WO2008116163A1

WO2008116163A1 - Therapeutic drug combinations for treatment of b-cell malignancies

Info

Publication number: WO2008116163A1
Application number: PCT/US2008/057843
Authority: WO
Inventors: Elliot Epner; Richard Maziarz
Original assignee: Oregon Health & Science University
Priority date: 2007-03-22
Filing date: 2008-03-21
Publication date: 2008-09-25

Abstract

Embodiments of the present invention provide novel treatments for individuals with B-cell malignancies, such as CLL and NHL, including MCL. In embodiments, individuals that may be treated with drug combinations as described herein include those with newly diagnosed and/or relapsed MCL, newly diagnosed and/or relapsed CLL, or relapsed/refractory indolent NHL. In an embodiment, there is provided a method for treating an individual having a B-cell malignancy comprising providing the individual with an effective dose of a DNA methylation inhibitor, providing the individual with an effective dose of an antibody that is cytotoxic to B-cells, and optionally providing the individual with an effective dose of one or more of a histone deacetylase inhibitor, a proteasome inhibitor, and an mTOR inhibitor.

Description

THERAPEUTIC DRUG COMBINATIONS FOR TREATMENT OF B-CELL MALIGNANCIES

Cross Reference to Related Applications

[0001] The present application claims priority to U.S. Provisional

Patent Application No. 60/896,311 , filed March 22, 2007, entitled "Curative Combined Epigenetic (Cladhbine) and Immunotherapy (Rituximab) in Mantle Cell Lymphoma," the entire disclosure of which is hereby incorporated by reference in its entirety.

Technical Field

[0002] Embodiments of the present invention relate to the field of medical treatments, and, more specifically, to therapeutic drug combinations for the treatment of B-cell malignancies.

Background

[0003] B-cell malignancies are heterogenous in their clinical behavior.

They include a spectrum of aggressive highly proliferative neoplasms such as Burkitt's lymphoma and diffuse large B-cell lymphoma to more indolent diseases such as B-cell chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). Current therapies are able to cure some but not all patients with aggressive B-cell lymphoproliferative disorders. Other B-cell disorders, such as CLL, relapsed/refractory indolent non-Hodkin's lymphoma (NHL), and mantle cell lymphoma (MCL), are not considered curable with current therapy. Thus, novel therapies are clearly needed. [0004] CLL is a B-cell malignancy defined by lymphocytosis of mature-appearing small lymphocytes (>10,000/ μL); a normocellular to hypercellular bone marrow consisting of > 30 percent lymphocytes, and usual expression of one or more of the following B-cell markers: CD19, CD 20, CD 21 , CD 23, and CD 24; and the presence of CD5 positivity. It is associated with prolonged survival although this is influenced by disease stage-patients with early stage disease living more than ten to fifteen years and patients with more advanced stage disease living less than one year. Therapy has been aimed at alleviating symptoms and improving cytopenias and patients may go many years only requiring intermittent treatment. However, ultimately, patients generally progress requiring more therapy. Standard therapies have included alkylating agents such as chlorambucil and/or cyclophosphamide as well as steroids.

[0005] Despite significant advances in lymphoma care, indolent NHL also continues to be a challenging entity. In fact, the majority of patients with relapsed disease are not cured with conventional therapy and despite response rates of 50% with salvage regimens, less than ten percent of patients have significant disease free survival with current treatment strategies. Furthermore, the majority of patients with refractory disease - those who do not achieve a complete response with standard therapy - do not achieve meaningful remissions. A number of salvage regimens have been studied, many of which have incorporated high dose therapy with stem cell rescue and it appears that those patients who have longer initial remissions also have higher response rates.

