Management of Mantle Cell Lymphoma: Key Challenges and Next Steps

Review

Management of Mantle Cell Lymphoma: Key Challenges and Next Steps Michael E. Williams,1 Martin Dreyling,2 Jane Winter,3 Sabeeha Muneer,4 John P. Leonard5 Abstract Mantle cell lymphoma (MCL) is regarded as an aggressive lymphoid malignancy that exhibits varied clinical behavior and prognoses, reflecting the biologic heterogeneity of the disease. In most cases, patients with MCL achieve a shorter median survival compared with more common B-cell lymphomas, such as follicular lymphoma, and are less likely to achieve a durable response with chemotherapy. Currently, there is no defined standard of care for patients with MCL. Rituximab-containing immunochemotherapy strategies are commonly used, but the addition of rituximab to conventional induction chemotherapy has produced suboptimal responses that are relatively short-lived and have not resulted in a survival advantage. Further intensification of the chemotherapy component, including autologous stem cell transplantation, has increased response and survival rates but has not proven to be curative while being associated with higher toxicity. Clearly, there is a need for developing novel agents and strategies that will improve clinical outcomes for patients with MCL. Targeted therapies and new cytotoxic agents are showing great promise and may have a role in maintenance and/or initial therapy. This summary highlights current challenges in the management of MCL, and outlines expert perspectives, key questions, and future directions. For the third consecutive year, a panel of global experts in MCL assembled to deliberate on topical issues in MCL including advances in pathobiology, strategies for risk-adapted therapy, front-line treatment options, consolidation approaches, and novel therapeutic strategies. The proceedings of this workshop, held December 3, 2009 in New Orleans, LA, are summarized here. It must be emphasized that this synopsis is not meant to serve as an exhaustive review of MCL biology and management, but is a distillation of the expert discussions, highlighting key questions and future directions identified. Clinical Lymphoma, Myeloma & Leukemia, Vol. 10, No. 5, 336-346, 2010; DOI: 10.3816/CLML.2010.n.066 Keywords: Bendamustine, HyperCVAD, Lenalidomide, MIPI, R-CHOP, Rituxumab, Temsirolimus, Transplantation

Advances in Molecular and Cellular Biology The management of patients with MCL poses a clinical challenge, partly because current therapies generally fail to produce durable remissions, and also owing to the heterogeneity of the disease. It is hoped that a better understanding of the pathobiology of the disease will pave the way for identification of crucial molecular targets and rational development of targeted agents that might herald a new armamentarium of drugs for the treatment of MCL. 1University

of Virginia School of Medicine, Charlottesville, VA Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany 3Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 4Physicians’ Education Resource, Dallas, TX 5Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY 2University

Submitted: Jul 21, 2010; Revised: Aug 13, 2010; Accepted: Aug 30, 2010 Address for correspondence: John P. Leonard, MD, Weill Medical College of Cornell University New York Presbyterian Hospital, Starr 340, 520 East 70th St, New York, NY 10803 Fax: 212-746-3844; e-mail: [email protected]

Additionally, prognostic models can be developed that will allow more tailored therapies to be designed. Though the oncogenic potential of dysregulated cell cycle pathways in the pathogenesis of MCL is irrefutable, it is also increasingly being recognized that additional alterations in the p53MDM2–ARF DNA damage response pathway and cell survival pathways might also be required for the initiation and progression of the disease.1 The genetic hallmark of MCL, in most cases, is the chromosomal translocation t(11;14)(q13;q32) that results in the constitutive overexpression of cyclin-D1.2-4 Among other effects, cyclin-D1 protein binds to cyclin-dependent kinases (CDKs) 4 and 6, and promotes the transition from the gap 1 (G1) to the synthesis (S) phase of the cell cycle.1 Although it might seem intuitive to focus drug development efforts on targeting the cell cycle in MCL, this approach has seen limited success thus far, largely because of lack of specificity of available drugs, and consequently unacceptable toxicity. Recently, the development of multiple cell cycle inhibitors, including a highly specific CDK4/6 inhibitor, PD-0332991 that results in cell cycle arrest in G1 phase, has led to renewed interest in targeting

This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #2152-2650, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.

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the cell cycle in MCL.5 Disruption of the G1-S phase regulatory checkpoint via genetic dysregulation of CDK4 and CDK6 has been noted in MCL cell lines and appears to be sensitive to PD0332991.6 Dr. Selina Chen-Kiang outlined a novel mechanismbased concept for combination therapy developed by her group, involving sequential induction of G1 arrest and synchronous S phase entry with PD0332991. In experimental MCL models, such a strategy was found to disrupt the coupling of gene expression from the cell cycle, thereby sensitizing tumor cells to cytotoxic killing via activation of intrinsic apoptosis pathways. Importantly, this rational combination therapy design also appeared to allow the use of lower doses of drugs. Based on this strategy, a phase I/II trial of PD0332991/bortezomib/dexamethasone has been initiated in multiple myeloma (MM), and has demonstrated promising results.7 Discussions also centered on other potential molecular targets for therapeutic intervention that might be implicated in DNA damage, apoptotic, or cell survival pathways involved in the pathogenesis of MCL. Some of these targets and their respective inhibitors include TAK1 (AZ-Tak-1), HDACs, JAK2 (SB1518), Hsp90 (17-AAG), and TRAIL-R2 (AMG-655), all of which have exhibited promising anti-lymphoma activities in preclinical or early clinical studies in MCL.8-12 Preclinical work is also propelling the development of rational combinations comprised of these targeted agents with chemotherapy and/or other emerging novel agents. Based on demonstrations of synergism between HDAC inhibitors and proteasome inhibitors, a pilot study of vorinostat and the proteasome inhibitor bortezomib in patients with non-Hodgkin lymphoma including MCL has been initiated.13 Other rational combination strategies of interest will be discussed in later sections.

