Safety and Activity of Lenalidomide and Rituximab in Previously Untreated Marginal Zone Lymphoma: Subgroup Analysis and Long-Term Follow-up of an Open-Label Phase II Trial

Introduction :

There is no consensus on front line treatment for marginal zone lymphoma (MZL). Cytotoxic treatments have proven effective but often result in significant toxicity. Furthermore, subtypes of immunotherapeutic agents have been an attractive alternative to cytotoxic therapies and have yielded robust outcomes that are associated with favorable toxicity profiles. B-cell malignancies, such as follicular lymphoma (FL) and MZL, with known dependence on microenvironmental signaling may be especially sensitive to immunomodulatory approaches. We previously reported on the durable responses and efficacy noted with lenalidomide and rituximab (R2) in untreated FL, MZL, and small lymphocytic lymphoma (SLL) patients. However, initial responses and progression-free survival (PFS) in MZL were inferior to FL. To further analyze these differences, we performed a subgroup analysis of MZL patients treated with R2.

Methods :

The original open label, phase II investigator-initiated study included 103 untreated patients with stage III or IV indolent lymphoma. Patients with FL or MZL (nodal or extra nodal) were treated with lenalidomide 20mg/day on days 1-21 of each 28-day cycle and rituximab 375mg/m2 on day 1 of each cycle. For SLL, the initial dose of lenalidomide was 10mg/day in cycle 1, 15mg/day in cycle 2, and then 20mg/day. Patients were restaged after every third cycle. For responders, treatment continued for at least 6 cycles and could continue for up to 12 cycles. The primary endpoint was overall survival (OS); secondary endpoints were complete and partial response (CR, PR), and PFS. In this subgroup analysis of MZL, we evaluated the association between various categorical patient characteristics (age, sex, stage, B symptoms, splenomegaly, effusions/ascites, hemoglobin, ACL, high tumor burden, GELF) with response to R2 as well as the length of disease control.

Results :

Of the 30 patients with MZL (27 were evaluable), 18 (60%) had nodal MZL, 11 (37%) extra nodal MZL, and 1 (3%) splenic MZL. Median age was 58 years (range, 36-77); 60% were female. All had stage III or IV disease. The median follow up was 75.1 months. For MZL, the most frequently reported non-hematologic adverse events (AE) (all grades) were fatigue (93%), nausea/vomiting (73%), cough/dyspnea (63%), eye irritation (60%), pain/myalgia (60%), edema (50%), constipation (47%), diarrhea (47%), and rash (40%). There were no grade 4 non-hematologic AEs. The most common grade 3 non-hematologic AEs were pain/myalgia (10%), cough/dyspnea (7%), and rash (7%). The only grade 4 hematologic AEs were thrombocytopenia (3%) and leukopenia (3%). The only grade 3 hematologic AEs were neutropenia (33%) and leukopenia (7%). Of the grade 3 and 4 AEs, hematologic AEs occurred more frequently in nodal MZL (80% neutropenia, 100% leukopenia were in the nodal subtype). Non-hematological AEs occurred more frequently in extra nodal MZL (100% rash, 100% neuropathy, and 66% pain were in the extra nodal subtype). Of note, the 1 patient with splenic MZL did not experience grade 3 or 4 toxicity. With extended follow up, the ORR was 92.6%, 19 (70.4%) patients achieved CR, 6 (22.2%) patients achieved PR. Two patients died during follow-up, both from secondary malignancies. There have been no treatment-related fatalities to date. Median PFS was 59.8 months; the median OS has not been reached. Patients with FL however had ORR 97.8%; 91% CR; median PFS and OS not yet reached. MZL cohort had more stage IV patients compared to the FL cohort (66.7% vs. 52.2%). Of the various patient characteristics assessed, none was significantly associated with response. Among all subtypes of MZL, there was an observed trend towards improved PFS in patients with stage IV disease compared to stage III , but this difference was not statistically significant. Similarly, though not significant, males appear to have an improved PFS within the first 48 months compared to females.

Conclusions :

With extended follow up, nearly all MZL patients treated with R2 remain alive, with a median PFS of 59 months, and no unexpected long-term or delayed toxicities. Although front line treatment with combination lenalidomide and rituximab in treatment-naïve patients with MZL is well tolerated and associated with high response rates that are durable, further prospective studies are warranted to determine the potential biological differences that could explain the differences in PFS and response in MZL compared to FL.

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