[0006] MCL is a malignancy of monomorphous small to medium-sized

B lymphocytes, the majority of which are CD5+, CD 23-, and exhibit the chromosome 11 ;14 translocation leading to deregulated expression of cyclin D1. MCL comprises about 7 percent of adult non-Hodgkin's lymphoma (NHL) diagnoses in Europe and the United States. MCL is considered moderately aggressive and incurable with standard chemotherapy with median survival of three to four years with shorter survival times in patients with the blastoid variant and with higher proliferation rates. [0007] A number of chemotherapy regimens have been employed for

MCL including CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) based chemotherapy regimens with complete responses of 30- 60%. More recently, aggressive regimens including hyperCVAD (high dose cyclophosphamide, vincristine, doxorubicin, dexamethasone) plus rituximab alternating with cytarabine and high dose methotrexate have been studied. In a study by Romaguera et al., which employed this more aggressive regimen, the complete response rate was found to be 87% with a failure free survival rate of 64% and overall survival of 82% at 3 years. Based on these data, hyperCVAD has become a popular chemotherapy regimen; however, it is associated with significant toxicities as well as disease recurrence. For example, of the 97 patients in the Romaguera trial, there were eight toxic deaths (8.3%) as well as four cases of treatment-related acute leukemias, three of which were fatal. Another study evaluating the use of hyperCVAD based chemotherapy in high risk patients resulted in a complete response rate of only 38%. Given these results, as well as the advanced age and comorbidities of patients with MCL, many patients are not good candidates for this aggressive regimen. Furthermore, given the high relapse rates, additional treatments are needed.

Brief Description of the Drawings

[0008] Embodiments of the present invention will be readily understood by the following detailed description in conjunction with the accompanying drawings. Embodiments of the invention are illustrated by way of example and not by way of limitation in the figures of the accompanying drawings.

[0009] Figure 1 illustrates methyl donor pool recycling via SAH hydrolase in accordance with a disclosed embodiment.

Detailed Description of Disclosed Embodiments [0010] In the following detailed description, reference is made to the accompanying drawings which form a part hereof, and in which are shown by way of illustration embodiments in which the invention may be practiced. It is to be understood that other embodiments may be utilized and structural or logical changes may be made without departing from the scope of the present invention. Therefore, the following detailed description is not to be taken in a limiting sense, and the scope of embodiments in accordance with the present invention is defined by the appended claims and their equivalents. [0011] Various operations may be described as multiple discrete operations in turn, in a manner that may be helpful in understanding embodiments of the present invention; however, the order of description should not be construed to imply that these operations are order dependent. [0012] The description may use perspective-based descriptions such as up/down, back/front, and top/bottom. Such descriptions are merely used to facilitate the discussion and are not intended to restrict the application of embodiments of the present invention.

[0013] For the purposes of the description, a phrase in the form "A/B" or in the form "A and/or B" means (A), (B), or (A and B). For the purposes of the description, a phrase in the form "at least one of A, B, and C" means (A), (B), (C), (A and B), (A and C), (B and C), or (A, B and C). For the purposes of the description, a phrase in the form "(A)B" means (B) or (AB) that is, A is an optional element.

[0014] The description may use the phrases "in an embodiment," or

"in embodiments," which may each refer to one or more of the same or different embodiments. Furthermore, the terms "comprising," "including," "having," and the like, as used with respect to embodiments of the present invention, are synonymous.

[0015] Embodiments of the present invention provide novel treatments for individuals with B-cell malignancies, such as CLL and NHL, including MCL. In embodiments, individuals that may be treated with drug combinations as described herein include those with newly diagnosed and/or relapsed MCL, newly diagnosed and/or relapsed CLL, or relapsed/refractory indolent NHL. In an embodiment, indolent NHL may refer to grade 1 or grade 2 follicular lymphoma, lymphoplasmocytic lymphoma/Waldenstrom's macroglobulinemia, B-cell prolymphocytic leukemia, and/or marginal zone lymphoma.

