Mantle cell lymphoma (MCL) is an uncommon non-Hodgkin lymphoma with a heterogeneous natural history. Significant strides have been made in the management of MCL. Clinical follow-up exceeds a decade with long-term remission durations in some patients. Modern induction strategies employ rituximab; a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like backbone; and cytarabine (in alternating or sequential regimens). However, bendamustine/rituximab therapy is challenging these induction strategies. The role of transplant is in clinical evolution. Up-front high-dose therapy and autologous stem cell transplant remains an attractive option for those with chemosensitive disease regardless of the induction regimen chosen, whereas this approach in the relapsed or refractory setting has not yielded long-term disease-free intervals. Reduced-intensity allogeneic stem cell transplant remains a viable option in those with relapsed or refractory MCL.

Mantle cell lymphoma (MCL) represents 6% of all cases of B-cell non-Hodgkin lymphoma (NHL) and affects approximately 4,000 persons each year in the United States.[1,2] Similar to chronic lymphocytic leukemia, MCL expresses the mature B-cell markers CD19 and CD20 and aberrantly expresses CD5, a characteristic T-cell marker.[3] These pathologic characteristics shrouded the diagnosis of MCL until the early 1990s, when the translocation of t(11;14)(q13;q32) was identified and later found to elicit deregulation of cyclin D1.[4,5] Subsequently, the immunohistochemical stain for cyclin D1 became clinically available, which allowed more reliable diagnosis of MCL.[6,7]

The clinical behavior of MCL is heterogeneous, unlike its clinicopathologic characteristics: men are primarily affected (75% to 80% of patients), and the majority present with advanced-stage disease. The MCL International Prognostic Index (MIPI) categorizes patients with newly diagnosed disease into three risk groups: low (44% of patients, median survival not reached), intermediate (35%; median survival, 51 months), and high (21%; median survival, 29 months) based on age, performance status, lactate dehydrogenase levels, and white blood cell count.[8]

MCL is generally an incurable malignancy with a high rate of response to therapy but an historically discouraging duration of remission. Modern induction regimens for MCL vary but often employ rituximab plus multiagent chemotherapy. Rituximab in addition to cyclophosphamide, vincristine, doxorubicin, and prednisone (R-CHOP)-the current standard of care for diffuse large B-cell lymphoma-has high overall response rates but short progression-free survival (PFS).[9] Intensified multiagent regimens are now common induction therapies for transplant-eligible patients with MCL, including R-hyperCVAD (rituximab, fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with rituximab, high-dose methotrexate, and cytarabine)[10]; intensified (maxi) R-CHOP with alternating high-dose cytarabine[11]; and the cytarabine-containing regimen DHAP (dexamethasone, cytarabine, and cisplatin), replacing an anthracycline-based approach.[12] These regimens have yielded promising responses that afford patients an option to proceed to consolidative high-dose therapy and autologous stem cell transplant (HDT-ASCT). In those considered not to be optimal candidates for HDT-ASCT, induction with R-CHOP followed by maintenance rituximab therapy provided an overall survival (OS) advantage in a phase III randomized trial when compared with R-FC (rituximab plus fludarabine and cyclophosphamide) and maintenance interferon alfa.[13]

Large retrospective studies have demonstrated that OS for patients with MCL is improving.[14] However, the place of autologous and allogeneic stem cell transplant (alloSCT) remains a topic of considerable debate.

More than 2 decades ago, physicians at the University of Nebraska Medical Center (UNMC) were among the first to report outcomes in patients with relapsed and refractory MCL who had chemosensitive disease consolidated with HDT-ASCT.[15] A disappointing 2-year event-free survival (EFS) of 36% was seen in a cohort of 34 patients. Those who had received more than two regimens had a 2-year EFS of 0%, and those who had received two or fewer had a 2-year EFS of 45%.

A group at MD Anderson Cancer Center reported that 20 patients with previously treated MCL had obtained a complete response (CR) with salvage hyperCVAD followed by consolidative HDT-ASCT. The 3-year EFS and OS in the HDT-ASCT cohort of patients were 17% and 25%, respectively.[16] However, in the same study, untreated patients who underwent the same approach had significantly improved 3-year EFS and OS of 72% and 92%, respectively.

