Methods of Treating B-Cell Lymphoma Using Combination Therapy

Abstract

Provided herein are methods of using 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharmaceutically acceptable salt thereof, in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or equivalents thereof, to treat, prevent, or manage B-cell lymphoma.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 177,639, filed April 21, 2021, which is incorporated by reference in its entirety.

[0002] Provided herein are methods of using 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof, in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or equivalents, to treat, prevent, or manage B-cell lymphoma. [Background technology]

[0003] Cancer is primarily characterized by an increase in the number of abnormal cells originating from a given normal tissue, the invasion of adjacent tissues by these abnormal cells, or the lymphatic or hematogenous spread and metastasis of malignant cells to regional lymph nodes. Clinical data and molecular biology studies indicate that cancer is a multi-step process that may begin with minor precancerous changes and progress to neoplasia under certain conditions. Neoplastic lesions may develop clonally and develop increased capacities for invasion, growth, metastasis, and heterogeneity, especially under conditions where neoplastic cells evade the host's immune surveillance. Current cancer therapies may require surgery, chemotherapy, hormonal therapy, and / or radiation therapy to eradicate neoplastic cells in patients. Recent advances in cancer therapy are described by Non-Patent Document 1.

[0004] All current cancer therapies have significant drawbacks for patients. Surgery may be contraindicated, for example, due to the patient's health, or may not be tolerated by the patient. Furthermore, surgery may not be able to completely remove the neoplastic tissue. Radiotherapy is only effective if the neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue. Radiotherapy can also often induce serious side effects. Hormonal therapy is rarely administered as a single agent. Although hormonal therapy can be effective, it is often used to prevent or delay the recurrence of cancer after other treatments have removed the majority of the cancer cells.

[0005] Regarding chemotherapy, there are various chemotherapeutic agents available for the treatment of cancer. The majority of cancer chemotherapeutic agents act by inhibiting DNA synthesis by directly or indirectly inhibiting the biosynthesis of deoxyribonucleotide triphosphate precursors, thereby preventing DNA replication and the associated cell division. Non-Patent Document 2.

[0006] Despite the availability of a variety of chemotherapy agents, chemotherapy has many drawbacks. Non-Patent Document 3. Nearly all chemotherapy agents are toxic, and chemotherapy causes significant and often dangerous side effects, including severe nausea, bone marrow suppression, and immunosuppression. Furthermore, even when a combination of chemotherapy agents is administered, many tumor cells are resistant to or develop resistance to the chemotherapy agents. In fact, cells that are resistant to a particular chemotherapy agent used in a treatment protocol often prove to be resistant to other drugs, even if those agents act by a mechanism different from that of the drug used in the particular treatment. This phenomenon is called pleiotropic drug or multidrug resistance. Due to drug resistance, many cancers prove or become refractory to standard chemotherapy treatment protocols.

[0007] Lymphoma represents a broad range of neoplasms derived from normal lymphoid cells and is divided into non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma. The World Health Organization (WHO) classification is used to define subtypes based on clinical, pathological, phenotypic, and molecular features (Non-Patent Document 4).

[0008] Among patients affected by NHL, the majority belong to the aggressive B-cell lymphoma (a-BCL) subtype. Various entities, defined according to the 2016 WHO classification, fall into this category. The most common are diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) (including germinal center B-cell [GCB] and activated B-cell [ABC] types); high-grade B-cell lymphoma with MYC and B-cell lymphoma 2 (BCL2) and / or B-cell lymphoma 6 (BCL6) rearrangements; primary mediastinal (thymic) large B-cell lymphoma (PMBCL); T-cell / histiocyte-rich large B-cell lymphoma; primary cutaneous DLBCL, leg type; intravascular large B-cell lymphoma; anaplastic lymphoma kinase-positive (ALK+) large B-cell lymphoma; plasmablastic lymphoma; primary effusion lymphoma (PEL); Epstein-Barr virus-positive (EBV+) DLBCL, NOS; and rarer subtypes. Grade 3b follicular lymphoma (FL) is included in a-BCL. Diffuse large B-cell lymphoma (DLBCL) and other a-BCLs account for 35%-40% of NHL cases in North America and Europe.

[0009] There remains a great need for safe and effective methods of treating, preventing and managing aggressive B-cell lymphoma.

[0010] Citation or identification of any reference in this section of this application shall not be construed as an admission that the reference is prior art to the present application. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Rajkumar et al.in Nature Reviews Clinical Oncology 11,628-630(2014) [Non-Patent Document 2] Gilman et al., Goodman and Gilman's: The Pharmacological Basis of Therapeutics, Tenth Ed. (McGraw Hill, New York) [Non-Patent Document 3] Stockdale,Medicine,vol.3,Rubenstein and Federman,eds.,ch.12,sect.10,1998 [Non-Patent Document 4] Swerdlow et al.,Blood 2016,127(20):2375-90 Summary of the Invention [Means for solving the problem]

[0012] Provided herein are methods of using (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof, in combination with a second therapeutic agent to treat, prevent, or manage B-cell lymphoma. The second therapeutic agent is a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or equivalents thereof. In one embodiment, the second therapeutic agent is R-CHOP.

[0013] In certain embodiments, a method of treating B cell lymphoma comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): [ka] or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof, in combination with a second therapeutic agent, where the second therapeutic agent is R-CHOP.

[0014] In certain embodiments, provided herein is a method of treating B-cell lymphoma, comprising administering to a subject in need thereof a therapeutically effective amount of the hydrochloride salt of the compound of Formula (I) in combination with a second therapeutic agent, where the second therapeutic agent is R-CHOP.

[0015] In one embodiment, the BCL is aggressive B-cell lymphoma (a-BCL). In one embodiment, the a-BCL is newly diagnosed and / or untreated a-BCL.

[0016] Embodiments of the present invention may be more fully understood by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments. [Brief description of the drawings]

[0017] [Figure 1] 1 shows the dose escalation design of compound 1 added to an R-CHOP-21 regimen for first-line treatment of a-BCL. [Diagram 2] 1 shows the dose expansion design of compound 1 added to an R-CHOP-21 regimen for first-line treatment of a-BCL. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions for terms herein, the definitions in this section prevail unless otherwise stated.

[0019] As used herein, and in this specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular referents unless the context clearly dictates otherwise.

[0020] As used herein, the terms "comprising" and "including" may be used synonymously. The terms "comprising" and "including" should be interpreted as specifying the presence of the features or components described as referred to, but do not exclude the presence or addition of one or more features, or components thereof, or groups. Furthermore, the terms "comprising" and "including" are intended to include examples encompassed by the term "consisting of". As a result, the term "consisting of" may be used in place of the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0021] The term "consisting of" means that the object has at least 90%, 95%, 97%, 98% or 99% of the recited features or components of which it is composed. In another embodiment, the term "consisting of" excludes from the scope of any succeeding recitation any other features or components, excepting those that are not essential to the technical effect to be achieved.

[0022] As used herein, the term "or" should be interpreted as an inclusive "or" meaning any one or any combination. Thus, "A, B or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B and C." Exceptions to this definition will occur only where combinations of elements, features, steps or acts are in some way inherently mutually exclusive.

[0023] As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of the compounds provided herein include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include inorganic and organic acids such as, but are not limited to, acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Others are known in the art and are described, for example, in Remington's Pharmaceutical Sciences, 18. th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).

[0024] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" refers to one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound comprises more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomers of the compound, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. The compounds may have chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof, and all such isomers are included within the embodiments provided herein, including mixtures thereof.

[0025] The use of stereoisomerically pure forms of such compounds, as well as mixtures of those forms, are encompassed by the embodiments provided herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound may be used in the methods and compositions provided herein. These isomers may be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. For example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p.268(ELEliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN,1972);Todd,M.,Separation Of Enantiomers:Synthetic Methods(Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2014);Toda,F.,Enantiomer Separation:Fundamentals and Practical Methods(Springer Science&Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0026] It should be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be either (R) or (S) configuration, or may be a mixture thereof. It should be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. Thus, those skilled in the art will recognize that administration of a compound in its (R) form is equivalent to administration of a compound in its (S) form in the case of compounds that undergo epimerization in vivo.

[0027] Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography on chiral stationary phases.

[0028] "Tautomers" refer to isomers of a compound that are in equilibrium with each other. The concentration of isomers depends on the environment in which the compound is found, and may vary depending on, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in an aqueous solution, pyrazole may exhibit the following isomers, which are called tautomers of each other: [ka]

[0029] As will be readily appreciated by one of ordinary skill in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds are within the scope of the compounds provided herein.

[0030] It should also be noted that the compounds provided herein may contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), Sulfur-35( 35 S), or carbon-14 ( 14 It may be radiolabeled with a radioisotope such as C, or with deuterium ( 2H), Carbon-13( 13 C), or nitrogen-15 ( 15 As used herein, an "isotopologue" is an isotope-enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variants of a compound, whether radioactive or not, are intended to be encompassed within the scope of the compounds provided herein. In certain embodiments, isotopologues of a compound are provided herein, e.g., isotopologues include deuterium, carbon-13 ( 13 C), and / or nitrogen-15 ( 15 As used herein, "deuterated" refers to a compound that is enriched in at least one hydrogen (H) by replacing it with a deuterium (D or 2 H), that is, the compound is enriched with deuterium in at least one position.

[0031] It is understood that each compound provided herein can be provided in the form of any of the pharmaceutically acceptable salts provided herein, independent of stereochemistry or isotopic composition.Similarly, it is understood that the isotopic composition can vary independently from the stereochemistry of each compound provided herein.Furthermore, the isotopic composition is limited to those elements present in each compound or its salt, but can otherwise vary independently from the selection of the pharmaceutically acceptable salt of each compound.

[0032] It should be noted that if there is a discrepancy between a depicted structure and the name of that structure, the depicted structure is to be given weight.

[0033] As used herein, and unless otherwise indicated, the term "treating" means the total or partial alleviation of a disorder, disease or condition, or one or more symptoms associated with a disorder, disease or condition, or the slowing or halting of further progression or worsening of those symptoms, or reducing or eradicating the cause of the disorder, disease or condition itself.

[0034] As used herein, and unless otherwise indicated, the term "prevent" means a method of delaying and / or eliminating the onset, recurrence or spread of a disorder, disease or condition, in whole or in part; a method of preventing a subject from contracting a disorder, disease or condition; or a method of reducing the risk that a subject will contract a disorder, disease or condition.