[0016] In accordance with an embodiment, the purine analog cladhbine in combination with the CD20 monoclonal antibody rituximab has significant activity in treating CLL and MCL, in particular newly diagnosed MCL. Evidence indicates that cladribine acts as an epigenetic agent capable of inhibiting DNA methylation and activating genes or microRNAs (miRNAs). An embodiment is directed to the combination of cladribine and rituximab as an epigenetic therapy, which provides a novel, effective, and nontoxic therapeutic approach in treating CLL and MCL. [0017] In an embodiment, it is suggested that genes that are required for rituximab efficacy are silenced in B-cell lymphoproliferative disorders. Treatment with the DNA hypomethylating agent cladribine augments the activity of rituximab and may lead to durable complete remissions in newly diagnosed patients with B-cell malignancies. It is suggested that cladribine reactivates expression of one or more genes that augment htuximab's activity, for example, in newly diagnosed MCL patients. Additional details regarding the mechanisms of action of, and treatment with, cladribine, rituximab, and other drugs may be found in Yu et al., The Epigenetics of Mantle Cell Lymphoma, Current Treatment Options in Oncology, 8:375-381 , 2007, the entire disclosure of which is hereby incorporated by reference. [0018] Cladribine (2-chloro-2-deoxyadenosine) is a purine nucleoside analog anti-metabolite. Specifically, it is a deoxyadenosine analog substituted at the 2 position with chlorine which limits deamination by adenosine deaminase (ADA) thus increasing intracellular accretion. Once intracellular, cladribine is phosphorylated by deoxycitidine kinase. These phosphorylated metabolites are converted to active triphosphate deoxynucleotides whose accumulation leads to cell death by interfering with DNA repair. Once incorporated into DNA, these metabolites inhibit DNA synthesis and cell proliferation. Cladribine affects both resting and dividing lymphocytes. Evidence suggests that the primary cytotoxic effect of cladribine is due to its inhibition of DNA synthesis. Data also shows that cladribine is a hypomethylating agent which may be important to its antitumor activity.

[0019] Promotor DNA methylation silences the expression of genes.

Two factors generally must be present for methylation to occur: a sufficient methyl pool recycled from folate or methionine and functioning DNA methyltransferases. There are a number of other factors that influence DNA methylation. Cellular concentrations of S-adenosylmethionine may vary among individuals as a result of differences in diet. Folate, vitamin B6, vitamin B2, zinc, methionine, choline, and selenium deficiencies have all been shown to contribute to methyl depletion. Polymorphisms that reduce the activity of the enzymes that recycle S-adenosylmethionine can also lead to hypomethylation. Certain drugs may be used to control, or inhibit, DNA methylation.

[0020] Cladhbine inhibits DNA methylation through the inhibition of the enzyme S-adenosylhomocysteine hydrolase (SAH). For example, as a single agent for treating CLL, cladhbine not only works through chemotherapeutic mechanisms but also inhibits S-adenosylhomocysteine (SAH) hydrolase, a key enzyme for methyl donor pool recycling (see Figure 1 ). Specifically, cladribine decreases DNA methylation by an indirect effect on DNA methyltransferase (DNMT). Referring to Figure 1 , cladribine indirectly inhibits DNA methylation by decreasing the S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) ratio via its inhibition of SAM formation. This is achieved by blocking the activity of S- adenosylhomocysteine hydrolase which leads to the accumulation of SAH. SAH excess, coupled with a deficiency of SAM, then inhibits DNMT thus preventing further DNA methylation. Higher concentrations of SAH, capable of DNMT inhibition, are achieved when SAH hydrolase is inhibited. The inhibition of SAH hydrolase may also inhibit the donation of methyl groups to histones and other proteins in addition to DNA. The inhibition of histone methyltransferases may also have an epigenetic effect that may play a role in cladribine's efficacy in B-cell maligancies.

[0021] In an embodiment, other DNA methylation inhibitors that may be used for various treatments described herein include 5'-azacytidine (Vidaza) and 5-aza-2-deoxycytidine (Dacogen).

