or more different dosages of the compound of formula (III) over the cycle. In some embodiments, the dosage of the compound of formula (III) is different over successive cycles. In some embodiments, the dosage of the compound of formula (III) is increased over successive cycles. In some embodiments, the dosage of the compound of formula (III) is the same over successive cycles.

[0110] Furthermore, the compounds of the present disclosure may be used in combination with additional active ingredients in the treatment of the above-mentioned conditions.The additional active ingredients may be administered separately or simultaneously with the compounds of the present disclosure, or such agents may be included in the pharmaceutical compositions of the present disclosure.This combination may help to increase efficacy, reduce one or more side effects, or reduce the required dose of the active agent of the present disclosure (e.g., by including in the combination a compound that enhances the potency or effectiveness of the active agent of the present disclosure).

[0111] The compounds of the present disclosure are used alone or in combination with one or more additional active ingredients to formulate pharmaceutical compositions of the present disclosure, which include (a) an effective amount of at least one compound according to the present disclosure, and (b) a pharma- ceutical acceptable excipient.

[0112] In some embodiments, the compound of formula (III) may be administered in combination with one or more additional therapeutic agents. In some embodiments, one of the additional therapeutic agents is cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP).

[0113] In some embodiments, when a subject suffers from DLBCL or any subset thereof, an anti-cancer agent is administered to the subject in addition to the compound of formula (III). In one embodiment, the anti-cancer agent is an inhibitor of mitogen-activated protein kinase signal transduction, such as U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002. When used for the treatment of cancer, the compound of formula (III) can be administered as a single agent. Alternatively, when used for the treatment of cancer or malignant tumors, the compound of formula (III) can be administered in combination with other agents known to be useful in the treatment of cancer.

[0114] In some embodiments, the compound of formula (III) may be administered in combination with one or more additional therapeutic agents. In some embodiments, one of the further additional therapeutic agents is a Bcl2 inhibitor. In some embodiments, the Bcl2 inhibitor is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide), also known as venetoclax. In some embodiments, 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin5-yloxy)benzamide) is administered according to a weekly escalating dosage regimen, the weekly escalating dosage regimen comprising administering about 20 mg / day in the first week, about 50 mg / day in the second week, about 100 mg / day in the third week, 200 mg / day in the third week, and 400 mg / day in the fourth week and thereafter. In some embodiments, 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) is administered orally. In some embodiments, the compound of formula (III) may be administered in combination with 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) and rituximab.In some embodiments, the compound of formula (III) may be administered in combination with 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) and obinutuzumab.