These results and others in the relapsed and refractory setting are considered by most to be disappointing, with no clear stabilization of the EFS/PFS curves.[15-18] The success with an up-front consolidation approach was replicated in a larger series from European and North American registries (N = 195). Patients derived a significant PFS (hazard ratio = 2.95; 

 =.001) benefit if they received consolidative HDT-ASCT following a CR to induction therapy when compared with those treated later in the disease course.[19]

The European Mantle Cell Lymphoma Network performed the only randomized attempt to assess the application of HDT-ASCT in first chemosensitive response using a CHOP backbone for induction.[20,21] Patients with chemosensitive disease (N = 122) were subsequently randomized to interferon alfa (n = 60) or HDT-ASCT (n = 62) after four cycles of therapy. In the intent-to-treat analysis, the median OS was higher in the HDT-ASCT group (7.5 years vs 5.3 years; 

 = .031). Furthermore, in an unplanned subset analysis of the HDT-ASCT group, patients with a CR did significantly better than those with chemosensitive but persistent disease. Thus, it became apparent in the pre-rituximab era that induction therapy followed by HDT-ASCT was an attractive approach that provided remission durability for those with a CR to initial chemotherapy. This concept has not faded in the rituximab era for transplant-eligible patients.

The addition of rituximab to established induction regimens for newly diagnosed MCL has likely increased the transplant-eligible pool. Because MCL is uncommon, despite well-recognized diagnostic criteria, few randomized trials have compared induction strategies, let alone established the role of consolidative HDT-ASCT (Table 1). An early–rituximab era pair-matched retrospective analysis from Canada demonstrated superior outcomes in patients treated with a single dose of rituximab as part of stem cell purging and two post-transplant maintenance doses following either an anthracycline or cyclophosphamide/fludarabine induction regimen plus HDT-ASCT (n = 20) vs standard non-rituximab combination chemotherapy without HDT-ASCT (n = 40). The rituximab plus HDT-ASCT arm demonstrated a 3-year PFS of 89% vs 21% in the control arm.[22]

The Nordic Lymphoma Group and the Cancer and Leukemia Group B (CALGB) reported long-term study outcomes. In the MCL-2 study led by the Nordic Lymphoma Group, 160 patients were treated with rituximab plus the intensified (maxi)-CHOP/cytarabine alternating regimen followed by HDT-ASCT.[11,23] The dose of cytarabine used in the alternating regimen was 3 g/m

, not unlike what is used with part B of hyperCVAD (cytarabine, 2 g/m

). At a median follow-up of 6.5 years among survivors, the 10-year EFS and OS were 43% and 58%, respectively. The CALGB prospectively studied in 78 patients a rituximab and methotrexate plus intensified CHOP regimen with cytarabine-containing mobilization followed by HDT-ASCT.[24] This study included two doses of post-ASCT rituximab maintenance therapy. With a median follow-up of more than 4 years, the 5-year PFS and OS were 56% and 64%, respectively. Notably, the CALGB regimen did not include a significant cytarabine component. Sequential regimens have also been studied.

Recently, the Groupe d’Ãtude des Lymphomes de l’Adulte reported the results of a phase II study of R-CHOP followed by rituximab plus DHAP and HDT-ASCT in chemosensitive patients.[25] Sixty patients were treated with a sequential regimen; this strategy achieved a CR rate of 57% at the end of planned therapy and a 5-year OS of 75%. Notably, a CR was seen in only 12% of patients after receiving CHOP for three cycles plus one dose of rituximab.

A more recent study in 497 patients < 65 years of age with MCL randomized participants to R-CHOP plus HDT-ASCT (arm A) or sequential R-CHOP (three cycles) followed by R-DHAP (three cycles) plus high-dose cytarabine-containing conditioning and ASCT (arm B).[26,27] A higher CR rate was seen in arm B-54%-than in arm A-36% (

 = .0003). Despite similar outcomes immediately after HDT-ASCT, arm B had a superior remission duration (49 months in arm A vs 84 months in arm B; 

Within the limitations of cross-study comparisons, the CALGB and European approaches are comparable. These studies allow some insight into the importance of rituximab in MCL induction regimens, question the role of maintenance rituximab therapy, and validate the use of high-dose (2 g/m

) cytarabine-containing regimens. Alternating R-CHOP/cytarabine-containing therapy has yet to be compared with sequential R-CHOP followed by cytarabine-containing therapy.