[0022] Data derived from treating CLL indicates that DNA methylation may serve as a general predictor of disease progression. Thus, in accordance with an embodiment, the global DNA methylation index (Ml) may be used as a predictor of progressive disease, and, in an embodiment, drug response may be correlated to a decrease in DNA Ml. In an embodiment, global DNA Ml may be reported as a percentage of 5-methyldeoxycytosine relative to the sum of 5-methyldeoxycytosine and deoxycytosine. In a further embodiment, the DNA Ml may be correlated with the number of tumor suppressor genes that are silenced, and one or both criteria may be used to track the progress of a particular treatment.

[0023] In an embodiment, a DNA methylation inhibitor may be used in combination with rituximab to treat an individual having a B-cell malignancy. Rituximab is a mouse/human chimeric monoclonal antibody consisting of human IgGI heavy and kappa light chain constant regions with murine variable regions from the murine IgGI kappa anti-human CD20 monoclonal antibody. The rituximab antibody is produced by a Chinese hamster ovary transfection. Rituximab has B-cell cytotoxic effects. [0024] Although all of its mechanisms of action are not known, rituximab exerts its cytotoxic effects in a number of ways. By binding to CD20 on the surface of B lymphocytes, rituximab leads to complement mediated cell death and via its binding to Fc receptors also leads to antibody dependent cellular cytotoxicity. Indirect effects also include chemotherapy sensitization, apoptosis and structural changes.

[0025] A prior study by the North Central Cancer Group of previously untreated MCL patients using the combination of rituximab and cladribine showed positive activity. Results showed a 52% complete response rate, and with median follow up of 14.3 months, 1 of 15 patients who experienced a complete response had relapsed. However, the treatment regimen utilized differs from a regimen presented herein in accordance with a present embodiment. Thus, in accordance with an embodiment, this novel treatment regimen may result in complete response rates greater than 80% or approximately 90% as well as durable responses (at least 10 years) and potential cures in the majority of patients. While some of the difference in complete response rates may be due to the age of the treated patients and/or the stage of the disease in those patients, the particular novel treatment regimen also accounts for these far more positive results. [0026] The term complete response generally refers to the disappearance of all measurable and non-measurable disease, but may have some limited exceptions such as the limited presence of small nodal masses.

[0027] In embodiments, as particular drug forms are available, the drugs described herein may be delivered to an individual through any suitable delivery mechanism, including intravenous infusion, orally, etc. [0028] In an embodiment, the particular delivered dosages for each of the drugs provided to the individual may be determined based on a variety of factors, including a determined safe and effective dose, and the size, age, health, etc. of the patient. In an embodiment, an effective dose of each of the delivered drugs may be provided to the particular treated individual. In an embodiment, an effective dose may be the minimum dose that produces the desired effect.

[0029] In an embodiment, patients may be treated with cladribine and rituximab for one or more cycles of treatment. The duration of one or more cycles may be adjusted as needed, however, in an embodiment, a suitable cycle duration may be 20-30 days, such as 28 days. In embodiments, 1 -10 cycles, such as 4-6 cycles may be utilized.

[0030] Thus, in an embodiment, a method for treating an individual having mantle cell lymphoma is provided comprising providing the individual with an effective dose of cladribine delivered to the individual on each day of a period of days during each of a plurality of periodic treatment cycles; and providing the individual with an effective dose of rituximab delivered to the individual once each week for a first treatment cycle and then once during each additional periodic treatment cycle.