[0115] In some embodiments, the compound of formula (III) may be administered in combination with one or more additional therapeutic agents selected from the group consisting of chemotherapeutic agents, steroids, immunotherapeutic agents, targeted therapy, and any combination thereof. In some embodiments, the one or more additional therapeutic agents include, but are not limited to, B cell receptor pathway inhibitors, B cell receptor signaling inhibitors, PI3K inhibitors, IAP inhibitors, mTOR inhibitors, radioimmunotherapeutic agents, DNA damaging agents, proteosome inhibitors, histone deacetylase inhibitors, protein kinase inhibitors, hedgehog inhibitors, Hsp90 inhibitors, telomerase inhibitors, Jakl / 2 inhibitors, protease inhibitors, PKC inhibitors, PARP inhibitors, and any combination thereof. In some embodiments, the B cell receptor pathway inhibitors include, but are not limited to, CD79A inhibitors, CD79B inhibitors, CD 19 inhibitors, Lyn inhibitors, Syk inhibitors, PI3K inhibitors, Blnk inhibitors, PLCy inhibitors, PKCP inhibitors, or any combination thereof. In some embodiments, the one or more additional therapeutic agents include, but are not limited to, chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, rituximab, bendamustine, etoposide, prednisolone, and any combination thereof. In some embodiments, the one or more therapeutic agents are nitrogen mustards, including but not limited to, bendamustine, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, prednimustine, trofosfamide; alkyl sulfonates, including but not limited to, busulfan, mannosulfan, treosulfan; ethyleneimines, carboquones, thiotepa, triaziquones;Nitrosoureas, for example, but not limited to, carmustine, fotemustine, lomustine, nimustine, ranimustine, semustine, streptozocin; epoxides, for example, but not limited to, etoglucide; other alkylating agents, for example, but not limited to, dacarbazine, mitobronitol, pipobroman, temozolomide; folic acid analogs, for example, but not limited to, methotrexate, permetrexed, pralatrexate, raltitrexed; purine analogs, for example pyrimidine analogs, such as, but not limited to, azacitidine, capecitabine, carmofur, cytarabine, decitabine, fluorouracil, gemcitabine, tegafur; vincas; alkaloids, such as vinblastine, vincristine, vindesine, vinflunine, vinorelbine; podophyllotoxin derivatives, such as, but not limited to, etoposide, tetanus, Niposide; colchicine derivatives, including but not limited to demecolcine; taxanes, including but not limited to docetaxel, paclitaxel, paclitaxel poliglumex; other plant alkaloids and natural products, including but not limited to trabectedin; actinomycins, including but not limited to dactinomycin; anthracyclines, including but not limited to aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pirarubicin, valrubicin, zorbincin; other cytotoxic antibiotics, including but not limited to, bleomycin, ixabepilone, mitomycin, plicamycin; platinum compounds, including but not limited to, carboplatin, cisplatin, oxaliplatin, satraplatin; methylhydrazines, including but not limited to, procarbazine; sensitizers, including but not limited to, aminolevulinic acid, efaproxiral, methyl aminolevulinate, porfimer sodium, temoporfin;Protein kinase inhibitors, including but not limited to dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazonanib, sorafenib, sunitinib, temsirolimus; other anti-tumor drugs, including but not limited to alitretinoin, altretamine, amzacrine, anagrelide, arsenic trioxide, asparaginase, bexarotene, bortezomib, celecoxib, denileukin diftitox, estramustine, hydroxycarbamide, irinotecan, lonidamine , masoprocol, miltephosine, mitoguazone, mitotane, oblimersen, pegaspargase, pentostatin, romidepsin, sitimagine seradenovec, tiazofurin, topotecan, tretinoin, vorinostat; estrogens, such as, but not limited to, diethylstilbeno, ethinyl estradiol, fosfestrol, polyestradiol phosphate; progestogens, such as, but not limited to, gestnorone, medroxyprogesterone, megestrol; gonadotropes, such as, but not limited to, gonadotropes, tropin releasing hormone analogs, for example, but not limited to, buserelin, goserelin, leuprorelin, triptorelin; antiestrogens, for example, but not limited to, fulvestrant, tamoxifen, toremifene; antiandrogens, for example, but not limited to, bicalutamide, flutamide, nilutamide, enzyme inhibitors, aminoglutethimide, anastrozole, exemestane, formestane, letrozole, vorozole; other hormone antagonists, for example, but not limited to, avarelin, immunodeficients, such as, but not limited to, histamine dihydrochloride, mifamurtide, pidotimod, plerixafor, roquinimex, thymopentin; immunosuppressants, such as, but not limited to, everolimus, gusperimus, leflunomide, mycophenolic acid, sirolimus; calcineurin inhibitors, such as, but not limited to, cyclosporine, tacrolimus; other immunosuppressants, such as, but not limited to, azathioprine, lenalidomide, methotrexate, thalidomide;and radiopharmaceuticals, such as, but not limited to, iobenguane, interferons, interleukins, tumor necrosis factors, or growth factors; immunostimulants, such as, but not limited to, ancestim, filgrastim, lenograstim, molgramostim, pegfilgrastim, sargramostim; interferons, such as, but not limited to, natural interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon alfacon-1, interferon alfa-nl, natural interferon beta, interferon beta-la, interferon beta-lb, interferon gamma, peginterferon alpha-2a, peginterferon alpha-2b; interleukins, such as, but not limited to, aldesleukin, oprelvekin; other immunostimulants, such as, but not limited to, BC G vaccine, glatiramer acetate, histamine dihydrochloride, immunocyanin, lentinan, melanoma vaccine, mifamurtide, pegademase, pidotimod, plerixafor, poly I:C, poly ICLC, rokinimex, tasonermin, thymopentin; immunosuppressants, including but not limited to abatacept, avetimus, alefacept, antilymphocyte immunoglobulin (horse), antithymocyte