Role of Tumor Microenvironment The role of tumor microenvironment in the pathogenesis, progression, and clinical outcome of MCL is poorly understood, and was the subject of discussion at the workshop. Provocative data were recently reported from a retrospective analysis of MCL diagnostic tissue biopsies that evaluated the association of microenvironment components such as cytotoxic T cells and macrophages with clinical outcomes.14,15 It was hypothesized that differences in the non-neoplastic composition of the tumor microenvironment might account for the heterogeneity of clinical behavior in MCL. Though some data suggests that macrophage number in the tumor microenvironment is an important prognostic indicator in follicular lymphoma (FL) that is independent of International Prognostic Index (IPI), Ki-67, and p53 expression, it might not be true for all disease types and might additionally be dependent on the type of therapy administered.16-18 Intriguingly, early findings in MCL suggest that the negative effect of macrophages might be diminished with the use of rituximab-containing therapies.15 On a cautious note, it is plausible that the immune cells found in the tumor microenvironment might be function-compromised cells that have been stripped of their function following exposure to several lines of previous therapies, and might not have any role in MCL tumorigenesis. Though these preliminary results are hypothesis generating at this time and need rigorous validation, it might be speculated that a rational therapeutic strategy might be to combine agents that target the microenvironment and the tumor itself.

Understanding and Targeting Mantle Cell Lymphoma Heterogeneity Heterogeneity of Mantle Cell Lymphoma It is well-accepted that MCL is not a homogenous disease and can be variable in terms of its biology, morphology, clinical presentation and behavior, and consequently, prognosis.19,20 Different MCL variants, namely classic, blastoid, and pleomorphic types, have been recognized based on morphology alone.21 The blastoid variants are associated with a higher proliferative activity and a more aggressive clinical behavior than the classic type, and consequently might require different treatment approaches.21 Moreover, the blastoid variant is associated with a high level of chromosomal imbalances and DNA amplifications.22 However, there do not appear to be formal criteria defined by the World Health Organization or other groups that distinguishes these variants.

Utility of Mantle Cell Lymphoma International Prognostic Index It is notable that despite MCL being regarded as an aggressive neoplasm with a median survival of 3-5 years, it also includes a subset of patients that exhibits an indolent clinical course who can survive for more than 10 years. However, the current treatment algorithm in MCL does not easily distinguish between these different subtypes and many clinicians treat most patients in a relatively similar manner. With several novel treatment approaches now available, accurate stratification of patients is required based on their biologic and clinical risk that will eventually be used routinely to guide treatment decisions. When the International Prognostic Index (IPI) and the FL IPI prognostic models failed to predict the prognosis of patients in MCL, a MCL IPI (MIPI) was developed specifically for risk assessment in MCL.23 The MIPIclinical risk score incorporates the independent clinical risk factors of performance status (PS), age, lactose dehydrogenase, and leukocyte count that categorizes patients into 3 risk categories, that correlated with clinical outcome.23 It allows individual risk estimation within and outside of clinical studies, but so far no data are available that supports the benefit of an appropriately risk-adapted therapeutic approach. Although the majority of patients included in the original MIPI analysis had not been exposed to rituximab, inclusion of rituximab therapy did not appear to affect the results of the analysis. These results were corroborated independently by other groups, albeit in small singlecenter validations.24 However, the utility of MIPI in the context of treatment with novel targeted agents is currently unknown and remains to be assessed. Rosenwald et al demonstrated using gene expression profiling methods that MCL has a unique proliferation signature that allowed the subclassification of patients into 4 groups, which correlated closely with prognosis.25 In particular, Ki-67 is an important independent prognostic marker in MCL. However, it appears to lose its relevance when expressed at high levels which might possibly be related to inaccurate Ki-67 assessments. Recognizing the prognostic value of Ki-67, Hoster et al conducted an explorative analysis of inclusion of Ki-67 to MIPI, which showed a high prognostic relevance independent of the MIPIclinical score.23 However,

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Management of Mantle Cell Lymphoma the MIPI biologic index is not yet considered to be ready for clinical application, and requires further validation. Moreover, the subjective nature of manual Ki-67 assessments raises concerns of reproducibility and accuracy. Recently, a standardized method has been established and alternative automated methods are currently being explored to overcome this issue.26,27

Are We Implementing Risk-Adapted Therapy? In-depth discussions were centered on whether we are or should be implementing risk-adapted therapy in routine clinical practice. Most panelists agreed that a clinical paradox was emerging in MCL, with low-risk patients being treated aggressively and high-risk patients being treated less intensively, potentially resulting in some patient subsets being over- or under-treated. This might partly stem from the prevalent notion that the majority of patients with MCL are high-risk, and hence, require high-dose therapy (HDT). In current trials that evaluate aggressive therapies such as the rituximab plus fractionated cyclophosphamide/vincristine/doxorubicin/dexamethasone (R-hyper–CVAD) and/or autologous stem cell transplantation (ASCT) as consolidation, the majority of patients enrolled are low- to intermediate-risk categories, patient subgroups that possibly might not require HDT. As mentioned earlier, the existence of a subset of patients with a more indolent clinical course has also been recognized in MCL. These patients might not require HDT and may be treated less aggressively. Conversely, one contention is that young patients at low risk might have a potential for cure and so might benefit from aggressive therapy to achieve a cure. Emerging recent data appears to suggest that low-risk patients derive benefit from HDT.28 Unlike Hodgkin lymphoma, which is considered to be very chemosensitive; MCL might require more aggressive approaches in order to produce durable remissions owing to its relative chemoresistance. An emerging proposition is that current treatment decisions in clinical practice appear to be based not on risk but on tolerability. Consequently, younger patients are treated with intensive therapies solely based on their ability to tolerate them more effectively than older patients. A contention was that perhaps the risk-adapted concept should be abandoned because it is not an accurate description of current clinical practice, which raises the question of whether a different paradigm should be considered. In this context, it remains to be determined if age alone or minimal residual disease (MRD) status might serve as independent surrogates for risk-adapted therapy.