[0031] In an embodiment, an effective dose of cladribine may be approximately 3-6 mg/m2, such as 5 mg/m2. Cladribine may be delivered to an individual on one or more days during a treatment cycle, whether delivered one or more times during each day. In an exemplary embodiment, cladribine may be delivered to an individual once each day for a period of days during each cycle. In an embodiment, cladribine may be delivered on each of the first 4, 5, or 6 days, such as the first 5 days (days 1 , 2, 3, 4, and 5), of each cycle. In an embodiment, cladribine may be delivered by intravenous infusion, such as, for example, a daily 2 hour infusion. In embodiments, alternative treatment regimens may be utilized, whether the delivery is on consecutive or non-consecutive days, the number of individual treatments is more or less than mentioned above, and so on. [0032] In an embodiment, an effective dose of rituximab may be approximately 350-400 mg/m2, such as 375 mg/m2. Rituximab may be delivered to an individual on one or more days during a treatment cycle, whether delivered one or more times during each day. In an exemplary embodiment, rituximab may be delivered to an individual once each week for a period of weeks during the first cycle, and then once each cycle for any subsequent cycles. In an embodiment, during the first treatment cycle, rituximab may be delivered on day 1 , 2, 3, 4, or 5, and then repeated each week thereafter for the remainder of the first cycle, for example delivered on days 3, 10, 17, and 24. In an embodiment, during subsequent cycles, rituximab may be delivered once each month on a selected day, such as day 3, which may be adjusted as needed. In embodiments, alternative treatment regimens may be utilized, whether an initial delay of one or more days is utilized, the delivery is on consecutive or non-consecutive days, the number of individual treatments is more or less than mentioned above, the delivery is daily, weekly, or monthly, and so on.

[0033] In an embodiment, a therapeutic combination of cladribine and rituximab may be further enhanced by inclusion in the treatment regimen of one or more additional drugs, for example a histone deacetylase inhibitor, such as valproic acid or suberoylanilide hydroxamic acid (SAHA, marketed as Vorinostat), a proteasome inhibitor, such as bortezomib, and an mTOR (mammalian target of rapamycin) inhibitor.

[0034] Histone deacetylase inhibitors (HDACIs) act through an epigenetic mechanism. Although their mechanism of anti-cancer activity is complex and not yet fully understood, it is in part related to the accumulation of acetylated histones which leads to an open chromatin structure thus resulting in transcriptional activation of regulatory genes. Specifically, cells treated with HDACIs exhibit increased expression of cycl in-dependent inhibitor p21 while decreasing transcription of cyclin A and D genes. This coupled with thymidylate synthase inhibition is thought to help lead to cell cycle arrest. There is also some evidence suggesting that histone deacetylase (HDAC) inhibition contributes to a pro-apoptotic state via up- regulation of pro-apoptotic genes while simultaneously decreasing pro- survival gene expression. Furthermore, HDACIs may work through their anti- angiogenic effects.

[0035] In particular, in MCL cell lines, SAHA, a particular HDACI, has anti-proliferatiive activity. Some of this activity may be due to its ability to inhibit cyclin D1 expression. Specifically, SAHA down-regulates cyclin D1 protein levels after 8 hours of exposure to the drug via inhibition of translation. This inhibition may be the result of up-stream inhibition of the phosphatidylinosositide 3-kinase (PI3K) pathway which has been shown to be up-regulated in MCL lines.

[0036] The exact mechanism of the anti-neoplastic activity of SAHA is complex and has not yet been fully elucidated. SAHA inhibits HDAC1 , HDAC2 and HDAC3 (Class I) and HDAC6 (Class II). Histone deacetylases (HDACs) are known to catalyze the removal of acetyl groups from the lysine residues of a number of proteins including transcription factors and histones. It has been shown that some cancer cells over-express HDACs or inappropriately recruit HDACs to oncogenic transcription factors leading to increased tumor survival. Inhibition of HDACs leads to the accumulation of acetylated histones, resulting in cell cycle arrest induction and/or apoptosis of some transformed cells.

[0037] SAHA is an orally available HDACI marketed as Vohnostat.

The oral formulation of Vohnostat is currently available as a 100 mg capsule, although other formulations are possible.