A retrospective analysis by institutions within the National Comprehensive Cancer Network (NCCN) reviewed the outcomes of 167 younger (age < 65) patients with newly diagnosed MCL who had undergone induction with R-CHOP or R-HyperCVAD with or without HDT-ASCT.[28] The cohort that received R-CHOP without HDT-ASCT (n = 29) did significantly worse than the other three cohorts. Interestingly, those who received R-hyperCVAD alone (n = 83) did as well as those who received R-CHOP plus HDT-ASCT (n = 34) and those who received R-hyperCVAD plus HDT-ASCT (n = 21). These results support those of the MD Anderson group’s earlier study of the use of R-hyperCVAD alone for six to eight cycles.[10] The MD Anderson results were nearly replicated in a cooperative group experience (Southwest Oncology Group [SWOG] 0213), but high-grade toxicity led to discontinuation of the regimen in 39% of those enrolled and to the recommendation of its use only in those < age 65.[29]

These results suggest that the incremental benefit of minimal residual disease control with consolidative HDT-ASCT may not be present if R-hyperCVAD is used as induction, perhaps sparing patients the small but measurable risk of transplant-related mortality and more inpatient days compared with the other regimens. This is significant because hyperCVAD is associated with notable cumulative toxicity.[29] A counterpoint to the SWOG 0213 toxicity report is that in the NCCN series only one patient died of treatment-related complications despite the fact that more than 50% of patients received the studied induction regimens. This may reflect patient selection, better supportive measures, and/or greater familiarity with the regimens’ potential toxicities at centers included in this series than at those in the SWOG 0213 study. The NCCN study has many limitations, including the retrospective nature of the analysis; moreover, the number of hyperCVAD cycles received before HDT-ASCT likely varies at participating centers. Still, there are no data from European groups or others outside of the United States that suggest that an alternating or sequential cytarabine-containing induction approach without HDT-ASCT is inferior to induction plus consolidative HDT-ASCT.

A caveat about the NCCN analysis and a frequently encountered dilemma is that of the patient’s transplant status at the time of diagnosis of MCL. Often the transplant status is questionable, and patients may receive standard R-CHOP induction; their response and toleration of the regimen dictate whether they proceed to HDT-ASCT or maintenance rituximab therapy. In the hyperCVAD series from MD Anderson, patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1 before enrollment. This is a very attractive decision tree, given recent data demonstrating a survival advantage with maintenance rituximab therapy and the NCCN data. Currently, the NCCN guidelines recommend consolidation with HDT-ASCT in patients who obtain a CR or partial response to induction therapy.[30] Whether those patients who achieve a CR to induction therapy followed by maintenance rituximab therapy have similar PFS after consolidative HDT-ASCT is unknown.

In the pre-rituximab era, patients with relapsed or refractory MCL had poor remission durability with HDT-ASCT, even with a chemosensitive response. Currently, novel regimens incorporating bortezomib and/or bendamustine are efficacious in inducing a subsequent chemosensitive response and therefore provide an opportunity to consolidate with alloSCT. Because MCL is uncommon and occurs in older patients, no randomized clinical trials have compared ASCT and alloSCT in patients with relapsed and refractory MCL. Moreover, alloSCT data solely about patients with MCL are also uncommon because they are often included with other NHL subtypes in center-specific studies (Table 2).

A comparative analysis from UNMC retrospectively reviewed the outcomes of 97 patients who underwent either HDT-ASCT (n = 80) or myeloablative alloSCT (n = 17).[18] The patients in the alloSCT cohort were more heavily pretreated-which is inherent to alloSCT-but all were chemosensitive at the time of transplant. The relapse rate was higher in the HDT-ASCT cohort (56% vs 21%; 

 = .1), but transplant-related mortality, as expected, was higher in the alloSCT cohort.

In patients with relapsed and refractory MCL, consideration of alloSCT requires considerable planning and referrals; the work-up should parallel reinduction therapy in order not to miss the transplant window. Furthermore, reduced-intensity conditioning regimens likely have opened up this modality to many more patients than in the total body irradiation–based myeloablative era; however, this conditioning remains an option for younger persons. Nonetheless, alloSCT in a transplant-eligible patient with a human leukocyte antigen–identical donor remains a curative option. There are few, if any, scenarios in which alloSCT in patients with newly diagnosed MCL can routinely be recommended in the first chemosensitive response.

HDT-ASCT is recommended by the NCCN guidelines in transplant-eligible patients with newly diagnosed MCL who have a chemosensitive response to initial therapy. The induction chemotherapy regimens that were evaluated in the pre-rituximab era have stood the test of time, but less intense regimens such as rituximab plus bendamustine are attempting in clinical trials (eg, NCT01412879) to challenge the intensive multiagent regimen paradigm. Bendamustine has already demonstrated an impressive induction response rate and differing toxicity profiles in both the Study Group Indolent Lymphomas (StiL) and Bendamustine Hydrochloride and Rituximab Compared With R-CVP or R-CHOP in the First-Line Treatment of Patients With Advanced Indolent Non-Hodgkin’s Lymphoma or Mantle Cell Lymphoma (BRIGHT) studies compared with R-CHOP.[27,31] The role of HDT-ASCT in the relapsed 

 refractory setting is historical and has been replaced by alloSCT studies testing whether the risk is worth the potential reward of a long-term disease-free interval or cure.