immunoglobulin (rabbit), eculizumab, efalizumab Mabs, everolimus, gusperimus, leflunomide, muromab-CD3, mycophenolate, natalizumab, sirolimus; TNF-alpha inhibitors, such as adalimumab, afelimomab, certolizumab pegol, etanercept, golimumab, infliximab; interleukin inhibitors, such as, but not limited to, anakinra, basiliximab, canakinumab, daclizumab, mepolizumab, rilonacept, tocilizumab, ustekinumab; calcineurin inhibitors, such as, but not limited to, cyclosporine, tacrolimus; other immunosuppressants, such as, but not limited to, azathioprine, lenalidomide, methotrexate, thalidomide, adalimumab, alemtuzumab, basiliximab, bevacizumab, cetuximab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, ibritumomab tiuxetan, infliximab, muromonab-CD3, natalizumab, panitumumab, ranibizumab, rituximab, tositumomab, trastuzumab; and additional cancer treatment regimens include monoclonal antibodies, such as, but not limited to, For example, but not limited to, alemtuzumab, bevacizumab, catumaxomab, cetuximab, edrecolomab, gemtuzumab, ofatumumab, panitumumab, rituximab, trastuzumab, immunosuppressants, eculizumab, efalizumab, muromab-CD3, natalizumab; TNF alpha inhibitors, for example, but not limited to, adalimumab, afelimomab, certolizumab pegol, golimumab, infliximab, interleukin inhibitors, basiliximab, canakinumab, daclizumab, mepolizumab, tocilizumab, ustekinumab, radiopharmaceuticals, ibritumomab tiuxetan, tositumomab;Other monoclonal antibodies, such as, but not limited to, abagovomab, adecatumumab, alemtuzumab, anti-CD30 monoclonal antibody Xmab2513, anti-MET monoclonal antibody MetMab, apolizumab, apomab, arcitumomab, basiliximab, bispecific antibody 2B1, blinatumomab, brentuximab vedotin, capromab pendetide, cixutumumab, claudiximab, conatumumab, dacetuzumab, denosumab, eculizumab, epratuzumab, ertumaxomab, etaracizumab, figitumumab, fresolimumab, galixima These include, but are not limited to, ganitumab, gemtuzumab ozogamicin, glembatumumab, ibritumomab, inotuzumab ozogamicin, ipilimumab, lexatumumab, lintuzumab, lintuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, monoclonal antibody CC49, necitumumab, nimotuzumab, ofatumumab, oregovomab, pertuzumab, lamaclimab, ranibizumab, siplizumab, sonepcizumab, tanezumab, tositumomab, trastuzumab, tremelimumab, tucotuzumab-celmoleukin, veltuzumab, visilizumab, volociximab, and zalutumumab. Additional cancer treatment regimens include agents that affect the tumor microenvironment, including but not limited to, cell signaling networks (e.g., phosphatidylinositol 3-kinase (PI3K) signaling pathway, signaling from B cell receptors and IgE receptors). In some embodiments, one or more therapeutic agents are PI3K signaling inhibitors or syc kinase inhibitors. In one embodiment, the syk inhibitor is R788. In another embodiment, the PKCy inhibitor is, including but not limited to, enzastaurin. Examples of agents that affect the tumor microenvironment include, but are not limited to, PI3K signaling inhibitors, syc kinase inhibitors, protein kinase inhibitors, including but not limited to, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazonanib, sorafenib, sunitinib, temsirolimus;Other angiogenesis inhibitors, including but not limited to GT-111, JI-101, R1530; other kinase inhibitors, including but not limited to AC220, AC480, ACE-041, AMG 900, AP24534, Arry-614, AT7519, AT9283, AV-951, axitinib, AZD1 152, AZD7762, AZD8055, AZD8931, bafetinib, BAY 73-4506, BGJ398, BGT226, BI 811283, BI6727, BIBF 1120, BIBW 2992, BMS-690154, BMS-777607, BMS-863233, BSK-461364, CAL-101, CEP-11981, CYC116, DCC-2036, dinaciclib, dovitinibractate, E7050, EMD 1214063, ENMD-2076, fostamatinib disodium, GSK2256098, GSK690693, INCB18424, INNO-406, JNJ-26483327, JX-594, KX2-391, linifanib, LY2603618, MGCD265, MK-0457, MK1496, MLN8054, MLN8237, MP470, NMS-1116354, NMS-1286937, ON 01919.Na, OSI-027, OSI-930, Btk inhibitor, PF-00562271, PF-02341066, PF-03814735, PF-04217903, PF-04554878, PF-04691502, PF-3758309, PHA-739358, PLC3397, progenipoetin, R547, R763, ramucirumab, regorafenib, R05185426, SAR103168, S3333333CH 727965, SGI-1176, SGX523, SNS-314, TAK-593, TAK-901, TKI258, TLN-232, TTP607, XL147, XL228, XL281R05126766, XL418, XL765, inhibitors of mitogen-activated protein kinase signaling, such as, but not limited to, U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors;and antibodies (e.g., Rituxan), adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adzelesin; aldesleukin; altretamine; ambomycin; amethanthrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; biceresin ;bleomycin sulfate;brequinar sodium;bropirimine;busulfan;cactinomycin;calsterone;caracemide;carbetimer;carboplatin;carmustine;carbicin hydrochloride;carzercin;cedefingol;chlorambucil;ciloremycin;cladribine;crisnatol mesylate;cyclophosphamide;cytarabine;dacarbazine;daunorubicin hydrochloride;decitabine;dexormaplatin;dezaguanine;dezaguanine mesylate;diaziquone;doxorubicin;doxorubicin hydrochloride;droloxifene;drolone Xifene citrate;Dromostanolone propionate;Duazomycin;Edatrexate;Eflornithine hydrochloride;Elsamitrucin;Enloplatin;Empromate;Epipropizine;Epirubicin hydrochloride;Elbrozole;Esorubicin hydrochloride;Estramustine;Estramustine sodium phosphate;Etanidazole;Etoposide;Etoposide phosphate;Etoprine;Fadrozole hydrochloride;Fazarabine;Fenretinide;Floxuridine;Fludarabine phosphate;Fluorouracil;Flurocitabine;Fosquidone;Fostriecine nat sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II (including recombinant interleukin II or rlL2); interferon alpha-2a; interferon alpha-2b; interferon alpha-nl; interferon alpha-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride;Lometerexol sodium;Lomustine;Losoxantrone hydrochloride;Masoprocol;Maytansine;Mechlorethamine hydrochloride;Megestrol acetate;Melengestrol acetate;Melphalan;Menogaril;Mercaptopurine;Methotrexate;Methotrexate sodium;Metoprine;Meturedepa;Mitindomide;Mitocalcine;Mitochromine;Mitogillin;Mitomarcin;Mitomycin;Mitosper;Mitotane;Mitoxantrone