COUNTERPOINT: The Role of Stem Cell Transplantation in Mantle Cell Lymphoma

December 15, 2016
Leo I. Gordon, MD
Leo I. Gordon, MD

Volume 30, Issue 12

Management strategies for patients with mantle cell lymphoma continue to demonstrate pendulum-like swings between those appropriate for low-grade lymphoma, and those appropriate for very aggressive lymphoma.

The Pendulum Swings Again: Time to Reassess the Role of ASCT in First Complete Remission

Advances in Biology

More recent insights into mantle cell lymphoma biology and resultant clinical trials have advanced our understanding of this disease, and treatment outcomes have improved.[1,2] Further, newer agents such as bortezomib, lenalidomide, and ibrutinib, as well as a clearer picture of the molecular biology, have significantly changed our approach to management.[3-6]

Treatment Alternatives

High-dose therapy with transplant in first complete remission

Initial attempts at more aggressive immunochemotherapy with rituximab (R) and a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or with purine analog–containing regimens, improved the response and time to treatment failure, but did not have an impact on overall survival.[7,8]

Therefore, in an effort to improve patient outcomes, over the last 2 decades, investigators in the United States and Europe have explored algorithms for intensified treatment, including high-dose chemotherapy followed by autologous stem cell rescue-a strategy that had proven to be effective in patients with diffuse large B-cell lymphoma. Most recently, a project by the European Mantle Cell Lymphoma Network and the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation studying the role of autologous stem cell transplantation (ASCT) and allogeneic stem cell transplantation in mantle cell lymphoma reached consensus in support of ASCT as standard first-line consolidation therapy, but concluded that it should not be used before the patient has achieved a complete or partial response.[9]

However, because these regimens also incorporated rituximab and cytarabine, drugs that on their own resulted in improved outcomes in mantle cell lymphoma,[10] there are some limitations to interpretation of these phase II transplant trials.[11-14]

Intensive chemotherapy: cytarabine and rituximab

Romaguera and colleagues at the MD Anderson Cancer Center published and then updated data in a single-institution study of 97 patients treated with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyper-CVAD) without transplant.[15,16] The initial analysis in the nontransplanted patients indicated that with a median follow-up of 40 months, the 3-year failure-free survival (FFS) and overall survival (OS) rates were 64% and 82%, respectively, with no plateau in the survival curves. For patients < 65 years of age, the 3-year FFS rate was 73%.[15] At 10 years (median, 8 years), the median OS for all patients was not reached, and median time to failure (TTF) was 4.6 years.[16] For patients < 65 years old, the median TTF was 5.9 years. Patients > 65 years old, who are generally not considered good candidates for transplant, did not do as well.[17] In the pre-rituximab era, the MD Anderson group also looked at 45 patients who had been treated with hyper-CVAD (without rituximab) followed by ASCT. Of these patients, 25 had no prior therapy, and this group had an OS rate of 92% at 3 years and an event-free survival (EFS) rate of 72%, while the 20 previously treated patients had OS and EFS rates of 25% and 17%, respectively.[18]

In a retrospective analysis from the National Comprehensive Cancer Network, LaCasce et al found that the outcomes were identical for patients treated with R-hyper-CVAD with vs without transplant, and only patients treated with R-CHOP appeared to benefit from transplant.[19]

In 1996, at the dawn of the rituximab era, to address the issue of the role of transplant in first remission, the European Mantle Cell Lymphoma Network initiated a randomized trial of CHOP (without rituximab or cytarabine) followed by either interferon maintenance or myeloablative radiochemotherapy (high-dose cyclophosphamide + 12-Gy total body irradiation) and ASCT. This remains the only trial to compare transplant vs no transplant in patients with mantle cell lymphoma in first complete remission, and it was completed before clinical use of cytarabine or maintenance therapy with rituximab was widespread. Patients in the transplant group had longer durations of progression-free survival, but at first analysis there was no difference in OS outcomes between the groups.[8]

An interim analysis that was presented but not published (Hoster, 2009 American Society of Hematology Annual Meeting) suggested that transplant conferred a survival advantage (P = .034), but the final analysis has not been completed (Dreyling, personal communication). These data, from the era before treatment of mantle cell lymphoma with rituximab or cytarabine, suggest that even when the control treatment is less than adequate by today’s standards, high-dose chemoradiotherapy and ASCT have not been shown to improve overall survival. Final analysis of these data in a manuscript format should be forthcoming. Despite the lack of convincing data, subsequent studies-all phase II nonrandomized trials-incorporated high-dose chemotherapy followed by transplant as part of the treatment algorithm for patients in first complete remission, elevating transplant to a standard of care with no compelling data[9,20] and despite late recurrences.[21]

Maintenance rituximab

What other alternatives exist for patients affected by this chronic disease? In 2006, Forstpointner and colleagues examined the role of maintenance rituximab and found its use was associated with prolonged progression-free survival.[22] The European Mantle Cell Lymphoma Network randomized patients over 65 years of age who were not candidates for transplant to receive either R-CHOP or a purine analog–containing regimen (rituximab, fludarabine, and cyclophosphamide) and then to lifetime rituximab maintenance vs interferon maintenance. They found that the remission duration was 23 months in the interferon arm and was not reached at the time of publication in the rituximab arm.[23] Further, in the Nordic trials, Andersen et al made a very strong case for rituximab maintenance therapy. They published data showing that, post transplant, when patients with an apparent complete response were monitored by disease-specific primers, of 36 patients who had molecular relapse without signs of clinical relapse, 26 had undergone preemptive treatment with rituximab. Of these 26 patients, 24 (92%) reverted to polymerase chain reaction–negative status for a median duration of 1.5 years.[12]