Finally, the treatment of MCL has benefited from a wealth of agents through a committed pipeline that has resulted in US Food and Drug Administration approval and/or signs of efficacy of several novel agents in the relapsed and refractory setting. These novel agents-including the proteasome inhibitor bortezomib, the immunomodulatory agent lenalidomide, and a number of other oral compounds such as ibrutinib-are being targeted in up-front strategies to hopefully maintain efficacy, decrease patient length of stay, and reduce treatment-related toxicity. Outcomes in MCL have improved, but the relative contributions of rituximab, induction chemotherapy, consolidative transplant, and maintenance therapies remain unknown.

Dr. Armitage serves as a consultant to GlaxoSmithKline, Seattle Genetics, Genentech, Roche, Spectrum Pharmaceuticals, and Ziopharm Oncology; he is also a member of the Board of Directors of Tesaro, Inc. Dr. Lunning has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. The article was fully funded by Celgene.

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 Williams ME, Nichols GE, Swerdlow SH, Stoler MH. In situ hybridization detection of cyclin D1 mRNA in centrocytic/mantle cell lymphoma. Ann Oncol. 1995;6:297-9.

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 Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008;111:558-65.

 Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005;23:1984-92.

 Romaguera JE, Fayad LE, Feng L, et al. Ten-year follow-up after intense chemoimmunotherapy with Rituximab-HyperCVAD alternating with Rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma. Br J Haematol. 2010;150:200-8.

 Geisler CH, Kolstad A, Laurell A, et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008;112:2687-93.

 Le Gouill S, Callanan M, Macintyre E, et al. Clinical, metabolic and molecular responses after 4 courses of R-DHAP and after autologous stem cell transplantation for untreated mantle cell lymphoma patients included in the LyMa trial, a Lysa study [abstract 152]. Blood. 2012;120:21.

 Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012;367:520-31.

 Herrmann A, Hoster E, Zwingers T, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol. 2009;27:511-8.

 Vose JM, Bierman PJ, Weisenburger DD, et al. Autologous hematopoietic stem cell transplantation for mantle cell lymphoma. Biol Blood Marrow Transplant. 2000;6:640-5.

 Khouri IF, Romaguera J, Kantarjian H, et al. Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma. J Clin Oncol. 1998;16:3803-9.

 Freedman AS, Neuberg D, Gribben JG, et al. High-dose chemoradiotherapy and anti-B-cell monoclonal antibody-purged autologous bone marrow transplantation in mantle-cell lymphoma: no evidence for long-term remission. J Clinical Oncol. 1998;16:13-8.

 Ganti AK, Bierman PJ, Lynch JC, et al. Hematopoietic stem cell transplantation in mantle cell lymphoma. Ann Oncol. 2005;16:618-24.

 Vandenberghe E, Ruiz de Elvira C, Loberiza FR, et al. Outcome of autologous transplantation for mantle cell lymphoma: a study by the European Blood and Bone Marrow Transplant and Autologous Blood and Marrow Transplant Registries. Br J Haematol. 2003;120:793-800.

 Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. 2005;105:2677-84.

 Dreyling M, Hoster E, Van Hoof A, et al. Early consolidation with myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission in mantle cell lymphoma: long term follow up of a randomized trial of the European MCL Network [abstract 285]. Blood. 2008;112:11.

 Mangel J, Leitch HA, Connors JM, et al. Intensive chemotherapy and autologous stem-cell transplantation plus rituximab is superior to conventional chemotherapy for newly diagnosed advanced stage mantle-cell lymphoma: a matched pair analysis. Ann Oncol. 2004;15:283-90.

 Geisler CH, Kolstad A, Laurell A, et al. Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur. Br J Haematol. 2012;158:355-62.

 Damon LE, Johnson JL, Niedzwiecki D, et al. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol. 2009;27:6101-8.

 Delarue R, Haioun C, Ribrag V, et al. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d’Etude des Lymphomes de l’Adulte. Blood. 2013;121:48-53.

 Hermine O, Hoster E, Walewski J, et al. Alternating courses of 3x CHOP and 3x DHAP plus rituximab followed by a high dose ARA-C containing myeloablative regimen and autologous stem cell transplantation (ASCT) is superior to 6 courses CHOP plus rituximab followed by myeloablative radiochemotherapy and ASCT in mantle cell lymphoma: results of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net) [abstract 151]. Blood. 2010;116:110.

 Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381:1203-10.

 LaCasce AS, Vandergrift JL, Rodriguez MA, et al. Comparative outcome of initial therapy for younger patients with mantle cell lymphoma: an analysis from the NCCN NHL Database. Blood. 2012;119:2093-9.

 Bernstein SH, Epner E, Unger JM, et al. A phase II multicenter trial of hyperCVAD MTX/Ara-C and rituximab in patients with previously untreated mantle cell lymphoma; SWOG 0213. Ann Oncol. 2013;24:1587-93.

 Zelenetz AD, Wierda WG, Abramson JS, et al. Non-Hodgkin’s lymphomas, version 3.2012. J Natl Compr Canc Netw. 2012;10:1487-98.

 Flinn IW, Van der Jagt RH, Kahl B, et al. An open-label, random ized study of bendamustine and rituximab (BR) compared with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line treatment of patients with advanced indolent non-Hodgkin’s lymphoma (NHL) or mantle cell lymphoma (MCL): the Bright study [abstract 902]. Blood. 2012;120:902.

 Maris MB, Sandmaier BM, Storer BE, et al. Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma. Blood. 2004;104:3535-42.

 Cook G, Smith GM, Kirkland K, et al. Outcome following Reduced-Intensity Allogeneic Stem Cell Transplantation (RIC AlloSCT) for relapsed and refractory mantle cell lymphoma (MCL): a study of the British Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2010;16:1419-27.

 Tam CS, Bassett R, Ledesma C, et al. Mature results of the M. D. Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma. Blood. 2009;113:4144-52.

 Le Gouill S, Kroger N, Dhedin N, et al. Reduced-intensity conditioning allogeneic stem cell transplantation for relapsed/refractory mantle cell lymphoma: a multicenter experience. Ann Oncol. 2012;23:2695-703.

Articles

The role of transplant in MCL is in clinical evolution. Up-front high-dose therapy and autologous stem cell transplant remains an attractive option for those with chemosensitive disease regardless of the induction regimen chosen, whereas this approach in the relapsed or refractory setting has not yielded long-term disease-free intervals.

The Place of Transplantation in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a distinct subtype of non-Hodgkin lymphoma that has been associated with a poor prognosis. Despite improvements in frontline management strategies, including the incorporation of cytarabine, intensification of chemotherapeutic regimens, and consolidation with transplant, MCL remains incurable. Our current understanding of MCL biology affords the opportunity to investigate novel, molecularly targeted therapeutic approaches. This review will focus on innovative drug development for the treatment of relapsed or refractory MCL, including therapies aimed at disrupting the B-cell receptor signaling pathway, regulators of apoptosis, and immunomodulators.

Mantle cell lymphoma (MCL) is an uncommon but distinct subtype of non-Hodgkin lymphoma (NHL) associated with a poor prognosis.[1] The incidence of MCL has increased over the past decade, a change that may in part reflect development of more sensitive diagnostic technologies that have resulted in improvements in classification over the same period. However, the rising incidence of MCL in elderly persons, particularly white men, remains unexplained.[2] Typically, patients present in their late 60s with advanced-stage disease, and they often have concomitant extranodal involvement.[3,4]

With the introduction of high-dose cytarabine, intensification of induction therapy, and consolidation with autologous transplant, responses and disease-free intervals have improved for patients with previously untreated MCL.[5-10] Despite these advances, most patients eventually relapse and die from MCL or related complications. In addition, this disease affects elderly patients, many of whom may not be candidates for intensive therapy. Therefore, more effective therapies for this patient population are needed. This review will cover innovative therapeutic approaches in relapsed or refractory MCL, many of which have the potential to alter treatment paradigms toward the development of strategies that do not involve conventional chemotherapy agents.

Molecular Targets in Mantle Cell Lymphoma

MCL is characterized by overexpression of cyclin D1, a cell cycle regulator that promotes cellular proliferation. Secondary genetic events that enhance cell growth, activate cell survival pathways, inhibit apoptosis, and promote interactions with the tumor microenvironment also serve as potential targetable mechanisms of lymphomagenesis.[11-13] More specifically, evidence that MCL pathogenesis is antigen-dependent[14] and that these tumors exhibit constitutive B-cell receptor (BCR) activation[15] posits the BCR signaling pathway as a rational prospect for drug development.