[0035] As used herein and unless otherwise indicated, the term "managing" includes preventing the recurrence of a particular disease or disorder in a patient suffering from such disease or disorder, extending the time that a patient suffering from a disease or disorder remains in remission, reducing patient mortality, and / or maintaining a reduction in the severity or avoidance of symptoms associated with the disease or condition being managed.

[0036] As used herein and unless otherwise indicated, the term "effective amount" in reference to a compound means an amount capable of treating, preventing, or managing a disorder, disease or condition, or a symptom thereof.

[0037] As used herein and unless otherwise indicated, the terms "co-administration" and "in combination with" include administration of one or more therapeutic agents (e.g., a compound provided herein and another anti-BCL agent, anti-cancer agent, or supportive care agent) simultaneously, in parallel, or sequentially, without any specific time limit. In one embodiment, the agents are present in the cell or in the patient's body at the same time or exert their biological or therapeutic effects simultaneously. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In another embodiment, the therapeutic agents are in separate compositions or unit dosage forms.

[0038] As used herein and unless otherwise specified, the "therapeutic agent" provided herein is not limited to a single therapeutic agent, and in certain embodiments, it may be a combination of one or more different therapeutic agents. One or more therapeutic agents may be administered in combination with each other as described herein. As used herein and unless otherwise specified, the "therapeutic agent" may be used synonymously with "therapeutic therapy" and is not limited to a therapeutic substance. For example, the therapeutic agent may be a cancer treatment such as radiation therapy or CAR-T therapy.

[0039] "Cycling therapy" refers to a regimen or therapy that includes dosing periods as described herein and, optionally, rest periods as described herein.

[0040] The term "administration period" as used herein refers to the period during which a subject is continuously or actively administered a compound or composition described herein.

[0041] The term "rest period" as used herein refers to a period (often following an administration period) during which a subject is not administered a compound or composition described herein (e.g., a cessation of treatment). In certain embodiments, a "rest period" refers to a period during which a single agent is not administered to a subject or treatment with a particular compound is discontinued. In such embodiments, a second therapeutic agent (e.g., an agent different from the compound or composition administered during the previous administration period) may be administered to the subject.

[0042] As used herein and unless otherwise indicated, the term "subject" includes animals, including, but not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, in one embodiment, mammals, and in another embodiment, humans.

[0043] In the context of cancer, inhibition may be assessed by, among others, inhibition of disease progression, inhibition of tumor growth, reduction of primary tumors, alleviation of tumor-related symptoms, inhibition of tumor secreted factors, delay in the appearance of primary or secondary tumors, delay in the occurrence of primary or secondary tumors, reduction in the occurrence of primary or secondary tumors, delay or reduction in the severity of secondary effects of the disease, arrest of tumor growth and tumor regression, increase in time to progression (TTP), increase in progression-free survival (PFS), increase in overall survival (OS). OS as used herein means the time from the start of treatment to death from any cause. TTP as used herein means the time from the start of treatment to tumor progression; TTP does not include death. In one embodiment, PFS means the time from the start of treatment to tumor progression or death. In one embodiment, PFS means the time from the first administration of the compound to the first occurrence of disease progression or death from any cause. In one embodiment, the PFS rate is calculated using the Kaplan-Meier estimator. Event-free survival (EFS) refers to the time from initiation of treatment to any treatment failure (including disease progression, treatment interruption for any reason, or death). In one embodiment, overall response rate (ORR) refers to the percentage of patients who achieve a response. In one embodiment, ORR refers to the sum of the percentage of patients who achieve a complete and partial response. In one embodiment, ORR refers to the percentage of patients whose best response is ≧ partial response (PR). In one embodiment, duration of response (DoR) is the time from achieving a response to relapse or disease progression. In one embodiment, DoR is the time from achieving a response ≧ partial response (PR) to relapse or disease progression. In one embodiment, DoR is the time from first demonstration of response to first demonstration of disease progression or death. In one embodiment, DoR is the time from first demonstration of response ≧ partial response (PR) to first demonstration of disease progression or death. In one embodiment, time to response (TTR) refers to the time from the first administration of a compound to first demonstration of response. In one embodiment, TTR refers to the time from the first administration of a compound to the first demonstration of a response >= partial response (PR). At the extreme, complete inhibition is referred to herein as prevention or chemoprevention.In this regard, the term "prevention" includes either preventing the development of clinically evident cancer altogether or preventing the development of cancer at a pre-clinically evident stage. Prevention of transformation to malignant cells or halting or halting the progression of pre-malignant cells to malignant cells is also intended to be encompassed by this definition. This includes prophylactic treatment of subjects at risk of developing cancer.

[0044] In certain embodiments, treatment of NHL may be evaluated by the International Workshop Criteria for Malignant Lymphoma (see Cheson et al., J. Clin. Oncol. 2014, 32(27):3059-3068) and the Deauville Criteria for fluorodeoxyglucose-positron emission tomography (FDG-PET) scan interpretation (Itti et al., Eur. J. Nucl. Med. Mol. Imaging, 2013, 40(9):1312-20; Meignan et al., Leuk Lymphoma, 2014, 55(1):31-37) ("Lugano Criteria") using the response and endpoint definitions set forth in Tables 1-3.

[0045] [Table 1]

[0046] [Table 2]

[0047] [Table 3]

[0048] [Table 4]

[0049] In certain embodiments, stability or lack thereof may be determined by methods known in the art, such as evaluation of the patient's symptoms, physical examination, visualization of the tumor imaged using, for example, FDG-PET (fluorodeoxyglucose positron emission tomography), PET / CT (positron emission tomography / computed tomography) scans, MRI (magnetic resonance imaging) brain / spine, CSF (cerebrospinal fluid), ophthalmic examination, vitreous fluid sampling, retinal photography, bone marrow evaluation, and other commonly accepted evaluation methods.

[0050] The term "supportive care agent" refers to any substance that treats, prevents, or manages side effects from treatment with another therapeutic agent.

[0051] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or a dosage form, refer to a dose, amount, or weight percent that is recognized by one of skill in the art to produce an equivalent pharmacological effect to that obtained from the stated dose, amount, or weight percent. In one embodiment, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent within 30%, within 20%, within 15%, within 10%, or within 5% of the stated dose, amount, or weight percent.

[0052] compound In one embodiment, the compound used in the methods provided herein is (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione, having the following formula: [ka] or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharma- ceutically acceptable salt thereof. (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione is also referred to herein as “Compound 1.”

[0053] In one embodiment, the compound used in the methods provided herein is (R)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione (herein referred to as “Compound 2”) of the following formula: [ka] or a tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

[0054] In one embodiment, the compound used in the methods provided herein is 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione (herein referred to as “Compound 3”) of the following formula: [ka] or a tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

[0055] In one embodiment, Compound 1 is used in the methods provided herein. In one embodiment, a tautomer of Compound 1 is used in the methods provided herein. In one embodiment, an isotopologue of Compound 1 is used in the methods provided herein. In one embodiment, a pharma- ceutically acceptable salt of Compound 1 is used in the methods provided herein. In one embodiment, the hydrochloride salt of Compound 1 is used in the methods provided herein. In one embodiment, the monohydrochloride salt of Compound 1 is used in the methods provided herein. Certain salts and polymorphic forms of Compound 1 are described in U.S. Patent Application Serial No. 17 / 075,359, the entirety of which is incorporated herein by reference.

[0056] In one embodiment, compound 2 is used in the methods provided herein. In one embodiment, a tautomer of compound 2 is used in the methods provided herein. In one embodiment, an isotopologue of compound 2 is used in the methods provided herein. In one embodiment, a pharma- ceutically acceptable salt of compound 2 is used in the methods provided herein. In one embodiment, the hydrochloride salt of compound 2 is used in the methods provided herein.

[0057] In one embodiment, compound 3 is used in the methods provided herein. In one embodiment, an enantiomer of compound 3 is used in the methods provided herein. In one embodiment, a mixture of enantiomers of compound 3 is used in the methods provided herein. In one embodiment, a tautomer of compound 3 is used in the methods provided herein. In one embodiment, an isotopologue of compound 3 is used in the methods provided herein. In one embodiment, a pharma- ceutically acceptable salt of compound 3 is used in the methods provided herein. In one embodiment, the hydrochloride salt of compound 3 is used in the methods provided herein.

[0058] The synthesis and certain uses of the compounds provided herein are described in U.S. Patent Application Publication Nos. 2019 / 0322647 A1 and 2020 / 0325129 A1, and U.S. Patent Application Nos. 17 / 075,496, 17 / 075,523, and 17 / 075,125, each of which is incorporated by reference in its entirety.

[0059] Treatment and prevention methods In one embodiment, provided herein is a method of using (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof, in combination with a second therapeutic agent to treat, prevent, or manage BCL. In one embodiment, the second therapeutic agent is a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or equivalents thereof.

[0060] In one embodiment, a method of treating BCL is provided comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): [ka] or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt (e.g., hydrochloride salt) thereof in combination with a second therapeutic agent, wherein the second therapeutic agent is a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or equivalents thereof. Unless otherwise specified, "compound of formula (I)" and "compound 1" are used interchangeably herein.

[0061] In one embodiment, provided herein is a method of preventing BCL comprising administering to a subject in need thereof a therapeutically effective amount of Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt (e.g., the hydrochloride salt) thereof, in combination with a second therapeutic agent, wherein the second therapeutic agent is a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or equivalents thereof.

[0062] In one embodiment, provided herein is a method of managing BCL comprising administering to a subject in need thereof a therapeutically effective amount of Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt (e.g., the hydrochloride salt) thereof, in combination with a second therapeutic agent, wherein the second therapeutic agent is a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or equivalents thereof.

[0063] In certain embodiments, the BCL is an aggressive B-cell lymphoma (a-BCL). In one embodiment, the aggressive B-cell lymphoma is determined according to the 2016 WHO classification (Swerdlow et al., Blood 2016, 127(20):2375-90, which is incorporated herein by reference in its entirety).

[0064] In certain embodiments, the BCL is primary mediastinal (thymic) large B-cell lymphoma (PMBCL).

[0065] In one embodiment, the BCL is primary cutaneous DLBCL. In one embodiment, the BCL is primary cutaneous DLBCL-leg type.

[0066] In one embodiment, the BCL is anaplastic lymphoma kinase positive (ALK+) large B-cell lymphoma.

[0067] In one embodiment, the BCL is follicular lymphoma (FL). In one embodiment, the BCL is grade 3b follicular lymphoma (FL).