Utility of Minimal Residual Disease Monitoring in Mantle Cell Lymphoma Though MCL is essentially incurable, it is apparent that complete disease eradication in all patients cannot be achieved with current therapies, irrespective of whether they are detected by early MRD monitoring or not. However, while patients who achieve MRD negativity might not be cured, they might achieve long-term remissions, which is a desirable outcome for this poor-prognosis patient population. The prognostic utility of MRD monitoring in MCL for early response assessment to guide subsequent treatment decisions is controversial, particularly in the context of modern combined treatment modalities. Howard et al reported that MRDpositivity did not correlate with clinical outcomes in patients with

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MCL following rituximab-containing induction chemotherapy, albeit in a small patient population.29 In contrast, the German Low Grade Lymphoma Study Group (GLSG) reported recently that MRD monitoring was a powerful predictive tool for treatment outcome in patients enrolled in 2 large randomized intergroup trials that evaluated ASCT in younger patients or maintenance therapy in older patients, following induction chemotherapy.30 In this analysis, molecular response correlated with significantly prolonged response duration in both young and elderly patients following both induction and post-induction therapy, irrespective of the clinical response achieved, suggesting that molecular response is more clinically relevant than quality of clinical remission. This prognostic significance also appeared to be independent of whether the MRD assessments were done in the peripheral blood or bone marrow. However, assessment in the peripheral blood gave a less accurate depiction of MRD compared with the bone marrow. This appeared to be particularly true for rituximab-containing therapies, largely because rituximab results in profound B-cell depletion in the peripheral blood compartment. Additionally, in the GLSG study, the rate of molecular response was significantly increased from 55% with induction therapy to 72% after HDT/ASCT, favoring an aggressive treatment approach in younger patients with MCL.30 Based on such studies, the Nordic Lymphoma Group (NLG) hypothesized that early therapeutic intervention at molecular relapse might change the natural course of the disease by either delaying or even preventing clinical relapses.31 Of the 160 patients with MCL that were enrolled in the MCL-2 protocol, 26 patients in molecular relapse, as assessed by reverse transcriptase polymerase chain reaction (RT-PCR) MRD monitoring following aggressive cytarabinecontaining induction therapy, underwent pre-emptive treatment with rituximab maintenance. This strategy led to reconversion to molecular remission in the majority of patients. Nevertheless, no plateau in the molecular relapse-free survival (RFS) curve with preemptive therapy was observed; the median molecular RFS was 1.5 years. However, the rituximab maintenance schedule, duration and timing have not yet been optimized. In both these studies, detection of molecular remission was found to precede that of clinical relapse in the majority of patients; however, the interval and rate varied. The most widely used MRD monitoring method for the assessment of circulating residual lymphoma cells was quantitative PCR immunoglobulin heavy locus. However, both the GLSG and NLG studies illustrated that sampling is limited to only patients that have a PCR-detectable marker, which accounted for only about half the patients enrolled in their studies, Moreover, a practical limitation of current PCR methodology is that MRD analysis sampling is currently from peripheral blood and bone marrow and might not correlate with signals in other compartments such as the gastrointestinal (GI) tract, lymph nodes, or spleen, which might partly explain the high false-negative rate observed. Furthermore, given the need for designing specific PCR primers for each individual patient, this method might not be pragmatic for routine clinical use and might be limited to clinical research settings. It was also pointed out that using flow cytometry instead of PCR as a monitoring tool might be restricted to patients treated with chemotherapy alone and might not be useful when rituximab is included because of the efficacy of rituximab in clearing the peripheral blood of clonal B cells.

Michael E. Williams et al Initial Therapeutic Options for Mantle Cell Lymphoma Management of Young/Fit Patients

Table 1 Efficacy of Current Treatment Strategies in Mantle Cell Lymphoma: Selected Studies Study