Several key components of this pathway have been explored as potential targets in MCL therapy. Spleen tyrosine kinase (SYK) is amplified in some patients with MCL, and its inhibition leads to the arrest of cell proliferation and apoptosis.[11] Acting downstream of SYK, Bruton tyrosine kinase (BTK) is a promising target in a variety of B-cell malignancies, including MCL.[16,17] In addition, BCR ligation activates the prosurvival phosphoinositide-3 kinase (PI3K) pathway via AKT, which itself has been implicated in MCL pathogenesis.[12,18,19] The development of specific tyrosine kinase inhibitors that target elements in these pathways has allowed molecularly driven clinical investigation in MCL.

Cyclin D1 overexpression is the distinguishing aberrancy in MCL. The broad cyclin-dependent kinase (CDK) inhibitor flavopiridol leads to downregulation of cyclin D1 and induces apoptosis of malignant lymphocytes in vitro and in murine lymphoma models.[20] In a phase I study of flavopiridol, 7 of 46 patients had relapsed MCL; of these, 2 achieved a partial response (PR).[21] Hematologic toxicity was common, with grade 3/4 leukopenia observed in 60% of patients, but infection was infrequent. Common nonhematologic toxicities included diarrhea and fatigue. Biochemical tumor lysis was observed in two patients, but neither required hemodialysis.

Flavopiridol has also shown activity in combination with fludarabine and rituximab or bortezomib in phase I clinical trials.[22,23] A direct CDK 4/6 inhibitor, PD0332991, demonstrated clinical benefit in 17 patients with MCL; 5 patients achieved progression-free survival (PFS) of > 1 year, with 1 complete response (CR) and 2 PRs (overall response rate [ORR] = 18%).[24] Despite the promise of direct CDK inhibition for a disease characterized by cyclin overexpression, CDK inhibitors have had little clinical impact in MCL to date.

Targeting the B-cell receptor signaling pathway

Recent clinical research has targeted the BCR signaling pathway. BCR activation engages the prosurvival nuclear factor kappa B (NF-ÎºB) pathway.[25] Bortezomib, a proteasome inhibitor that inhibits NF-ÎºB, received approval from the US Food and Drug Admin­istration (FDA) for use in the setting of relapsed MCL based on results of the phase II multicenter PINNACLE study,[26,27] with additional supporting data from smaller single-center and multicenter phase II studies.[28,29]

The PINNACLE study included 155 patients with relapsed or refractory MCL who had received one to three previous lines of therapy. Bortezomib was associated with an ORR of 32% (8% CR or complete response/unconfirmed [CRu]), median response duration of 9.2 months, median time to progression of 6.7 months, and median overall survival (OS) of 23.5 months. In patients who achieved a CR, median response duration and time to progression were not reached after a median follow-up of 26.4 months, with median OS of 36 months. The most common grade ≥ 3 adverse events were peripheral neuropathy, fatigue, and thrombocytopenia. Single-agent bortezomib was associated with remarkable survival in patients with relapsed or refractory MCL, given that 98% of patients had previously received multiagent therapy involving an anthracycline. Immunohistochemical analyses of archival tumor specimens (N = 73) used in preplanned exploratory analyses of candidate biomarkers of bortezomib activity indicated that elevated NF-ÎºB p65 demonstrated a trend for better response and longer OS, elucidating the role of NF-ÎºB pathway inhibition in MCL treatment.[30] Other proteasome inhibitors are now available that can also be explored in MCL.

Because constitutive BCR signaling plays a role in NF-ÎºB activation in MCL and other lymphoma subtypes, upstream inhibition of the BCR signaling pathway has also been explored. Ibrutinib is an orally available, highly selective, irreversible inhibitor of BTK that provides more direct targeting of the BCR signaling pathway upstream. Early clinical studies involving ibrutinib have demonstrated activity in several B-cell malignancies.[17,31,32] A recent phase II international study investigated the efficacy and safety of ibrutinib in patients with relapsed or refractory MCL.[16] A total of 115 patients were enrolled (111 received study drug) and were classified as bortezomib-exposed (≥ 2 cycles of bortezomib) or bortezomib-naive (no prior exposure or < 2 cycles of bortezomib). The median age of patients was 68 years; 77% were male; 49% had a high Mantle Cell Lymphoma International Prognostic Index (MIPI) score; median number of prior therapies was three (including 11% who had undergone stem cell transplant); and 45% had refractory disease. With a median follow-up of just over 15 months, the ORR in patients who received ibrutinib was 68%, with a CR in 21% and a PR in 47%. Response did not vary according to baseline characteristics or prior therapy, and responses improved over time with continued therapy. Estimated median response duration was 17.5 months, median time to response was 1.9 months, and median time to CR was 5.5 months. The estimated median PFS among treated patients was 13.9 months. The median OS for this study was not reached (estimated OS rate was 58% at 18 months). Grade 3/4 adverse events were uncommon; the most frequent treatment-related effects were mild or moderate diarrhea, fatigue, and nausea. Grade 3/4 hematologic adverse events included neutropenia in 16% of patients, thrombocytopenia in 11%, and anemia in 10%. The authors concluded that ibrutinib demonstrates efficacy as a single agent in patients with relapsed or refractory MCL and is associated with a favorable toxicity profile.