hydrochloride;Mycophenolic acid;Nocodazoie;Nogalamycin;Ormaplatin;Oxisuran;Pegaspar Gauze;Periomycin;Pentamustine;Peplomycin sulfate;Perfosfamide;Pipobroman;Piposulfan;Piroxantrone hydrochloride;Plicamycin;Promestane;Porfimer sodium;Porfiromycin;Prednimustine;Procarbazine hydrochloride;Puromycin;Puromycin hydrochloride;Pyrazofurin;Riboprin;Logretimide;Safumugol;Safumugol hydrochloride;Semustine;Simtrazene;Sparphosate sodium;Sparsomycin;Spirogermanium hydrochloride;Spiromustine;Spiroplatin;Streptomycin Ptonigrin;Streptozocin;Sulofenur;Tallysomycin;Tecogalan sodium;Tegafur;Teroxantrone hydrochloride;Temoporhum;Teniposide;Teroxylon;Testolactone;Thiamiprine;Thioguanine;Thiotepa;Tiazofurin;Tirapazamine;Toremifene citrate;Trestorone acetate;Triciribine phosphate;Trimetrexate;Trimetrexate glucuronate;Triptorelin;Tubrozole hydrochloride;Uracil mustard;Uredep;Vapreotide;Verteporhum;Vinblastine sulfate;Vincristine sulfate Salts;Vindesine;Vindesine sulfate;Binepidine sulfate;Vinglisinate sulfate;Vinleurosine sulfate;Vinorelbine tartrate;Vinrocidine sulfate;Vinzolidine sulfate;Vorozole;Zeniplatin;Zinostatin;Zorubicin hydrochloride;20-epi-l,25-dihydroxyvitamin D3;5-ethynyluracil;Abiraterone;Aclarubicin;Acylfulvene;Adesipenol;Adozelesin;Aldesleukin;ALL-TK antagonists;Altretamine;Ambamustine;Amidox;Amifostine;Aminolevulinic acid;Amrubicin;Amsacrine;Anagrelide;Anastrozole;Andrographolide;Angiogenesis inhibitors;Antagonist D;Antagonist G;Antarelix;Anti-dorsalized morphogenetic protein 1;Anti-androgens, prostate cancer;Anti-estrogens;Antineoplastons;Antisense oligonucleotides;Aphidicolin glycinate;Apoptosis gene modulators;Apoptosis regulators;Apurinic acid;ara-CDP-DL-PTBA; Arginine deaminase;Aslaculin;Atamestane;Atrimustine;Axinastatin 1;Axinastatin 2;Axinastatin 3;Azasetron;Azatoxin;Azatyrosine;Baccatin III derivatives;Balanol;Batimastat;BCR / ABL antagonists;Benzochlorins;Benzoylstaurosporines;Beta-lactam derivatives;Beta-arretin;Betaclamycin B;Betulinic acid;bFGF inhibitors;Bicalutamide;Bisantrene;Bisazilidinyl spermine;Bisnafide;Bistratin A;Biceresin;Brefrathate;Bropirimine;Budotitanium;Buthionine sulfoximine;Calcipotriol;Calfostin C;Camptothecin derivatives;Canarypox IL-2;Capecitabine;Carboxamido-amino-triazoles;Carboxamidotriazoles;CaRest M3;CARN 700;Cartilage-derived inhibitors;Carzelcin;Casein kinase inhibitor (ICOS);Castanospermine;Cecropin B;Cetrorelix;Clorans;Chloroquinoxaline sulfonamides;Cicaprost;Cis-porphyrins;Cladribine;Clomiphene analogs;Clotrimazole;Colismycin A;Colismycin B;Combretastatin A4;Combretastatin analogs;Conagenin;Crambecidin 816;Crisnatol;Cryptophycin 8;Cryptophycin A derivatives;Cracin A;Cyclopentane thraquinone;Cycloplatam;Sipemycin;Cytarabine ocfosfate;Cytolytic factors;Cytostatin;Dacliximab;Decitabine;Dehydrodidemnin B;Deslorelin;De Xamethasone dexifosfamide;Dexrazoxane;Dexverapamil;Diaziquone;Didemnin B;Didox;Diethylnorspermine;Dihydro-5-azacytidine;9-dioxamycin;Diphenylspiromustine;Docosanol;Dolasetron;Doxifluridine;Droloxifene;Dronabinol;Duocarmycin SA;Ebselen;Ecomustine;Edelfosine;Edrecolomab;Eflornithine;Elemene;Emiteflu;Epirubicin;Epristeride;Estramustine analogues;Estrogen agonists;Estrogen antagonists;Etanidazole;Etoposide phosphate;Exemestane;Fadrozole;Fazarabine;Fenretinide;Filgrastim;Finasteride;Flavopiridol;Flazelastine;Fluasterone;Fludarabine;Fluorodaunornithine hydrochloride;Forfenimex;Formestane;Fostriecin;Fotemustine;Gadolinium texaphyrin;Gallium nitrate;Galocitabine;Ganirelix;Gelatinase inhibitors;Gemcitabine;Glutathione inhibitors;Hepsulfame;Heregulin;Hexamethylene bisacetamide;Hypericin;Ibandronate;Idarubicin;Idoxifene;Idramantone;Ilmofosine;Ilomastat;Imidazoacridone;Imiquimod; Immunostimulant peptides;insulin, e.g., growth factor 1 receptor inhibitors;interferon agonists;interferons;interleukins;iobenguane;iododoxorubicin;4-ipomeanol;iropract;irsogladine;isobengazole;isohomohalichondrin B;itasetron;jasplakinolide;kahalalide F;lamellarin-N triacetate;lanreotide;leinamycin;lenograstim;lentinan sulfate;leptolstatin;lerozole;leukemia inhibitory factor;leukocyte alpha interferon;leupro Lidocazone + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; risoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lisofylline; lytic peptides; maytansine; mannostatin A; marimastat; massoprocol; maspin; matrilysine inhibitors; matrix metalloproteinase inhibitors; menogaril; mervalone; methacridine Relin;Methioninase;Metoclopramide;MIF inhibitors;Mifepristone;Miltefosine;Mirimostim;Mismatched double-stranded RNA;Mitoguazone;Mitolactol;Mitomycin analogs;Mitonafide;Mitotoxin fibroblast growth factor-saporin;Mitoxantrone;Mofalotene;Molgramostim;Monoclonal antibodies, human chorionic gonadotropin;Monophosphoryl lipid A+Myobacterium cell wall sk;Mopidamol;Multidrug resistance gene inhibitors;Multiple tumor suppressor 1-based therapy;Mustard anticancer drugs;Mycaperoxide B;Mycobacterial cell wall extracts;Myriaporone;N-acetyldinaline;N-substituted benzamides;Nafarelin;Nagrestip;Naloxone + pentazocine;Napavine;Naphterpin;Nartograstim;Nedaplatin;Nemorubicin;Neridronic acid;Neutral endopeptidase;Nilutamide;Nisamycin;Nitric oxide modulators;Nitroxide antioxidants;Nitrulline;06-benzylguanine;Octreotide;Oxenone;Oligonucleotides;O Napristone;Ondansetron;Ondansetron;Oracin;Oral cytokine inducers;Ormaplatin;Osateron;Oxaliplatin;Oxaunomycin;Palauamine;Palmitoylrhizoxin;Pamidronic acid;Panaxytriol;Panomyphen;Parabactin;Pazeliptin;Pegaspargase;Perdecin;Pentosan polysulfate sodium;Pentostatin;Pentrozole;Perflubron;Perfosfamide;Perillyl alcohol ;Phenazinomycin;Phenylacetate;Phosphatase inhibitors;Picibanil;Pilocarpine hydrochloride;Pirarubicin;Piritrexim;Prasetin A;Prasetin B;Plasminogen activator inhibitors;Platinum complexes;Platinum compounds;Platinum-triamine complexes;Porfimer sodium;Porfiromycin;Prednisone;Propyl bis-acridone;Prostaglandin J2;Proteasome inhibitors;Protein