WO2024015757A9

WO2024015757A9 - Combination of abemaciclib and venetoclax for use in the treatment of mantle cell lymphoma (mcl)

Info

Publication number: WO2024015757A9
Application number: PCT/US2023/069918
Authority: WO
Inventors: Luhua Wang
Original assignee: Board Of Regents, The University Of Texas System
Priority date: 2022-07-12
Filing date: 2023-07-11
Publication date: 2024-03-07
Also published as: WO2024015757A1

Abstract

Provided herein is a combination therapy for use in a method of treating mantle cell lymphoma in a patient in need thereof.

Description

COMBINATION OF ABEMACICLIB AND VENETOCLAX FOR USE IN THE TREATMENT OF MANTLE CELL LYMPHOMA (MCL)

Cross-Reference to Related Applications

The present application claims the benefit of priority to U.S. Provisional Application No. 63/388,387, filed on July 12, 2022, the content of which is incorporated herein by reference in its entirety.

Field

The present disclosure relates to a combination of abemaciclib or a pharmaceutically acceptable salt thereof and venetoclax or pharmaceutically acceptable salt thereof, for use in the treatment of mantle cell lymphoma (MCL).

Background

Mantle cell lymphoma is a relatively rare, aggressive form of B cell non-Hodgkin lymphoma (NHL) that accounts for around 5-10% of all NHL diagnoses.

Non-Hodgkin lymphoma is a cancer type which affects the lymphatic system. Mantle cell lymphoma is a rare form of NHL which results from a malignant transformation of B cell lymphocytes in the outer edge of a lymph node follicle, known as the mantle zone. Mantle cell lymphoma is a recognised pathological condition in the art and currently affects around 5000 patients per year in the US alone.

Mantle cell lymphoma is an aggressive, fast-growing class of NHL and is associated with poor prognosis due to limited suitable therapeutic options. Overall prospects are poor, with median overall survival of around 6-7 years, which is significantly shorter than median overall survival for indolent subtypes of NHL such as follicular lymphoma.

First line therapy for MCL typically consists of intensive chemotherapy with autologous stem cell transplant for fit, transplant-eligible patients. Patients typically eventually relapse with a progressive clinical course. No specific chemotherapy is established as the standard of care for MCL and practice differs between institutions. Some common treatment regimens for relatively fit patients include rituximab/ dexamethasone/ cytarabine/ cisplatin (R-DHAP), alternating with rituximab/ cyclophosphamide/ doxorubicin/ vincristine/ prednisone (R-CHOP) (R-CHOP/R-DHAP), or rituximab/hyperfractionated cyclophosphamide/ vincristine/ doxorubicin/ dexamethasone alternating with high-dose methotrexate and cytarabine (R-hyperCVAD). For less fit patients, regimes such as bendamustine/ rituximab (BR) or R-CHOP with or without maintenance rituximab are administered. Following disease progression, targeted agents such as ibrutinib, lenalidomide, bortezomib, or venetoclax are often used in succession as monotherapies. Unfortunately, treatment is typically ultimately unsuccessful, and recurrence and progression are typically observed. A further complication is that therapies which may be successful for other forms of B cell malignancy or NHL are often ineffective against MCL.

Furthermore, treatment regimens that are used in attempts to treat MCL are often associated with significant adverse side effects. For example, common side effects associated with chemotherapies used for MCL include neutropenia, infections, leukopenia, fatigue, nausea, alopecia, stomatitis, diarrhoea, anemia, rash, asthenia, thrombocytopenia, vomiting, decreased appetite, dry skin, pyrexia, and dysgeusia. These and other side effects contribute to issues surrounding patient compliance, the need to provide further medications to address such side effects, etc.

There is thus a pressing need for new treatments for MCL, which may expand the range of treatment options for patients and/or which may be associated with reduced side effects and/or increased patient compliance, and/or which may reduce the need for additional therapies in order to mitigate such side effects.

Summary

Provided herein is a method of treating mantle cell lymphoma in a patient in need thereof, said method comprising administering to said patient an effective amount of abemaciclib or a pharmaceutically acceptable salt thereof, in combination with venetoclax or a pharmaceutically acceptable salt thereof.

Also provided is abemaciclib or a pharmaceutically acceptable salt thereof for use in treating mantle cell lymphoma in a patient in need thereof, wherein said use comprises administering to said patient said abemaciclib or pharmaceutically acceptable salt thereof in combination with venetoclax or a pharmaceutically acceptable salt thereof.

Also provided is venetoclax or a pharmaceutically acceptable salt thereof for use in treating mantle cell lymphoma in a patient in need thereof, wherein said use comprises administering to said patient said venetoclax or pharmaceutically acceptable salt thereof in combination with abemaciclib or a pharmaceutically acceptable salt thereof. In some embodiments, said use comprises the simultaneous, separate or sequential use of said abemaciclib or pharmaceutically acceptable salt thereof and said venetoclax or pharmaceutically acceptable salt thereof to said patient.

Also provided is the use of a combination of abemaciclib or a pharmaceutically acceptable salt thereof and venetoclax or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating mantle cell lymphoma in a patient in need thereof.

Also provided is the use of abemaciclib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating mantle cell lymphoma in a patient in need thereof by administering to said patient said abemaciclib or a pharmaceutically acceptable salt thereof in combination with venetoclax or a pharmaceutically acceptable salt thereof.

Also provided is the use of venetoclax or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating mantle cell lymphoma in a patient in need thereof by administering to said patient said venetoclax or a pharmaceutically acceptable salt thereof in combination with abemaciclib or a pharmaceutically acceptable salt thereof.

Brief Description of the Figures

FIG. 1A and FIG. IB show abemaciclib exerts anti-lymphoma efficacy through inhibiting cell cycle progression and increasing apoptosis in vitro and in vivo. Immunoblot assessment of cell cycle regulators are expressed in primary MCL patients and MCL cell lines.

FIG. 1C shows abemaciclib can inhibit cell growth after exposure to different concentrations of abemaciclib for 72 h (0.2E6/ml) in MCL cell lines. IC50 values are shown on the right table. Data are indicated as mean ± SD. Results are representative of three biological replicates.

FIG. ID shows abemaciclib causes cell cycle arrest at G1 phase after exposure to abemaciclib for 24 h. Data are indicated as mean ± SD. Results are representative of three biological replicates.

FIG. IE shows representatives of immunoblot which represent the downregulation of p-Rb after treatment with the same dose of abemaciclib as shown in FIG ID for 12 h. FIG. IF shows apoptosis with increasing concentrations of abemaciclib for MCL cell lines after 48h. Results are representative of three biological replicates.

FIG. 1G shows tumor volume of a PDX mouse model derived from a patient with resistance to CD 19 CAR T-cell therapy after treatment with abemaciclib at a dose of lOmg/kg for five days per week.

