Originally published as JCO Early Release 10.1200/JCO.2008.19.5032 on December 15 2008

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Martin, P. Articles by Leonard, J. P. Search for Related Content PubMed PubMed Citation Articles by Martin, P. Articles by Leonard, J. P. Related Articles Related Article Social Bookmarking                            What's this?

Progress in Mantle-Cell Lymphoma

Center for Lymphoma and Myeloma, Division of Hematology and Medical Oncology; and Department of Medicine, Weill Cornell Medical College and NewYork-Presbyterian Hospital, New York, NY

Recognition of mantle-cell lymphoma (MCL) in the 1994 Revised European-American Lymphoma classification of lymphoid neoplasms as a distinct entity enabled several groups to describe their clinical experiences.^1–6 The investigators found that MCL had the unfortunate characteristics of being incurable as with indolent lymphomas, yet often rapidly progressive, similar to aggressive histologies. Median overall survival (OS) cited in these early series was in the range of 2 to 4 years, prompting several groups to propose novel therapeutic approaches to improve patient outcomes.

One common strategy in MCL involved intensification of therapy. Several early reports described single-center experiences with high-dose chemotherapy and autologous stem-cell transplantation (ASCT).^7–15 Patient numbers were generally small, and OS rates varied considerably—from 24% at 3 years¹⁰ to 80% at 4 years.¹⁴ Since 2000, multiple phase II studies using ASCT in first or later remission reported progression-free survival (PFS) and OS rates comparing favorably with those of historical cohorts.^16–28 Dreyling et al²⁹ conducted an important randomized trial, which demonstrated that after initial chemotherapy with cyclophosphamide, vincristine, doxorubicin, and prednisone, patients with MCL who were randomly assigned to ASCT rather than interferon, had a significant PFS—but not OS—benefit. Varying interpretations of these and other data have led many to advocate for the use of ASCT, despite its yet unproven impact on survival.

Concurrently, Romaguera et al³⁰ at The University of Texas M. D. Anderson Cancer Center (Houston, TX) published the results of a single-center, phase II trial of rituximab combined with alternating cycles of hyperfractionated cyclophosphamide/vincristine/doxorubicin/dexamethasone and methotrexate/cytarabine. The response rate was 97%, with 82% 3-year OS. These data supported the idea that intensive treatment approaches might improve long-term outcomes. Since then, other investigators have published variations on the regimen, some including ASCT, with encouraging results.^31–33 It is debatable, however, to what degree the data from these trials are influenced by biases based on the characteristics of patients (younger and more fit) who are candidates for such approaches.³⁴ In a recent multicenter Southwest Oncology Group trial examining rituximab combined with alternating cycles of hyperfractionated cyclophosphamide/vincristine/doxorubicin/dexamethasone and methotrexate/cytarabine, nearly half of all patients were unable to complete therapy because of toxicity.³⁵

The goal of any treatment is to cure when possible, to extend survival when cure is not possible, and to improve quality of life. How do aggressive therapies fit into this schema with respect to MCL? With the debatable exception of allogeneic stem-cell transplantation, there is little evidence that cure can be achieved for most patients with MCL. Therefore, a key question is whether OS can be extended by the choice of a specific therapy. A secondary, but important, issue is whether PFS benefits, clearly achievable with more intensive treatments, translate into improved quality of life. More specifically, is the benefit of being in remission longer worth the toxicity from more aggressive treatment? Currently, this seems to be a very individualized issue based on pace of disease, MCL-related symptoms, risks of the treatment, age, comorbid illness, performance status, and patient preferences. In the near term, if approached in an evidence-based fashion, the choice of a treatment approach for a patient with MCL will remain a complex problem requiring significant discussion and consideration.