A-based immunomodulators;Protein kinase C inhibitors;Protein kinase C inhibitors, microalgae;Protein tyrosine phosphatase inhibitors;Purine nucleoside phosphorylase inhibitors;Purpurin;Pyrazoloacridines;Pyridoxylated hemoglobin polyoxyethylerythrin conjugates;raf antagonists;Raltitrexed;Ramosetron;Ras farnesyl protein transferase inhibitors;Ras inhibitors;Ras-GAP inhibitors;Demethylated reterliptin;Rhenium Re 186 Etidronate; Rhizoxin; Ribozyme; RII retinamide; Rogletimide; Rohitucine; Lomurtide; Roquinimex; Rubiginone Bl; Ruboxil; Safingol; Signopine; SarCNU; Sarcophytol A; Sargramostim; Sdi 1 mimetic; Semustine; Senescence derived inhibitor 1; Sense oligonucleotide; Signal transduction inhibitor; Signal transduction modulator;Single-chain antigen-binding protein;Sizofiran;Sobuzoxane;Borocaptate sodium;Sodium phenylacetate;Sorberol;Somatomedin-binding protein;Sonermin;Sparfosic acid;Spicamycin D;Spiromustine;Splenopentin;Spongistatin 1;Squalamine;Stem cell inhibitors;Stem cell division inhibitors;Stypiamide;Stromelysin inhibitors;Sulfinosine;Superactive vasoactive intestinal peptide antagonists;Sladista;Suramin;Swainsonine;Synthetic glycosaminoglycans; Talimustine;Tamoxifen methiodide;Tauromustine;Tazarotene;Tecogalan sodium;Tegafur;Terlapyrylium;Telomerase inhibitors;Temoporfin;Temozolomide;Teniposide;Tetrachlorodecaoxide;Tetrazomine;Taliblastine;Thiocoraline;Thrombopoietin;Thrombopoietin mimetics;Thymalfasin;Thymopoietin receptor agonists;Thymotrinan;Thyroid-stimulating hormone;Ethyl etiopurinse;Tirapazamine;Titanocene dichloride;Topsentin; Toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector systems, red blood cell gene therapy; veraresol; veramine; verdine; verteporhum; vinorelbine; vinxartin; vitaxin; vorozole; zanoterone; zeniplatin; zilascorub; and zinostatin stimalamer. Still other anti-cancer agents that can be used in combination with the compounds of formula (III) include alkylating agents, antimetabolites, natural products, or hormones, such as, but not limited to, nitrogen mustards (e.g., but not limited to, mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., but not limited to, busulfan), nitrosoureas (e.g., but not limited to, carmustine, romcitone, etc.), or triazenes (e.g., decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., but not limited to, methotrexate), or pyrimidine analogs (e.g., but not limited to, cytarabine), purine analogs (e.g., but not limited to, mercaptopurine, thioguanine, pentostatin). Examples of alkylating agents that may be used in combination with the compounds of formula (III) include, but are not limited to, nitrogen mustards (e.g., but are not limited to, mechloroethamine, cyclophosphamide, chlorambucil, meifaran, etc.), ethylenimines and methylmelamines (e.g., but are not limited to, hexamethymelamine, thiotepa), alkyl sulfonates (e.g., but are not limited to, busulfan), nitrosoureas (e.g., but are not limited to, carmustine, lomustine, semustine, streptozocin, etc.), or triazenes (e.g., decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., but are not limited to, methotrexate), or pyrimidine analogs (e.g.,Anticancer agents that act by arresting cells in the G2-M phase due to stabilized microtubules and that may be used in combination with the compounds of formula (III) include, but are not limited to, the following marketed and investigational drugs: elbrozole (also known as R-55104), dolastatin 10 (also known as DLS-10 and NSC-376128), mibobulin isethionate (also known as CI-980), vincristine, NSC-639829, discodermolide (also known as NVP-XX-A-296). , ABT-751 (Abbott; also known as E-7010), altorhyrtins (e.g., altorhyrtin A and altorhyrtin C), spongistatins (e.g., spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9), cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), epothilones (e.g., epothilone A, epothilone B, epothilone C (also known as desoxyepothilone A or dEpoA), epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B), epothilone E, epothilone F, epothilone B, N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as desoxyepothilone F and dEpoF), 26-fluoroepothilone), auristatin PE (also known as NSC-654663), sobridotin (also known as TZT-1027), LS-4559-P (Pharmacia; also known as LS-4577), LS-4578 (Pharmacia; also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi),FR-182877 (Fujisawa; also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF; also known as ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto; also known as AVE-8063A and CS-39.HCI), AC-7700 (Ajinomoto; also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCI, and RPR-258062A), bitilebuamide, tubulysin A, canadensol, centaureydin (also known as NSC-106969), T-138067 (Tularik; also known as T-67, TL-138067, and ΤI-138067), COBRA-1 (Parker Hughes Institute; also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), oncocidin Al (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), physianolide B, laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute; also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine; also known as MF-569), narcosine (also known as NSC-5366), nascapine, D-24851 (Asta Medica), A-105972 (Abbott), hemiasterin, 3-BA ABU (Cytoskeleton / Mt. Sinai School of Medicine; also known as MF-191),TMPN (Arizona State University), vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, lunanocin (also known as NSC-698666), 3-1AABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik; also known as T-900607), RPR-115781 (Aventis), eleutherobin (e.g., desmethyleleutherobum, desethyleleutherobin, isoeleutherobin A, and Z-eleutherobin), carybeoside, carybeolin, halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), diozostatin, (-)-phenylahistine (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), myoseverin B, D-43411 (Zentaris; also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), resbellastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