FIG. 1H shows tumor masses and weights were measured at the end of treatment.

FIG. II shows abemaciclib causes cell cycle arrest at G1 phase after exposure to abemaciclib for 24h.

FIG. 1 J shows apoptosis with increasing concentrations of abemaciclib for MCL cell lines after treatment with 48h.

FIG. IK shows spleen weights after treatment with abemaciclib at lOmg/kg or vehicle.

FIG. IL shows the CD5⁺CD20⁺ dual positive cells from spleens in a CD 19 CAR T cell therapy resistant PDX model detected by flow cytometry.

FIG. IM shows immunoblot of apoptosis-related protein from subcutaneous tumor tissue were validated after treatment with abemaciclib versus vehicle.

FIG. 2A and FIG. 2B show the combination of abemaciclib and venetoclax can synergistically induce cytotoxicity after treatment for 72 h in MCL cell lines and primary patients’ cells for 24 h. The combination indices (Cis < 1) demonstrated a synergistic effect in the combination group.

FIG. 2C shows abemaciclib combined with venetoclax can enhance the apoptosis in MCL cell lines after treatment for 48 h.

FIG. 2D shows representatives of immunoblot indicating that proapoptotic markers were upregulated after treatment with the corresponding single agent or combination shown in FIG. 2C for 12 h.

FIG. 2E shows mino-venetoclax-resistant tumors treated with abemaciclib (25 mg/kg, daily, orally) and venetoclax (5 mg/kg, daily, orally) and the combo as indicated. Tumor burden was calculated by measuring tumor volume (n = 5,/? < 0.0001).

FIG. 2F shows the liver function (AST and ALT), kidney function (creatine) and blood urea nitrogen (BUN) tested from the mouse tumors treated with vehicle, abemaciclib, venetoclax and combo group.

FIG. 2G shows a volcano plot indicating the difference in gene expression by RNA- sequencing of tumors derived from mice treated with vehicle and the combo group. The significance with an inclusion level > 0.5 log fold change and adjusted P < 0.01 are shown in red.

FIG. 2H shows the mRNA expression of HSP27 from mouse tumors treated with vehicle, abemaciclib, venetoclax, and the combo group.

FIG. 21 shows an immunoblot demonstrating the HSP27 expression derived from mouse tumors in vehicle, abemaciclib, venetoclax, and the combo group.

FIG. 2 J shows the protein level of HSP27, pro-apoptotic markers including cleaved PARP and caspase 3 after abemaciclib combined with venetoclax in MCL cell lines JeKo-1 and Mino-Ven-R validated by western blotting.

FIG. 2K shows overexpression of HSP27 in JeKo-1.

FIG. 2L shows a cell proliferation assay of JeKo-1 Control in comparison with JeKo-1 HSP27 OE after treatment with abemaciclib combined with venetoclax for 48h.

FIG. 2M shows the combination of abemaciclib and venetoclax can synergistically induce cytotoxicity after treatment for 72 h in MCL cell lines.

FIG. 2N and FIG. 20 show the combination indices in MCL cell lines and primary patients’ cells were calculated using CompuSyn software with the Chou-Talalay equation. The value of CI demonstrates the magnitude of two drugs interaction: synergism (CI < 1), additive effect (CI = 1), and antagonism (CI > 1).

FIG. 2P shows abemaciclib combined with venetoclax can enhance the apoptosis in MCL cell lines after treatment for 48 h.

FIG. 2Q shows representatives of immunoblot indicating that proapoptotic markers were upregulated after treatment with the corresponding single agent or combination for 12 h. FIG. 2R shows the overlap genes between the downregulated genes in the combo group compared with those in the abemaciclib group, and the downregulated genes in the combo group compared with those in the venetoclax group. The cutoffs were defined as an FDR- adjusted P<0.05.

FIG. 2S shows the mRNA expression of SCARNA2 from mouse tumors treated with vehicle, abemaciclib, venetoclax, and the combo group.

FIG. 2T shows the top 10 genes most downregulated in the combo group compared with the abemaciclib group.

FIG. 2U shows the top 10 genes most downregulated in the combo group compared with the venetoclax group. FIG. 2 V shows a cell proliferation assay after treatment with abemaciclib, venetoclax, and the combination in JeKo-1 HSP27 OE compared with JeKo-1 Control.

Detailed Description

Provided herein is a combination of abemaciclib, or a pharmaceutically acceptable salt thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, as a treatment strategy for MCL, including relap sed/refractory MCL. The combination therapy of abemaciclib and venetoclax exhibits synergistic anti-cancer activity against preclinical relap sed/refractory MCL models in vitro and in vivo.

The following terms or definitions are provided solely to aid in the understanding of the invention. Unless specifically defined herein, all terms used herein have the same meaning as they would to one skilled in the art of the present invention. Practitioners are particularly directed to Remington: The Science and Practice of Pharmacy, L.V. Allen, Editor, 22^nd Edition, Pharmaceutical Press, 2012, for definitions and terms of the art. The definitions provided herein should not be construed to have a scope less than understood by a person of ordinary skill in the art.

The singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise.

"About" as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ± 20 % or ± 10 %, more preferably ± 5 %, even more preferably ± 1 %, and still more preferably ± 0.1 % from the specified value, as such variations are appropriate to perform the disclosed methods.

As used herein, the term "kit" refers to a package comprising at least two separate agents. Typically, a first agent is abemaciclib, or a pharmaceutically acceptable salt thereof, and a second agent is venetoclax, or a pharmaceutically acceptable salt thereof. A "kit" may also include instructions to administer all or a portion of these agents to a cancer patient, preferably a mantle cell lymphoma patient. The mantle cell lymphoma referred to in such context is preferably a mantle cell lymphoma as defined herein.

As used herein, the terms "treating", "to treat", or "treatment" refer to restraining, slowing, stopping, reducing, shrinking, maintaining stable disease, or reversing the progression or severity of an existing symptom, disorder, condition, or disease. As used herein, the term "patient" refers to a mammal, preferably a human, more preferably a human female. Preferably the patient is a male or female of age from about 18 to about 90, such as from about 20 to about 85, e.g. from about 30 to about 80 such as from about 50 to about 70. As used herein, the terms “subject” and “patient” are used interchangeably unless demanded otherwise by the context.

As used herein, the terms "cancer" and "cancerous" refer to or describe the physiological condition in patients that is typically characterized by unregulated cell proliferation. Included in this definition are benign and malignant cancers. Typically, in the invention the cancer is mantle cell lymphoma. Cancer may be assessed according to classifications usual in the art including the American Joint Committee on Cancer (AJCC) TNM system.