In this issue of Journal of Clinical Oncology, Hermann et al³⁶ provide data vital to the discussion of patient outcomes in MCL. The investigators compared the outcomes of 134 patients from two Kiel Lymphoma Study Group trials between 1975 and 1986 with those of 202 patients evaluated on two German Lymphoma Study Group trials performed since 1996. Although not a randomized comparison, OS in the latter cohort nearly doubled, from 2.7 to 4.8 years. Similar findings have been observed in follicular lymphoma.^37,38 In both cases, it is of interest to postulate what changes were responsible for such a significant apparent improvement. Patients in the GLSG cohort of the current study received anthracycline- or anthracenedione-containing chemotherapy, approximately one third received rituximab, and a small number (fewer than 7%) received ASCT in first remission. Data from randomized trials, however, do not support the hypothesis that any of these differences prolong OS.³⁹ Enhanced supportive care may have had a small, but significant, impact. We believe that the greatest advances in MCL outcomes are due to improved second-, third-, and fourth-line therapeutic options. This hypothesis is encouraging, because it suggests that although patients with MCL are not cured, we may be improving our ability to achieve disease control over time, even after relapse. Whether the results described by Herman et al are fully valid or could better by explained by bias must also be considered. Improved diagnostic techniques have likely changed the characteristics of the patient population over time. In addition, there may be lead time bias in the timing of initiation of therapy (study entry after observation and delayed first treatment v study entry and therapy immediately at diagnosis). As the authors point out, "patient selection is a great caveat of historical comparisons." Using careful statistical methodology, the investigators have attempted to identify and correct for bias as much as possible. Indeed, it is encouraging that patients with MCL seem to be doing better. Importantly, although a survival estimate of 5 years still leaves considerable room for improvement, Hermann et al³⁶ have provided a contemporary benchmark that future trials will need to exceed.

What do we need to do to continue to make progress in MCL? The following directions are necessary:

• Improve the understanding of the heterogeneity of MCL. Clinical experience has shown that MCL is quite variable in its clinical course. Some patients have indolent disease that can be observed for months to years before needing therapy.⁴⁰ Most others need treatment soon after diagnosis and many have an aggressive course, often with rapid progression. Molecular and clinical prognostic scores have been developed, but to date have not been validated for selection of therapy. Further efforts, and larger prospective studies, need to be pursued to allow selection of therapies based on disease characteristics and to match treatment to the individual setting.
  
• Develop novel therapies targeting relevant biologic mechanisms. A variety of new agents are in the clinic, including bortezomib, the first drug specifically approved for this lymphoma subtype. Rituximab has made a modest impact in MCL, and other newly available antilymphoma agents, including bendamusine, mTOR inhibitors, and lenalidomide, have clear single-agent activity. As understanding of the pathogenesis of MCL continues to emerge, additional development of new agents, such as cell cycle inhibitors, needs to be prioritized. Efficient assessment of treatment combinations through preclinical and then clinical studies is required for greatest impact.
  
• Enhance clinical trials. Although phase II studies play a vital role in MCL, they have been overemphasized in establishing standards of care. It is critical that treatment selection be ultimately defined by phase III trials that are adequately powered to assess OS, rather than just PFS. More patients and physicians need to participate in such studies. In addition, quality-of-life assessments are crucial in this entity because some patients can live well with the disease present, whereas intensive and maintenance treatments can be associated with significant toxicity.
  
• Continue to expand cooperation and collaboration. MCL is a rare disease, and single centers and even cooperative groups are limited in the number of MCL cases that can be accrued to clinical and correlative studies. Adequately powered studies require large numbers of patients and benefit from involvement with translational researchers providing varied expertise. The European MCL Network is an exemplar of an international cooperative group that, through its collaborative efforts, has made a significant impact in moving the field forward. The leadership shown by Andrew Madoff and the Lymphoma Research Foundation in the establishment of the Mantle Cell Lymphoma Consortium is another remarkable contribution. This effort has directed more than $20 million specifically to MCL translational research and facilitated educational efforts and collaborative programs in the field. Such initiatives serve to foster interactions among researchers and bring forward new approaches to understanding and managing the disease.
  