[0068] In one embodiment, the BCL is diffuse large B-cell lymphoma (DLBCL). In one embodiment, the DLBCL is DLBCL-not otherwise specified (NOS). In one embodiment, the DLBCL is of germinal center B-cell (GCB) type. In one embodiment, the DLBCL is of activated B-cell (ABC) type.

[0069] In one embodiment, the BCL is an aggressive B cell lymphoma. In one embodiment, the aggressive B cell lymphoma has a MYC rearrangement. In one embodiment, the aggressive B cell lymphoma has a BCL2 rearrangement. In one embodiment, the aggressive B cell lymphoma has a BCL6 rearrangement. In one embodiment, the aggressive B cell lymphoma has a MYC and BCL2 and / or BCL6 rearrangement. As used herein and unless otherwise specified, aggressive B cell lymphoma with "MYC and BCL2 and / or BCL6 rearrangement" means that the aggressive B cell lymphoma has either or both of a MYC rearrangement and a BCL2 and BCL6 rearrangement. In one embodiment, the aggressive B cell lymphoma has a MYC and BCL2 rearrangement. In one embodiment, the aggressive B cell lymphoma has a MYC and BCL6 rearrangement. In one embodiment, the aggressive B cell lymphoma has MYC, BCL2, and BCL6 rearrangements.

[0070] In one embodiment, the BCL is Epstein-Barr virus positive (EBV+) DLBCL. In one embodiment, the EBV+ DLBCL is EBV+ DLBCL, not otherwise specified (NOS).

[0071] In one embodiment, the BCL is T-cell / histiocyte-rich large B-cell lymphoma (THRLBCL). In one embodiment, the BCL is intravascular large B-cell lymphoma. In one embodiment, the BCL is plasmablastic lymphoma. In one embodiment, the BCL is primary effusion lymphoma (PEL).

[0072] The International Prognostic Index (IPI) score is an important prognostic predictor. Five clinical features (age, lactate dehydrogenase [LDH], number of extranodal sites, Ann Arbor stage, and Eastern Cooperative Oncology Group [ECOG] performance status) are used to classify patients into four risk categories: low risk (0–1 risk factor), low-intermediate risk (2 risk factors), high-intermediate risk (3 risk factors), and high risk (4–5 risk factors). Other prognostic factors include phenotypic or molecular features of lymphoma cells such as cell of origin, double hits and double expression, and factors related to the tumor microenvironment.

[0073] In one embodiment, the BCL is a high-risk aggressive B-cell lymphoma. In one embodiment, the BCL is a high-risk aggressive B-cell lymphoma. In one embodiment, the BCL has an International Prognostic Index (IPI) score of 3 to 5. In one embodiment, the BCL has an IPI score of 3. In one embodiment, the BCL has an IPI score of 4. In one embodiment, the BCL has an IPI score of 5.

[0074] In one embodiment, the BCL is untreated. In one embodiment, the BCL is untreated aggressive B cell lymphoma. In one embodiment, the BCL is untreated DLBCL, NOS (including GCB and ABC types). In one embodiment, the BCL is untreated high-grade B cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements. In one embodiment, the BCL is untreated PMBCL. In one embodiment, the BCL is untreated primary cutaneous DLBCL, leg type. In one embodiment, the BCL is untreated ALK+ large B cell lymphoma. In one embodiment, the BCL is untreated EBV+ DLBCL, NOS. In one embodiment, the BCL is untreated grade 3b follicular lymphoma.

[0075] In one embodiment, the BCL is newly diagnosed. In one embodiment, the BCL is newly diagnosed aggressive B cell lymphoma. In one embodiment, the BCL is newly diagnosed DLBCL, NOS (including GCB and ABC types). In one embodiment, the BCL is newly diagnosed high-grade B cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements. In one embodiment, the BCL is newly diagnosed PMBCL. In one embodiment, the BCL is newly diagnosed primary cutaneous DLBCL, leg type. In one embodiment, the BCL is newly diagnosed ALK+ large B cell lymphoma. In one embodiment, the BCL is newly diagnosed EBV+ DLBCL, NOS. In one embodiment, the BCL is newly diagnosed grade 3b follicular lymphoma.

[0076] In one embodiment, a compound provided herein (e.g., Compound 1, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt)) is administered in combination with a second therapeutic agent provided herein as a first-line treatment for BCL.

[0077] In one embodiment, the second therapeutic agent used in the methods provided herein is a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or equivalents thereof.

[0078] In certain embodiments, the second therapeutic agent is R-CHOP. As used herein and unless otherwise specified, R-CHOP therapy refers to chemotherapy with a course of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (or equivalents such as prednisolone). In certain embodiments, R-CHOP therapy is given as a series of several cycles of treatment over several months. In certain embodiments, each cycle of R-CHOP is 21 days (3 weeks), where rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 of the 21-day cycle, and a 5-day course of prednisone (or prednisolone) is also initiated on days 1-5 of the 21-day cycle.

[0079] In one embodiment, prednisone is administered in the methods provided herein. In one embodiment, an equivalent of prednisone is administered instead of prednisone. In one embodiment, prednisolone is administered. In one embodiment, a corticosteroid equivalent of prednisone is administered. In one embodiment, a corticosteroid equivalent of prednisone is administered intravenously (e.g., conveniently on day 1 of the cycle).

[0080] In certain embodiments, the second therapeutic agent is a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.

[0081] In certain embodiments, the second therapeutic agent is a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone.

[0082] In certain embodiments, the doxorubicin is not liposomal doxorubicin.

[0083] Rituximab is an anti-CD20 monoclonal antibody. In one embodiment, rituximab is administered in an amount according to the physician's discretion. In one embodiment, rituximab is administered according to the locally approved label or pharmaceutical manual for preparation, administration, and storage information. In one embodiment, rituximab is administered according to the RITUXAN® label. In one embodiment, rituximab is administered at a dose of about 375 mg / m 2 In one embodiment, rituximab is administered at a dose of about 1400 mg / day. In one embodiment, rituximab is administered on day 1 of a 21 day cycle. In one embodiment, rituximab is administered intravenously. In one embodiment, rituximab is administered by intravenous injection. In one embodiment, rituximab is administered by intravenous infusion. In one embodiment, rituximab is administered subcutaneously. In one embodiment, rituximab is administered by subcutaneous infusion.

[0084] In one embodiment, rituximab is administered at about 375 mg / m on day 1 of a 21-day cycle. 2 / day. In one embodiment, rituximab is administered subcutaneously at a dose of about 1400 mg / day on day 1 of a 21 day cycle.

[0085] In one embodiment, cyclophosphamide is administered in an amount according to the physician's discretion. In one embodiment, cyclophosphamide is administered according to the locally approved label or pharmaceutical manual for preparation, administration, and storage information. In one embodiment, cyclophosphamide is administered according to the CYTOXAN® label. In one embodiment, cyclophosphamide is administered according to the NEOSAR® label. In one embodiment, cyclophosphamide is administered at a dose of about 750 mg / m 2In one embodiment, cyclophosphamide is administered at a dose of 100 mg / day. In one embodiment, cyclophosphamide is administered on day 1 of a 21-day cycle. In one embodiment, cyclophosphamide is administered intravenously. In one embodiment, cyclophosphamide is administered by intravenous injection. In one embodiment, cyclophosphamide is administered by intravenous infusion.

[0086] In one embodiment, cyclophosphamide is administered at about 750 mg / m on day 1 of a 21-day cycle. 2 It is given intravenously at a dose of 100 mg / day.

[0087] In one embodiment, doxorubicin is administered in an amount according to the physician's discretion. In one embodiment, doxorubicin is administered according to the locally approved label or pharmaceutical manual for preparation, administration, and storage information. In one embodiment, doxorubicin is administered according to the ADRIAMYCIN® label. In one embodiment, doxorubicin is administered according to the RUBEX® label. In one embodiment, doxorubicin is administered at a dose of about 50 mg / m 2 In one embodiment, doxorubicin is administered at a dose of 0.1 mg / day. In one embodiment, doxorubicin is administered on day 1 of a 21 day cycle. In one embodiment, doxorubicin is administered intravenously. In one embodiment, doxorubicin is administered by intravenous injection. In one embodiment, doxorubicin is administered by intravenous infusion.

[0088] In one embodiment, doxorubicin is administered at about 50 mg / m on day 1 of a 21 day cycle. 2 It is given intravenously at a dose of 100 mg / day.

[0089] In one embodiment, vincristine is administered in an amount according to the physician's discretion. In one embodiment, vincristine is administered according to the locally approved label or pharmaceutical manual for preparation, administration, and storage information. In one embodiment, vincristine is administered according to the ONCOVIN® label. In one embodiment, vincristine is administered at a dose of about 1.4 mg / m2 In one embodiment, vincristine is administered at a dose of 0.1 mg / day. In one embodiment, vincristine is administered at a maximum amount of 2.0 mg / day. In one embodiment, vincristine is administered on day 1 of a 21 day cycle. In one embodiment, vincristine is administered intravenously. In one embodiment, vincristine is administered by intravenous injection. In one embodiment, vincristine is administered by intravenous infusion.

[0090] In one embodiment, vincristine is administered at a maximum dose of 2.0 mg / day, and at about 1.4 mg / m on day 1 of a 21-day cycle. 2 It is given intravenously at a dose of 100 mg / day.

[0091] In one embodiment, prednisone or its equivalent is administered in an amount according to the physician's discretion. In one embodiment, prednisone or its equivalent is administered according to the locally approved label or pharmaceutical manual for preparation, administration, and storage information. In one embodiment, prednisone or its equivalent is administered according to the DELTASONE® label. In one embodiment, prednisone or its equivalent is administered at a dose of about 100 mg / day. In one embodiment, prednisone or its equivalent is administered on days 1-5 of a 21 day cycle. In one embodiment, prednisone or its equivalent is administered intravenously. In one embodiment, prednisone or its equivalent is administered by intravenous injection. In one embodiment, prednisone or its equivalent is administered by intravenous infusion. In one embodiment, prednisone or its equivalent is administered orally. In one embodiment, prednisone or its equivalent is administered orally with food. In one embodiment, prednisone or its equivalent is administered orally without food.

[0092] In one embodiment, prednisone is administered orally at a dose of about 100 mg / day on days 1-5 of a 21 day cycle. In one embodiment, prednisone is administered intravenously on day 1 of a 21 day cycle and orally on days 2-5 of a 21 day cycle at a dose of about 100 mg / day. In one embodiment, prednisolone is administered orally at a dose of about 100 mg / day on days 1-5 of a 21 day cycle. In one embodiment, prednisolone is administered intravenously on day 1 of a 21 day cycle and orally on days 2-5 of a 21 day cycle at a dose of about 100 mg / day.