The term “mantle cell lymphoma” refers to a lymphoma characterized as aggressive, usually diffuse non-Hodgkin lymphoma composed of small to medium sized B-lymphocytes (centrocytes). Most patients present with advanced stage disease with lymphadenopathy, hepatosplenomegaly, and bone marrow involvement. The diagnosis and determination of mantle cell lymphoma is readily determined by one of skill in the art, e.g., in accordance with the current accepted guidelines. For example, guidelines set forth by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) are widely accepted. Markers for mantle cell lymphoma include surface markers of B cells (e.g. CD20); overexpression of cyclin DI; and (11; 14) translocation.

As used herein, the term "effective amount" refers to the amount or dose of abemaciclib, or a pharmaceutically acceptable salt thereof, and the amount or dose of venetoclax, or a pharmaceutically acceptable salt thereof, which provides an effective response in the patient under diagnosis or treatment. For embodiments of the present invention which comprise the administration of a further active agent to the subject being treated, an “effective amount” of such agent is the amount or dose thereof which provides an effective response in such patient when administered in combination with an effective amount of abemaciclib, or a pharmaceutically acceptable salt thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, as described herein.

As used herein, the term "effective response" of a patient or a patient's "responsiveness" to treatment with a combination of agents refers to the clinical or therapeutic benefit imparted to a patient upon administration of abemaciclib or a pharmaceutically acceptable salt thereof and venetoclax, or a pharmaceutically acceptable salt thereof, and, if present, any further active agent.

As used herein, the term "in combination with" refers to the administration of abemaciclib, or a pharmaceutically acceptable salt thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially in any order, such as for example, at repeated intervals as during a standard course of treatment for a single cycle or more than one cycle, such that one agent can be administered prior to, at the same time, or subsequent to the administration of the other agent, or any combination thereof. In embodiments of the present invention which comprise the administration of a further active agent, said administration of the further agent may be either simultaneously or sequentially in any order with either or both of the abemaciclib or a pharmaceutically acceptable salt thereof and venetoclax or a pharmaceutically acceptable salt thereof.

A main advantage of the combination treatments of the invention is the ability of producing marked anti-cancer effects in a patient without causing significant toxicities or adverse events, so that the patient benefits from the combination treatment method overall. The efficacy of the combination treatment of the invention can be measured by various endpoints commonly used in evaluating cancer treatments, including but not limited to, tumor regression, tumor weight or size shrinkage, time to progression, overall survival, progression free survival, overall response rate, duration of response, and quality of life. The therapeutic agents used in the invention may cause inhibition of locally advanced or metastatic spread without shrinkage of the primary tumor, may induce shrinkage of the primary tumor, or may simply exert a tumoristatic effect. Because the invention relates to the use of a combination of anti-tumor agents, novel approaches to determining efficacy of any particular combination therapy of the present invention can be optionally employed, including, for example, measurement of plasma or urinary markers of angiogenesis and/or cell cycle activity, tissue-based biomarkers for angiogenesis and/or cell cycle activity, and measurement of response through radiological imaging.

References herein to a compound or combination for use in treating a particular condition are herein interchangeable with references to the compound or combination for use in a method for treating the condition. Thus, for example, provided herein is a combination of abemaciclib or a pharmaceutically acceptable salt thereof and venetoclax or a pharmaceutically acceptable salt thereof, for use in treating mantle cell lymphoma in a patient in need thereof; and therefore equivalently provided herein is a combination of abemaciclib or a pharmaceutically acceptable salt thereof and venetoclax or a pharmaceutically acceptable salt thereof, for use in a method of treating mantle cell lymphoma in a patient in need thereof. Similarly, provided herein is abemaciclib or a pharmaceutically acceptable salt thereof for use in treating mantle cell lymphoma in a patient in need thereof, wherein said use comprises administering to said patient said abemaciclib or a pharmaceutically acceptable salt thereof in combination with venetoclax or a pharmaceutically acceptable salt thereof; and therefore equivalently provided herein is abemaciclib or a pharmaceutically acceptable salt thereof for use in a method of treating mantle cell lymphoma in a patient in need thereof, wherein said use comprises administering to said patient said abemaciclib or a pharmaceutically acceptable salt thereof in combination with venetoclax or a pharmaceutically acceptable salt thereof. Similarly, provided herein is venetoclax or a pharmaceutically acceptable salt thereof for use in treating mantle cell lymphoma in a patient in need thereof, wherein said use comprises administering to said patient said venetoclax or a pharmaceutically acceptable salt thereof in combination with abemaciclib or a pharmaceutically acceptable salt thereof; and therefore similarly provided herein is venetoclax or a pharmaceutically acceptable salt thereof for use in a method of treating mantle cell lymphoma in a patient in need thereof, wherein said use comprises administering to said patient said venetoclax or a pharmaceutically acceptable salt thereof in combination with abemaciclib or a pharmaceutically acceptable salt thereof.

References herein to mantle cell lymphoma being selected from, associated with, or characterised by one of a plurality of alternatives should be understood as embracing the situation wherein the mantle cell lymphoma is selected from, associated with, or characterised by more than one of the recited characteristics, such as two or more of the recited characteristics.

It will be understood by the skilled reader that the compounds described herein can be used as a free base. Similarly, said compounds can react with any of a number of inorganic and organic acids to form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et al, Handbook of Pharmaceutical Salts: Properties, Selection and Use (VCHA/Wiley-VCH, 2002); L.D. Bighley, et al., Encyclopedia of Pharmaceutical Technology, 453-499 (1995); S.M. Berge, et al., Journal of Pharmaceutical Sciences, 66, 1, (1977). The hydrochloride and mesylate salts are preferred salts for abemaciclib. The mesylate salt is an especially preferred salt for abemaciclib.

Preferably the abemaciclib or pharmaceutically acceptable salt thereof is formulated for oral administration. Preferably the abemaciclib, or pharmaceutically acceptable salt thereof, is formulated into a tablet or capsule. Preferably the abemaciclib, or pharmaceutically acceptable salt thereof, is formulated into a tablet. Also preferably, the abemaciclib, or pharmaceutically acceptable salt thereof, is formulated into a capsule. Preferably the abemaciclib, or pharmaceutically acceptable salt thereof, is formulated into a tablet or capsule containing from about 50 mg to about 200 mg of abemaciclib. Preferably the abemaciclib, or pharmaceutically acceptable salt thereof, is formulated into a tablet or capsule containing about 50 mg, about 100 mg, about 150 mg, or about 200 mg of abemaciclib. Preferably the abemaciclib, or pharmaceutically acceptable salt thereof, is formulated into a tablet or capsule containing 50 mg of abemaciclib. Also preferably, the abemaciclib, or pharmaceutically acceptable salt thereof, is formulated into a tablet or capsule containing 100 mg of abemaciclib. Also preferably, the abemaciclib, or pharmaceutically acceptable salt thereof, is formulated into a tablet or capsule containing 150 mg of abemaciclib. Also preferably, the abemaciclib, or pharmaceutically acceptable salt thereof, is formulated into a tablet or capsule containing 200 mg of abemaciclib.