[0116] A pharmaceutical composition delivery form containing one or more dosage units of an active agent can be prepared using suitable pharmaceutical excipients and compounding techniques known or available to those skilled in the art. The composition can be administered in the methods of the invention by a suitable delivery route, for example, oral, parenteral, rectal, topical, or ocular routes, or by inhalation.

[0117] The preparations may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories.Preferably, the compositions are formulated for intravenous injection, topical administration, or oral administration.

[0118] For oral administration, the compounds of the present disclosure may be provided in the form of tablets or capsules, or as solutions, emulsions, or suspensions. To prepare oral compositions, the compounds may be formulated to yield dosages of, for example, about 0.05 to about 100 mg / kg per day, about 0.05 to about 35 mg / kg per day, or about 0.1 to about 10 mg / kg per day. For example, a total daily dosage of about 5 mg to 5 g per day may be achieved by administering once, twice, three times, or four times per day.

[0119] Oral tablets may contain the compound according to the present disclosure mixed with pharma- ceutical acceptable excipients, such as inert diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorings, and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary oral liquid excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrants. Binders may include starch and gelatin. Lubricants, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0120] Capsules for oral administration include hard gelatin capsules and soft gelatin capsules.To prepare hard gelatin capsules, the compound of the present disclosure can be mixed with solid, semi-solid or liquid diluents.Soft gelatin capsules can be prepared by mixing the compound of the present disclosure with water, oil such as peanut oil or olive oil, liquid paraffin, mixture of monoglycerides and diglycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0121] The liquid for oral administration may be in the form of suspension, solution, emulsion, or syrup, or may be lyophilized or presented as a dry product, to be reconstituted with water or other suitable vehicle before use.Such liquid compositions may optionally contain pharma- ceutically acceptable excipients, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous vehicles, such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (e.g., methyl or propyl p-hydroxybenzoate, or sorbic acid); wetting agents such as lecithin; and flavorings or colorings as required.

[0122] The active agent of the present disclosure may also be administered by parenteral routes. For example, the composition may be formulated as a suppository for rectal administration. For parenteral applications, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the present disclosure may be provided in a sterile aqueous solution or suspension buffered to an appropriate pH and isotonicity, or in a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit dose forms, such as ampoules or disposable injection devices, multi-dose forms, such as vials from which the appropriate dose can be withdrawn, or in solid forms or pre-concentrates that can be used to prepare injectable formulations. An illustrative injection dose may range from about 1-1000 μg / kg / min of the compound mixed with a pharmaceutical carrier, over a period ranging from a few minutes to several days.

[0123] For topical administration, the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administration of the compounds of the present disclosure may utilize a patch formulation to achieve transdermal delivery.

[0124] Alternatively, compounds of the present disclosure may be administered in the methods of the present disclosure by inhalation via the nasal or oral routes, for example, in an aerosol formulation also containing a suitable carrier.

[0125] The compounds of the present disclosure can be prepared using the knowledge of those skilled in the art in combination with the present disclosure.For example, the compounds of the present disclosure can be prepared according to the schemes and examples disclosed in U.S. Patent No. 10,717,745, U.S. Patent No. 10,934,310, and International Application No. 2017 / 100662, each of which is incorporated herein in its entirety.

[0126] Kits and articles of manufacture are also described herein for use in the diagnostic and therapeutic applications described herein. Such kits can include a carrier, package, or container that is compartmentalized to receive one or more containers, such as vials, tubes, and the like, each of which includes one of the separate elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from any acceptable material, such as, for example, glass or plastic. In some embodiments, the kits provided herein are for use in determining the level of expression of biomarker genes or alterations of biomarker genes. In some embodiments, the kits provided herein are for use as companion diagnostics with compounds of formula (III). In some embodiments, the kits are used to select patients for treatment with compounds of formula (III), to identify subjects as susceptible to compounds of formula (III), and to evaluate treatment with compounds of formula (III). In some embodiments, the kit is used to select patients for treatment with a compound of formula (III), to identify subjects as resistant or likely to become resistant to a compound of formula (III), to monitor the development of resistance to a compound of formula (III), or a combination thereof.

[0127] The kits provided herein contain one or more reagents for detecting expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, CD10, BCL6, MUM1, or any combination thereof. In some embodiments, the kits provided herein contain one or more reagents for detecting alterations in MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, PRDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, or HNF1B. Exemplary reagents include, but are not limited to, antibodies, buffers, nucleic acids, microarrays, ELISA plates, substrates for enzyme staining, chromagens, or other materials such as slides, containers, microtiter plates, and, optionally, instructions for carrying out the method. Those of skill in the art will recognize many other possible containers and plates and reagents that can be used to contact the various materials.

