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Evolving Treatment Strategies for Mantle Cell Lymphoma

Fakhri, Bita MD; Kahl, Brad MD

doi: 10.1097/01.COT.0000520679.57776.2b
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Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma, which has classically been considered an aggressive and incurable lymphoma. The median age at diagnosis is 68, with a 3:1 male predilection. The genetic hallmark is the chromosomal translocation t(11;14)(q13;q32) resulting in overexpression of cyclin D1. In terms of clinical presentation, one-third of MCL patients present with high levels of lactate dehydrogenase (LDH) and 25 percent of patients present with B symptoms. CNS involvement is extremely rare. In a work by the European MCL Network, it has been shown a combination of the Ki-67 index, independent of blastoid cytology and growth pattern, and MIPI score including four independent prognostic factors (i.e., age, performance status, LDH, and leukocyte count) provides strong prognostic value. The modified combined Ki-67 index and MIPI score has been increasingly utilized in clinical practice to further inform treatment decisions in patients with MCL.

Newly diagnosed MCL patients with low tumor burden and Ki-67 index ≤ 30 percent can be managed through a wait-and-watch strategy and defer therapy to the time of disease progression. Although MCL typically responds to frontline chemotherapy, it remains incurable with standard approaches. For patients in need of treatment, the critical decision is whether to proceed with an intensive treatment strategy versus a non-intensive treatment strategy. Given the discouraging risk-benefit profile, older MCL patients should be spared intensive strategies while younger/fit patients can be considered for intensive strategies. In the absence of solid criteria to differentiate older and younger, many European studies have used an age cutoff of 65.

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Treatment-Naïve MCL Patients

Treatment Strategies in Elderly Patients

In terms of induction strategies for treatment-naïve elderly patients, multiple regimens have been investigated in clinical trials. The University of Texas MD Anderson Cancer Center experience employing R-hyper-CVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with high-dose methotrexate/cytarabine (R-MTX/AraC) showed a median failure-free survival (FFS) of 3 years in patients aged > 65 years versus 5.5 years in patients aged ≤ 65 years, revealing the inferior results achieved in the older patients. The University of Pennsylvania group reported the outcomes for 38 patients with MCL aged ≥ 60 years who received R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-Hyper-CVAD with or without autologous stem cell transplantation (ASCT). This study demonstrated R-CHOP alone to be a less-effective treatment for older patients. The median progression-free survival (PFS) of R-CHOP + ASCT was 3.2 years versus 4 years in R-Hyper-CVAD alone. Both strategies provided longer PFS than that of R-CHOP alone, 1.6 years. The rates of adverse events were similar for R-Hyper-CVAD alone and R-CHOP + ASCT. While these two groups demonstrated that intensive strategies are superior to historical outcomes recognized with R-CHOP, newer approaches appear to produce outcomes similar to intensive strategies while causing less toxicity. For instance, replacing vincristine in R-CHOP by bortezomib in frontline therapy has shown superior outcomes for VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone) compared to R-CHOP at the price of a mild increase in hematologic toxicity.

Bendamustine-rituximab (BR) has been shown to be an effective induction strategy in older MCL patients. The StiL trial has compared BR with R-CHOP as first-line treatment for patients with indolent and mantle cell lymphomas. The median PFS was 35.4 months in the BR group versus 22.1 months in the R-CHOP group. Increased PFS, along with a significantly better tolerated side effect profile has made the BR regimen a preferred and popular first-line treatment option in treatment-naïve older MCL patients.

A recent phase II study has explored the combination of rituximab and lenalidomide (R2 regimen) with induction and maintenance phases. Although this combination biologic therapy provided a promising early signal, longer follow-up and validation in a larger cohort is needed before this strategy can be endorsed.

In summary, there is no convincing motive to consider R-CHOP as the platform of choice in elderly MCL patients. Based on the Stil trial, BR appears to be superior in terms of clinical outcomes combined with fewer treatment-associated toxicities. VR-CAP is a reasonable treatment strategy if bendamustine is not a feasible option. Ongoing trials (SHINE and E1411) are testing novel agents (SHINE—ibrutinib; E1411—bortezomib) onto a BR backbone to determine if outcomes can be further improved in the elderly patient population with MCL.

In terms of maintenance approaches, given the high response rates to induction strategies but relatively short-lived duration of remission, the idea of maintenance therapy is naturally appealing in MCL. Multiple studies have explored the role of maintenance strategies upon the conclusion of induction therapy to improve the outcomes of older patients with MCL.

A study by the European MCL Network determined rituximab maintenance following R-CHOP induction regimen can improve response duration and potentially overall survival (OS). However, R-CHOP is a suboptimal induction strategy. BR, with good efficacy and acceptable toxicity profile, appears to be a better platform for older MCL patients. To date, no clinical trial has provided statistical evidence supporting the benefit of rituximab maintenance after BR in the treatment of older patients with MCL. More study is needed to decisively answer this question.