These findings suggest that a targeted maintenance strategy has validity, but when disease-specific primers are not routinely available, it is rational, based on these data, to conclude that regular maintenance therapy may indeed provide benefit. This argument is made even stronger by recent data suggesting that in a randomized trial by the Lymphoma Study Association (known as the Lysa group), maintenance rituximab following transplant results in prolonged disease-free survival compared with transplant without maintenance.[24] Together with the other previously described data, this raises the question of whether transplant benefits only a very select group of patients. Indeed, recent reviews on the subject call into serious question the value of transplant in mantle cell lymphoma patients in first complete remission.[2,25]

Summary

Management strategies for patients with mantle cell lymphoma continue to demonstrate pendulum-like swings between those appropriate for low-grade lymphoma, and those appropriate for very aggressive lymphoma. As research advances, it now appears that we are dealing with not one disease entity but several diseases; this will be delineated more clearly as we continue to uncover relevant molecular and clinical features.[26] Our approach in the future will be dictated by a better understanding of biology; until then, we cannot mandate aggressive treatment (eg, transplant) or nonaggressive treatment as the standard for all patients. There will be some patients who can be observed as an alternative to immediate treatment[27,28]; some patients (with blastoid variants or high-risk molecular features) who may require intensive therapy including allogeneic or autologous transplant and a maintenance regimen[29-31]; and some who may be treated with immunochemotherapy or targeted agents (ibrutinib), with or without maintenance, and without transplant. The use of patient-specific molecular probes to detect disease after therapy will ultimately drive our treatment algorithms and will enable us to follow a more personalized and rational therapeutic approach to the management of 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.

References:

1. Gordon LI, Bernstein SH, Jares P, et al. Recent advances in mantle cell lymphoma: report of the 2013 Mantle Cell Lymphoma Consortium Workshop. Leuk Lymphoma. 2014;55:2262-70.

2. Dreyling M, Ferrero S; European Mantle Cell Lymphoma Network. The role of targeted treatment in mantle cell lymphoma: is transplant dead or alive? Haematologica. 2016;101:104-14.

3. El Halabi L, Ghez D, Ribrag V. Novel targeted therapeutics for mantle cell lymphoma – What’s on the horizon? Expert Rev Hematol. 2016;9:271-81.

4. Robak T. Novel therapies under investigation for mantle cell lymphoma. Expert Opin Investig Drugs. 2016;25:375-80.

5. Ruan J, Leonard JP. Lenalidomide plus rituximab for mantle-cell lymphoma. N Engl J Med. 2016;374:793.

6. Simonsen AT, Schou M, Sørensen CD, et al. SOX11, CCND1, BCL1/IgH and IgH-VDJ: a battle of minimal residual disease markers in mantle cell lymphoma? Leuk Lymphoma. 2015;56:2724-7.

7. Forstpointner R, Dreyling M, Repp R, et al. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004;104:3064-71.

8. 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.

9. 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.

10. Lefrere F, Delmer A, Suzan F, et al. Sequential chemotherapy by CHOP and DHAP regimens followed by high-dose therapy with stem cell transplantation induces a high rate of complete response and improves event-free survival in mantle cell lymphoma: a prospective study. Leukemia. 2002;16:587-93.

11. Gianni AM, Magni M, Martelli M, et al. Long-term remission in mantle cell lymphoma following high-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting (R-HDS regimen). Blood. 2003;102:749-55.

12. Andersen NS, Pedersen LB, Laurell A, et al. Pre-emptive treatment with rituximab of molecular relapse after autologous stem cell transplantation in mantle cell lymphoma. J Clin Oncol. 2009;27:4365-70.

13. Dreyling M, Hoster E, Bea S, et al. Update on the molecular pathogenesis and clinical treatment of mantle cell lymphoma (MCL): minutes of the 9th European MCL Network conference. Leuk Lymphoma. 2010;51:1612-22.

14. 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.

15. 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.

16. 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.

17. Romaguera JE, Khouri IF, Kantarjian HM, et al. Untreated aggressive mantle cell lymphoma: results with intensive chemotherapy without stem cell transplant in elderly patients. Leuk Lymphoma. 2000;39:77-85.

18. 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.

19. 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.

20. 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.

21. 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.

22. Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006;108:4003-8.

23. 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.

24. Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab maintenance versus wait and watch after four courses of R-DHAP followed by autologous stem cell transplantation in previously untreated young patients with mantle cell lymphoma: first interim analysis of the phase III prospective Lyma trial, a Lysa study. Blood. 2014;124:abstr 146.

25. Geisler CH. Autologous transplantation and management of younger patients with mantle cell lymphoma. Best Pract Res Clin Haematol. 2012;25:211-20.

26. Cheah CY, Seymour JF, Wang ML. Mantle cell lymphoma. J Clin Oncol. 2016;34:1256-69.

27. Furtado M, Rule S. Indolent mantle cell lymphoma. Haematologica. 2011;96:1086-8.

28. Martin P. Watching and waiting in mantle cell lymphoma. Clin Adv Hematol Oncol. 2013;11:794-5.

29. Laszlo T, Matolcsy A. Blastic transformation of mantle cell lymphoma: genetic evidence for a clonal link between the two stages of the tumour. Histopathology. 1999;35:355-9.

30. M’Kacher R, Farace F, Bennaceur-Griscelli A, et al. Blastoid mantle cell lymphoma: evidence for nonrandom cytogenetic abnormalities additional to t(11;14) and generation of a mouse model. Cancer Genet Cytogenet. 2003;143:32-8.

31. Kasamon YL, Burns KH. Blastic transformation of mantle cell lymphoma. Blood. 2012;120:2359.