[0128] Aspects The present disclosure is also directed to the following aspects:

[0129] Aspect 1. A compound of formula (III):

[0130] [ka]

[0131] Aspect 2. The compound of formula (III) according to aspect 1, wherein the compound of formula (III) is a pharma- ceutically acceptable salt, hydrate, polymorph, or solvate thereof.

[0132] Aspect 3. A pharmaceutical composition comprising a compound of formula (III), or a pharma- ceutically acceptable salt, hydrate, polymorph, or solvate thereof, and a pharma- ceutically acceptable excipient.

[0133] Embodiment 4. A method of inhibiting Bruton's tyrosine kinase, comprising contacting the kinase with a compound of formula (III).

[0134] Aspect 5. A compound of formula (III), or a pharma- ceutically acceptable salt, hydrate, polymorph, or solvate thereof, for use in a method of treating DLBCL in a patient.

[0135] Aspect 6. The compound for use according to aspect 5, wherein the DLBCL is ABC-DLBCL, germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL), or non-germinal center B-cell diffuse large B-cell lymphoma (non-GCB-DLBCL).

[0136] Aspect 7. A compound of formula (III) for use in treating DLBCL in a subject, the treatment comprising: (a) determining the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof in a sample from the subject; and (b) administering a therapeutically effective amount of a compound of formula (III) if expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof is increased relative to a control or reference level.

[0137] Aspect 8. A compound of formula (III) for use in treating ABC-DLBCL in a subject, the treatment comprising: (a) determining the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof in a sample from the subject; and (b) administering a therapeutically effective amount of a compound of formula (III) if expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof is increased relative to a control or reference level.

[0138] Aspect 9. The compound for use according to aspect 7, wherein the control or reference level is the level of expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GENl, HDAC9, or any combination thereof in a normal subject.

[0139] Aspect 10. A compound of formula (III) for use in treating GCB-DLBCL in a subject, the treatment comprising: (a) determining expression levels of CD10, BCL6, and MUM1 in a sample from the subject; and (b) administering a therapeutically effective amount of a compound of formula (III) if expression of CD10 and BCL6 is increased relative to a control or reference level and expression of MUM1 is not increased relative to a control or reference level.

[0140] Embodiment 11. The compound for use according to embodiment 10, wherein the reference levels are the levels of expression of CD10, BCL6 and MUM1 in a normal subject.

[0141] Aspect 12. A compound of formula (III) for use in treating DLBCL in a subject, the treatment comprising: (a) determining the presence or absence of an alteration in one or more biomarker genes in the subject, the biomarker genes being selected from MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, PRDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, or HNF1B; and (b) if an alteration in the one or more biomarker genes is present, administering to the subject a therapeutically effective amount of a compound of formula (III).

[0142] Aspect 13. A compound of formula (III) for use in selecting a subject having diffuse large B-cell lymphoma (DLBCL) for treatment with a compound of formula (III), wherein the selecting comprises: (a) determining the presence or absence of an alteration in one or more biomarker genes in the subject, the biomarker genes being MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA and (b) determining whether an alteration in one or more biomarker genes is present; and (b) selecting a subject if an alteration in one or more biomarker genes is present; and administering to the subject a therapeutically effective amount of a compound of formula (III).

[0143] Aspect 14. A compound of formula (III) for use in monitoring whether a subject receiving a compound of formula (III) for the treatment of DLBCL has developed or is likely to develop resistance to the therapy, wherein the monitoring comprises determining the presence or absence of an alteration in one or more biomarker genes in the subject, the biomarker genes being MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, and determining whether or not an alteration in one or more biomarker genes is present in the subject, the subject being likely to develop resistance to the therapy if an alteration in one or more biomarker genes is present.

[0144] Aspect 15. A compound of formula (III) for use in optimizing therapy of a subject receiving a compound of formula (III) for the treatment of diffuse large B-cell lymphoma (DLBCL), wherein optimizing comprises (a) determining the presence or absence of an alteration in one or more biomarker genes in the subject, the biomarker genes being CARD11, CD79A, CD79B, BCL10, KLHL6, BTK, SYK, NFKBIA, TNFAIP3, CDKN2A, CDKN2B, SMARCA4, TNFRSF14, HIST1H1D, ARID1A, EPHA3, AS and (b) determining whether or not an alteration in one or more biomarker genes is present; and (b) modifying treatment based on the presence or absence of an alteration in one or more biomarker genes.

[0145] Embodiment 16. The compound for use according to embodiments 10 to 15, wherein the alteration in one or more biomarker genes comprises a base substitution, an insertion, a deletion, a DNA rearrangement, a translocation, a copy number change, or a combination thereof.

[0146] Aspect 17. The compound for use according to aspects 5 to 16, wherein the therapeutically effective amount of the compound of formula (III) is from about 140 mg to about 560 mg.

[0147] Aspect 18. The compound for use according to aspects 5 to 16, wherein the therapeutically effective amount of the compound of formula (III) is about 140 mg.

[0148] Aspect 19. The compound for use according to aspects 5 to 16, wherein the therapeutically effective amount of the compound of formula (III) is about 280 mg.

[0149] Aspect 20. The compound for use according to aspects 5 to 16, wherein the therapeutically effective amount of the compound of formula (III) is about 560 mg.

[0150] Aspect 21. A compound for use according to aspects 5 to 20, wherein a therapeutically effective amount of a compound of formula (III) is administered once a day.

[0151] Aspect 22. A compound for use according to aspects 5 to 20, wherein a therapeutically effective amount of a compound of formula (III) is administered twice daily.

[0152] Aspect 23. A compound for use according to aspects 5 to 20, wherein a therapeutically effective amount of a compound of formula (III) is administered three times a day.

