My Approach to Mantle Cell Lymphoma

Kristie Blum, MD
Associate Professor of Internal Medicine, Division of Hematology

Mantle cell lymphoma (MCL) represents 3-10% of all non-Hodgkin’s lymphoma (NHL). Clinical features include a male predominance, median age at presentation of 60-65 years, and involvement of lymph nodes, spleen, bone marrow or peripheral blood.¹ Extranodal sites are commonly encountered at diagnosis and relapse; these include Waldeyer’s ring/tonsils, the gastrointestinal tract or the skin. Central nervous system involvement is rare at diagnosis, but the incidence at relapse ranges from 4-22%.² Typical pathologic features of MCL include a monomorphic lymphoid proliferation of small to medium-sized cells in a nodular, diffuse or mantle zone pattern, although some cases have larger cells resembling lymphoblasts with increased proliferation rates that are classified as blastic MCL. Expression of CD5, bright CD20, and lack of CD10 and CD23 are typical. Cyclin D1 overexpression or the presence of a t(11;14) is required for diagnosis and often distinguishes MCL from chronic lymphocytic leukemia (CLL).¹

A variety of prognostic characteristics has been described and includes the International Prognostic Index (IPI: age, stage, performance status, lactic dehydrogenase and extranodal involvement), the Mantle Cell International Prognostic Index (MIPI: age, performance status, LDH and leukocyte count),³ and Ki-67 proliferation index.⁴ However, none of these prognostic features is universally accepted, and clinical features of the patient often have to be carefully considered, including age, stage, sites of disease involvement, extranodal involvement, elevated WBC or cytopenias, and clinical symptoms. In my experience, patients with disease predominantly within lymph nodes or the tonsillar bed with limited bone marrow and peripheral blood involvement behave more indolently than patients presenting with splenomegaly, extensive bone marrow involvement, circulating disease or a high WBC, or involvement of the gastrointestinal tract, although some investigators have described an indolent population with non-nodal leukemic disease with mutated IgVH genes similar to CLL.^{5, 6} Furthermore, the rare patient with stage IA disease at diagnosis confined to a lymph node or tonsil may do quite well with radiation therapy alone, with remission durations of several years.

Due to the paucity of randomized clinical trials in this uncommon subtype of NHL, treatment approaches vary for newly diagnosed patients. My approach depends primarily upon the age and clinical features of the patient. In patients < 65-70 years of age, aggressive combination chemotherapy options, including rituximab-hyperCVAD,⁷ rituximab with methotrexate and augmented CHOP followed by autologous transplant,⁸ or the Nordic regimen of maxi-CHOP alternating with rituximab-high dose cytarabine followed by autologous transplant9, have led to 3-6 year progression-free or failure-free survivals of 56-73%. R-hyperCVAD consists of 6-8 alternating cycles of rituximab, fractionated cyclophosphamide, infusional doxorubicin, vincristine, and dexamethasone (RHyperCVAD) and rituximab, methotrexate and cytarabine⁷. In responding patients < 65 years of age, autologous transplant is not routinely performed with this regimen, and responses in a trial of 100 patients treated at MD Anderson are reported to be as high as 97%, with 89% CR, 3-year FFS of 73%, and 7-year FFS of 52%.^{7, 10} For patients over the age of 65, ORR was 84%; however, 3-FFS was 50%, and toxicity was increased with greater numbers of dose reductions required in the older patients. In a multicenter study conducted by the Southwest Oncology Group utilizing 8 cycles of RHyperCVAD in patients < age 70, ORR was 88% and 2-year PFS was 64%, although excessive toxicity was reported in patients > 65.¹¹ Therefore, I typically do not recommend RHyperCVAD in patients age 65-70 and also find that administration of > 6 cycles is challenging due to toxicity. Furthermore, if autologous transplantation is planned, stem cell collection may be difficult after 6 cycles of RHyperCVAD, and I do not routinely recommend this regimen if transplantation is a consideration. For patients < 70 who are transplant candidates, I favor treatment with combined rituximab, methotrexate and augmented CHOP previously published by the Cancer and Leukemia Group B.⁸ Damon and colleagues reported an ORR of 88%, CR of 69%, 2-year PFS of 76% and 5-year PFS of 56% with this regimen of: 2-3 cycles of rituximab, methotrexate and augmented CHOP; 1 cycle of rituximab, etoposide and cytarabine (EAR); stem cell mobilization; and autologous transplant. These results compare favorably with the 2-year PFS of 64% in the previous SWOG study of RHyperCVAD¹¹, and toxicity was manageable with only a 5% event rate by day 100 post-transplant.⁸ A Nordic regimen of rituximab-maxi-CHOP alternating with rituximab-high-dose cytarabine and autologous transplant has demonstrated 6-year PFS of 66% and non-relapse mortality of 5%.⁹ Furthermore, a recent randomized trial of alternating RCHOP/RDHAP vs. RCHOP followed by autologous transplant demonstrated superiority of the RDHAP-containing arm with respect to CR and TTF.¹² Therefore, in newly diagnosed patients with MCL who are < 70 years of age and transplant candidates, I favor treatment with a cytarabine-containing induction regimen followed by autologous transplant, typically utilizing the CALGB regimen⁸ due to its tolerability and proven efficacy after a limited number of induction cycles. Several clinical trials in this patient population are planned or have been recently completed. Through the CALGB, Ohio State participated in a recently completed phase II study utilizing the R-methotrexate-augmented CHOP, EAR and autologous transplant backbone published by Damon et al,⁸ followed by up to 2 years of bortezomib maintenance.