Regimen

No. of ORR, Patients %

Survival Mantle cell lymphoma does not appear Conventional Regimens to behave as do other aggressive lymphoHoward et al29 R-CHOP 40 96% Median PFS: 16.6 months mas in terms of its response and cure with 35 chemotherapy. Despite the availability of Lenz et al R-CHOP 122 94% TTF: 21 months several remittive treatment strategies for Forstpointner et al36 R-FCM → R maintenance 56 58% NR young/fit patients with MCL (Table 1), the Aggressive Regimens optimal frontline treatment is currently not Romaguera et al37 R-hyper–CVAD-M/C 97 NR 8-year TTF: 43%; 8-year OS: 56% defined.32 Historically, chemotherapy alone 38 Epner et al R-hyper–CVAD-M/C 40 88% 2-year PFS: 63%; 1-year OS: 91% has only produced a marginal survival benefit ASCT Consolidation in patients with MCL.33,34 The integration of rituximab to standard purine analogue/ Geisler et al45 R-maxiCHOP-R/Ara-C → ASCT 160 96% 6-year PFS: 66%; 6-year OS: 70% anthracycline-based chemotherapy regimens Novel Agents such as cyclophosphamide/doxorubicin/ Rummel et al43 (phase III) Bendamustine + Rituximab 260a 93% Median PFS: 54.9 months vincristine/prednisone (CHOP) improved Goy et al65 (phase II) 141 Bortezomib 32% Median TTP: 6.7 months responses compared with chemotherapy aA total of 45 patients with MCL. alone but demonstrated a more limited benAbbreviations: ASCT = autologous stem cell transplantation; FFS = failure-free survival; NR = not reported; ORR = objective efit compared with that achieved in follicular response rate; OS = overall survival; PFS = progression-free survival; R-CHOP = rituximab/cyclophosphamide/doxorubicin/ lymphoma.28,29,35,36 Although these convincristine/prednisone; R-FCM = rituximab/cyclophosphamide/fludarabine/mitoxantrone, R-hyper–CVAD-M/C = rituximab plus fractionated cyclophosphamide/vincristine/doxorubicin/dexamethasone alternating with high doses of methotrexate/cytarabine; ventional strategies resulted in initial high R-maxi–CHOP-R/Ara-C → ASCT = rituximab plus dose-intensified CHOP alternating with rituximab/high-dose cytarabine; TFS responses including high complete response = treatment-free survival; TTF = time to treatment failure; TTP = time to progression (CR) rates, these were not long-lasting and nance therapy without methotrexate/cytarabine, resulting in lower were not predictive of prolonged survival. Moreover, consolidatoxicity and a CR rate of 64%.39 The median PFS was 37 months, tion strategies such as the use of ASCT in eligible patients in the recently updated European MCL network trial resulted in a remarkalbeit with a short median follow-up time of 37 months. However, ably improved progression-free survival (PFS) in comparison with the long-term effectiveness of the modified regimen is questioned interferon-α but demonstrated only a trend toward an improved because of cytarabine (Ara-C) is now considered by many to be a overall survival (OS), underscoring the treatment resistance of this key determinant of efficacy in the original R-hyper–CVAD regimen. malignancy and the need for additional strategies.28 Consequently, the consensus of the panel was that intensive theraThe lymphoma group at MD Anderson Cancer Center pies such as the MDACC R-hyper–CVAD regimen might be con(MDACC) pioneered the development of an aggressive treatment sidered for high-risk patients or those with blastoid MCL. However, regimen of R-hyper–CVAD alternating with rituximab plus highrecent data by Martin et al suggesting that comparable OS outcomes dose methotrexate/cytarabine every 21 days, resulting in CR rates of to those reported with R-hyper–CVAD regimen might be achieved 87%; the median OS had not been reached at a median follow-up of with less intensive R-CHOP-like strategies; the 3-year OS from 8 years.37 Notwithstanding the risks of cross-trial comparisons, these diagnosis was 86% and median OS was 7.1 years in their series.40 reported outcomes are better than those achieved with conventional Taken together, the results of these several trials indicate a need for anthracycline-based therapies.29,35,36 However, it was generally both better therapies and a risk-adapted treatment approach. agreed that the R-hyper–CVAD regimen is selected for the fittest An apparent change in the natural history of the disease might patients, favoring those who are young, with good PS, and transbe emerging, which may be attributed to better diagnosis and treatplant-eligible, which might partly account for the apparent supements.41 However, it is clear that currently available aggressive or riority of this regimen. Moreover, the MDACC R-hyper–CVAD conventional treatment strategies are not able to produce durable regimen does not appear to be curative; relapses continue to occur, disease control for all patients or show curative potential, highlightindicating persistent MRD. Also, tolerability of the R-hyper–CVAD ing the need for further optimization or alternative strategies. With regimen, with nonhematologic toxicities and myelosuppression, is the main goal of therapy being reduction in the rate of relapse, cona significant issue. Though these results have been reproduced to a solidation strategies with stem cell transplantation (SCT) and/or lesser extent by a phase II multicenter effort,38 they need to be valithe integration of novel agents in maintenance regimens are viable dated in larger randomized trials. Because of this reason, a practical management strategies that are being actively evaluated in young/fit consideration is that administration of 8 cycles of R-hyper–CVAD patients with MCL, and will be discussed in a subsequent section. might not be feasible in routine practice and that 4-6 cycles (ie, 2-3 Management of Elderly/Frail Patients R-hyper–CVAD and 2-3 R-methotrexate/cytarabine) might be a Considering that the incidence of MCL significantly increases more reasonable target to achieve. In another modification, Kahl with age (median age at diagnosis: 68 years), the unmet treatment et al evaluated a modified R-hyper–CVAD regimen, administering needs of this older patient population would be considered by most only 4-6 cycles of R-hyper–CVAD followed by rituximab mainte-

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Management of Mantle Cell Lymphoma to be the most clinically relevant for the practicing physician.42 Although adopting a watch-and-wait strategy for a period of time might be a reasonable initial option for patients with low-burden disease who are asymptomatic, the majority of patients will require active treatment at the time of, or shortly after, initial diagnosis. However, there is no consensus on the optimal induction regimen for older/frail patients. Addition of rituximab to less intense CHOPlike regimens has generally been used in older patients; however, such measures have typically only improved PFS but not OS.28,29,35 In light of recent data with bendamustine plus rituximab (BR) in patients with indolent NHL including MCL, the role of anthracyclines is questionable in the elderly patient subset.43 Rummel et al demonstrated an overall response rate (ORR) of 88% and CR rate of 42% with BR combination therapy in patients with MCL that also showed a more favorable toxicity profile compared with R-CHOP, making it a viable frontline treatment alternative for these patients43; in this study, 23% of patients were age > 70 years. Moreover, a European MCL Network analysis demonstrated that patients > 65 years who received rituximab or interferon-α maintenance therapy following induction chemotherapy with either R-CHOP or R-FC achieved high rates of molecular response, supporting the use of consolidation strategies in this patient population.44 In the novel agent era, the elderly patient subgroup might benefit from addition of targeted agents either at induction, for consolidation, or to maintain remission. In this regard, of particular interest is the planned intergroup phase II trial of frontline BR versus bendamustine/rituximab/bortezomib followed by lenalidomide consolidation in patients with MCL who are > 65 years or those who are 60-64 years of age and not candidates for high-dose therapy/SCT.

Transplantation Versus Consolidation/Maintenance Strategies A goal of induction therapy in MCL is to achieve maximal initial responses by reducing tumor burden and ultimately prolonging survival; however, disease recurrence is inevitable in most patients. Consequently, it is imperative that additional strategies are used to either maintain or improve the quality of the initial responses achieved. Though consolidation strategies typically seek to improve the depth of response achieved with induction therapy and eradicate any MRD to prolong the relapse-free interval, maintenance therapy is a long-term strategy that aims to delay relapse by maintaining or improving the best response achieved with induction.

