The landscape of mantle cell lymphoma is clearly evolving, due to the availability of new treatment options incorporating novel biologic agents. To optimize therapy, we should build on what has been accomplished over the last 3 decades.
The management of mantle cell lymphoma has evolved dramatically since 1994, when the Revised European-American Lymphoma Classification recognized it as a separate disease entity. This was based not only on the distinct molecular features (hallmark t(11;14) translocation) and immunophenotype of mantle cell lymphoma but also on its distinct clinical course, with much poorer outcomes than those of other patients with so-called indolent lymphomas. Such challenges led to exploration of novel approaches, contributing to an improvement in median overall survival (OS) over the last 4 decades, from 2.5 years in the late 1970s to 4.5 years in the mid-1990s and 5 to 7 years or longer in the late 2000s.[1,2] Several factors underlie this continued upswing in survival outcomes for patients with mantle cell lymphoma.These range from better supportive care; to the use of dose-intensive therapy (DIT), leading to prolonged disease-free intervals well in excess of 5 to 7 years; to the development of promising novel therapies for a disease in which patients commonly become chemoresistant in the relapsed setting.
The mantle cell lymphoma treatment landscape is changing rapidly, based on novel combinations, including biologics, as well as on a better understanding of the impressive molecular diversity of this disease. With the availability of new therapeutic options, it is naturally tempting to revisit-not abandon-previous milestones. Although the optimal treatment of mantle cell lymphoma remains controversial, some cornerstone therapies have emerged that have extended the duration of first complete remission, a critical factor for durable long-term clinical benefit in mantle cell lymphoma. These include the addition of rituximab to induction therapy regimens, as well as the use of cytarabine-based induction and DIT, with or without autologous stem cell transplantation (ASCT) consolidation.
In a randomized prospective trial by the German Low-Grade Lymphoma Study Group, the addition of rituximab (R) to a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (without ASCT) clearly increased the overall response rate, complete response (CR) rate, and time to treatment failure in patients with mantle cell lymphoma, but R-CHOP had no significant impact on progression-free survival (PFS; median rate of 25% at 2 years) or OS compared with CHOP alone. Based on the poor results of standard induction therapy, the natural shift was to use high-dose therapy (HDT) followed by ASCT as consolidation in first remission. The initial favorable results of smaller phase II trials were confirmed by a large randomized German trial in which patients responding to CHOP were randomized between maintenance interferon (IFN-Î±) and HDT-ASCT. While there was a significant improvement of both PFS and duration of response in favor of the HDT-ASCT consolidation arm, there was no difference in OS outcomes, likely because of the crossover design of the trial.
Several subsequent studies of DIT/HDT have repeatedly confirmed an extension of the median PFS by well over 5 years.[7-9] In contrast, the median PFS with R-CHOP remains in the 14- to 18-month range, even in the recent LYM-3002 phase III trial in patients not eligible for HDT-ASCT (R-CHOP vs R-CHOP + bortezomib, with 244 patients per arm). Although the combination of bendamustine plus rituximab (BR) was reported to be superior to R-CHOP (median PFS, 22 months vs 35 months; P = .06) in the mantle cell lymphoma cohort (92 patients) from the Study Group for Indolent Lymphomas trial, superiority of BR over R-CHOP was not suggested by results of the attempted confirmatory BRIGHT trial in the United States (with the exception of the CR rate, but the control arm had pooled both patients treated with R-CHOP and patients treated with R-CVP [cyclophosphamide, vincristine, and prednisone]). BR was piloted by the Southwest Oncology Group as induction therapy prior to HDT, with promising updated results from a small trial that was interrupted because of failure to mobilize stem cells in the R-hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) arm (which was done only after cycle 1A and 1B). Typically, DIT/HDT strategies are associated with much higher CR rates-about 55% prior to ASCT and over 85% to 90% post ASCT (vs a CR rate of approximately 30% for patients treated with R-CHOP or BR); as might be expected, these results translate into much more durable remissions and disease-free intervals.
It also became clear through the use of these DIT/HDT strategies that incorporating cytarabine as part of induction therapy pre-ASCT was critical. The benefit of cytarabine, as part of the DHAP regimen (dexamethasone, high-dose cytarabine, and cisplatin), was initially shown by the French Groupe d’Ãtude des Lymphomes de l’Adulte (R-CHOP/R-DHAP → ASCT, which tripled the CR rate and produced a median event-free survival [EFS] time of 83 months). The initial impressive results of the Nordic MCL2 trial (maxi-CHOP alternating with cytarabine → ASCT) were recently updated with a median PFS of 8.5 years and a median OS of 12.7 years (at a median follow-up of 11.4 years) in an intent-to-treat analysis.