For patients > age 70 or who are not transplant candidates, treatment options include RCHOP, R-bendamustine or observation. In 2009, investigators from Cornell reported that in 31 patients with previously untreated, asymptomatic MCL without cytopenias, a large tumor burden or organ involvement who were observed without therapy, the median time to treatment was 12 months (range 4-128 months).¹³ Survival of these observed patients was superior to survival of patients treated within 3 months of diagnosis (OS not reached vs. 64 months, p=0.004).¹³ In my experience, only highly selected patients can be safely observed, as MCL typically progresses quickly, and patients develop symptomatic cytopenias, organ involvement or bulky splenomegaly. The patients for whom I may consider observation typically include a very limited subset of patients with lower-risk disease as manifested by predominantly non-bulky lymphadenopathy with a low Ki-67, normal WBC, no cytopenias, limited bone marrow involvement, minimal peripheral blood involvement (normal ALC but flow-detectable population only), no splenomegaly and no gastrointestinal involvement. For other patients, options include RCHOP, RCVP, R-fludarabine or R-bendamustine. Based on a randomized study of RCHOP vs. R-bendamustine by Rummel and colleagues where improved ORR and PFS were observed in the R-bendamustine arm,¹⁴ I typically recommend R-bendamustine, although I find a bendamustine dose of 60 mg/m2 on days 1 and 2 to be better tolerated in older patients than the dose of 90 mg/m2 utilized in the trial. A randomized trial of front-line R-bendamustine vs. R-bendamustine-bortezomib induction, followed by a second randomization to either bortezomib or lenalidomide maintenance for patients who are not transplant candidates, is being conducted through the CALGB and Eastern Co-operative Group (ECOG) and is available at Ohio State. Lastly, I would consider the use of maintenance rituximab after initial combination chemotherapy in this patient population based on a recently published trial from the European MCL Network that demonstrated a superior 4-year OS and remission duration in elderly patients receiving RCHOP followed by maintenance rituximab.¹⁸

In the relapsed setting, options depend upon the age, performance status, prior treatment, toxicities and treatment goals for a patient. These options include ibrutinib, R-bendamustine, bortezomib and lenalidomide. In selected patients with available donors, allogeneic stem cell transplantation may also be considered (see Dr. Jaglowski’s review of allogeneic transplant in MCL in this issue). In these patients with available donors, or in patients who have not received previous cytarabine or autologous transplant, aggressive combination salvage regimens, including RESHAP, RICE, RGEMOX or RDHAP, may be considered. For the majority of relapsed patients, however, I typically recommend ibrutinib. Ibrutinib is a novel inhibitor of Bruton’s tyrosine kinase, a downstream mediator in the B-cell receptor signaling pathway, which has excellent activity in patients with relapsed MCL.¹⁹ In a phase I trial of this agent in patients with relapsed and refractory NHL, 29 patients were enrolled, including 4 patients with MCL.¹⁷ Two of the patients with MCL responded, and the ORR in all histologies was 42%. In a multicenter phase II study of this agent in 115 patients with relapsed or refractory mantle cell lymphoma that Ohio State participated in, the ORR was 68% with a CR rate of 21% and rapid median time to response of 1.9 months.¹⁹ This study helped lead to recent FDA approval of ibrutinib for the treatment of patients with relapsed MCL. OSU 10052, a single-institution, phase I/II study of combined R-bendamustine and ibrutinib, is completing accrual at Ohio State in patients with relapsed or refractory MCL, diffuse large cell lymphoma and follicular lymphoma. In addition, OSU 13022 is exploring combined lenalidomide and ibrutinib in patients with relapsed MCL. Finally, due to the promising activity of ibrutinib, several other studies of this agent and similar B-cell receptor pathway inhibitors are in development at Ohio State or through the CALGB and will likely be available in the next 1-2 years.