The phase I/II clinical trial investigating the oral SYK inhibitor fostamatinib in relapsed NHL and chronic lymphocytic leukemia (CLL) enrolled 3 MCL patients in the phase I cohort and 9 MCL patients in the phase II cohorts.[32] The most common grade 3/4 adverse events were neutropenia and anemia in 18% and 7% of patients, respectively. Of the MCL patients in the phase II portion of the trial, one achieved a PR and four demonstrated stable disease, with median PFS of 3.8 months. This clinical trial was one of the first to demonstrate that disruption of the BCR signaling pathway represents a novel and active therapeutic approach for NHL, but the efficacy of SYK inhibition in MCL remains unclear.

Protein kinase C beta (PKCÎ²) acts downstream of SYK as the major PKC isoform involved in BCR signaling. PKCÎ² is an important modulator of the angiogenic activity of vascular endothelial growth factor (VEGF). Notably, elevated baseline levels of VEGF and increased vascularity are associated with poor prognosis in NHL patients, including those with MCL.[34] Enzastaurin is an oral inhibitor of signaling through the PKCÎ²/PI3K/AKT pathways. A phase II trial of enzastaurin enrolled 60 patients (median age = 66 years) with relapsed or refractory MCL.[35] Although no objective tumor responses occurred, 22 patients (37%) were free from progression for ≥ 3 cycles (one cycle = 28 days), with 6 free from progression for > 6 months. The most common toxicity was fatigue; no grade 4 toxicities were reported.

As mentioned earlier, BCR ligation activates the PI3K signaling pathway. In fact, constitutive activation of BCR signaling independent of receptor ligation appears to be mediated by class 1 isoforms (Î±, Î², Î´, Î³) of PI3K, with the p110Î´ isoform highly expressed in cells of hematopoietic origin and strongly upregulated in various hematologic malignancies.[36] Idelalisib is an orally available selective inhibitor of the p110Î´ isoform of PI3K. A phase I study investigating idelalisib includes 18 patients with MCL; preliminary results were presented in 2010.[37] Grade ≥ 3 hematologic adverse events included neutropenia (9%), lymphopenia (5%), and thrombocytopenia (5%). Two to 8 weeks after initiation of the study drug, about one-third of patients had a grade 3 elevation in liver enzymes, which resolved 2 to 4 weeks after drug interruption. After liver enzyme abnormalities resolved, most patients were rechallenged with idelalisib at either initial or reduced dose, and the majority were able to resume treatment without recurrence of transaminase elevations. In evaluable MCL patients, 62% achieved a PR. The median duration of response in MCL patients was 3 months. The authors concluded that targeting the PI3KÎ´ isoform in relapsed NHL remains promising and has an acceptable safety profile.

Mammalian target of rapamycin (mTOR) kinase is a key downstream component of the PI3K/AKT pathway. Temsirolimus, a specific inhibitor of mTOR kinase, was compared with standard chemotherapeutic single agents in an open-label, randomized phase III study of patients with relapsed or refractory MCL, and was associated with significant improvement in PFS (4.8 months vs 1.9 months, respectively) and in objective response rates (22% vs 2%, respectively).[38] However, there was no significant difference in median OS between the temsirolimus 175/75 mg group and the investigator’s choice group: 12.8 months vs 9.7 months, respectively (

 = .3519). The most frequent grade 3/4 adverse events in the temsirolimus groups were thrombocytopenia, anemia, neutropenia, and asthenia. Based on this study, temsirolimus is approved for relapsed MCL in Europe.