[0093] In one embodiment, rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 of a 21 day cycle, and prednisone, or its equivalent, is administered on days 1-5 of a 21 day cycle.

[0094] In one embodiment, rituximab is administered intravenously or subcutaneously; cyclophosphamide, doxorubicin, and vincristine are administered intravenously; and prednisone or its equivalent is administered orally.

[0095] In one embodiment, rituximab is administered at about 375 mg / m on day 1 of a 21-day cycle. 2 or subcutaneously at a dose of about 1400 mg; cyclophosphamide is administered at a dose of about 750 mg / m on day 1 of a 21-day cycle. 2 doxorubicin is administered intravenously at a dose of approximately 50 mg / m on day 1 of a 21-day cycle. 2 Vincristine is administered intravenously at a dose of approximately 1.4 mg / m on day 1 of a 21-day cycle. 2 prednisone or its equivalent is given orally at a dose of approximately 100 mg on days 1-5 of a 21-day cycle.

[0096] In one embodiment, a first therapy provided herein (e.g., a prophylactic or therapeutic agent such as Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof) is administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to) administration of a second therapy provided herein to the subject.

[0097] In one embodiment, a first treatment provided herein (e.g., a prophylactic or therapeutic agent such as Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof) is administered simultaneously with the administration of a second treatment provided herein to a subject.

[0098] In one embodiment, a first therapy provided herein (e.g., a prophylactic or therapeutic agent such as Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof) is administered after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of a second therapy provided herein to the subject.

[0099] In one embodiment, a compound described herein, e.g., Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered at a dose of about 0.2 mg to about 0.6 mg per day. In one embodiment, the compound is administered at a dose of about 0.2 mg to about 0.4 mg per day. In one embodiment, the compound is administered at a dose of about 0.4 mg to about 0.6 mg per day.

[0100] In one embodiment, a compound described herein, e.g., Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered at a dose of about 0.2 mg to about 0.6 mg once daily. In one embodiment, the compound is administered at a dose of about 0.2 mg to about 0.4 mg once daily. In one embodiment, the compound is administered at a dose of about 0.4 mg to about 0.6 mg once daily.

[0101] In certain embodiments, a compound described herein, such as Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered at a dose of about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, or about 0.6 mg per day. In certain embodiments, the compound is administered at a dose of about 0.2 mg per day. In certain embodiments, the compound is administered at a dose of about 0.3 mg per day. In certain embodiments, the compound is administered at a dose of about 0.4 mg per day. In certain embodiments, the compound is administered at a dose of about 0.5 mg per day. In certain embodiments, the compound is administered at a dose of about 0.6 mg per day.

[0102] In certain embodiments, a compound described herein, such as Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered at a dose of about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, or about 0.6 mg once daily. In certain embodiments, the compound is administered at a dose of about 0.2 mg once daily. In certain embodiments, the compound is administered at a dose of about 0.3 mg once daily. In certain embodiments, the compound is administered at a dose of about 0.4 mg once daily. In certain embodiments, the compound is administered at a dose of about 0.5 mg once daily. In certain embodiments, the compound is administered at a dose of about 0.6 mg once daily.

[0103] In one embodiment, a compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered.In one embodiment, the hydrochloride salt of a compound of formula (I) is administered.

[0104] In one embodiment, a compound described herein, such as Compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is orally administered. In one embodiment, a compound described herein, such as Compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered after an overnight fast lasting at least 6 hours (e.g., in the morning with about 8 oz or 240 ml of water). In one embodiment, the subject refrains from food or other drug intake for at least 2 hours after the compound is administered.

[0105] In one embodiment, a compound described herein, e.g., Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered once daily for 7 days, followed by the remaining 14 days. In one embodiment, the compound is administered once daily for 10 days, followed by the remaining 11 days.

[0106] In one embodiment, a compound described herein, e.g., Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered on days 1-7 of a 21 day cycle. In one embodiment, the compound is administered on days 1-10 of a 21 day cycle. In one embodiment, the period of compound administration is followed by a rest of the compound for the remaining days of the 21 day cycle.

[0107] In one embodiment, a compound described herein, e.g., Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered at a dose of about 0.2 mg to about 0.6 mg once daily on days 1-7 of a 21-day cycle. In one embodiment, the compound is administered at a dose of about 0.2 mg once daily on days 1-7 of a 21-day cycle. In one embodiment, the compound is administered at a dose of about 0.3 mg once daily on days 1-7 of a 21-day cycle. In one embodiment, the compound is administered at a dose of 0.4 mg once daily on days 1-7 of a 21-day cycle. In one embodiment, the compound is administered at a dose of about 0.5 mg once daily on days 1-7 of a 21-day cycle. In one embodiment, the compound is administered at a dose of about 0.6 mg once daily on days 1-7 of a 21-day cycle. In one embodiment, the compound administration period is followed by a rest period on days 8-21 of a 21 day cycle.

[0108] In one embodiment, a compound described herein, e.g., Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered at a dose of about 0.2 mg to about 0.6 mg once daily on days 1-10 of a 21-day cycle. In one embodiment, the compound is administered at a dose of about 0.2 mg once daily on days 1-10 of a 21-day cycle. In one embodiment, the compound is administered at a dose of about 0.3 mg once daily on days 1-10 of a 21-day cycle. In one embodiment, the compound is administered at a dose of about 0.4 mg once daily on days 1-10 of a 21-day cycle. In one embodiment, the compound is administered at a dose of about 0.5 mg once daily on days 1-10 of a 21-day cycle. In one embodiment, the compound is administered at a dose of about 0.6 mg once daily on days 1-10 of a 21 day cycle. In one embodiment, the compound administration period is followed by a rest period on days 11-21 of a 21 day cycle.

[0109] In one embodiment, provided herein is a method for treating aggressive B-cell lymphoma (a-BCL), comprising: (i) administering compound 1, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of compound 1), on days 1-7 of a 21-day cycle; (ii) administering rituximab, cyclophosphamide, doxorubicin, and vincristine on day 1 of a 21-day cycle; and (iii) administering prednisone or prednisolone on days 1-5 of a 21-day cycle. In one embodiment, the a-BCL is DLBCL (e.g., DLBCL, NOS, including GCB and ABC types). In one embodiment, the a-BCL is high-grade B cell lymphoma (e.g., high-grade B cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements). In one embodiment, the a-BCL is PMBCL. In one embodiment, the a-BCL is primary cutaneous DLBCL-leg type. In one embodiment, the a-BCL is ALK+ large B cell lymphoma. In one embodiment, the a-BCL is EBV+ DLBCL (e.g., EBV+ DLBCL, NOS). In one embodiment, the a-BCL is grade 3b follicular lymphoma. In one embodiment, the a-BCL is untreated. In one embodiment, the a-BCL is newly diagnosed. In one embodiment, the a-BCL is high-risk a-BCL (e.g., having an IPI score of 3-5).

[0110] In one embodiment, provided herein is a method for treating aggressive B-cell lymphoma (a-BCL), comprising: (i) administering compound 1, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of compound 1), on days 1-10 of a 21-day cycle; (ii) administering rituximab, cyclophosphamide, doxorubicin, and vincristine on day 1 of a 21-day cycle; and (iii) administering prednisone or prednisolone on days 1-5 of a 21-day cycle. In one embodiment, the a-BCL is DLBCL (e.g., DLBCL, NOS, including GCB and ABC types). In one embodiment, the a-BCL is high-grade B cell lymphoma (e.g., high-grade B cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements). In one embodiment, the a-BCL is PMBCL. In one embodiment, the a-BCL is primary cutaneous DLBCL-leg type. In one embodiment, the a-BCL is ALK+ large B cell lymphoma. In one embodiment, the a-BCL is EBV+ DLBCL (e.g., EBV+ DLBCL, NOS). In one embodiment, the a-BCL is grade 3b follicular lymphoma. In one embodiment, the a-BCL is untreated. In one embodiment, the a-BCL is newly diagnosed. In one embodiment, the a-BCL is high-risk a-BCL (e.g., having an IPI score of 3-5).

[0111] In one embodiment, a method for treating aggressive B-cell lymphoma (a-BCL) is provided comprising: (i) orally administering Compound 1, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), at a dose of about 0.2 mg once daily on days 1-7 of a 21-day cycle; (ii) orally administering about 375 mg / m 2 or subcutaneously at a dose of about 1400 mg / m on day 1 of a 21-day cycle; (iii) administering rituximab at a dose of about 750 mg / m on day 1 of a 21-day cycle; 2 (iv) cyclophosphamide administered intravenously at a dose of about 50 mg / m on day 1 of a 21-day cycle. 2(v) administering doxorubicin intravenously at a dose of about 1.4 mg / m on day 1 of a 21-day cycle; 2 and (vi) orally administering prednisone or prednisolone at a dose of about 100 mg / day on days 1-5 of a 21 day cycle (intravenous administration of prednisone or prednisolone on day 1 is permitted). In one embodiment, the a-BCL is DLBCL (e.g., DLBCL, NOS, including GCB and ABC types). In one embodiment, the a-BCL is high-grade B cell lymphoma (e.g., high-grade B cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements). In one embodiment, the a-BCL is PMBCL. In one embodiment, the a-BCL is primary cutaneous DLBCL-leg type. In one embodiment, the a-BCL is ALK+ large B cell lymphoma. In one embodiment, the a-BCL is EBV+ DLBCL (e.g., EBV+ DLBCL, NOS). In one embodiment, the a-BCL is grade 3b follicular lymphoma. In one embodiment, the a-BCL is untreated. In one embodiment, the a-BCL is newly diagnosed. In one embodiment, the a-BCL is high-risk a-BCL (e.g., having an IPI score of 3-5).