Autologous Transplantation Strategies in Mantle Cell Lymphoma With the advent of novel therapeutic agents and development of rituximab-containing aggressive chemotherapy regimens, an intensely debated question is whether there is a role for autologous transplantation in MCL, either in first remission or as a salvage option. The NLG MCL-2 phase II study that evaluated rituximab plus dose-intensified CHOP (maxi-CHOP) induction therapy alternating with rituximab/high-dose Ara-C followed by rituximab- purged ASCT in first remission reported a 6-year OS rate of 70% and event-free survival (EFS) rate of 56%.45 Importantly, this intensive regimen eventually resulted in plateauing of the survival

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curves, suggestive of a cured patient fraction. Consistently, Tam et al reported, notwithstanding the retrospective single-center nature of this study, that rituximab-containing induction therapy/ASCT in first remission may result in long-term disease control with plateaus emerging in the survival curves at 3-8 years.46 However, this analysis revealed that such a HDT/ASCT approach was ineffective when administered beyond first remission.46 Though these results are preliminary and need further validation, they clearly support a role for an aggressive rituximab-containing treatment strategy involving HDT/ASCT when administered at first remission, with a potential for complete disease eradication. Particular emphasis was placed on the fact that ASCT is not generally a recommended strategy when considered later in the disease course of a patient with MCL. For selected patients, timely allogeneic stem cell transplantation might be an alternative curative strategy. The unsatisfactory results of ASCT in relapsed/refractory setting might likely be because of the selection of chemo- and/or rituximab-resistant clones. In a recent report, the estimated 1-year survival of patients transplanted in first remission was 75% compared with 28% when transplanted beyond first remission.47 Worse outcomes might also be expected in patients who receive total body irradiation-based HDT, have a high MIPI score, and who relapse < 1 year from transplant. From a practical standpoint, stem cell collection should be attempted early; preferably before cycle 4, in patients receiving intensive chemoimmunotherapy for prolonged periods.46 Moreover, because achieving a CR is considered desirable before transplant, it is recommended that efforts are made to attain the best response possible. However, it must be cautioned that potentially improved efficacy has to be balanced against increased toxicity and feasibility of any approach.

How Important is Pre-Transplantation Induction Therapy? Several studies have reported higher RR with more aggressive regimens.48-51 However, in a recent report from a National Comprehensive Cancer Network analysis, ASCT following R-CHOP regimen was equivalent to R-hyper–CVAD therapy without ASCT consolidation, but each was superior to R-CHOP therapy alone in terms of PFS.51 This analysis did not include data on R-hyper–CVAD followed by ASCT. Dr. Vose discussed unpublished preliminary results from a University of Nebraska Cancer Center analysis that suggested a better outcome with R-hyper– CVAD induction rather than the R-CHOP regimen before ASCT, suggesting that further intensification of R-hyper–CVAD regimen may be beneficial for eligible patients. A consolidative ASCT component might not be required at all if the R-hyper–CVAD induction regimen or other intensive regimens are used.37,52 Clearly, this is an area that warrants future investigations. The role of Ara-C in induction regimens pre-transplant is unknown. Several studies have shown that addition of high-dose Ara-C and rituximab to intensive CHOP or dexamethasone/ high-dose cytarabine/cisplatin (DHAP) regimens have increased RR.45,49,53 Though the NLG advocates the early and intense use of cytarabine, nearly a quarter of all patients achieved a suboptimal median PFS of 4 years in the MCL-2 protocol, underscoring the need for perhaps more effective preparative regimens and better use of the MIPI index.45 Two ongoing trials are expected to address the

Michael E. Williams et al importance of Ara-C in the management of MCL, the European Younger MCL trial evaluating the efficacy of frontline R-CHOP followed by myeloablative radiation therapy/ASCT compared with R-CHOP/R-DHAP followed by a high-dose Ara-C–containing regimen and ASCT, and the planned Nordic MCL5 trial outlined by Dr. Geisler that involves rituximab/Ara-C induction therapy before rituximab-purged ASCT.54

Role of Allogeneic Transplantation in Mantle Cell Lymphoma Another subject of intense debate is whether allogeneic transplantation fits into the treatment algorithm for patients with MCL. Several reduced intensity regimens that vary in their degree of aggressiveness are available.46,55,56 However, they are also associated with a prohibitive non-relapse mortality (NRM) that limits its application. The challenge is to identify the patient subgroups that should undergo non-myeloablative allogeneic transplantation (NMAT). In terms of patient selection for NMAT, the primary criterion appears to be chemosensitivity, followed by the presence of non-bulky disease, good PS, and less comorbidity. Indeed, NMAT might be an effective strategy for patients with chemosensitive MCL despite previous ASCT, as evidenced by the plateau in the survival curve that is suggestive of a curative potential in a subset of patients.46 Tam et al reported that NMAT treatment resulted in a 6-year actuarial PFS and OS rate of 46% and 53%, respectively, in relapsed/refractory patients with MCL who had previously received ASCT.46 The use of peripheral blood stem cells (PBSC) as the graft source and achieving 95% donor chimerism are considered to be major determinants of disease control following NMAT. The major cause of transplant-related mortality (TRM) was chronic graft-versus-host disease (GVHD), with an actuarial risk of 60%, and its attendant requirement for long-term immunosuppression.46 More effective strategies for GVHD prophylaxis and treatment are needed, perhaps with novel agents such as mammalian target of rapamycin (mTOR) inhibitors and use of steroid sparing regimens. Also, patients with bulky disease might benefit from further debulking strategies before NMAT. It is notable that only a minority of relapsed patients are offered allogeneic SCT at transplant centers, which is more pronounced in cases following relapse to ASCT. Based on the Budde et al data, only 14% of the 134 patients who received HDT/ASCT underwent NMAT upon relapse.47 As front-line therapy, however, NMAT does not appear to be a viable option owing to the unacceptably high rate of NRM, particularly because there is a possibility of prolonging the survival of these patients for several years by sequential application of currently available therapies. Lachance et al reported that 5 out of 8 patients with MCL who underwent sequential R-CHOP chemotherapy, ASCT, and NMAT as frontline therapy are disease-free at a median follow-up of 43 months, while 3 patients died of NRM.57 Longterm follow-up of the surviving patients will be required to better assess the contribution of the allotransplant.