Preferably the abemaciclib is formulated with one or more pharmaceutically acceptable excipient. Suitable excipients include microcrystalline cellulose (e.g. microcrystalline cellulose 102, microcrystalline cellulose 101), lactose monohydrate, croscarmellose sodium, sodium stearyl fumarate, silicon dioxide (e.g. colloidal hydrated silica), etc.

Preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 50 mg to 200 mg twice a day. Also preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 100 mg to 150 mg twice a day. Also preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 200 mg twice a day. Also preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg twice a day. Also preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 100 mg twice a day. Also preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 50 mg twice a day. Preferably the venetoclax or pharmaceutically acceptable salt thereof is formulated for oral administration. Preferably the venetoclax, or pharmaceutically acceptable salt thereof, is formulated into a tablet or capsule. Preferably the venetoclax, or pharmaceutically acceptable salt thereof, is formulated into a tablet. Also preferably, the venetoclax, or pharmaceutically acceptable salt thereof, is formulated into a capsule. Preferably the venetoclax, or pharmaceutically acceptable salt thereof, is formulated into a tablet or capsule containing from about 10 mg to about 100 mg of venetoclax. Preferably the venetoclax, or pharmaceutically acceptable salt thereof, is formulated into a tablet or capsule containing about 10 mg, about 50 mg, or about 100 mg of venetoclax. Preferably the venetoclax, or pharmaceutically acceptable salt thereof, is formulated into a tablet or capsule containing 10 mg of venetoclax. Also preferably the venetoclax, or pharmaceutically acceptable salt thereof, is formulated into a tablet or capsule containing 50 mg of venetoclax. Also preferably, the venetoclax, or pharmaceutically acceptable salt thereof, is formulated into a tablet or capsule containing 100 mg of venetoclax.

Preferably the venetoclax is formulated with one or more pharmaceutically acceptable excipient. Suitable excipients include copovidone, colloidal anhydrous silica, polysorbate 80, sodium stearyl fumarate, anhydrous calcium hydrogen phosphate, etc.

Preferably venetoclax, or a pharmaceutically acceptable salt thereof, is administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg. Also preferably, venetoclax is administered for the first time on Day 8 with a starting dose of 20 mg followed by a weekly ramp-up dosing of 50 mg, 100 mg, 200 mg, and 400 mg. Also preferably, venetoclax is administered for the first time on Day 8 with a starting dose of 20 mg followed by a weekly ramp-up dosing of 50 mg, 100 mg, 200 mg, and 400 mg followed by a daily dosing of 400 mg.

In some embodiments, the patient is a human subject. In some embodiments the patient is a human female subject. In some embodiments the patient is a human male subject.

In some embodiments, the patient is aged from about 18 to about 80 years, such as from about 20 to about 75, e.g. from about 25 to about 60 such as from about 30 to about 50 years. Often the patient is less than 60 years of age, such as less than 55 years, e.g. less than 50 years, such as less than 45 years, e.g. less than 40 years of age. Mantle cell lymphoma may be characterised according to the Mantle Cell International Prognostic Index (MIPI). Patients may be assigned in accordance with the following table

ECOG PS, Eastern Cooperative Oncology Group Performance Status; LDH (ULN), lactate dehydrogenase (upper limit of the normal range); WBC, white blood cell (leukocyte) count. Total point score: 0 3, low; 4 5, intermediate and 6-11, high risk.

In some embodiments, the subject may have stage 1 mantle cell lymphoma. Stage 1 mantle cell lymphoma is typically associated with detected lymphoma at one lymph node region or a single organ. In some embodiments, the subject may have stage 2 mantle cell lymphoma. Stage 2 mantle cell lymphoma is typically associated with detected lymphoma at two or more lymph node regions on the same side of the diaphragm. In some embodiments, the subject may have stage 3 mantle cell lymphoma. Stage 3 mantle cell lymphoma is typically associated with detected lymphoma at two or more lymph node regions above and below the diaphragm. In some embodiments, the subject may have stage 4 mantle cell lymphoma. Stage 4 mantle cell lymphoma is typically associated with widespread disease in lymph nodes and/or other parts of the body. The stage of the mantle cell lymphoma can be readily assessed by the skilled person.

In some embodiments, the patient may have cancer metastatic to one or more sites selected from lung/pleura, liver, bone, breast/chest wall, soft tissue, distant lymph nodes, regional lymph nodes, central nervous system/brain, bone marrow, bloodstream, and bowel.

In some embodiments the patient has one or more mutations associated with mantle cell lymphoma. In some embodiments, the patient has one or more mutations in one or more of ATM; TP53; CCND1; KMT2D; CDK2NA; BIRC3; CDKN2B; KHSC1; SMARCA4; SDHD; UBR5; NOTCH1; CARD11; SAMHD1; BCL10; MEF2B; IRS2; FGF19; FGF4; FGF3; FAT1; ROBO1; DIS3; CRLF2; CDKN2C; ARID2; ARID 1 A; ARID IB; NOTCH2; and BCOR. The patient may have one or more mutations in one or more of TRAF2, TRAF3, MAP3K14, MYD88, BKT, PCLG2, BCL2, KMT2D, and CELSR3.

In some embodiments, the patient has one or more mutations in one or more of ATM, TP53, CCND1, KMT2D, and CDKN2A.

In some embodiments, the patient has one or more mutations in ATM. In some embodiments, the patient has one or more mutations in TP53. In some embodiments, the patient has one or more mutations in CCND1. In some embodiments, the patient has one or more mutations in KMT2D. In some embodiments, the patient has one or more mutations in CDKN2A. Mutations in such genes can be detected using techniques available to those skilled in the art, for example by DNA sequencing of a biological sample from the patient, e.g. a blood sample, with optional PCR to amplify the DNA encoding the gene to be assessed.

In some embodiments, the patient has mantle cell lymphoma which is resistant to treatment with a BCL-2 inhibitor such as venetoclax or navitoclax. The patient may have mantle cell lymphoma which has acquired resistance to the BCL-2 inhibitor. Resistance to BCL-2 inhibitors can be determined by failed therapeutic treatment of the mantle cell lymphoma with the BCL-2 inhibitor (e.g. by administering the inhibitor to the patient and the mantle cell lymphoma progressing during or after such treatment), or by determining the mantle cell lymphoma as being associated with a genetic profile known to be resistant to BCL-2 inhibitors.