[0112] In one embodiment, a method for treating aggressive B-cell lymphoma (a-BCL) comprises: (i) orally administering Compound 1, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), at a dose of about 0.4 mg once daily on days 1-7 of a 21-day cycle; (ii) orally administering about 375 mg / m 2 or subcutaneously at a dose of about 1400 mg / m on day 1 of a 21-day cycle; (iii) administering rituximab at a dose of about 750 mg / m on day 1 of a 21-day cycle; 2 (iv) cyclophosphamide administered intravenously at a dose of about 50 mg / m on day 1 of a 21-day cycle. 2 (v) administering doxorubicin intravenously at a dose of about 1.4 mg / m on day 1 of a 21-day cycle; 2and (vi) orally administering prednisone or prednisolone at a dose of about 100 mg / day on days 1-5 of a 21 day cycle (intravenous administration of prednisone or prednisolone on day 1 is permitted). In one embodiment, the a-BCL is DLBCL (e.g., DLBCL, NOS, including GCB and ABC types). In one embodiment, the a-BCL is high-grade B cell lymphoma (e.g., high-grade B cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements). In one embodiment, the a-BCL is PMBCL. In one embodiment, the a-BCL is primary cutaneous DLBCL-leg type. In one embodiment, the a-BCL is ALK+ large B cell lymphoma. In one embodiment, the a-BCL is EBV+ DLBCL (e.g., EBV+ DLBCL, NOS). In one embodiment, the a-BCL is grade 3b follicular lymphoma. In one embodiment, the a-BCL is untreated. In one embodiment, the a-BCL is newly diagnosed. In one embodiment, the a-BCL is high-risk a-BCL (e.g., having an IPI score of 3-5).

[0113] In one embodiment, a method for treating aggressive B-cell lymphoma (a-BCL) is provided comprising: (i) orally administering Compound 1, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), at a dose of about 0.6 mg once daily on days 1-7 of a 21-day cycle; (ii) orally administering about 375 mg / m 2 or subcutaneously at a dose of about 1400 mg / m on day 1 of a 21-day cycle; (iii) administering rituximab at a dose of about 750 mg / m on day 1 of a 21-day cycle; 2 (iv) cyclophosphamide administered intravenously at a dose of about 50 mg / m on day 1 of a 21-day cycle. 2 (v) administering doxorubicin intravenously at a dose of about 1.4 mg / m on day 1 of a 21-day cycle; 2and (vi) orally administering prednisone or prednisolone at a dose of about 100 mg / day on days 1-5 of a 21 day cycle (intravenous administration of prednisone or prednisolone on day 1 is permitted). In one embodiment, the a-BCL is DLBCL (e.g., DLBCL, NOS, including GCB and ABC types). In one embodiment, the a-BCL is high-grade B cell lymphoma (e.g., high-grade B cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements). In one embodiment, the a-BCL is PMBCL. In one embodiment, the a-BCL is primary cutaneous DLBCL-leg type. In one embodiment, the a-BCL is ALK+ large B cell lymphoma. In one embodiment, the a-BCL is EBV+ DLBCL (e.g., EBV+ DLBCL, NOS). In one embodiment, the a-BCL is grade 3b follicular lymphoma. In one embodiment, the a-BCL is untreated. In one embodiment, the a-BCL is newly diagnosed. In one embodiment, the a-BCL is high-risk a-BCL (e.g., having an IPI score of 3-5).

[0114] In one embodiment, a method for treating aggressive B-cell lymphoma (a-BCL) comprises: (i) orally administering Compound 1, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), at a dose of about 0.4 mg once daily on days 1-10 of a 21-day cycle; (ii) orally administering about 375 mg / m 2 or subcutaneously at a dose of about 1400 mg / m on day 1 of a 21-day cycle; (iii) administering rituximab at a dose of about 750 mg / m on day 1 of a 21-day cycle; 2 (iv) cyclophosphamide administered intravenously at a dose of about 50 mg / m on day 1 of a 21-day cycle. 2 (v) administering doxorubicin intravenously at a dose of about 1.4 mg / m on day 1 of a 21-day cycle; 2and (vi) orally administering prednisone or prednisolone at a dose of about 100 mg / day on days 1-5 of a 21 day cycle (intravenous administration of prednisone or prednisolone on day 1 is permitted). In one embodiment, the a-BCL is DLBCL (e.g., DLBCL, NOS, including GCB and ABC types). In one embodiment, the a-BCL is high-grade B cell lymphoma (e.g., high-grade B cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements). In one embodiment, the a-BCL is PMBCL. In one embodiment, the a-BCL is primary cutaneous DLBCL-leg type. In one embodiment, the a-BCL is ALK+ large B cell lymphoma. In one embodiment, the a-BCL is EBV+ DLBCL (e.g., EBV+ DLBCL, NOS). In one embodiment, the a-BCL is grade 3b follicular lymphoma. In one embodiment, the a-BCL is untreated. In one embodiment, the a-BCL is newly diagnosed. In one embodiment, the a-BCL is high-risk a-BCL (e.g., having an IPI score of 3-5).

[0115] In one embodiment, the method further comprises administering a growth factor to the subject. In one embodiment, the growth factor is administered for prophylactic purposes (e.g., to prevent the subject from developing neutropenia (e.g., grade 3 / 4 neutropenia, prolonged severe neutropenia, febrile neutropenia)). In one embodiment, the growth factor is administered for therapeutic purposes (e.g., to treat or manage neutropenia in a subject who has developed neutropenia (e.g., grade 3 / 4 neutropenia, prolonged severe neutropenia, febrile neutropenia). In one embodiment, the method further comprises administering granulocyte colony stimulating factor (G-CSF) or pegylated granulocyte colony stimulating factor (peg-G-CSF) to the subject.

[0116] In one embodiment, G-CSF is administered on days 5-13 of a 21 day cycle. In one embodiment, pegylated G-CSF is administered on day 2 of a 21 day cycle.

[0117] In one embodiment, G-CSF is administered on days 5-13 of a 21 day cycle and a compound described herein, e.g., Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered on days 1-7 of the 21 day cycle. In one embodiment, G-CSF is administered on days 5-13 of a 21 day cycle, while a compound described herein, e.g., Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered on days 1-10 of the 21 day cycle.

[0118] In one embodiment, pegylated G-CSF is administered on day 2 of a 21-day cycle, and a compound described herein, e.g., Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered on days 1-7 of the 21-day cycle. In one embodiment, pegylated G-CSF is administered on day 2 of a 21-day cycle, while a compound described herein, e.g., Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered on days 1-10 of the 21-day cycle.

[0119] In one embodiment, the method further comprises administering antithrombotic prophylaxis to the subject. In one embodiment, the method further comprises administering intrathecal (IT) prophylaxis for central nervous system (CNS) lesions to the subject.

[0120] In another embodiment, provided herein is a method for achieving a complete response, partial response, or stable disease as determined by Lugano response criteria in a patient, the method comprising administering to a patient having BCL an effective amount of a compound described herein, e.g., Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or equivalents thereof. In another embodiment, provided herein is a method for obtaining an increase in overall survival, progression-free survival, symptom-free survival, progression-free time, or disease-free survival in a patient, the method comprising administering to a patient having BCL an effective amount of a compound described herein, e.g., Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or equivalents thereof. In another embodiment, provided herein is a method for increasing overall survival in a patient, comprising administering to a patient with BCL an effective amount of a compound described herein, for example, Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1) in combination with a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or equivalents thereof. In another embodiment, provided herein is a method for increasing progression-free survival in a patient, comprising administering to a patient with BCL an effective amount of a compound described herein, for example, Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1) in combination with a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or equivalents thereof.In another embodiment, provided herein is a method for obtaining disease-free survival in a patient, comprising administering an effective amount of a compound described herein, for example, Compound 1, or its enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt (e.g., the hydrochloride salt of Compound 1) to a patient with BCL in combination with a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or equivalents. In another embodiment, provided herein is a method for obtaining an increase in progression-free time in a patient, comprising administering an effective amount of a compound described herein, for example, Compound 1, or its enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt (e.g., the hydrochloride salt of Compound 1) to a patient with BCL in combination with a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or equivalents. In another embodiment, provided herein is a method for obtaining an increased disease-free survival rate in a patient, comprising administering to a patient having BCL an effective amount of a compound described herein, e.g., Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or equivalents thereof. In one embodiment, the BCL is a-BCL.

[0121] Pharmaceutical Compositions and Routes of Administration The compounds provided herein may be administered to a subject orally, topically or parenterally in conventional forms of formulation, such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable formulations may contain conventional organic or inorganic additives, such as excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), lubricants (e.g., cellulose ... and the like. , magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), flavoring agents (e.g., citric acid, menthol, glycine or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben or propylparaben), stabilizers (e.g., citric acid, sodium citrate or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone or aluminum stearate), dispersing agents (e.g., hydroxypropylmethylcellulose), diluents (e.g., water), and base wax (e.g., cacao butter, white petrolatum or polyethylene glycol) can be prepared by a commonly used method. The effective amount of the compound in the pharmaceutical composition can be a level that can exert the desired effect; about 0.001 mg / kg (body weight of the subject) to about 1 mg / kg (body weight of the subject) in a unit dose for both oral and parenteral administration.

[0122] The compounds provided herein may be administered orally. In one embodiment, when administered orally, the compounds provided herein are administered with food and water. In another embodiment, the compounds provided herein are dispersed in water or fruit juice (e.g., apple juice or orange juice) and administered orally as a liquid or suspension. In one embodiment, the compounds provided herein are administered when the subject is fed a meal. In one embodiment, the compounds provided herein are administered when the subject is fed a high-fat and / or high-calorie meal. In one embodiment, the compounds provided herein are administered when the subject is fed an FDA standard high-fat high-calorie breakfast. In one embodiment, the compounds provided herein are administered when the subject is fasting. In one embodiment, the compounds provided herein are administered after the subject has fasted overnight for at least 8 hours. In one embodiment, the compounds provided herein are administered with or without food.

[0123] Compounds provided herein may also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, intrarectally, mucosally, by inhalation, or topically to the ear, nose, eye, or skin. The method of administration is left to the discretion of the medical practitioner and may depend, in part, on the site of the medical condition.

[0124] In one embodiment, provided herein is a capsule that contains the compound provided herein without additional carrier, excipient or vehicle.In another embodiment, provided herein is a composition that comprises an effective amount of the compound provided herein and a pharma- ceutically acceptable carrier or vehicle, wherein the pharma- ceutically acceptable carrier or vehicle can include an excipient, a diluent, or a mixture thereof.In one embodiment, the composition is a pharmaceutical composition.

[0125] The composition may be in the form of tablets, chewable tablets, capsules, liquids, parenteral solutions, troches, suppositories, suspensions, and the like. The composition may be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule or a convenient volume of liquid. In one embodiment, the liquid is prepared from a water-soluble salt. In general, all compositions are prepared according to methods known in medicinal chemistry. Capsules may be prepared by mixing the compound provided herein with a suitable carrier or diluent and filling the appropriate amount of the mixture into a capsule. Common carriers and diluents include, but are not limited to, inert powdered substances, such as many different types of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars, such as fructose, mannitol and sucrose, grain flours, and similar edible powders.