For at least the near term, management of individual patients with MCL will remain challenging. Sorting through the available data and their limitations to devise a strategy for an individual patient requires thoughtful consideration. Clinical trials should be a priority when therapy is being considered. Data such as those provided by Hermann et al³⁶ are particularly important, because they highlight that research efforts are making a difference and that patients with MCL can do better with newer approaches. Collaboration among physicians, researchers, and patients will continue to improve outcomes, and all those involved can make an important difference in making increased survival a reality.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: John P. Leonard, Genentech (C), Biogen Idec (C), Millenium (C), Johnson and Johnson (C), Celgene (C), Novartis (C), Cephalon (C); Morton Coleman, Genentech (C), Biogen Idec (C), Genzyme (C), Celgene (C), Immunomedics (C), Medtronics (C) Stock Ownership: Morton Coleman, Immunomedics Honoraria: John P. Leonard, Genentech, Biogen Idec, Millenium, Johnson and Johnson, Celgene, Novartis, Cephalon; Morton Coleman, Genzyme Research Funding: None Expert Testimony: John P. Leonard, Genentech (C) Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Peter Martin, Morton Coleman, John P. Leonard

Manuscript writing: Peter Martin, Morton Coleman, John P. Leonard

Final approval of manuscript: Peter Martin, Morton Coleman, John P. Leonard

REFERENCES

1. Harris NL, Jaffe ES, Stein H: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361–1392, 1994.[Free Full Text]

2. Norton AJ, Matthews J, Pappa V, et al: Mantle cell lymphoma: Natural history defined in a serially biopsied population over a 20-year period. Ann Oncol 6:249–256, 1995.[Abstract/Free Full Text]

3. Teodorovic I, Pittaluga S, Kluin-Nelemans JC, et al: Efficacy of four different regimens in 64 mantle-cell lymphoma cases: Clinicopathologic comparison with 498 other non-Hodgkin's lymphoma subtypes—European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 13:2819–2826, 1995.[Abstract]

4. Fisher RI, Dahlberg S, Nathwani BN, et al: A clinical analysis of two indolent lymphoma entities: Mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories)—A Southwest Oncology Group study. Blood 85:1075–1082, 1995.[Abstract/Free Full Text]

5. Zucca E, Roggero E, Pinotti G, et al: Patterns of survival in mantle cell lymphoma. Ann Oncol 6:257–262, 1995.[Abstract/Free Full Text]

6. Argatoff LH, Connors JM, Klasa RJ, et al: Mantle cell lymphoma: A clinicopathologic study of 80 cases. Blood 89:2067–2078, 1997.[Abstract/Free Full Text]

7. Blay J-Y, Sebban C, Surbiguet C, et al: High-dose chemotherapy with hematopoietic stem cell transplantation in patients with mantle cell or diffuse centrocytic non-Hodgkin's lymphomas: A single center experience on 18 patients. Bone Marrow Transplant 21:51–54, 1998.[CrossRef][Medline]

8. Haas R, Brittinger G, Meusers P, et al: Myeloablative therapy with blood stem cell transplantation is effective in mantle cell lymphoma. Leukemia 10:1975–1979, 1996.[Medline]

9. Stewart DA, Vose JM, Weisenburger DD, et al: The role of high-dose therapy and autologous hematopoietic stem cell transplantation for mantle cell lymphoma. Ann Oncol 6:263–266, 1995.[Abstract/Free Full Text]

10. Ketterer N, Salles G, Espinouse D, et al: Intensive therapy with peripheral stem cell transplantation in 16 patients with mantle cell lymphoma. Ann Oncol 8:701–704, 1997.[Abstract/Free Full Text]

11. Kröger N, Hoffknecht M, Dreger P, et al: Long-term disease-free survival of patients with advanced mantle-cell lymphoma following high-dose chemotherapy. Bone Marrow Transplant 21:55–57, 1998.[CrossRef][Medline]

12. Freedman AS, Neuberg D, Gribben JG, et al: High-dose chemoradiotherapy and anti-B-cell monoclonal antibody-purged autologous bone marrow transplantation in mantle-cell lymphoma: No evidence for long-term remission. J Clin Oncol 16:13–18, 1998.[Abstract/Free Full Text]