Those skilled in the art will appreciate that treatment of a mantle cell lymphoma which has acquired resistance to an inhibitor such as a BCL-2 inhibitor is a different challenge to treatment of a mantle cell lymphoma which has innate or primary resistance to said inhibitor. Treatment of mantle cell lymphoma which has acquired resistance to an inhibitor is provided by the therapies provided herein.

For example, in some embodiments the patient has mantle cell lymphoma which is resistant to treatment with venetoclax. The patient may have mantle cell lymphoma which has acquired resistance to venetoclax. Resistance to venetoclax can be determined by failed therapeutic treatment of the mantle cell lymphoma with venetoclax (e.g. by administering venetoclax to the patient and the mantle cell lymphoma progressing during or after such treatment), or by determining the mantle cell lymphoma as being associated with a genetic profile known to be resistant to venetoclax. For example, mutations associated with venetoclax resistance may include one or more mutations in one or more of TRAF2, TRAF3, MAP3K14, CARD11, MYD88, CCND1, BKT, and PCLG2.

In some embodiments the patient has mantle cell lymphoma which is characterised by or associated with one or more of cyclin DI overexpression; t(l 1 ; 14) and/or t(l 1 ; 14)(ql3;q32) translocation; Ki67 overexpression; lactate dehydrogenase overexpression; and beta-2 microglobulin overexpression.

In some embodiments, the patient has mantle cell lymphoma which is characterised by or associated with cyclin DI overexpression. The patient may have mantle cell lymphoma which is characterised by or associated with cyclin DI, D2 and/or D3 overexpression. Cyclin overexpression can be easily determined by those skilled in the art.

In some embodiments, the patient has mantle cell lymphoma which is characterised by or associated with t(l 1 ; 14) translocation. In some embodiments, the patient has mantle cell lymphoma which is characterised by or associated with t(l 1 ; 14)(ql 3 ;q32) translocation. In t(l 1 ; 14), the result is juxtaposition of the immunoglobulin heavy-chain (IgH) locus and the cyclin DI gene (CCND1, PRAD1, BCL1). Without being bound by theory, it is believed that this translocation drives the overexpression of cyclin DI by juxtaposition of a transcriptional enhancer from the IgH locus (14q32) next to the CCND1 gene (11 ql 3). Cyclin DI is a nuclear protein that promotes entry of cell from Gi-phase to S-phase in the cell cycle. Detection of such translocation is routine for those skilled in the art. For example, the t(l 1 ; 14) translocation may be detected using cytogenetics, Southern blot, polymerase chain reaction (PCR) analysis, or interphase fluorescence in situ hybridization.

In some embodiments, the patient has mantle cell lymphoma which is characterised by or associated with overexpression of Ki67, lactate dehydrogenase, and/or beta-2 microglobulin. In some embodiments, the patient has mantle cell lymphoma which is characterised by or associated with Ki67 overexpression. In some embodiments, the patient has mantle cell lymphoma which is characterised by or associated with lactate dehydrogenase overexpression. In some embodiments, the patient has mantle cell lymphoma which is characterised by or associated with beta-2 microglobulin overexpression. Determination of such overexpression is routine for those skilled in the art.

In some embodiments, the patient has refractory and/or relapsed mantle cell lymphoma. As used herein, the term “refractory” relates to mantle cell lymphoma which does not respond to treatment or wherein said response is short term. The term “relapsed” refers to mantle cell lymphoma that reappears or grows again after a period of remission.

In some embodiments, the patient has mantle cell lymphoma which is selected from, or characterised as one of, nodal mantle cell lymphoma; and leukaemic non-nodal mantle cell lymphoma. Nodal mantle cell lymphoma affects lymph nodes but often spreads to other parts of the body, such as the bone marrow, bloodstream, bowel, and liver. In some embodiments, the nodal mantle cell lymphoma is selected from or characterised by one or more of blastoid mantle cell lymphoma and pleomorphic mantle cell lymphoma.

Retinoblastoma (Rb) is a protein which exerts a tumour suppression function. Deregulation of Rb has been associated with various cancer types. Lymphoma cells may be Rb proficient (also referred to as Rb positive, Rb+) or Rb deficient (also referred to as Rb negative, Rb-). Rb status has been shown to be independent of susceptibility to many chemotherapeutic agents such as cisplatin (CDDP), 5 -fluorouracil, idarubicin, epirubicin, PRIMA-lmet, fludarabine, and PD-0332991.

In some embodiments provided herein, the patient has Rb-negative mantle cell lymphoma. Thus, in some embodiments, the patient has mantle cell lymphoma which is Rb deficient. In some embodiments provided herein, the patient has Rb-positive mantle cell lymphoma. Thus, in some embodiments, the patient has mantle cell lymphoma which is Rb proficient.

Mantle cell lymphoma may be characterised in some embodiments by expression of androgen receptor (AR) (e.g. in LAR mantle cell lymphoma). Androgen receptor (AR) is a steroid hormone receptor that links a transcription factor that controls specific genes involved in different, sometimes opposite, cellular processes: it can stimulate or suppress both cell proliferation and apoptosis, depending on the concurrent signaling pathways activated. AR is expressed in some, but not all, mantle cell lymphoma.

Accordingly, in some embodiments the subject has mantle cell lymphoma which is AR positive (AR proficient). However, in other embodiments, the subject has mantle cell lymphoma which is AR negative (AR deficient).

In some embodiments, e.g. in embodiments wherein the subject has mantle cell lymphoma which is AR positive, the subject may be administered an anti-AR therapy. In embodiments wherein an anti-AR therapy is administered to the subject, any suitable anti- AR therapy may be used. The preferred anti-AR therapy may be determined according to various parameters, especially according to the severity and histology of the mantle cell lymphoma, age, weight and condition of the subject to be treated; the route of administration; and the required regimen. A physician will be able to determine the preferred anti-AR therapy to use and the required route of administration and dosage for any particular subject. Preferably, an anti-AR therapy may be selected from AR inhibitors such as bicalutamide (Casodex), enzalutamide (Xtandi), and abiraterone acetate (Zytiga). For example, bicalutamide may be administered at a dose of about 50 mg per day. Enzalutamide may be administered at a dose of about 160 mg per day. Abiraterone acetate may be administered at a dose of about 1000 mg once daily.

Mantle cell lymphoma may be characterised in some embodiments by expression of PD-L1. PD-L1 (Programmed Cell Death Ligand 1) is a ligand of PD-1 (Programmed Cell Death Protein 1) which is an immune checkpoint receptor that limits T cell effector function within tissues. PD-L1 expression may be promoted by loss of PTEN expression or function e.g. via mutation.