[0126] Tablets can be prepared by direct compression, wet granulation, or dry granulation. These preparations usually incorporate diluents, binders, lubricants, and disintegrants and compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin, and sugars such as lactose, fructose, glucose, and the like. Natural and synthetic gums are also convenient, including acacia, alginate, methylcellulose, polyvinylpyrrolidine, and the like. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.

[0127] Lubricants may be necessary in tablet formulations to prevent the tablet and punch from sticking to the die. Lubricants may be selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oil. Tablet disintegrants are substances that swell when wetted to disintegrate the tablet and release the compound. They include starches, clays, cellulose, algins and gums. More specifically, for example, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose may be used as well as sodium lauryl sulfate. Tablets may be coated with sugar as flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet. The composition may also be formulated as a chewable tablet, for example, by using a substance such as mannitol in the formulation.

[0128] When it is desired to administer the compound provided herein as suppository, typical base can be used.Cocoa butter is the conventional suppository base, and it can be modified by adding wax to slightly raise its melting point.In particular, the water-miscible suppository base, which comprises polyethylene glycols of various molecular weights, is widely used.

[0129] The effect of the compound provided herein can be delayed or sustained by suitable formulation. For example, a slowly soluble pellet of the compound provided herein can be prepared and incorporated into a tablet or capsule, or as a slow-release implantable device. This technique also includes making pellets of several different dissolution rates and filling a capsule with a mixture of the pellets. The tablet or capsule can be coated with a film that resists dissolution for a predictable period of time. Even parenteral formulations can be made long-acting by dissolving or suspending the compound provided herein in an oily or emulsified vehicle that allows it to disperse gradually in serum.

[0130] Certain pharmaceutical compositions and formulations of Compound 1 are described in US Patent Application Serial No. 17 / 075,447, which is incorporated herein by reference in its entirety.

[0131] The methods provided herein encompass treating patients regardless of their age. In some embodiments, the subject is 18 years of age or older. In other embodiments, the subject is over 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years of age. In other embodiments, the subject is under 65 years of age. In other embodiments, the subject is over 65 years of age.

[0132] Depending on the disease state to be treated and the pathology of the subject, Compound 1, or its enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt, may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intrapelvic injection or infusion, subcutaneous injection, or implant), inhalation, intranasal, intravaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. Compound 1, or its enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt, may be formulated alone or in suitable dosage units together with pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of administration.

[0133] In one embodiment, Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered orally. In another embodiment, a compound of Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered parenterally. In yet another embodiment, a compound of Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered intravenously.

[0134] Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), may be administered as a single dose, e.g., as a single bolus injection or oral capsule, tablet, or pill; or over an extended period of time, e.g., as a continuous infusion over an extended period of time or as divided bolus doses over an extended period of time. The compounds described herein may be administered repeatedly as necessary, e.g., until the patient experiences stable disease or remission, or until the patient experiences disease progression or unacceptable toxicity.

[0135] Compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), may be administered once a day (QD) or divided into multiple daily doses, such as twice a day (BID), three times a day (TID), and four times a day (QID). Furthermore, administration may be continuous (i.e., every day for consecutive days, or every day), intermittent, e.g., cyclic (i.e., with days, weeks, or months off). As used herein, the term "daily" is intended to mean that a therapeutic compound, such as Compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharma-ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered once or more than once each day, e.g., over a period of time. The term "continuous" is intended to mean that a therapeutic compound, such as Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered daily without interruption for at least 7 days to 52 weeks. The term "intermittent" or "intermittently" as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), can be administered 1-6 days per week, cyclically (e.g., daily administration for 2-8 consecutive weeks followed by a rest period of up to 1 week without administration), or every other day. The term "cycling" as used herein is intended to mean that a therapeutic compound, such as Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered daily or continuously, but with rest periods.

[0136] In some embodiments, the frequency of administration ranges from about once a day to about once a month. In certain embodiments, administration is once a day, twice a day, three times a day, four times a day, every other day, twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of compound 1), is administered once a day. In another embodiment, compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharmaceutically acceptable salt thereof, is administered twice a day. In yet another embodiment, Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered three times per day. In yet another embodiment, Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered four times per day.

[0137] In one embodiment, the methods provided herein comprise administration of a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in one or more 21-day treatment cycles. In another embodiment, the methods provided herein comprise administration of a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in days 1-10 of a 21-day cycle. In another embodiment, the methods provided herein comprise administration of a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in days 1-14 of a 21-day cycle.

[0138] In one embodiment, Compound 1, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered once daily for 10 days, followed by the remaining 11 days. In one embodiment, Compound 1, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), is administered once daily for 14 days, followed by the remaining 7 days.

[0139] In one embodiment, the methods provided herein include: (i) administering a compound provided herein (e.g., Compound 1, or a pharma- ceutically acceptable salt thereof, e.g., the hydrochloride salt of Compound 1) in a cycle beginning on day 1 of a first 21-day cycle, once daily for 10 days, then for the remaining 11 days; and (ii) administering a second therapeutic agent provided herein in the cycle described herein.

[0140] In one embodiment, the methods provided herein include: (i) administering a compound provided herein (e.g., Compound 1, or a pharma- ceutically acceptable salt thereof, e.g., the hydrochloride salt of Compound 1) in a cycle beginning on day 1 of a first 21-day cycle, once daily for 14 days, then for the remaining 7 days; and (ii) administering a second therapeutic agent provided herein in the cycle described herein.

[0141] The treatment cycles described herein may be repeated for at least 1, 2, 3, 4, 5, 6, 7, 8, or more cycles. In certain cases, the treatment cycles described herein include 1 to about 24 cycles, about 2 to about 16 cycles, or about 2 to about 6 cycles. In certain cases, the treatment cycles described herein include 1 to about 4 cycles. In certain embodiments, a therapeutically effective amount of compound 1, or a pharma- ceutically acceptable salt thereof (e.g., the hydrochloride salt of compound 1), and / or a second therapeutic agent provided herein (e.g., a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone or equivalents thereof) is administered for one or more 21-day cycles (e.g., six 21-day cycles). In certain cases, the cyclic therapy is not limited to a number of cycles, and the therapy is continued until disease progression. The cycles may include, in certain cases, varying the administration period and / or rest period described herein. EXAMPLES

[0142] The following examples are offered by way of illustration and not by way of limitation.

[0143] Example 1: Phase 1b Clinical Trial A Phase 1b, open-label, global, multicenter, dose-ranging, randomized dose-expansion study to determine the maximum tolerated dose of Compound 1 in combination with R-CHOP-21 and to evaluate its safety and tolerability, pharmacokinetics, and preliminary efficacy will be conducted in subjects with previously untreated, high-risk (IPI 3-5), aggressive B-cell lymphoma.

[0144] Indications Subjects with newly diagnosed aggressive B-cell lymphoma (a-BCL) are eligible for the study.

[0145] the purpose Primary Objective for Part 1: To define the maximum tolerated dose (MTD) and / or recommended Phase 2 dose (RP2D) of Compound 1 in combination with R-CHOP-21 in subjects with untreated, high-risk (IPI 3-5), a-BCL.

[0146] Primary Objective for Part 2: To further evaluate the safety and tolerability associated with Compound 1 at the RP2D in combination with R-CHOP-21 in subjects with untreated, high-risk (IPI 3-5), a-BCL.

[0147] Secondary objectives for Part 1: To determine the safety and tolerability of Compound 1 in combination with R-CHOP-21 in subjects with treatment-naïve, high-risk (IPI 3-5), a-BCL. To characterize the pharmacokinetics (PK) of Compound 1 in combination with R-CHOP-21 in subjects with treatment-naïve, high-risk (IPI 3-5), a-BCL. To evaluate the preliminary efficacy of Compound 1 in combination with R-CHOP-21 in subjects with untreated, high-risk (IPI 3-5), a-BCL.

[0148] Secondary objectives for Part 2: To evaluate the preliminary efficacy of Compound 1 in combination with R-CHOP-21 in subjects with untreated, high-risk (IPI 3-5), a-BCL. To characterize the pharmacokinetics (PK) of Compound 1 in combination with R-CHOP-21 in subjects with treatment-naïve, high-risk (IPI 3-5), a-BCL.

[0149] Exploratory purpose: To correlate the PK of compound 1 with safety profile, clinical activity, and pharmacodynamic (PD) biomarkers. To evaluate the PK of the R-enantiomer of Compound 1 in subjects with treatment-naïve, high-risk (IPI 3-5), a-BCL. To examine the dose, exposure, and response relationship of Compound 1 on the rate of CRBN substrate degradation in tumors by fine needle aspiration. To examine dose, exposure, and response relationships on the rate of CRBN substrate degradation in peripheral blood. To examine the dose, exposure, and response relationship of Compound 1 on peripheral immune cell populations by immunophenotyping. To assess the correlation of protein expression, gene expression or genomic aberrations in tumor cells to response or recurrence to Compound 1. To assess correlation of baseline and changes in immune cell composition of the tumor microenvironment to Compound 1 treatment and response or recurrence. To investigate changes and mutations in circulating tumor DNA (ctDNA) levels and their correlation with radiological and metabolic response. To evaluate the impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) on subjects receiving Compound 1 for the treatment of lymphoma and to support requests from health authorities. To examine correlations between biomarkers and efficacy endpoints.

[0150] Study design The study is designed as a two-part Phase 1b study: dose escalation of compound 1 added to a standard R-CHOP-21 regimen for first-line treatment of a-BCL (Part 1); and expansion in the RP2D of compound 1 added to a standard R-CHOP-21 regimen for first-line treatment of a-BCL (Part 2).

[0151] Part 1 (dose escalation) is to define the maximum tolerated dose (MTD) and / or recommended phase 2 dose (RP2D) and schedule of Compound 1 when administered with standard dose R-CHOP-21 for up to six cycles. Part 1 will include approximately 18 subjects treated with standard dose R-CHOP-21 and escalating doses of Compound 1 (Figure 1). Part 1 will be conducted using a modified toxicity probability interval-2 (mTPI-2) design. Dose-limiting toxicities (DLTs) will be assessed during the first two treatment cycles to determine the MTD / RP2D.

[0152] Part 2 (Dose Expansion): After the RP2D is established for Compound 1 in Part 1, the corresponding Part 2 of the study will begin. Approximately 20 subjects will be enrolled and randomized into the Compound 1 and R-CHOP-21 combination arm (Figure 2).

[0153] The study will be conducted in accordance with the International Council for Harmonisation (ICH) Good Clinical Practices (GCP).