13. Jindra P, Koza V, Svojgrová M, et al: Frontline transplantation of autologous CD34+ selected blood cells for advanced mantle cell lymphoma: No evidence of long-term cure—A single centre experience. Bone Marrow Transplant 26:1138–1139, 2000.[CrossRef][Medline]

14. Milpied N, Gaillard F, Moreau P, et al: High-dose therapy with stem cell transplantation for mantle cell lymphoma: Results and prognostic factors, a single center experience. Bone Marrow Transplant 22:645–650, 1998.[CrossRef][Medline]

15. Vose JM, Bierman PJ, Weisenburger DD, et al: Autologous hematopoietic stem cell transplantation for mantle cell lymphoma. Biol Blood Marrow Transplant 6:640–645, 2000.[CrossRef][Medline]

16. Dreger P, Martin S, Kuse R, et al: The impact of autologous stem cell transplantation on the prognosis of mantle cell lymphoma: A joint analysis of two prospective studies with 46 patients. Hematol J 1:87–94, 2000.[CrossRef][Medline]

17. Josting A, Reiser M, Wickramanayake PD, et al: Dexa-BEAM: An effective regimen for cytoreduction prior to high-dose chemotherapy with autologous stem cell support for patients with relapsed/refractory mantle-cell lymphoma. Leuk Lymphoma 37:185–187, 2000.[Medline]

18. Decaudin D, Brousse N, Brice P, et al: Efficacy of autologous stem cell transplantation in mantle cell lymphoma: A 3-year follow-up study. Bone Marrow Transplant 25:251–256, 2000.[CrossRef][Medline]

19. 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 102:749–755, 2003.[Abstract/Free Full Text]

20. Gopal AK, Rajendran JG, Petersdorf SH, et al: High-dose chemo-radioimmunotherapy with autologous stem cell support for relapsed mantle cell lymphoma. Blood 99:3158–3162, 2002.[Abstract/Free Full Text]

21. Lefrère F, Delmer A, Levy V, et al: Sequential chemotherapy regimens followed by high-dose therapy with stem cell transplantation in mantle cell lymphoma: An update of a prospective study. Haematologica 89:1275–1276, 2004.[Abstract/Free Full Text]

22. Mangel J, Leitch HA, Connors JM, et al: Intensive chemotherapy and autologous stem-cell transplantation plus rituximab is superior to conventional chemotherapy for newly diagnosed advanced stage mantle-cell lymphoma: A matched pair analysis. Ann Oncol 15:283–290, 2004.[Abstract/Free Full Text]

23. de Guibert S, Jaccard A, Bernard M, et al: Rituximab and DHAP followed by intensive therapy with autologous stem-cell transplantation as first-line therapy for mantle cell lymphoma. Haematologica 91:425–426, 2006.[Abstract/Free Full Text]

24. Dreger P, Rieger M, Seyfarth B, et al: Rituximab-augmented myeloablation for first-line autologous stem cell transplantation for mantle cell lymphoma: Effects on molecular response and clinical outcome. Haematologica 92:42–49, 2007.[Abstract/Free Full Text]

25. Brugger W, Hirsch J, Grunebach F, et al: Rituximab consolidation after high-dose chemotherapy and autologous blood stem cell transplantation in follicular and mantle cell lymphoma: A prospective, multicenter phase II study. Ann Oncol 15:1691–1698, 2004.[Abstract/Free Full Text]

26. Kasamon YL, Jones RJ, Diehl LF, et al: Outcomes of autologous and allogeneic blood or marrow transplantation for mantle cell lymphoma. Biol Blood Marrow Transplant 11:39–46, 2005.[Medline]

27. Laudi N, Arora M, Burns L, et al: Efficacy of high-dose therapy and hematopoietic stem cell transplantation for mantle cell lymphoma. Am J Hematol 81:519–524, 2006.[CrossRef][Medline]

