Oreofe O. Odejide, MD, and Ann S. LaCasce, MD
Dr. Odejide and Dr. LaCasce indicated no relevant conflicts of interest.
1. Clinical Fellow, Hematology and Oncology, Dana-Farber/Partners Cancer Care Fellowship Program
2. Assistant Professor of Medicine, Lymphoma Program, Dana-Farber Cancer Institute
What is the optimal, upfront management of mantle cell lymphoma?
Mantle cell lymphoma (MCL) is a rare type of lymphoma, representing about 6 percent of all cases of non-Hodgkin lymphoma.1 Median age at diagnosis is 68 years, and the vast majority of patients are diagnosed with advanced-stage disease. Patients with MCL typically present with generalized lymphadenopathy and extranodal involvement, particularly in the bone marrow, spleen, and GI tract. Cyclin D1 expression as a result of t(11;14)(q13;q32) translocation is present in more than 95 percent of cases. Notably, MCL has a poor prognosis with a median survival of about five years.
Given the small number of randomized clinical trials in previously untreated patients with MCL, none of which have demonstrated an improvement in overall survival (OS), the optimal initial approach to MCL has not been clearly established. As such, patient participation in well-designed clinical trials is highly recommended. This article will focus on treatment strategies that have been shown to offer the best chance of prolonged remission.
A Watch-and-Wait Strategy Is Appropriate for a Subset of Patients
Given the burden of disease, the majority of patients with MCL require therapy at diagnosis. However, a subset of patients with splenomegaly and circulating lymphoma cells with a low ki-67, typically without significant lymphadenopathy, may have an indolent course. Data from Cornell also suggest that, for selected patients with asymptomatic disease, there is no survival disadvantage to expectant management.2 For those requiring therapy, patients may be divided into categories of young and fit (≤ 65 years without significant comorbidity), or older (> 65 years with inability to tolerate high-dose therapy).
Younger and Fit Adults With MCL
Although the addition of rituximab (R) to conventional chemotherapy regimens has significantly improved prognosis in nearly all subtypes of B-cell non-Hodgkin lymphoma, its addition to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in MCL has not translated into improved outcomes. The German Low Grade Lymphoma Study Group found that, due to the short durability of the response, R-CHOP compared with CHOP did not improve progression-free survival (PFS) despite an improvement in overall response rate (94% vs. 75%).3 Given the disappointing outcome with R-CHOP therapy alone in younger patients, emphasis has been placed on intensification of induction therapies and consolidation strategies with high-dose therapies followed by autologous stem cell rescue (ASCR).
A randomized trial comparing myeloablative radiochemotherapy and ASCR versus maintenance interferon-α in patients ≤ 65 years achieving a partial or complete response with CHOP-like induction, with or without rituximab, demonstrated an improved PFS in the radiochemotherapy arm (median PFS of 39 months vs. 17 months) though there was no OS difference.4 This study is the basis of adoption of high-dose therapies and ASCR as consolidative strategies in younger patients. The Nordic Lymphoma Group in the MCL2 study adopted a cytarabinecontaining induction regimen consisting of six cycles of dose-intensified CHOP alternating with high-dose cytarabine with rituximab in cycles two through six, followed by high-dose therapy (HDT) and ASCR. The four- and 10-year PFS were highly encouraging at 73 percent and 55 percent, respectively.5 An improved median event-free survival of 83 months was also recently reported by the French group in a phase II trial using an induction regimen consisting of three cycles of CHOP and three cycles of rituximab with DHAP (dexamethasone, high-dose cytarabine, and cisplatin) followed by HDT and ASCR.6
Another approach to increase the durability of remission in MCL patients employs the use of intensified doses of chemotherapy including cytarabine without stem cell transplantation. A phase II trial of R-HyperCVAD (rituximab, fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) by the MD Anderson group showed a high complete remission rate of 87 percent and three-year failure-free survival of 64 percent. However, this therapy has significant toxicity with 8 percent treatment-related mortality. Also, a preliminary report of the regimen used in the cooperative group setting by the Southwest Oncology Group demonstrated a less favorable outcome.7 Therefore, this therapy should be reserved for young and fit patients with close monitoring for toxicity. Finally, a comparative effectiveness study from the NCCN NHL database comparing initial MCL therapy in younger patients demonstrated that R-CHOP alone was inferior to aggressive therapies such as R-HyperCVAD or R-CHOP followed by HDT and ASCR.8
In general, we favor an aggressive treatment approach consisting of an induction regimen followed by HDT and ASCR for patients who are ≤ 65 years without significant comorbidity. The optimal induction chemotherapy has not been established, and options include standard or intensified R-CHOP with or without the addition of cytarabine-containing regimens. An ongoing intergroup, randomized phase II study comparing R-HyperCVAD versus R-bendamustine followed by HDT and ASCR in MCL patients ≤ 65 years will contribute to the identification of the optimal induction chemotherapy.
Older Adults With MCL
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The use of dose-intensified, cytarabine-containing induction regimens followed by HDT and ASCR is not feasible for most elderly patients due to excessive toxicity. Therefore, treatment strategies focus on regimens that improve PFS while minimizing toxicity.
Results of a double randomized trial comparing R-CHOP versus R-FC (rituximab, fludarabine, and cyclophosphamide) in patients > 60 years who were ineligible for HDT, with second randomization of responders (complete or partial response) to either maintenance rituximab or maintenance interferon-α showed a clear OS benefit as well as less toxicity for R-CHOP compared with R-FC. The remission duration was also doubled in the maintenance rituximab versus the interferon-α arm. Furthermore, among patients who had a response to R-CHOP induction, maintenance rituximab significantly improved OS when compared with maintenance interferon-α (4-year OS, 87% vs. 63%), while it had no influence in the group that received R-FC induction.9 Given these compelling data, we favor R-CHOP therapy followed by maintenance rituximab as an upfront therapy in older patients with MCL.
The role of R-bendamustine has also been explored in the treatment of MCL. Preliminary results from a randomized controlled trial by the German Low Grade Lymphoma Study Group comparing R-bendamustine versus R-CHOP in indolent B-cell NHL or MCL (MCL made up 18% of total cohort) demonstrated better tolerability of R-bendamustine and a significant 20-month improvement in PFS over R-CHOP, but there was no OS improvement.10 Based on these preliminary data, R-bendamustine can be considered in older patients, especially when there is concern for the tolerability of a more aggressive treatment regimen. An ongoing U.S. Intergroup randomized phase II trial in older MCL patients is comparing bendamustine with rituximab with or without bortezomib, with a second randomization to maintenance rituximab with or without lenalidomide.
Interest in developing new approaches to treatment of MCL, including Bruton tyrosine kinase (BTK) and PI3 kinase inhibitors, remains high. But presently, a careful approach that incorporates available trial data in the decision making process should be used in selecting upfront therapy for patients with MCL (Figure).
1. The Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood. 1997;89: 3909-3918.
2. Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol. 2009;27:1209-1213.
3. 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;23:1984-1992.
4. 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;105:2677-2684.
5. 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: 2687-2693.
6. Delarue R, Haioun C, Ribrag V, et al. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL): a phase II study from the GELA. Blood. 2012. Epub ahead of print.
7. 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: 7013-7023.
8. L aCasce 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: 2093-2099.
9. Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012;367:520-531.
10. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood. ASH Annual Meeting Abstract. 2009;114:405.
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