The Bcl family of proteins are key regulators of apoptosis, making them attractive targets in many hematologic malignancies. The anti-apoptotic protein Bcl-2 is often constitutively overexpressed in MCL, which may contribute to resistance to apoptosis.[39] A phase I study is evaluating the selective Bcl-2 inhibitor ABT-199 in patients with relapsed or refractory NHL; preliminary results have been presented.[40] In the 31 patients enrolled as of January 11, 2013, the median age was 68 years, the median number of prior therapies was 3, and 13 (42%) and 4 (13%) patients had bulky disease (> 5 and > 10 cm, respectively). The most common adverse events were nausea (36%), diarrhea (26%), dyspepsia, vomiting, fatigue, pyrexia, and cough (16% each).Grade 3/4 adverse events were anemia (13%), neutropenia (13%), febrile neutropenia (6%), and thrombocytopenia (10%). Grade 3 tumor lysis occurred after the initial dose in one patient with bulky adenopathy (> 10 cm). With a median follow-up of 5 months, ORR was 55% in the 29 evaluable patients, with 1 CR (in a patient with diffuse large B-cell lymphoma) and 15 PRs (52%). Of note, 8/8 MCL patients achieved a PR. Additional follow-up and further studies are planned.

Although the precise mechanisms of action of lenalidomide, an analog of thalidomide, are unknown, its efficacy has been attributed to targeting the tumor microenvironment by enhancing the proliferative and functional capacity of T cells and increasing natural killer cell–mediated antibody-dependent cell cytotoxicity.[41-44] Preliminary results of a multicenter phase II study of single-agent lenalidomide in 134 MCL patients who had relapsed after or were refractory to bortezomib therapy led to FDA approval of lenalidomide in this setting.[45] Median age was 67 years (≥ 65 years in two-thirds), and the median number of prior therapies was 4. ORR was 28% (CR or CRu, 8%), median duration of response was 16.6 months, median PFS was 4 months, and median OS was 19 months. The most common grade 3/4 adverse events were neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (8%), and fatigue (7%). Other adverse events (any grade) included tumor flare reaction (10%), deep venous thrombosis (4%), pulmonary embolism (2%), and invasive second primary malignancies (2%). In this heavily pretreated population, lenalidomide was associated with durable efficacy and with the expected toxicity profile.

Disruption of Adhesion and Chemotaxis of MCL cells

An interesting observation in early clinical trials investigating drugs that disrupt the BCR signaling pathway (eg, ibrutinib) was that rapid lymphocytosis often occurred concomitantly with marked reductions in lymphadenopathy following initiation of the study drug. This phenomenon was noted in both CLL and MCL.[17,31] In a phase II study of ibrutinib in MCL, 34% of patients had a transient increase in lymphocytosis; the peak occurred at a median of 4 weeks after initiation of treatment and substantially tapered off during cycle 4 or 5.[16] Peripheral blood samples from patients enrolled in phase I and II trials of ibrutinib have been analyzed[16,31]; CD19+CD5+ cells were found to have significant reduction in the expression of CXCR4, CD38, and Ki67 after 7 days of treatment.[46] In addition, plasma chemokines CCL22, CCL4, and CXCL13 were reduced 40% to 60% after treatment. This suggests a role for BCR signaling in chemokine-mediated adhesion and chemotaxis of MCL. Therapeutically, this has interesting implications and may affect how clinicians monitor and assess treatment response.

MCL is a subtype of NHL that remains a clinical challenge: with standard chemotherapeutic approaches, it is incurable, and most patients will succumb to the disease. Clearly, this disease warrants novel therapies with tolerable side effect profiles. Biologically, the known genetic aberrancies in MCL afford researchers the opportunity to investigate molecularly targeted therapy. We have summarized innovative single-agent therapies (Table) that hold promise in relapsed MCL, although many questions remain. How can the therapeutic efficacy of these targeted approaches be maximized? Will targeting multiple pathways simultaneously ward off resistance, or should single agents be used sequentially or in conjunction with multidrug chemoimmunotherapy instead? How will these innovative approaches be incorporated into front-line therapy? The future of lymphoma clinical research is at once full of hope and full of complexity. We will need to be adaptive in our approach in order to overcome the intricate mechanisms underlying mantle cell lymphomagenesis, but these promising agents provide the foundation for constructing treatment strategies for MCL that avoid or limit the use of chemotherapy.

 Dr. Flowers is a consultant to and has received research funding from Celgene Corporation and Spectrum Pharmaceuticals; is an unpaid consultant to Genentech/Roche; has received research funding from Gilead Sciences and Janssen Pharmaceuticals; is an unpaid consultant to and has received research funding from Millennium/Takeda; and is a consultant to Seattle Genetics. This article was fully funded by Celgene.

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This review will cover innovative therapeutic approaches in relapsed or refractory MCL, many of which have the potential to alter treatment paradigms toward the development of strategies that do not involve conventional chemotherapy agents.

Oncology Vol 27 No 10_Suppl_2

The Place of Transplantation in Mantle Cell Lymphoma

Novel Therapies in Mantle Cell Lymphoma: A Pathway to Chemotherapy-Free Strategies