Maintenance/Consolidation Strategies in Mantle Cell Lymphoma In order to sustain the best initial response achieved with induction therapy, several agents have been evaluated as maintenance

therapy including rituximab, radioimmunotherapy (RIT), and bortezomib.58,59 Rituximab maintenance following conventional therapy for relapsed disease has been previously reported in a subset of patients with MCL, where a significant prolongation of response duration was achieved by R-maintenance compared with observation only (P = .049).36 Moreover, 45% of patients who received maintenance therapy appeared to achieve ongoing remissions beyond 2 years (vs. 9%).36 However, planned rituximab maintenance did not appear to improve the survival outcome (EFS or OS) of patients with MCL who underwent upfront HDT/ASCT following R-CHOP induction therapy; consequently, its role when intensive therapy is used remains to be elucidated. Based on these contradictory results, the benefit of rituximab maintenance in patients with MCL is under discussion. Emerging results suggest that RIT consolidation might be a potentially effective treatment approach for patients with MCL, particularly because MCL is regarded as being highly radiosensitive.60 The targeted delivery of radiation with tositumomab/131I-tositumomab followed by CHOP chemotherapy in 24 previously untreated patients resulted in a CR rate of 70%, of which a 44% molecular remission rate was achieved after the RIT component demonstrating activity of RIT.61 The ECOG 1499 trial, which evaluated rituximab/90Y-Ibritumumab tiuxetan following R-CHOP induction therapy in the front-line setting, also demonstrated that RIT substantially increased the complete (confirmed/unconfirmed) remissions achieved (from 13% with R-CHOP to 55% following RIT).59 Moreover, this trial demonstrated that RIT can address minimal residual disease even in the presence of rituximab. However, RIT consolidation shows only limited benefit in patients with bulky disease and those with chemorefractory disease. Using bortezomib/rituximab maintenance following induction therapy in 23 patients with relapsed/refractory MCL was also found to be active; however, the occurrence of bortezomib-related grade 3 neurotoxicity in 56.5% of patients despite dose reductions was an issue.62 A variety of other agents such as lenalidomide and mTOR inhibitors have demonstrated activity in MCL, as will be discussed below, and as such might be appropriate to test as consolidation/maintenance therapy in MCL. In an ongoing phase III placebo-controlled trial, lenalidomide is being evaluated as maintenance therapy following completion of first-line rituximab-containing combination chemotherapy (RENEW) in MCL (Figure 1).63

Integration of Newer Drugs into the Treatment Continuum There is a great impetus to identify newer agents that can result in long-lasting remissions, and improve the therapeutic ratio and survival in MCL. Among others, particular promise is shown by next-generation proteasome inhibitors (PIs), alkylating agents, immunomodulatory agents, mTOR inhibitors, and BCL-2 inhibitors, which will be discussed below.

Proteasome Inhibitors Available clinical experiences with the PI bortezomib in MM have clearly validated the proteasome as a relevant target in anticancer therapy.64 Bortezomib is approved for use as a single-agent in

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Management of Mantle Cell Lymphoma Figure 1 Phase III Placebo-Controlled Study of Lenalidomide Maintenance Following First-line Combination Chemotherapy in Patients With Mantle Cell Lymphoma63

Induction Regimen: s2 #(/0 s

CR/PR

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Placebo days 1-21 every 4 weeks For a maximum of 2 years or until disease progression or unacceptable toxicity develops

activities of the 20S proteasome, with activity in bortezomib-resistant in vitro models.75 In early clinical testing, NPI-0052 is associated with fatigue, GI toxicity, and neurologic toxicity that affected mental status but not painful peripheral neuropathy.76