Accordingly, in some embodiments, the subject has mantle cell lymphoma which expresses PD-L1 (PD-L1 positive). However, in other embodiments, the subject has mantle cell lymphoma which does not express PD-L1 (PD-L1 negative).

In some embodiments, e.g. in embodiments wherein the subject has mantle cell lymphoma which is PD-L1 positive, the subject may be administered an inhibitor of PD-1 or PD-L1. In embodiments wherein an inhibitor of PD-1 or PD-L1 is administered to the subject, any suitable inhibitor of PD-1 or PD-L1 may be used. The preferred inhibitor of PD-1 or PD-L1 may be determined according to various parameters, especially according to the severity and histology of the mantle cell lymphoma, age, weight and condition of the subject to be treated; the route of administration; and the required regimen. A physician will be able to determine the preferred inhibitor of PD-1 or PD-L1 to use and the required route of administration and dosage for any particular subject. Preferably, an inhibitor of PD-1 or PD-L1 may be selected from Pembrolizumab (Keytruda), Nivolumab (Opdivo), Cemiplimab (Libtayo), Atezolizumab (Tecentriq), Avelumab (Bavencio) and Durvalumab (Imfinzi). For example, Pembrolizumab may be administered at a dose of about 200 mg every 3 weeks. Nivolumab may be administered at a dose of about 240 mg every 2 weeks or 480 mg every 4 weeks. Cemiplimab may be administered at a dose of about 350 mg once every 3 weeks. Atezolizumab may be administered at a dose of about 840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks. Avelumab may be administered at a dose of about 800 mg every 2 weeks. Durvalumab may be administered at a dose of about 10 mg/kg every 2 weeks or 1500 mg every 3 or 4 weeks.

Also provided herein is a product comprising abemaciclib, or a pharmaceutically acceptable salt thereof, and venetoclax, or a pharmaceutically acceptable salt thereof, as a combined preparation. The product may comprise one or more pharmaceutically acceptable components such as any one of the excipients, diluents, or adjuvants described herein. The product may comprise one or more additional active agents as described herein. The product may be formulated as a dosage form, e.g. as an oral dosage form or as a dosage form for injection or infusion as described herein. The product may be provided as a kit as described herein.

The following examples are provided to solely illustrate the invention and are nonlimiting. In particular, there are many assays available to demonstrate anti-cancer efficacy of combinations of pharmaceutically acceptable drugs and potential synergy, and so a negative result in any one assay is not determinative.

EXAMPLES

These examples illustrate the utility of the claimed therapy in treating mantle cell lymphoma.

Cell lines and culture

The MCL cell lines JeKo-1, Mino, Z138, Maver-1, and Rec-1 were obtained from the American Type Culture Collection (ATCC). The MCL cell line Granta519 was established by the Leibniz-Institute DSMZ and was a gift from F. Samaniego at the MD Anderson Cancer Center. The JeKo BTK KD was generated by the MD Anderson Core Facility. Venetocl ax-resistant MCL cell lines (Mino-Ven-R and Rec-Ven-R) were generated from the parental cell lines (Mino, Rec-1) by multistep exposures of cells to increasing doses (up to 1000 nM) of venetoclax for 8 weeks. All the MCL cell lines were maintained in RPMI1640 supplemented with 10% fetal bovine serum (FBS; Sigma-Aldrich), 1% penicillin/streptomycin, and 25 mmol/L of 4-(2-hy droxy ethyl)- 1 -piperazineethanesulfonic acid (HEPES). Cells were cultured in an incubator at 37°C, under an atmosphere of 5% CO₂. Primary patients’ cells and culture

Primary MCL cells were collected from patients diagnosed with MCL after obtaining informed consent and approval from the Institutional Review Board at the University of Texas MD Anderson Cancer Center. For apheresis process, Ficoll-Paque PLUS density centrifugation was used to isolate mononuclear cells. All procedures were performed in cold buffer or on ice. All the primary cells were maintained in RPMI1640 supplemented with 20% fetal bovine serum (FBS; Sigma-Aldrich), 1% penicillin/streptomycin, and 25 mmol/L HEPES and cultured in a 37°C incubator under an atmosphere of 5% CO2.

Cell viability and proliferation assay

IxlO⁴ cells per well were seeded in 96-well plates and treated with various doses of the indicated agents in triplicate for 72 h and then mixed with CellTiter-Glo Luminescent Cell viability Assay Reagent (Promega). The luminescence was read via the BioTek Synergy HTX Multi-mode microplate reader with the light absorbance at 495 nm. The experiments were repeated at least two times. For primary MCL cells, IxlO⁵ cells per well are seeded in 96-well plates and treated with the indicated doses of single agent in triplicate for 24 hours. Then, the results were recorded by the BioTek Synergy HTX Multi-mode microplate reader. For proliferation assay, cells were seeded at 2xl0⁵ cells per well in 24-well plates and treated with indicated inhibitors for 3 d. Trypan blue dye exclusion viability assay was utilized to count live cells.

Apoptosis assay

Annexin V/propidium iodide-binding assay was performed to detect apoptosis. 2xl0⁵/ml MCL cells per well were seeded in 24-well plated, treated with indicated doses of agents for 48 h, and then were stained with Annexin-V (BD Biosciences) and propidium iodide (Invitrogen). Flow cytometric results were conducted with the Novocyte Flow Cytometer (ACEA Biosciences) to calculate the percentages of Annexin-V positive cells. Data were analyzed with FlowJo vlO. The experiments were biologically repeated three times.

Cell cycle arrest assay

Cells were seeded in 6 well plates and treated with vehicle or abemaciclib for 24 h. Cells were fixed in 70% pre-cooled ethanol and stained with propidium iodide. The cell cycle stages were quantified through the Novocyte Flow Cytometer (ACEA Biosciences). The experiments were biologically repeated three times.

Western blot analysis

Cells were treated with indicated drugs for 12 h and then the cell pellets were lysed in lysis buffer with protease inhibitors. Cell lysates were maintained for 30 min on ice and centrifuged at 14,000 g for 15 min at 4°C. Samples were subjected to 12% SDS- polyacrylamide gel electrophoresis before transfer onto PVDF membranes. The membranes were blocked with 5% nonfat dry milk in Tris-buffered saline with 0.1% Tween 20 for 1 h and then immunoblotted with various antibodies. The antibodies were obtained from Cell Signaling Technology: HSP27 (D6W5V), Rb (4H1), Phospho-Rb (Ser780), Cyclin Dl (2922), PARP (9532), Caspase 3 (9662S), Cleaved Caspase-3 (9661), Cleaved Caspase-7 (9491), and Invitrogen: CDK4 (AHZ0202) and Santa Cruz: P-actin (sc- 47778).