28. Vandenberghe E, Ruiz de Elvira C, Loberiza FR, et al: Outcome of autologous transplantation for mantle cell lymphoma: A study by the European Blood and Bone Marrow Transplant and Autologous Blood and Marrow Transplant Registries. Br J Haematol 120:793–800, 2003.[CrossRef][Medline]

29. 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 105:2677–2684, 2005.[Abstract/Free Full Text]

30. 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 23:7013–7023, 2005.[Abstract/Free Full Text]

31. Kahl BS, Longo WL, Eickhoff JC, et al: Maintenance rituximab following induction chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: A pilot study from the Wisconsin Oncology Network. Ann Oncol 17:1418–1423, 2006.[Abstract/Free Full Text]

32. Ritchie DS, Seymour JF, Grigg AP, et al: The hyper-CVAD–rituximab chemotherapy programme followed by high-dose busulfan, melphalan and autologous stem cell transplantation produces excellent event-free survival in patients with previously untreated mantle cell lymphoma. Ann Hematol 86:101–105, 2007.[CrossRef][Medline]

33. Vose J, Loberiza F, Bierman P, et al: Mantle cell lymphoma (MCL): Induction therapy with HyperCVAD/High-dose methotrexate and cytarabine (M-C) (+/– rituximab) improves results of autologous stem cell transplant in first remission. J Clin Oncol 24:424s; 2006 (suppl) abstr 7511.

34. Martin P, Chadburn A, Christos P, et al: Intensive treatment strategies may not provide superior outcomes in mantle cell lymphoma: Overall survival exceeding 7 years with standard therapies. Ann Oncol 19:1327–1330, 2008.[Abstract/Free Full Text]

35. Epner EM, Unger J, Miller T, et al: A multi center trial of hyperCVAD + Rituxan in patients with newly diagnosed mantle cell lymphoma. Am Soc Hematol Annual Meeting 10:387; 2007 abstr 387.

36. Hermann A, Hoster E, Zwingers T, et al: Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol 27:511–518, 2009.[Abstract/Free Full Text]

37. Swenson WT, Wooldridge JE, Lynch CF, et al: Improved survival of follicular lymphoma patients in the United States. J Clin Oncol 23:5019–5026, 2005.[Abstract/Free Full Text]

38. Lister TA: Improved survival for patients with follicular lymphoma. J Clin Oncol 23:4830–4831, 2005.[Free Full Text]

39. Nickenig C, Dreyling M, Hoster E, et al: Combined cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) improves response rates but not survival and has lower hematologic toxicity compared with combined mitoxantrone, chlorambucil, and prednisone (MCP) in follicular and mantle cell lymphomas. Cancer 107:1014–1022, 2006.[CrossRef][Medline]

40. Martin P, Chadburn A, Christos P, et al: Initial observation without therapy in patients with asymptomatic, newly diagnosed mantle cell lymphoma. Ann Oncol 19:iv85–86, 2008.[Free Full Text]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Article

• Improvement of Overall Survival in Advanced Stage Mantle Cell Lymphoma
  Annina Herrmann, Eva Hoster, Thomas Zwingers, Günter Brittinger, Marianne Engelhard, Peter Meusers, Marcel Reiser, Roswitha Forstpointner, Bernd Metzner, Norma Peter, Bernhard Wörmann, Lorenz Trümper, Michael Pfreundschuh, Hermann Einsele, Wolfgang Hiddemann, Michael Unterhalt, and Martin Dreyling
  JCO 2009 27: 511-518 [Abstract] [Full Text]

This article has been cited by other articles:

				M. Ghielmini and E. Zucca How I treat mantle cell lymphoma Blood, August 20, 2009; 114(8): 1469 - 1476. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Martin, P. Articles by Leonard, J. P. Search for Related Content PubMed PubMed Citation Articles by Martin, P. Articles by Leonard, J. P. Related Articles Related Article Social Bookmarking                            What's this?