Alkylating Agents

The bifunctional alkylator bendamustine has shown considerable efficacy in patients with indolent NHL and MCL, either as monotherapy or as part of a combination Estimated enrollment: 382 patients regimen.77 As a single-agent in the pivotal multicenter trial of 100 patients with indo!BBREVIATIONS#2COMPLETERESPONSEFLUDARABINECYCLOPHOSPHAMIDERITUXIMAB02PARTIALRESPONSE2 #(/0 lent NHL, bendamustine therapy yielded RITUXIMABPLUSCYCLOPHOSPHAMIDEDOXORUBICINVINCRISTINEPREDNISONE impressive ORRs in the range of 70% that were recorded even in patients that were relapsed/refractory patients with MCL. This was based on a pivotal resistant to previous chemotherapy including alkylator therapy.78 phase II study that, at a recent updated analysis, reported an ORR Rational combination with rituximab (BR) yielded ORRs ≥ 90% of 32% and a median time to progression of 6.7 months.65 It is and CRs in the range of 60% in 2 phase II trials in patients with notable that about half the patients in this study had relapsed on MCL.79,80 Myelosuppression was the predominant toxicity noted 2 previous lines of therapy upon trial entry and might otherwise with bendamustine monotherapy that was not exacerbated with be considered to be reasonably good-prognosis patients. Based on addition of rituximab. These promising results served as an impetus preclinical evidence indicating additive interactions between bortfor the comparison of BR to R-CHOP regimen in a phase III trial ezomib and rituximab, ongoing trials are evaluating this combinaof 462 previously untreated patients with indolent lymphoma and tion with or without other agents in MCL, some of which will be MCL by the German Study Group of indolent lymphoma.43 In the 66 discussed in subsequent sections. recent final analysis, significant improvements in CR rates and PFS Despite the reported anti-lymphoma activity, it is increasingly were reported with frontline BR therapy compared with R-CHOP becoming evident that alternative PIs to bortezomib are needed. therapy; however, no difference in OS was observed at this early Treatment-emergent neurotoxicity occurs in about 35% of patients follow-up. Bendamustine/rituximab therapy was associated with treated with bortezomib; despite its reversibility, this toxicity and a more favorable toxicity profile in terms of myelosuppression, the emergence of resistance in the majority of treated patients has infectious complications, and neurotoxicity. However, the longhindered the clinical use of bortezomib in some MCL patients.67,68 term toxicity profile of bendamustine needs to be further defined The molecular basis of resistance appears to involve selective alteraparticularly with regard to development of secondary malignancies. tions of proteasome beta5-subunit (PSMB5) protein expression and In order to confirm these results, an ongoing international two-arm mutations in the PSMB5 gene.69 Moreover, bortezomib is a reversphase III trial is evaluating BR to either R-CHOP or rituximab/ ible PI that exhibits a lower affinity for target-binding sites, resultcyclophosphamide/vincristine/prednisone (R-CVP) in previously ing in practical limitations because of drug schedule and intensity, untreated patients with indolent NHL and MCL (Figure 2).81 suggesting that a more profound therapeutic effect might be generImportantly, BR might prove to be an especially useful alternative ated with a PI that binds irreversibly and/or to a greater number of for elderly patients who might not be able to tolerate more intensive proteasome subunits. chemotherapy or those with contraindications to anthracyclines. The next-generation PI, carfilzomib, is an irreversible PI that In efforts to further improve on the efficacy of BR, a recent phase is more selective than bortezomib. These characteristics favor a II study explored the addition of bortezomib to this combination prolonged dosing schedule that allows continuous suppression of (RBV).82 Based on the preliminary report, it does not appear that 70 proteasome activity for maximal benefit. In a phase 1 trial evaluata substantial efficacy benefit was derived with the addition of ing the safety and efficacy of carfilzomib on a consecutive day dosing bortezomib to BR. Moreover, the incidence of neurotoxicity was schedule in relapsed/refractory hematologic malignancies, the doseof significant concern. A planned trial of interest is the randomlimiting toxicity was myelosuppression.71 Encouragingly, clinical ized intergroup phase II trial of frontline BR versus RBV followed experiences in MM and in other hematologic malignancies have by lenalidomide consolidation in elderly or younger transplantshown that carfilzomib therapy is associated with only minimal painineligible patients with MCL. ful peripheral neuropathy.71,72 Recent data indicates that responses Immunomodulatory Agents with carfilzomib monotherapy can be achieved even in patients that The immunomodulatory agent lenalidomide, exhibits pleotropic had failed previous bortezomib therapy.73 A higher ORR of 46% effects on the tumor cells and their microenvironment.83 In cliniwas achieved in bortezomib-naive patients with relapsed/refractory cal studies, lenalidomide has demonstrated considerable antitumor MM on a 2-day schedule.74 Another PI of interest is NPI-0052 that activity in hematologic malignancies, particularly MM and myeloproduces rapid, broad, and prolonged inhibition of all 3 catalytic

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Michael E. Williams et al dysplastic syndromes (MDS), leading to its Figure 2 Phase III Study Comparing Frontline Bendamustine/Rituximab to R-CHOP integration into standard therapies in these or R-CVP Therapy in Indolent Non-Hodgkin Lymphoma Including Mantle 2 disease types.84-86 In a recent update Cell Lymphoma: BRIGHT Study81 of the confirmatory international phase II study that included 57 patients with BendamustineMGM DAYSAND MCL, an ORR of 42% was achieved with Rituximab 375 mg/m, day 1 lenalidomide monotherapy, of which 21% every 4 weeks × 6 cycles R were CR/CRu, the median PFS was 5.7 A Eligibility Criteria: months.87 Responses were even achieved in Rituximab 375 mg/m, day 1 N + B-cell NHL s#$ Cyclophosphamide MGM, day 1 bortezomib-pretreated patients, as revealed D s0RESENCEOF"SYMPTOMSa Doxorubicin MGM, day 1 in a pooled analysis of 54 patients from O s0RESENCEOFLARGETUMORMASSa Vincristine 1.4 mg/m, day 1 s0RESENCEOFLYMPHOMA RELATED M 2 phase II studies.88 The primary toxicity Prednisone MG DAYS  complicationsa I every 3 weeks × 6 cycles with single-agent lenalidomide is reversible s.OPRIORTHERAPY or Z myelosuppression. Preliminary results with Rituximab 375 mg/m, day 1 E lenalidomide in combination with rituxCyclophosphamide ORMGM, day 1 Vincristine 1.4 mg/m, day 1 imab, dexamethasone, or bortezomib in Prednisone MG DAYS  %STIMATEDENROLLMENTPATIENTS relapsed/refractory patients with MCL suggest that although these combinations were aNot required for mantle cell lymphoma. associated with favorable safety profiles, Abbreviations: NHL = non-Hodgkin lymphoma; R-CHOP = rituximab plus cyclophosphamide/vincristine/doxorubicin/prednisone; longer follow-up data are awaited to deterR-CVP = rituximab plus cyclophosphamide/vincristine/prednisone 89-91 mine efficacy. Besides the RENEW trial mentioned earlier, other trials are underway to evaluate the with this class of drugs did not appear to translate into a higher rate role of lenalidomide monotherapy in patients who have relapsed of bleeding.98 Other toxicities include hyperlipidemia, hyperglyceor are refractory to bortezomib, and to compare lenalidomide to mia, mucositis, rash, pneumonitis, and dysgeusia.96,98 investigator’s choice of single-agent in patients with relapsed/refracOther Agents tory MCL.92,93 Open questions include the role of lenalidomide Bcl-2 family proteins are important mediators of apoptosis in in earlier lines of therapy and in combination with chemotherapy NHL, and are promising targets for therapeutic intervention. The backbones in MCL. Bcl-2 antisense oligonucleotide oblimersen was evaluated in combination with rituximab in a phase II study of patients with recurMammalian Target of Rapamycin Inhibitors rent B-cell NHL including MCL, demonstrating an ORR of 42% Using the dose and schedule determined from clinical studies including 10 CR.103 However, an ORR of only 20% was achieved in renal cell carcinoma,94,95 the mTOR inhibitor temsirolimus by patients with MCL. Another class of antiapoptotic agents, BH3 demonstrated a single-agent activity of 38% in a phase II study mimetics, has recently emerged. ABT-263, a prototype BH3 mimetin patients with relapsed/refractory MCL.96 However, significant ic has been shown to potentiate the antitumor activity of cytohematologic toxicities at the weekly 250 mg dose prompted dose toxic agents in preclinical models. Though early signals of antitumor reductions and evaluation of a much lower dose of 25 mg in patients activity in lymphoid malignancies have been reported, it might have with MCL.97 Comparing 2 dose schedules of temsirolimus, 175 to be combined with inhibitors of other pathways for optimal activmg/week for 3 weeks followed by either 75 mg/week or 25 mg/ ity.104 Another therapeutic agent of interest is 8-Chloro-adenosine, week, versus a single-agent investigator’s choice in a phase III trial a novel cytotoxic agent that inhibits RNA synthesis, which is in early of 162 heavily pretreated relapsed/refractory patients with MCL, a clinical testing in hematologic malignancies.105 significant improvement in ORR (22% vs. 2%; P = .0019) and PFS (HR, 0.44; P = .0009) compared with control was achieved with Conclusion high-dose temsirolimus.98 Though this data validated the proofThe issues examined by the global experts who participated in of-principle that targeting mTOR pathway is clinically relevant in the third MCL workshop led to identification of challenges and MCL, there was agreement that the goal is to develop combinations key questions in the management of MCL. The expert opinions incorporating mTOR inhibitors because the single-agent activity in and recommendations summarized in this article are expected to MCL is inadequate. Indeed, a recent report demonstrated that the have considerable clinical relevance for community physicians combination of temsirolimus (25 mg dose) and rituximab might in the management of this challenging lymphoma. It was unaniincrease the RR including CR rates, although thrombocytopenia mously acknowledged that large randomized studies are needed in still persisted albeit at a lower rate, warranting further comparaMCL; however, there was no consensus on what regimen should tive studies with this combination.99 An ongoing phase I/II trial is constitute the standard arm in these trials. The potential value of evaluating rituximab/temsirolimus/cladribine in newly diagnosed risk-adapted therapy in addressing the heterogeneity of MCL was elderly patients with MCL.100 Recently, 2 other mTOR inhibitors, recognized, with the caveat that its relevance will be affected by everolimus and deforolimus, have also shown encouraging responses the treatment received. Nevertheless, it was the contention of the in MCL, and are being evaluated in combination trials.101,102 panel that in current clinical practice MIPI allows individual risk Notably, the predominant toxicity of thrombocytopenia associated