[0154] Study population Approximately 38 subjects will be enrolled in the study (18 in Part 1 and 20 in Part 2).

[0155] Subjects must have an investigator-assessed diagnosis of a-BCL with an IPI score of 3 to 5. Subjects (male or female) aged 18 years or older must have at least one measurable lesion according to the Lugano classification of NHL (Cheson, 2014) and must have adequate bone marrow, liver, and kidney function.

[0156] Length of the exam The study consists of screening, treatment, and follow-up periods for all enrolled subjects.

[0157] The expected duration of the entire study is 53 months, which includes an enrollment period of approximately 12 months for Part 1 and 12 months for Part 2 plus 5 months of treatment plus 24 months of follow-up.

[0158] The end of the study will be defined as the date of the last visit of the last subject completing post-treatment follow-up or the date of receipt of the last data point from the last subject required for the primary, secondary and / or exploratory analyses, as pre-specified in the protocol, whichever is later.

[0159] Study treatment The compound (provided as the hydrochloride salt) will be supplied as a capsule for oral administration and will be appropriately labeled as the investigational new drug (IP) for this study. Capsules of Compound 1 will be administered orally (QD) on the scheduled dosing days. Compound 1 should be administered in the morning with approximately 8 oz or 240 ml of water after an overnight fast lasting at least 6 hours. Subjects should refrain from food or other medication intake for at least 2 hours after each morning dose.

[0160] Study treatment will include six 21-day cycles of R-CHOP-21 (intravenous (IV) or SC rituximab, doxorubicin, vincristine, and cyclophosphamide on day 1; prednisone or prednisolone daily on days 1-5), as shown in Table 4 below. Other anthracyclines cannot be substituted for doxorubicin. Liposomal doxorubicin is not permitted. In countries where prednisone is not available, local equivalent corticosteroids are acceptable for substitution. For convenience, corticosteroids given intravenously rather than orally on day 1 of the cycle are also acceptable.

[0161] [Table 5]

[0162] In addition to R-CHOP-21, the following doses and schedules of orally administered Compound 1 will be evaluated in the study: DL1: 0.4 mg, days 1-7 DL2a: 0.6 mg, days 1 to 7 DL2b: 0.4 mg, days 1 to 10 DL-1: 0.2 mg, days 1-7

[0163] The decision to escalate to dose level 2a or 2b will be based on clinical and PK / PD data from dose level 1.

[0164] Dose levels 2a and 2b deliver similar total doses of Compound 1 per cycle, with one delivering a larger dose at closer intervals and the other delivering smaller doses spread out over a longer period. The first day of IP administration of Compound 1 is considered day 1 of the cycle.

[0165] Dose interruptions and reductions are permitted throughout the study. Intrapatient dose escalation is not permitted in this study. Dose adjustments for management of toxicity are permitted.

[0166] Mandatory granulocyte colony-stimulating factor (G-CSF) will be administered on days 5-13 or pegylated granulocyte colony-stimulating factor (peg-G-CSF) will be administered on day 2 during each cycle. Antithrombotic prophylaxis is mandatory for all subjects in this study.

[0167] In high-risk subjects, intrathecal (IT) prophylaxis of central nervous system (CNS) lesions will be administered according to institutional practice.

[0168] [Table 6]

[0169] [Table 7]

[0170] [Table 8]

[0171] Overview of key efficacy measures Physical exam, including Eastern Cooperative Oncology Group (ECOG) performance status. ·Complete blood count. · Computed tomography (CT)-scan and / or Fluorodeoxyglucose-positron emission tomography (FDG-PET)-CT scan. · Bone marrow evaluation: biopsy, aspirate.

[0172] Overview of major safety evaluations · Complete physical exam including vital signs and Venous Thromboembolism (VTE) monitoring. · Clinical laboratory evaluation (hematology, blood chemistry). · Pregnancy testing / counseling. Concomitant medications and procedures. Adverse events (AEs).

[0173] statistical methods For each arm in the Part 1 portion of the study, the mTPI-2 design (Ji Y et al., Clin Trials, 7(6):653-63(2010); Ji Y et al., J Clin Oncol, 31(14):1785-91(2013); Guo W et al., Contemp Clin Trials, 58:23-33(2017)) will be applied to guide dose escalation. Approximately 18 subjects will be enrolled in the Compound 1 and R-CHOP-21 combination arm. The number of subjects will depend on the number of dose levels tested (based on the occurrence of DLT) and may exceed the approximate value.

[0174] The target toxicity rate of DLT relative to the MTD is 0.25. Subjects are enrolled in groups of size ≧3, with a maximum sample size of 9 for each dose level. The first dose level of Compound 1 is 0.4 mg administered for the first 7 days in combination with R-CHOP-21. The mTPI-2 algorithm, using a priori beta (1 / 3, 1 / 3) and an allowed toxicity probability interval (0.2, 0.3), is applied to recommend subsequent dose levels. A priori beta (1 / 3, 1 / 3) is "neutral" in the sense that the maximum likelihood estimate of toxicity rate is approximately the posterior median (Kerman J, http: / / arxiv.org / abs / 1111.0433v1(2011)).

[0175] The recommended dose is integrated using clinical evaluation of the toxicity profile observed at the time of analysis. To protect the safety of the subjects, a Safety Review Committee (SRC) monitors the dose escalation process and evaluates the decision of each dose level before it is assigned. The SRC may make recommendations to the sponsor regarding the allocation of dose levels, independent of the dose recommended by mTPI-2.

[0176] Eligibility Criteria Subjects must meet the following criteria to be enrolled in the study: 1. Subjects are 18 years of age or older at the time of signing the Informed Consent Form (ICF). 2. Subjects must understand and voluntarily sign the ICF before any study-related evaluations / procedures are performed. 3. Subject is willing and able to comply with the study visit schedule and other protocol requirements. 4. Subject is willing to undergo core needle biopsy or incisional / excision biopsy unless sufficient tissue is available from a diagnostic tumor / lymph node biopsy (from within 6 months prior to ICF signing) for translational research. 5. Subject has a histologically confirmed (according to local evaluation) diagnosis of de novo, untreated, a-BCL according to the 2016 WHO classification, including: Diffuse large B-cell lymphoma (DLBCL), NOS (including germinal center B cell [GCB] and activated B cell [ABC] types); b. High-grade B-cell lymphoma with MYC and BCL2 and / or BCL6 rearrangements; c. Primary mediastinal (thymic) large B-cell lymphoma (PMBCL); d. Primary cutaneous DLBCL / lower limb type; e. Anaplastic lymphoma kinase positive (ALK+) large B-cell lymphoma; f. Epstein-Barr virus positive (EBV+) DLBCL, NOS; g. Grade 3b follicular lymphoma (FL). 6. Subject is deemed a suitable candidate for induction therapy with 6 cycles of R-CHOP-21 chemoimmunotherapy (per investigator assessment). 7. Subject has high-risk disease defined as an International Prognostic Index (IPI) score of ≧3 (high-intermediate or high risk). 8. Subjects must have measurable disease as defined by at least one FDG-rich lesion of any FDG-rich subtype and one bidimensionally measurable (>1.5 cm longest diameter) disease by computed tomography (CT) or magnetic resonance imaging (MRI) as defined by the Lugano classification (Cheson, 2014). 9. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 10. Subject must have the following laboratory values: a.Absolute neutrophil count (ANC) ≥ 1.5 × 109 / L or, if documented bone marrow disease (> 50% or tumor cells), ≥ 1.0 × 109 / L without growth factor support for 7 days (14 days for peg-G-CSF); b. Hemoglobin (Hb) ≥ 8 g / dL; c. No transfusion for 7 days, platelet count (PLT) ≥ 75 × 109 / L or, if documented bone marrow disease (> 50% or tumor cells), ≥ 50 × 109 / L; d. Aspartate aminotransferase / serum glutamic oxaloacetic transaminase (AST / SGOT) and alanine aminotransferase / serum glutamic pyruvic transaminase (ALT / SGPT) ≦2.5×upper limit of normal (ULN). In cases of documented liver disease due to lymphoma, ALT / SGPT and AST / SGOT should be ≦5.0×ULN. e. Serum total bilirubin ≤ 2.0 mg / dL (34 μmol / L), except in cases of Gilbert syndrome, in which case ≤ 5.0 mg / dL (86 μmol / L); f. Estimated serum creatinine clearance of ≥ 50 mL / min using the Modification of Diet in Renal Disease (MDRD) formula. 11. All subjects must: a. Understand that the investigational drug may pose a potential risk of malformation. b. Agree to refrain from donating blood during study treatment, during any interruptions, and for at least 28 days after the last dose of study treatment. c. You must agree not to share the study medication with anyone. d. Must agree to comply with all requirements defined in the Contraceptive Program for Compound 1 Contraceptive Regimen for Subjects in Clinical Trials. 12. Females must agree to abstain from breast-feeding during study participation and for at least 28 days after discontinuation of Compound 1, and in accordance with the approved rituximab product / prescribing information. 13. Women of childbearing potential (FCBP^) * should be: a. Must have two negative pregnancy tests confirmed by the investigator before starting study treatment. Women must consent to continued pregnancy testing throughout the study and after completion of study treatment. This applies if the subject completely abstains from sexual contact with the opposite sex. * This also applies. b. Completely avoiding sexual contact with the opposite sex * must agree to use and be able to adhere to two forms of contraception (this must be reviewed monthly and the source must be documented): one highly effective and one additional effective (barrier) method of contraception uninterrupted for 28 days prior to starting IP, during study treatment (including dose interruptions), and for at least 28 days after the last dose of Compound 1 and for 12 months after the last dose of rituximab, whichever is longer. 14. Male subjects must be: a. Complete abstinence * (This must be reviewed monthly and the source must be documented) or, even if a vasectomy has been successful, participants must agree to use condoms during sexual contact with pregnant or potentially pregnant women while participating in the study, during any interruptions in treatment, and for at least 90 days after their last dose of Compound 1 or rituximab, whichever is longer. b. Agree to refrain from donating sperm during study treatment, during any treatment interruptions, and for at least 90 days after the last dose of Compound 1 or rituximab, whichever is longer. ^FCBP are women who 1) have achieved menarche at some point; 2) have not had a hysterectomy or bilateral oophorectomy; or 3) have not been naturally postmenopausal (i.e., have had menses at some point during the previous 24 consecutive months) for at least 24 consecutive months (amenorrhea after cancer treatment does not exclude the possibility of pregnancy). * Complete abstinence is acceptable if this is in keeping with the subject's preferred and usual lifestyle. Periodic abstinence methods (e.g., calendar methods, ovulation methods, symptom-temperature methods, postovulation methods) and withdrawal methods are not acceptable methods of contraception.