[0153] Aspect 24. A compound for use according to aspects 5 to 23, wherein the compound of formula (III) is administered orally.

[0154] Aspect 25. The compound for use according to aspects 5 to 24, further comprising administering 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide).

[0155] A compound for use according to embodiment 25, wherein 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) is administered according to a weekly escalating dosage regimen, the weekly escalating dosage regimen comprising administering about 20 mg / day in the first week, about 50 mg / day in the second week, about 100 mg / day in the third week, 200 mg / day in the third week, and 400 mg / day in the fourth week and thereafter.

[0156] Aspect 27. The compound for use according to aspects 5 to 24, further comprising administering cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab.

Claims

**Claim 1** A pharmaceutical composition comprising a compound of formula (III): 【Chemical 1】 which is used in a method for treating DLBCL in a subject, the method comprising: (a) determining the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof in a sample derived from a patient; and (b) administering a therapeutically effective amount of the compound of formula (III) when the expression of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof is increased relative to a control or reference level. **Claim 2** The pharmaceutical composition according to claim 1, wherein the DLBCL is ABC-DLBCL. **Claim 3** The pharmaceutical composition according to claim 1, wherein the control or reference level is the expression level of CCL3, CCL4, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, HDAC9, or any combination thereof in a normal patient. **Claim 4** A pharmaceutical composition comprising a compound of formula (III): 【Chemical 2】 which is used in a method for treating GCB-DLBCL in a subject, the method comprising: (a) determining the expression level of CD10, BCL6, and MUM1 in a sample derived from a patient; and (b) administering a therapeutically effective amount of the compound of formula (III) when the expression of CD10 and BCL6 is increased relative to a control or reference level and the expression of MUM1 is not increased relative to the control or reference level. **Claim 5** The pharmaceutical composition according to claim 4, wherein the reference level is the expression level of CD10, BCL6, and MUM1 in a normal patient. **Claim 6** A compound of formula (III): 【Chemical 1】 A pharmaceutical composition comprising the same, wherein the pharmaceutical composition is used in a method for treating DLBCL in a subject, the method comprising: (a) determining the presence or absence of a modification in one or more biomarker genes in the subject, wherein the biomarker genes are selected from MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, PRDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, or HNF1B; and (b) administering to the subject a therapeutically effective amount of a compound of formula (III) when a modification in the one or more biomarker genes is present. **Claim 7** A compound of formula (III): 【Chemical 1】 A pharmaceutical composition comprising the same, wherein the pharmaceutical composition is used in a method for selecting a subject having diffuse large B-cell lymphoma (DLBCL) for treatment with a compound of formula (III), the method comprising: (a) determining the presence or absence of a modification in one or more biomarker genes in the subject, wherein the biomarker genes are selected from MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, PRDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, or HNF1B; and (b) selecting the subject and administering to the subject a therapeutically effective amount of the compound of formula (III) when a modification in the one or more biomarker genes is present. **Claim 8** A compound of formula (III): 【Chemical Formula 1】 A pharmaceutical composition comprising, for use in a method of monitoring whether a subject receiving a compound of formula (III) is developing or is at risk of developing resistance to therapy for the treatment of DLBCL, the method comprising determining the presence or absence of a modification in one or more biomarker genes in the subject, wherein the biomarker genes are selected from MYD88, CD79B, PIM1, CDKN2A, HLA-B, OSBPL10, ETV6, SPIB, TOX, BTG1, BTG2, HLA-A, SETD1B, HLA-C, MPEG1, FOXC1, TBL1XR1, KLHL14, GRHPR, CD58, PRDM1, VMP1, PIM2, WEE1, BCL11A, CHST2, ARID5B, HASPIN, IL16, PPP1R9B, or HNF1B, and determining that the subject is at risk of developing resistance to the therapy if a modification in the one or more biomarker genes is present. **Claim 9** A compound of formula (III): 【Chemical 1】 A pharmaceutical composition comprising the compound of formula (III) for use in a method of optimizing therapy in a subject receiving the compound of formula (III) for the treatment of diffuse large B-cell lymphoma (DLBCL), the method comprising: (a) determining the presence or absence of a modification in one or more biomarker genes in a subject, wherein the biomarker genes are selected from CARDI1, CD79A, CD79B, BCL10, KLHL6, BTK, SYK, NFKBIA, TNFAIP3, CDKN2A, CDKN2B, SMARCA4, TNFRSF14, HIST1H1D, ARID1A, EPHA3, ASTML, MYD88, MLL2, FOXO1, PCL0, TP53, ICK, MAP3K13, HIST1H1E, SOCS1, mTOR, TBL1XR1, BTG1, NOTCH2, SPEN, PLCG, NFKBIZ, NFKBID, ATM, BCL2, CXCR4, EZH2, KMT2D, NOTCH1, PLCG2, ZC3H12D, ZC3H12A, RC3H1, CYLD, N4BP1, RELB, and RBCK1; and (b) modifying the treatment based on the presence or absence of the modification in the one or more biomarker genes.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (III) is from about 140 mg to about 560 mg.

11. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (III) is about 140 mg.

12. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (III) is about 280 mg.

13. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (III) is about 560 mg.

14. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (III) is administered once a day.

15. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (III) is administered twice a day.

16. The pharmaceutical composition according to any one of claims 1 to 9, wherein the therapeutically effective amount of the compound of formula (III) is administered three times a day.

17. The pharmaceutical composition according to any one of claims 1 to 9, wherein the compound of formula (III) is administered orally.

18. The pharmaceutical composition according to any one of claims 1 to 9, further comprising administering 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide).

19. The pharmaceutical composition according to any one of claims 1 to 9, further comprising administering cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab.

Images