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Management of Mantle Cell Lymphoma estimation but should not guide treatment decisions, which might partly be attributable to the prevalent notion that the majority of patients with MCL are high-risk and need to be treated accordingly. Intriguing alternatives proposed were whether age or tolerability should be considered as primary determinants of therapy instead. At the present time, achieving CR might be a surrogate for outcome, particularly if ASCT consolidation is used, possibly because it selects for patients that are chemosensitive. Based on the limited data available, the role of MRD monitoring as an early surrogate marker for risk adapted therapy is unknown. Currently, it appears that chemotherapy will remain as the backbone of treatment strategies in MCL in at least the near term; addition of rituximab to this backbone appears to improve RR and PFS but not OS. Though there was general agreement that select high-risk patient subsets might benefit from aggressive therapies, the use of aggressive induction therapy versus sequential less intensive chemotherapy remains uncertain. Incremental benefit from each additional therapy from mild to aggressive is an argument in favor of less intensive therapy up-front. Long-term disease control might be a reality with autologous transplantation in the front-line setting. For patients with relapsed or refractory disease, the results with autologous transplantation remain unsatisfactory, whereas the timely application of a nonmyeloablative allogeneic transplantation may be curative. For elderly patients who are ineligible for aggressive high-dose therapies, the use of less intensive non-anthracycline-based strategies such as bendamustine and other novel biologic agents offer promise for the future. Novel agents have typically resulted in RR of about 30% when used as monotherapy; however it must be cautioned that when comparing these agents, patient characteristics particularly their MIPI risk scores should be taken into account. Future goals are to develop approaches that incorporate novel molecular agents into immunochemotherapy backbones to improve clinical outcomes for patients with MCL.

Disclosures Michael E. Williams has served on the Board of Directors for the Lymphoma Research Foundation and the European Mantle Cell Lymphoma Network; has received research funding from Celgene Corporation, Cephalon, Inc., Genentech, Inc., and Novartis Pharmaceuticals Corporation; and has served as a consultant or been on an advisory/research panel for Celgene Corporation. Martin Dreyling has received research funding from and served as a consultant or been on an advisory/research panel for Celgene Corporation, Mundipharma International Limited, Pfizer Inc./Wyeth Pharmaceuticals, and Roche Pharmaceuticals; and has received honoraria from Bayer Pharmaceuticals Corporation, Mundipharma International Limited, Pfizer Inc./Wyeth Pharmaceuticals, and Roche Pharmaceuticals. Jane N. Winter has received research funding from Angen, Ambit Biosciences, BristolMyers Squibb Company, Chroma Therapeutics, Genentech, Inc., Millennium Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., and Seattle Genetics, Inc.; has served as a consultant or been on an advisory/research panel for Antisoma plc, Caremark, LLC, Eisai Inc., the Federal Drug Administration, Hana Biosciences, Inc., and Novartis Pharmaceuticals Corporation; and

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has recieved honoraria from the American Society of Hematology, Bristol-Myers Squibb Company, the Institute for Medical Education and Research, and Physicians’ Education Resource. John P. Leonard has served as a consultant or been on an advisory/research panel for Biogen Idec, Calistoga Pharmaceuticals, Inc., Celgene Corporation, Cell Therapeutics, Inc., Cephalon, Inc., EMD Serono, Inc., Facet Biotech Corporation, GlaxoSmithKline, Johnson & Johnson Services, Inc., Millennium Pharmaceuticals Corporation, Novartis Pharmaceuticals Corporation, and sanofi-aventis U.S.

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