RNA extraction and RNA sequencing

RNA was extracted from the tumors of Mino-venetoclax-R xenografts. Tissues were homogenized by a 23 ga needle and then isolated RNA was extracted with the RNeasy Micro Kit (Qiagen). The RNA from Mino-venetoclax-R xenografts was subjected to RNA sequencing.

HSP27 overexpression

For overexpression of HSP27, GFP gene in pLenti CMV GFP Puro (Addgene #17448) was replaced with HSP27 cDNA using BamHI and Sall restriction sites. Subsequently, lentiviral particles were generated by transfection of HEK-293T cells with constructs and the packaging vectors pMDLg/pRRE (Addgene #12251), pRSV-Rev (Addgene #12253), and pMD2.G (Addgene #12259). After transfection for 48 h, the supernatants with virus were collected. Cells were infected with viral supernatants and 8 mg/mL polybrene for 24 h. Puromycin at 1 mg/ml was utilized to select the infected cells. Overexpression of HSP27 was validated by western blotting. Patient-derived and mantle cell lymphoma cell line-derived xenograft mouse model

The Institutional Animal Care and Use Committee of the University of Texas MD Anderson Cancer Center approved the experimental protocols. To generate the PDX model, 6- to 8-week-old female NSG mice (the Jackson Laboratory) were injected with 5 x 10⁶ freshly isolated primary lymphoma cells. When the tumors became palpable, mice were treated with vehicle or abemaciclib (10 mg/kg, daily, orally). For the MCL cell line- derived model, 6- to 8-week-old female NSG mice (the Jackson Laboratory) were injected with 5xl0⁶ freshly isolated Mino-venetoclax-R cells subcutaneously. When the tumors became palpable, mice were treated with vehicle or abemaciclib (25 mg/kg, daily, orally), venetoclax (5 mg/kg, daily, orally), or the combination of abemaciclib and venetoclax. The tumor size was monitored twice a week and the tumor volume was calculated by V=(W² x L) / 2. The V is tumor volume, W is tumor width, and L is tumor length. When one diameter of tumor mass was measured at 15 mm or greater, the mice were dissected, and tumor cells were collected after dissection.

Statistical analysis

The IC50 values were calculated using GraphPad Prism 8 for each cell line. Combination index (CI) was calculated using the Chou-Talalay method. Student’s t-test was performed to compare the difference between vehicle and treated groups. Two-way analysis of variance (ANOVA) was conducted to analyze the tumor growth in vivo experiments. P values less than 0.05 were considered statistically significant.

Example 1

The cell cycle regulator CDK4 and cyclin DI were differentially expressed in primary MCL patients’ specimens and MCL cell lines (FIG. 1 A and IB). Abemaciclib displayed differential cytotoxic effect in MCL cell lines with IC50s ranging from 0.07 to 6.15 M (FIG. 1C). As a functional outcome, abemaciclib was confirmed to induce Gl- phase cell cycle arrest in MCL cell lines accompanied with downregulated phosphorylated Rb (p-Rb), indicating the inhibitory effect was potentially attributed to dysregulated cell cycle progression (FIG. ID and IE, FIG. II). Moreover, treatment of the MCL cell lines with 0.5 to 10 pM concentrations of abemaciclib for 48 h induced apoptosis in a dosedependent manner (FIG. IF and 1 J).

The efficacy of abemaciclib was examined in a patient-derived xenograft (PDX) mouse model derived from a patient with resistance to CD19 CAR T-cell therapy. Treatment with abemaciclib inhibited tumor growth compared with vehicle group, indicated by tumor volume (n = 5,/? < 0.0001; FIG. 1G) and tumor weight (n = 5, /? = 0.0006; FIG. 1H). In addition, tumor cells in the spleen were decreased based on the spleen weight and CD5/CD20 double positive cell numbers determined by flow cytometry in spleen tissues following treatment with abemaciclib (n = 5,/? = 0.0004; FIG. IK and IL). Compared with the vehicle group, abemaciclib enhanced apoptosis indicated by the apoptotic markers cleaved PARP and caspase 7 in an immunoblot assessment of the subcutaneous tumor lysates (FIG. IM).

Example 2

Efficacy of the combination of abemaciclib and venetoclax was evaluated in a panel of MCL cell lines. As shown in FIG. 2A and 2M, the combination of abemaciclib and venetoclax synergistically exerted cytotoxic effects with combination indices at ED75 between 0.120 and 0.772 in MCL cell lines (FIG. 2N). Additionally, this combination exhibited synergistic cytotoxic effects in a subset of primary MCL cells from the patients with Cis atED75 between 0.248 and 0.676 (FIG. 2B and 20). Furthermore, this combination regimen synergistically promoted apoptosis in MCL cell lines as compared to each singleagent treatment (FIG. 2C and 2P). Western blot analysis of the whole cell lysates demonstrated a decrease of p-Rb and enhanced PARP and caspase 7 cleavage in these MCL cells, indicating that the cytotoxic effect of this combination was potentially attributed to mitochondrial-mediated apoptosis (FIG. 2D and 2Q).

Example 3

To further investigate the therapeutic efficacy of the combination of abemaciclib and venetoclax, a venetoclax-resistant MCL xenograft mouse model was developed using Mino- venetocl ax-resistant (Mino-Ven-R) cells generated from the parental Mino cell line by stepwise exposures to increasing doses of venetoclax from 1 nM to 1000 nM for eight weeks (Huang, S., et al., PIK-75 overcomes venetoclax resistance via blocking PI 3K-AKT signaling and MCL- 1 expression in mantle cell lymphoma. Am J Cancer Res, 2022. 12(3): p. 1102- 1115). The combination of abemaciclib and venetoclax exhibited statistically significant anti-tumor efficacy compared with each single-agent treatment in Mino-Ven-R-derived xenograft models (n = 5, p < 0.0001, FIG. 2E). In addition, the examination of serum biochemical parameters indicated that the combinatorial therapy did not exhibit any obvious pathological changes in liver or kidney function compared with other treatment groups or the control group (FIG. 2F).

Example 4

To understand the mechanistic basis for the combinatorial anti-cancer effects, RNA sequencing (RNA-seq) was performed on all the groups from the aforementioned Mino- Ven-R mouse model. Transcriptome analysis revealed 358 genes that were significantly downregulated and 123 genes that were significantly upregulated in the combination treated group, compared to vehicle-treated group (FIG. 2G). To identify the differentially expressed genes between the combinatorial treatment group and the abemaciclib- and venetoclax- treated groups, the overlapping genes within the downregulated genes in the combination treatment group compared with those in abemaciclib or venetoclax treatment group were explored. Subsequently, the overlapping genes were subjected to gene set enrichment analysis (GSEA), which demonstrated a statistically significant enrichment for genes regulating hypoxia (FIG. 2R). The 10 most downregulated genes were verified in the combination treatment group compared with the abemaciclib- or venetoclax- treated group. Although the SCARNA2 gene was the highest downregulated gene, the difference between abemaciclib and the combination group was not significant for further analysis (FIG. 2S). Therefore, HSPB1 (encoding for heat shock protein HSP27) was considered the most significant downregulated gene in the combination group compared to the abemaciclib or venetoclax treated group (FIG. 2T and 2U).