[0038] In an embodiment, a HDACI, such as SAHA, may be added to a treatment regimen of cladhbine and rituximab to treat an individual having a B-cell malignancy, such as CLL or NHL. In an embodiment, an effective dose of SAHA is approximately 100-600 mg delivered once or twice per day orally or by intravenous infusion. In an exemplary embodiment, SAHA may be delivered to an individual once or multiple times each day for a period of days during each cycle. In an embodiment, SAHA may be delivered on each of the first 12, 13, 14, 15, or 16 days, such as the first 14 days, of each cycle. In embodiments, alternative treatment regimens may be utilized, whether the delivery is on consecutive or non-consecutive days, the number of individual treatments is more or less than mentioned above, and so on. [0039] Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins. This blockage can lead to the death of cancer cells. Bortezomib (marketed as Velcade) is a therapeutic proteasome inhibitor useful for treating B-cell malignacies, such as MCL. In an embodiment, bortezomib may act as an epigenetic modulator and may synergize with other drugs, such as cladhbine, in activating genes silenced in MCL cells. In an embodiment, in a combination therapy, bortezomib may act by stabilizing protein levels of the gene(s) activated by cladribine, for example, and/or by activating an additional gene(s).

[0040] In an embodiment, a proteasome inhibitor, such as bortezomib, may be added to a treatment regimen of cladribine and htuximab to treat an individual having a B-cell malignancy, such as MCL. [0041] In an embodiment, an effective dose of bortezomib is approximately 1 -2 mg/m2/dose, such as 1.3-1.6 mg/m2/dose delivered once or twice per week, for example by intravenous injection. In an embodiment, bortezomib may be delivered once each week, for example on days 10, 17, 24, etc. for one or more treatment cycles. After an initial cycle or cycles of treatment, a maintenance schedule may be utilized, in an embodiment, including a reduced dose or less frequent injections. In embodiments, alternative treatment regimens may be utilized, whether an initial delay of one or more days is utilized, the number of individual treatments is more or less than mentioned above, and so on. [0042] mTOR inhibitors, such as rapamycin (Sirolimus), CCI-779,

AP23573 and RAD-001 are cell-signaling proteins that regulate the response of tumor cells to nutrients and growth factors, as well as control tumor blood supply through effects on vascular endothelial growth factor, VEGF. mTOR inhibitors also starve cancer cells and shrink tumors by inhibiting the effect of mTOR.

[0043] mTOR inhibitors bind to the mTOR kinase. mTOR is a downstream mediator of the PI3K/AKT pathway, which may be over- activated in certain cancers and may account for the response of cancers to mTOR inhibitors. The over-activation of the upstream pathway would also normally cause mTOR kinase to be over-activated, however, in the presence of mTOR inhibitors, the process is blocked. The blocking effect prevents mTOR from signaling to downstream pathways that control cell growth. [0044] In an embodiment, an mTOR inhibitor may be added to a treatment regimen of cladhbine and rituximab to treat an individual having a B-cell malignancy.

[0045] In an embodiment, an effective dose of an mTOR inhibitor, such as RAD-001 , may be approximately 5-10 mg/day or approximately 25- 50 mg/week, whereas another mTOR inhibitor, such as rapamycin, may have an effective dose of approximately 1 -5 mg/day, and, in an embodiment, may also be front loaded with a bolus dose of, for example, 3-15 mg. In embodiments, various treatment regimens may be utilized, whether every day or staggered, using higher or lower doses, and so on. [0046] Thus, in an embodiment, a method for treating an individual having a B-cell malignancy is provided, comprising providing the individual with an effective dose of a DNA methylation inhibitor; providing the individual with an effective dose of an antibody that is cytotoxic to B-cells; and optionally providing the individual with an effective dose of at least one of a histone deacetylase inhibitor, a proteasome inhibitor, and an mTOR inhibitor. [0047] Although certain embodiments have been illustrated and described herein, it will be appreciated by those of ordinary skill in the art that a wide variety of alternate and/or equivalent embodiments or implementations calculated to achieve the same purposes may be substituted for the embodiments shown and described without departing from the scope of the present invention. Those with skill in the art will readily appreciate that embodiments in accordance with the present invention may be implemented in a very wide variety of ways. This application is intended to cover any adaptations or variations of the embodiments discussed herein. Therefore, it is manifestly intended that embodiments in accordance with the present invention be limited only by the claims and the equivalents thereof.