[0177] Exclusion criteria The presence of any of the following will exclude a subject from enrollment: 1. Subject has any significant medical condition, active infection (including suspected or confirmed SARS-CoV-2), laboratory abnormality, or psychiatric illness that may prevent the subject from participating in the study. 2. The subject has any medical condition, including the presence of laboratory abnormalities, that places the subject at unacceptable risk if the subject were to participate in the study. 3. The subject has any medical condition that confounds the ability to interpret data from the study. 4. The subject has any other subtype of lymphoma. 5. Subject has proven or suspected central nervous system (CNS) involvement due to lymphoma. 6. Subject has persistent diarrhea or malabsorption ≧ Grade 2 (NCI CTCAE v5.0) despite medical management. 7. Subject has peripheral neuropathy ≥ Grade 2 (NCI CTCAE v5.0). 8. Subject is receiving chronic systemic immunosuppressive therapy or corticosteroids (e.g., not to exceed 10 mg / day of prednisone or equivalent within the last 14 days); continued use of inhaled or topical corticosteroids is permitted. 9. Subject has cardiac dysfunction or clinically significant cardiac disease, including any of the following: a. Left ventricular ejection fraction (LVEF) < 45% as determined by multi-gate b. Acquisition scan (MUGA) or echocardiogram (ECHO); c. Heart failure (New York Heart Association class III or IV); d. Clinically significant abnormal electrocardiogram (ECG) findings at screening; e. Unstable angina or myocardial infarction ≤6 months prior to initiation; f. Persistent or uncontrollable ventricular arrhythmias or atrial fibrillation or cardiac conduction abnormalities not alleviated by a pacemaker. 10. Subject has undergone major surgery ≦2 weeks prior to starting Compound 1; subject must have recovered from any clinically significant effects of recent surgery. 11. Subject has any condition that causes difficulty swallowing tablets. 12. Subject has known seropositivity for Human Immunodeficiency Virus (HIV) or active viral infection with Human Immunodeficiency Virus (HIV); 13. Subject has known chronic active hepatitis B (hepatitis B surface antigen [HBsAg] positive and / or hepatitis B core antibody [anti-HBc] positive along with positive viral DNA) or hepatitis C (with positive serology and / or evidence of liver damage requiring treatment) infection; 14. Subject has a history of other malignancies unless disease-free for ≥ 3 years; exceptions to the ≥ 3 year time limit include a history of: Localized non-melanoma skin cancer; b. Carcinoma in situ of the cervix; c. Carcinoma in situ of the breast; d. Prostate cancer (T1a or T1b according to the tumor-node-metastasis [TNM] staging system) or incidental histologic evidence of prostate cancer treated with curative intent. 15. Subject has current treatment with a strong CYP3A4 / 5 modulator. 16. The subject has hypersensitivity to the active substance or to mouse proteins, or to any of the other excipients of Rituximab. 17. Subject has known hypersensitivity to any component of the CHOP regimen. 18. The subject has a known allergy to thalidomide, pomalidomide, or lenalidomide.

[0178] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entireties.

[0179] The embodiments described above are intended to be merely illustrative; those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the invention and are covered by the appended claims.

Claims

1. Compounds of formula (I) for treating B cell lymphoma (BCL): 【Chemistry 1】 or an enantiomer, a mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof, wherein the pharmaceutical composition is used such that the compound of formula (I) or an enantiomer, a mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof is administered to a subject in combination with a second therapeutic agent, wherein the second therapeutic agent is a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, or an equivalent thereof.

2. The pharmaceutical composition of claim 1, wherein the BCL is aggressive B-cell lymphoma (a-BCL).

3. The pharmaceutical composition according to claim 2, wherein the a-BCL is diffuse large B-cell lymphoma (DLBCL).

4. The pharmaceutical composition according to claim 3, wherein the DLBCL is DLBCL not otherwise specified (NOS).

5. The pharmaceutical composition according to claim 3, wherein the DLBCL is of the germinal center B cell (GCB) type or the activated B cell (ABC) type.

6. The pharmaceutical composition according to claim 2, wherein the a-BCL is an aggressive B-cell lymphoma.

7. The pharmaceutical composition of claim 6, wherein the aggressive B-cell lymphoma has MYC and BCL2 and / or BCL6 rearrangements.

8. The pharmaceutical composition according to claim 2, wherein the a-BCL is primary mediastinal (thymic) large B-cell lymphoma (PMBCL).

9. The pharmaceutical composition according to claim 2, wherein the a-BCL is primary cutaneous DLBCL-lower limb type.

10. The pharmaceutical composition according to claim 2, wherein the a-BCL is anaplastic lymphoma kinase positive (ALK+) large B-cell lymphoma.

11. The pharmaceutical composition of claim 2, wherein the a-BCL is Epstein-Barr virus positive (EBV+) DLBCL.

12. The pharmaceutical composition of claim 11, wherein the EBV+ DLBCL is EBV+ DLBCL, not specific (NOS).

13. The pharmaceutical composition of claim 2, wherein the a-BCL is grade 3b follicular lymphoma (FL).

14. 3. The pharmaceutical composition of claim 2, wherein the a-BCL is T-cell / histiocyte-rich large B-cell lymphoma (THRLBCL), intravascular large B-cell lymphoma, plasmablastic lymphoma, or primary effusion lymphoma (PEL).

15. 2. The pharmaceutical composition of claim 1, wherein the BCL has an International Prognostic Index (IPI) score of 3-5.

16. The pharmaceutical composition of claim 1 , wherein the BCL is untreated.

17. The pharmaceutical composition of claim 1 , wherein the BCL is newly diagnosed.

18. The pharmaceutical composition of any one of claims 1 to 17, wherein the second therapeutic agent is a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.

19. The pharmaceutical composition of any one of claims 1 to 17, wherein the second therapeutic agent is a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone.

20. 18. The pharmaceutical composition of any one of claims 1-17, wherein rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 of a 21 day cycle, and prednisone or its equivalent is administered on days 1-5 of a 21 day cycle.

21. 18. The pharmaceutical composition of any one of claims 1 to 17, wherein rituximab is administered intravenously or subcutaneously; cyclophosphamide, doxorubicin, and vincristine are administered intravenously; and prednisone or its equivalent is administered orally.

22. Rituximab is administered at approximately 375 mg / m on day 1 of a 21-day cycle. ２ or subcutaneously at a dose of about 1400 mg; and cyclophosphamide is administered at about 750 mg / m on day 1 of a 21-day cycle. ２ doxorubicin is administered intravenously at a dose of about 50 mg / m on day 1 of a 21-day cycle. ２ on day 1 of a 21-day cycle; ２ and prednisone or its equivalent is administered orally at a dose of about 100 mg on days 1 to 5 of a 21 day cycle.

23. A pharmaceutical composition according to any one of claims 1 to 17, comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

24. 24. The pharmaceutical composition of claim 23, comprising the hydrochloride salt of the compound of formula (I).

25. 18. The pharmaceutical composition of any one of claims 1 to 17, wherein the compound of formula (I) or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof is administered orally.

26. 18. The pharmaceutical composition of any one of claims 1-17, wherein the compound of formula (I) or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof is administered in a dose of about 0.2 mg to about 0.6 mg once daily (QD).

27. 27. The pharmaceutical composition of claim 26, wherein the compound of formula (I) or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof is administered once daily (QD) in a dose of about 0.2 mg, about 0.4 mg, or about 0.6 mg.

28. 28. The pharmaceutical composition of claim 27, wherein the compound of formula (I) or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof is administered at a dose of 0.4 mg once daily (QD).

29. 18. The pharmaceutical composition of any one of claims 1-17, wherein the compound of formula (I) or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof is administered at a dose of about 0.2 mg QD on days 1-7 of a 21 day cycle.

30. 18. The pharmaceutical composition of any one of claims 1-17, wherein the compound of formula (I) or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof is administered at a dose of about 0.4 mg QD on days 1-7 of a 21 day cycle.

31. 18. The pharmaceutical composition of any one of claims 1-17, wherein the compound of formula (I) or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof is administered at a dose of about 0.4 mg QD on days 1-10 of a 21 day cycle.

32. 18. The pharmaceutical composition of any one of claims 1-17, wherein the compound of formula (I) or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof is administered at a dose of about 0.6 mg QD on days 1-7 of a 21 day cycle.

33. 2. The pharmaceutical composition of claim 1 for treating a-BCL, wherein (i) the compound of formula (I) or its hydrochloride salt is administered on days 1 to 7 of a 21-day cycle; (ii) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 of a 21-day cycle; and (iii) prednisone or prednisolone is administered on days 1 to 5 of a 21-day cycle.

34. 2. The pharmaceutical composition of claim 1 for treating a-BCL, wherein (i) the compound of formula (I) or its hydrochloride salt is administered on days 1 to 10 of a 21-day cycle; (ii) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 of a 21-day cycle; and (iii) prednisone or prednisolone is administered on days 1 to 5 of a 21-day cycle.

35. The pharmaceutical composition according to any one of claims 1 to 17, characterized in that the compound of formula (I) or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharma- ceutically acceptable salt thereof is used for administration in further combination with granulocyte colony-stimulating factor (G-CSF) or pegylated granulocyte colony-stimulating factor (peg-G-CSF).

36. 36. The pharmaceutical composition of claim 35, wherein G-CSF is administered on days 5-13 of a 21 day cycle while the compound of formula (I) or its enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt is administered on days 1-7 of a 21 day cycle; or G-CSF is administered on days 5-13 of a 21 day cycle while the compound of formula (I) or its enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt is administered on days 1-10 of a 21 day cycle.

37. The pharmaceutical composition of claim 35, wherein peg-G-CSF is administered on day 2 of a 21 day cycle while the compound of formula (I) or its enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt is administered on days 1 to 7 of a 21 day cycle; or peg-G-CSF is administered on day 2 of a 21 day cycle while the compound of formula (I) or its enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt is administered on days 1 to 10 of a 21 day cycle.

38. 18. The pharmaceutical composition of any one of claims 1 to 17, wherein the compound of formula (I) or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone or equivalents thereof are administered in one or more 21 day cycles.

39. 39. The pharmaceutical composition of claim 38, wherein the compound of formula (I) or an enantiomer, mixture of enantiomers, tautomer, isotope, or pharma- ceutically acceptable salt thereof, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone or equivalents thereof is administered in six 21-day cycles.

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