HSP27 (also called HSPBP) is upregulated during cell stress and associated with protein misfolding, such as heat shock. Moreover, in the cancer setting, HSP27 can protect tumor cells against apoptosis and other types of cell death, promote tumor growth and metastasis, and provide a resistance mechanism to many anticancer therapeutic agents. In fact, many anticancer therapeutic agents can stimulate HSP27 expression in cancer cells.

The mRNA expression was quantified, indicating Axa H P l was markedly reduced at both the RNA and protein level in the combination treatment group (FIG. 2H-I). To further confirm the ability of abemaciclib combined with venetoclax to reduce HSP27 expression and induce apoptosis, western blot analysis showed that this combination could downregulate HSP27 and trigger an increase in pro-apoptotic markers including cleaved PARP and caspase 3 in the MCL cell lines JeKo-1 and Mino-Ven-R (FIG. 2 J). To further determine whether HSP27 is involved in cellular resistance to this combinatorial therapy, ectopic expression of HSP27 was performed in JeKo-1 lymphoma cells (FIG. 2K). Stable overexpression of HSP27 markedly promotes the proliferation of tumor cells and mediates the resistance to the combination of abemaciclib and venetoclax (FIG. 2L and 2V).

The foregoing examples demonstrate dual inhibition of CDK4/6 with abemaciclib and Bcl-2 with venetoclax exhibits synergistic anti-cancer activity against a variety of preclinical relapsed/refractory MCL in vitro and in vivo. This combinatorial approach also downregulated HSP27 as a potential mechanistic underpinning for the observed synergistic activity.

Claims

1. A method of treating mantle cell lymphoma in a patient in need thereof, said method comprising administering to said patient an effective amount of abemaciclib or a pharmaceutically acceptable salt thereof, in combination with an effective amount of venetoclax or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the mantle cell lymphoma has acquired resistance to one or more BCL-2 inhibitors.

3. The method of claim 1, wherein the mantle cell lymphoma has acquired resistance to venetoclax.

4. The method of claim 1, wherein the mantle cell lymphoma is selected from, or characterised as one of, nodal mantle cell lymphoma; and leukaemic non-nodal mantle cell lymphoma.

5. The method of claim 1, wherein the mantle cell lymphoma is selected from, or characterised as, refractory and/or relapsed mantle cell lymphoma.

6. The method of claim 1, wherein said mantle cell lymphoma is associated with one or more mutations in: ATM; TP53; CCND1; KMT2D; CDK2NA; BIRC3; CDKN2B; KHSC1; SMARCA4; SDHD; UBR5; NOTCH1; CARD11; SAMHD1; BCL10; MEF2B; IRS2; FGF19; FGF4; FGF3; FAT1; ROBO1; DIS3; CRLF2; CDKN2C; ARID2; ARID1A; ARID1B; NOTCH2; BCOR; TRAF2, TRAF3, MAP3K14, MYD88, BKT, PCLG2, BCL2, KMT2D, and CELSR3.

7. The method of claim 1, wherein said mantle cell lymphoma is associated with cyclin Dl overexpression; t(l l;14) and/or t(l 1; 14)(ql3;q32) translocation; Ki67 overexpression; lactate dehydrogenase overexpression; and/or beta-2 microglobulin overexpression.

8. The method of claim 1, wherein said mantle cell lymphoma is retinoblastoma protein (Rb) proficient.

9. A combination of abemaciclib or a pharmaceutically acceptable salt thereof and venetoclax or a pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential use in treating mantle cell lymphoma.

10. Abemaciclib or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with venetoclax or a pharmaceutically acceptable salt thereof in treating mantle cell lymphoma.

11. Venetoclax or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with abemaciclib or a pharmaceutically acceptable salt thereof in treating mantle cell lymphoma.

12. A combination for use, abemaciclib for use, or venetoclax for use according to any one of claims 9 to 11, wherein the mantle cell lymphoma has acquired resistance to one or more BCL-2 inhibitors.

13. A combination for use, abemaciclib for use, or venetoclax for use according to any one of claims 9 to 12, wherein the mantle cell lymphoma has acquired resistance to venetoclax.

14. A combination for use, abemaciclib for use, or venetoclax for use according to any one of claims 9 to 13, wherein the mantle cell lymphoma is selected from, or characterised as one of, nodal mantle cell lymphoma; and leukaemic non-nodal mantle cell lymphoma.

15. A combination for use, abemaciclib for use, or venetoclax for use according to any one of claims 9 to 14, wherein the mantle cell lymphoma is selected from, or characterised as, refractory and/or relapsed mantle cell lymphoma. A combination for use, abemaciclib for use, or venetoclax for use according to any one of claims 9 to 15, wherein said mantle cell lymphoma is associated with one or more mutations in: ATM; TP53; CCND1; KMT2D; CDK2NA; BIRC3; CDKN2B; KHSC1; SMARCA4; SDHD; UBR5; NOTCH1; CARD11; SAMHD1; BCL10; MEF2B; IRS2; FGF19; FGF4; FGF3; FAT1; ROBO1; DIS3; CRLF2; CDKN2C; ARID2; ARID1A; ARID1B; NOTCH2; BCOR; TRAF2, TRAF3, MAP3K14, MYD88, BKT, PCLG2, BCL2, KMT2D, and CELSR3. A combination for use, abemaciclib for use, or venetoclax for use according to any one of claims 9 to 16, wherein said mantle cell lymphoma is associated with cyclin DI overexpression; t(l 1; 14) and/or t(l 1 ; 14)(ql3;q32) translocation; Ki67 overexpression; lactate dehydrogenase overexpression; and/or beta-2 microglobulin overexpression. A combination for use, abemaciclib for use, or venetoclax for use according to any one of claims 9 to 17, wherein said mantle cell lymphoma is retinoblastoma protein (Rb) proficient. Use of abemaciclib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating mantle cell lymphoma, wherein the medicament also comprises venetoclax or a pharmaceutically acceptable salt thereof, or is to be administered simultaneously, separately or sequentially with venetoclax or a pharmaceutically acceptable salt thereof. Use of venetoclax or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating mantle cell lymphoma, wherein the medicament also comprises abemaciclib or a pharmaceutically acceptable salt thereof, or is to be administered simultaneously, separately or sequentially with abemaciclib or a pharmaceutically acceptable salt thereof.