Treatment Strategies in Young & Fit Patients

In general, intensive strategies produce more durable remissions in MCL. The impact of intensive treatment on OS is less clear. Intensive treatment refers to any strategy that includes ASCT as consolidation or intensive chemotherapy such as conventional R-hyper-CVAD with alternating R-MTX/AraC. If patients are appropriate candidates for intensive therapy, this is a very reasonable approach.

The University of Texas MD Anderson Cancer Center group experience with R-hyper-CVAD showed a 5-year FFS of 60 percent, with a median FFS of 5.5 years in patients aged ≤ 65 years. More recent studies have focused on exploring the role of high-dose cytarabine (HiDAC) as part of the induction regimen prior to ASCT in young, newly-diagnosed MCL patients. In a phase II trial by Delarue, et al, 3 cycles of R-CHOP followed by 3 cycles of R-DHAP (rituximab plus dexamethasone, high-dose cytarabine, and cisplatin) followed by ASCT in responding patients resulted in a median PFS of 84 months and 5-year OS rate of 75 percent. Based on the success of this phase II trial, the European MCL Network compared R-CHOP followed by ASCT versus alternating R-CHOP and R-DHAP followed by ASCT. The median PFS was 4.3 years in the R-CHOP + ASCT group, compared to 9.1 years in the cytarabine group. In another work by the Nordic MCL group, the feasibility and efficacy of dose-intensified R-CHOP (maxi-CHOP), alternating with R + HiDAC for a total of 6 cycles followed by ASCT was explored. The follow-up results published in 2012 revealed an EFS of 7.4 years.

Given these impressive results, immunochemotherapy containing high-dose cytarabine followed by ASCT has emerged as a worldwide standard of care in younger patients with MCL. More studies are currently being conducted aiming to reduce the toxicity of intense induction regimens without compromising survival outcomes (Triangle—ibrutinib; EA4151—fine-tuning treatment in MRD-negative patients).

In terms of maintenance strategies in younger MCL patients, until recently no current data existed to support rituximab maintenance in younger patients receiving intensive therapy. The LyMa trial explored the benefit of rituximab maintenance versus observation only post-ASCT in young MCL patients. The superior EFS, PFS, and OS in the rituximab maintenance arm compared with the observation arm strongly supported the efficacy of rituximab maintenance and established a new standard of care for young MCL patients.

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Management of Relapsed/Refractory MCL

In recent years, several novel therapeutic agents have been investigated in phase I/II clinical trials in the relapsed or refractory MCL setting. In the relapsed or refractory (R/R) setting, reduced intensity conditioning allogeneic hematopoietic stem cell transplantation may offer the highest likelihood of long-term survival in young (R/R) MCL patients at the cost of increased non-relapse mortality rate and chronic graft versus host disease. Novel agents targeting activated pathways in MCL cells, such as bortezomib (NFkB inhibitor), lenalidomide (angiogenesis inhibitor), ibrutinib (Bruton's tyrosine kinase [BTK] inhibitor), and temsirolimus (mammalian target of rapamycin [mTOR] inhibitor) can be used aiming to gain disease control while a donor search is carried out.

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Future Directions

MCL is a clinically heterogeneous disease with a highly variable clinical course, highlighting a need for personalized approaches to optimize survival outcomes. In the past decade, well-designed clinical trials have led to significant improvement in clinical outcomes. Moreover, an improved appreciation of disease biology and pathways involved in the lymphomagenesis of MCL has resulted in developing targeted agents. These agents are now being integrated in clinical trials in the upfront, maintenance, relapsed, and refractory settings.

For older MCL patients, the SHINE trial investigates the benefit of adding ibrutinib in combination with BR versus BR for treatment-naïve patients. In another trial for older patient population, Eastern Cooperative Oncology Group (ECOG) 1411 investigates whether the addition of bortezomib to the BR backbone in the induction setting and lenalidomide to rituximab in the maintenance setting would improve survival outcomes.

For younger MCL patients, the Triangle trial attempts to investigate whether adding ibrutinib to both induction and maintenance phases improves outcomes over R-CHOP/R-DHAP only followed by ASCT alone. The Triangle trial is also designed to examine whether adding ibrutinib to induction and maintenance eliminates the need of upfront ASCT.

The ECOG-ACRIN (EA4151) aims to explore the benefit of upfront ASCT in patients who have already achieved a negative minimal residual disease status. Prospective work should revolve around further individualizing treatment based on tumor biology through incorporating translational studies into clinical trials to advance survival outcomes while improving side effect profile associated with each treatment strategy.

BITA FAKHRI, MD, is a Fellow and BRAD KAHL, MD, is Professor in the Division of Medical Oncology, Washington University School of Medicine, St. Louis, Mo.

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
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