The benefit of high-dose cytarabine was definitively proven by a large and remarkable phase III study from the European Mantle Cell Lymphoma Network, in which more than 400 patients were randomized to treatment with R-CHOP/R-DHAP (alternating for 6 cycles) followed by HDT (using cytarabine plus melphalan in combination with total body irradiation) vs R-CHOP for 6 cycles followed by HDT (using cytarabine in combination with total body irradiation). The results showed the cytarabine-containing arm to be superior, in terms of time to treatment failure (the primary study endpoint), with a 30% reduction in the risk of progression, and this was verified across all Mantle Cell Lymphoma International Prognostic Index (MIPI) subgroups. The superior results were attributed to the quality of response seen in the high-dose cytarabine arm, which showed much earlier CRs and a higher CR rate compared with the R-CHOP arm, translating into a longer duration of first response and better treatment outcomes.
The molecular CR rate post induction was 83% in the cytarabine arm vs 51% in the control arm (P < .0001), translating to a new standard for DIT/HDT in frontline therapy for mantle cell lymphoma. In addition, built-in assessments of minimal residual disease (MRD) in this study revealed the profound impact on outcome of achieving negative MRD status (ie, a molecular CR). Indeed, given that several studies have now shown MRD status to be predictive of outcome across the board, negative MRD will likely become a key endpoint in future mantle cell lymphoma trials.
The agents used for induction in the Nordic MCL2 trial regimen (R-maxi-CHOP alternating with high-dose cytarabine) are not very different from the regimen of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyper-CVAD), alternating with methotrexate and high-dose cytarabine, another dose-intensive regimen frequently used in mantle cell lymphoma patients younger than 65 years (without ASCT consolidation). The initial experience with R-hyper-CVAD in a study of 97 patients, one-third of whom were over 65 years old, showed a CR rate of 87% and a 3-year failure-free survival rate of 73% in the under-65 group, consistent with the results seen with ASCT consolidation. In a recent update with 15-year follow-up, the median OS exceeded 10 years for all patients, while about one-third of the patients 65 years and older were still in their first remission. The R-hyper-CVAD regimen has been used as induction pre-ASCT with very strong results, although it is not clear in this population, particularly in patients achieving a CR, that the HDT-ASCT consolidation is needed. This question is being addressed by the ongoing TRIANGLE study in Europe, which aims to evaluate ibrutinib in the frontline setting, including a randomization of HDT vs maintenance ibrutinib post induction.
Although no one would argue about the progress achieved by the use of DIT/HDT compared with standard therapy, such dosing strategies are not always feasible in the mantle cell lymphoma population, whose median age at diagnosis is in the mid to late 60s. However, the presence of comorbidities-not just age-should guide patient management decisions, since selected patients over 65 years of age can enjoy clinical outcomes similar to those achieved in younger patients, even following treatment with HDT-ASCT. In reality, such patients are typically excluded from trials, and it then becomes important to evaluate results seen in real-world clinical practice, where unfortunately, overall outcomes for patients with mantle cell lymphoma have not changed appreciably since the mid-1990s, according to US registry data.
It is interesting, however, that the impact of DIT/HDT has been verified outside of clinical trials. A Scandinavian study of more than 1,300 patients confirmed the positive impact of both rituximab-containing regimens and ASCT consolidation on OS in mantle cell lymphoma patients. In the United States, data from the Surveillance, Epidemiology, and End Results (SEER) database comparing R-CHOP vs R-hyper-CVAD or R-CHOP/R-hyper-CVAD/ASCT confirmed, as we did in our series, that outcomes of treatment with R-CHOP are clearly inferior to those of DIT/HDT strategies, both in terms of PFS and OS when comparing pooled data from patients treated with DIT/HDT vs R-CHOP alone.
Unfortunately, despite the availability of DIT/HDT strategies, a significant number of patients relapse over time and then experience only transient benefit from additional chemotherapy. Several novel therapies have been approved by the US Food and Drug Administration over the last 10 years for patients with mantle cell lymphoma: bortezomib (in December 2006), lenalidomide (in June 2013), and ibrutinib (in November 2013); also, temsirolimus was approved in August 2009 in the European Union. These new biologic agents have produced durable responses even in chemotherapy-refractory patients. Recently reported promising results of biologic combinations in the frontline setting using lenalidomide plus rituximab (38 patients) or ibrutinib plus rituximab (50 patients) raise the possibility of future nonchemotherapy options in mantle cell lymphoma. However, the follow-up of these studies is rather short and we do not yet have any experience regarding patients’ response to salvage therapy in these settings. Mantle cell lymphoma is a disease that frequently becomes chemoresistant over time, including after the use of biologic agents, as shown by a median OS of only 2.9 months following cessation of ibrutinib in one study, justifying a degree of caution in moving forward.
Given their rather mild toxicity profile overall, the logical next step is to combine these biologic agents with current standard regimens used in mantle cell lymphoma. This approach has been applied successfully in elderly patients, for example, in treatment with R-CHOP plus bortezomib (leading to a new frontline standard). Investigation of additional combinations with BR, such as with bortezomib, lenalidomide, or ibrutinib, is underway. Similar strategies should be applied in younger patients to build on the success of DIT/HDT, in order to deepen the initial response to treatment (ie, to achieve MRD-negative status) and thereby further reduce the risk of relapse, and through maintenance/consolidation strategies. The role of maintenance therapy in mantle cell lymphoma is growing, including its use post HDT,[7,26] and this approach might even help to improve OS (with longer follow-up) in patients under 65 years of age, as it did in the elderly patient setting.