Claims

ClaimsWhat is claimed is:

1. A method for treating an individual having mantle cell lymphoma, comprising: providing the individual with an effective dose of cladhbine delivered to the individual on each day of a period of days during each of a plurality of periodic treatment cycles; and providing the individual with an effective dose of rituximab delivered to the individual once each week for a first treatment cycle and then once during each additional periodic treatment cycle.

2. The method of claim 1 , wherein the treated individual is one newly diagnosed with mantle cell lymphoma.

3. The method of claim 1 , wherein each treatment cycle is 20-30 days in duration.

4. The method of claim 1 , wherein the effective dose of cladribine is approximately 3-6 mg/m2.

5. The method of claim 1 , wherein cladribine is delivered to the individual on each of the first 4-6 days of each cycle.

6. The method of claim 1 , wherein the effective dose of rituximab is approximately 350-400 mg/m2.

7. The method of claim 1 , further comprising providing the individual with an effective dose of a proteasome inhibitor.

8. The method of claim 7, wherein said proteasome inhibitor comprises bortezomib.

9. The method of claim 1 , further comprising providing the individual with an effective dose of a histone deacetylase inhibitor.

10. The method of claim 9, wherein said histone deacetylase inhibitor comprises valproic acid.

11. The method of claim 9, wherein said histone deacetylase inhibitor comprises suberoylanilide hydroxamic acid.

12. The method of claim 1 , further comprising providing the individual with an effective dose of an mTOR inhibitor.

13. A method for treating an individual having chronic lymphocytic leukemia or indolent non-Hodgkin's lymphoma, comprising: providing the individual with an effective dose of cladhbine; providing the individual with an effective dose of rituximab; and providing the individual with an effective dose of a histone deacetylase inhibitor.

14. The method of claim 13, wherein the treated individual is one having mantle cell lymphoma.

15. The method of claim 13, wherein the treated individual is one having relapsed or refractory non-Hodgkin's lymphoma.

16. The method of claim 13, wherein cladribine is delivered to the individual on each day of a period of days during each of a plurality of periodic treatment cycles.

17. The method of claim 16, wherein cladribine is delivered to the individual on each of the first 4-6 days of each cycle.

18. The method of claim 13, wherein rituximab is delivered to the individual once each week for 4 weeks and then once during each additional periodic treatment cycle.

19. The method of claim 13, wherein the histone deacetylase inhibitor is suberoylanilide hydroxamic acid.

20. The method of claim 19, wherein suberoylanilide hydroxamic acid is delivered to the individual on each day of a period of days during each of a plurality of periodic treatment cycles.

21. The method of claim 20, wherein suberoylanilide hydroxamic acid is delivered to the individual on each of the first 7-15 days of each cycle.

22. The method of claim 19, wherein the effective dose of suberoylanilide hydroxamic acid is approximately 100-600 mg delivered once or twice per day orally or by intravenous infusion.

23. The method of claim 13, wherein the histone deacetylase inhibitor is valproic acid.

24. A method for treating an individual having mantle cell lymphoma, comprising: providing the individual with an effective dose of cladhbine; providing the individual with an effective dose of rituximab; and providing the individual with an effective dose of a proteasome inhibitor.

25. The method of claim 24, wherein the proteasome inhibitor is bortezomib.

26. The method of claim 24, wherein rituximab is delivered to the individual once each week for 4 weeks and then once during each additional periodic treatment cycle.

27. A method for treating an individual having a B-cell malignancy, comprising: providing the individual with an effective dose of a DNA methylation inhibitor; providing the individual with an effective dose of an antibody that is cytotoxic to B-cells; and providing the individual with an effective dose of at least one of a histone deacetylase inhibitor, a proteasome inhibitor, and an mTOR inhibitor.