• What is the approach to upfront therapy for MCL?
FRONTLINE THERAPY
Role of Watchful Waiting
A small proportion of MCL patients have indolent disease that can be observed. This population is more likely to have leukemic-phase MCL with circulating lymphocytes, splenomegaly, and bone marrow involvement and absent or minimal lymphadenopathy.4,5 A retrospective study of 97 patients established that deferment of initial therapy in MCL is acceptable in some patients.5 In this study, approximately one third of patients with MCL were observed for more than 3 months before initiating systemic therapy, and the median time to treatment for the observation group was 12 months. Most patients undergoing observation had a low-risk MIPI. Patients were not harmed by observation, as no OS differences were observed among groups. This study underscores that deferred treatment can be an acceptable alternative in selected MCL patients for a short period of time. In practice, the type of patient who would be appropriate for this approach is someone who is frail, elderly, and with multiple comorbidities. Additionally, expectant observation could be considered for patients with limited-stage or low-volume MCL, low Ki-67 index, and low-risk MIPI scores.
Approach to Therapy
Treatment of MCL is generally approached by evaluating patient age and fitness for treatment. While there is no accepted standard, for younger patients healthy enough to tolerate aggressive approaches, treatment often involves an intensive cytarabine-containing regimen, which is consolidated with an autoSCT. This approach results in the longest remission duration, with some series suggesting a plateau in survival after 5 years, with no relapses.21 Nonintensive conventional chemotherapy alone is often reserved for the frailer or older patient. Given that remission durations with chemotherapy alone in MCL are short, goals of treatment focus on maximizing benefit and remission duration and minimizing risk of toxicity.
Standard Chemotherapy: Elderly and/or Frail Patients
Conventional chemotherapy alone for the treatment of MCL results in a 70% to 85% overall response rate (ORR) and 7% to 30% complete response (CR) rate.22 Rituximab, a mouse humanized monoclonal IgG1 anti-CD20 antibody, is used as standard of care in combination with chemotherapy, since its addition has been found to increase response rates and extend both progression-free survival (PFS) and OS compared to chemotherapy alone.23,24 However, chemoimmunotherapy approaches do not provide long-term control of MCL and are considered noncurative. Various regimens have been studied and include anthracycline-containing regimens such as R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, prednisone),22 combination chemotherapy with antimetabolites such as R-hyper-CVAD (hyper-fractionated rituximab with cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with methotrexate and cytarabine),25 purine analogue–based regimens such as R-FC (rituximab with fludarabine and cyclophosphamide),26 bortezomib-containing regimens,27 and alkylator-based treatment with BR (bendamustine and rituximab) (Table 1).28,29 Among these, the most commonly used are R-CHOP and BR.
Two large randomized studies compared R-CHOP for 6 cycles to BR for 6 cycles in patients with indolent NHL and MCL. Among MCL patients, BR resulted in superior PFS compared to R-CHOP (69 months versus 26 months) but no benefit in OS.28,29 The ORR to R-CHOP was approximately 90%, with a PFS of 21 months in the Rummel et al study.29 This study included more than 80 centers in Germany and enrolled 549 patients with MCL, follicular lymphoma, small lymphocytic lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia. Patients were randomized in a 1:1 fashion. Among these, 46 patients received BR and 48 received R-CHOP (18% for both, respectively). It should be noted that patients in the BR group had significantly less toxicity and experienced fewer side effects than did those in the R-CHOP group. Similarly, BR-treated patients had a lower frequency of hematologic side effects and infections of any grade. However, drug-associated skin reactions and allergies were more common with BR compared to R-CHOP. The study by Flinn and colleagues was an international randomized, noninferiority phase 3 study designed to evaluate the efficacy and safety of BR compared with R-CHOP or R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) for treatment-naive patients with MCL or other indolent NHL. The primary endpoint was CR. In this study, BR was found to be noninferior to R-CHOP and R-CVP based on CR rate (31% versus 25%, respectively; P = 0.0225). Response rates in general were high: 97% for BR and 91% for R-CHOP/R-CVP (P = 0.0102). Here, BR-treated patients experienced more nausea, emesis, and drug-induced hypersensitivity compared to the R-CHOP and R-CVP groups.