In summary, use of DIT/HDT in conjunction with cytarabine-containing chemoimmunotherapy induction translates into long-term clinical benefit in mantle cell lymphoma, with an initial duration of response well beyond 7 to 8 years. Ongoing studies looking at combinations with biologic agents might help to further improve mantle cell lymphoma outcomes, including in patients with high MIPI scores, as well as in refined patient subsets identified by biologic prognostic markers (Ki-67/MIPI-b), p53 (17p deletion/mutation), or even microRNAs.
The landscape of mantle cell lymphoma is clearly evolving, due to the availability of new treatment options incorporating novel biologic agents. To optimize therapy, we should build on what has been accomplished over the last 3 decades-particularly through the use of DIT/HDT, which generated unprecedented rates of CR and molecular CR accompanied by very long durations of first remission. This implies that oncologists should continue to encourage clinical trials, implement MRD-based treatment decisions, and take into account the biologic diversity of the disease-and not just the patient’s age at diagnosis-with the goal of advancing “real-world” benefits for our patients with mantle cell lymphoma.
Financial Disclosure:The author has no significant interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
1. 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.
2. Abrahamsson A, Albertsson-Lindblad A, Brown PN, et al. Real world data on primary treatment for mantle cell lymphoma: a Nordic Lymphoma Group observational study. Blood. 2014;124:1288-95.
3. Skarbnik AP, Goy AH. Mantle cell lymphoma: state of the art. Clin Adv Hematol Oncol. 2015;13:44-55.
4. Campo E, Rule S. Mantle cell lymphoma: evolving management strategies. Blood. 2015;125:48-55.
5. 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.
6. 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.
7. 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.
8. Hermine O, Hoster E, Walewski J, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2015;388:565-75..
9. 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.
10. Robak T, Huang H, Jin J, et al. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med. 2015;372:944-53.
11. 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.
12. Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123:2944-52.
13. Chen R, Li H, Bernstein S, et al. Pre-transplant R-bendamustine induces high rates of minimal residual disease in MCL patients: updated results of S1106: US Intergroup study of a randomized phase II trial of R-HCVAD vs. R-bendamustine followed by autologous stem cell transplants for patients with mantle cell lymphoma. Blood. 2015;126:abstr 518.
14. 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.
15. 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.
16. Eskelund CW, Kolstad A, Jerkeman M, et al. 15-year follow-up of the Second Nordic Mantle Cell Lyjmphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016;175:410-8.
17. Romaguera JE, Fayad L, Rodriguez MA, et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005;23:7013-23.
18. Chihara D, Cheah CY, Westin JR, et al. Rituximab plus hyper-CVAD alternating with MTX/Ara-C in patients with newly diagnosed mantle cell lymphoma: 15-year follow-up of a phase II study from the MD Anderson Cancer Center. Br J Haematol. 2016;172:80-8.
19. Till BG, Gooley TA, Crawford N, et al. Effect of remission status and induction chemotherapy regimen on outcome of autologous stem cell transplantation for mantle cell lymphoma. Leuk Lymphoma. 2008;49:1062-73.
20. Dahi PB, Tamari R, Devlin SM, et al. Favorable outcomes in elderly patients undergoing high-dose therapy and autologous stem cell transplantation for non-Hodgkin lymphoma. Biol Blood Marrow Transplant. 2014;20:2004-9.
21. Chandran R, Gardiner SK, Simon M, Spurgeon SE. Survival trends in mantle cell lymphoma in the United States over 16 years 1992-2007. Leuk Lymphoma. 2012;53:1488-93.
22. Mato AR, Svoboda J, Feldman T, et al. Post-treatment (not interim) positron emission tomography-computed tomography scan status is highly predictive of outcome in mantle cell lymphoma patients treated with R-HyperCVAD. Cancer. 2012;118:3565-70.
23. Ruan J, Martin P, Shah B, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015;373:1835-44.
24. Wang ML, Lee H, Chuang H, et al. Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial. Lancet Oncol. 2016;17:48-56.
25. Martin P, Maddocks K, Leonard JP, et al. Postibrutinib outcomes in patients with mantle cell lymphoma. Blood. 2016;127:1559-63.
26. Callanan M, Delfau M, Macintyre E, et al. Predictive power of early, sequential MRD monitoring in peripheral blood and bone marrow in patients with mantle cell lymphoma following autologous stem cell transplantation with or without rituximab maintenance; interim results from the LyMa-MRD project, conducted on behalf of the Lysa Group. Blood. 2015;126:abstr 497.
27. Robinson S, Dreger P, Caballero D, et al. The EBMT/EMCL consensus project on the role of autologous and allogeneic stem cell transplantation in mantle cell lymphoma. Leukemia. 2015;29:464-73.
28. Delfau-Larue MH, Klapper W, Berger F, et al. High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma. Blood. 2015;126:604-11.
29. Husby S, Ralfkiaer U, Garde C, et al. miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator. Blood. 2015;125:2669-77.