By William B. Ershler, MD, Editor
SYNOPSIS:In a Phase 2 study, Ahmadi and colleagues demonstrate reasonably high response rates in rituximab-resistant indolent lymphoma patients sequentially treated with lenalidomide/dexamethasone (Part 1; 2 monthly cycles) followed by lenalidomide/dexamethasone + weekly rituximab (Part 2; 3 monthly cycles). Of the 24 evaluable patients, the overall response rate was 29% and 58% in Parts 1 and 2, respectively. The data suggest that lenalidomide treatment may result in a return of rituximab sensitivity in patients previously known to be resistant.
SOURCE: Ahmadi T, et al. Combined lenalidomide, low-dose dexamethasone, and rituximab achieves durable responses in rituximab-resistant indolent and mantle cell lymphomas. Cancer 2014;120:222-228.
Rituximab is widely used both as a single agent, and in combination with chemotherapy for treatment of B-cell non-Hodgkin lymphomas, and has been shown to improve outcomes.1,2 However, unfortunately, many patients develop resistance to rituximab, and this is associated with worse outcomes including reduced survival. A previous study by Abdollahi and colleagues examined patients with follicular lymphoma who developed resistance to rituximab and demonstrated a significant decrease in 5-year overall survival (58%) when compared to all patients with follicular lymphoma.3
Lenalidomide is an immunomodulatory drug shown to have benefit in the treatment of relapsed and refractory B-cell lymphomas when used as a single agent.4,5 It has been suggested that lenalidomide increases antibody-dependent, cell-mediated cytotoxicity and thus decreases tumor-induced resistance.6 Such an immunologic effect may potentially enhance the antitumor activity of rituximab.
Ahmadi and colleagues conducted a single-center, prospective, Phase 2 clinical trial to investigate the efficacy of lenalidomide combined with rituximab in patients with previously treated, rituximab-refractory or resistant, indolent B-cell or mantle cell lymphoma. Inclusion criteria were as follows: adults (aged ≥ 18 years) with histologically confirmed progressive CD20 antigen-expressing follicular (grades 1, 2, and 3a), marginal zone, small lymphocytic, lymphoplasmacytic, or mantle cell lymphomas, life expectancy > 3 months, and at least one measurable lesion that was ≥ 2 cm.
The protocol was divided into two parts. Part 1 consisted of two 28-day treatment cycles during which all patients received lenalidomide 10 mg PO daily. Dexamethasone was added to the treatment regimen based on clinical experience suggesting that it was beneficial in reducing the side effects of lenalidomide, particularly rash, as well as the previously described synergy between corticosteroids and lenalidomide.7 All patients received dexamethasone 8 mg weekly. Response evaluation, including CT or PET/CT, was performed at the end of the two treatment cycles (Part 1 response). All patients, regardless of Part 1 response, continued on to Part 2, which included three 28-day treatment cycles (cycles 3 through 5). During these 3 cycles, lenalidomide and dexamethasone were continued and all patients received rituximab 375 mg/m2 weekly. Response evaluation was reassessed at the end of cycle 5. Patients with stable disease or a partial response continued treatment with lenalidomide with or without dexamethasone until they developed disease progression or withdrew from the study. Restaging evaluations were done at 12, 18, and 24 months after study enrollment and then annually for a maximum of 5 years. The primary endpoint was the overall response rate (ORR) after cycle 5 (Part 2 response). Secondary endpoints included ORR after cycle 2 (Part 1 response), progression-free survival (PFS), response duration (RD), time to progression (TTP), and toxicity evaluation.
Twenty-seven patients with follicular (n = 18), mantle cell (n = 5), small lymphocytic (n = 3), and marginal zone (n = 1) lymphomas were enrolled between July 2008 and May 2010. The median age at enrollment was 60 years (range: 35-85) and time from diagnosis was 6.77 years (range: 0.89-26.12 years).
Three of the 27 enrolled patients discontinued treatment due to adverse events prior to cycle 3. Twenty-four patients received rituximab during cycle 3 and were evaluable for both part 1 and part 2 responses. For these patients, the ORR after part 1 was 29% (four patients had a complete response [CR] or CR unconfirmed [CRu], and three patients had a partial response [PR]). The ORR after part 2 was 58% (eight patients had a CR and six had a PR). The ORR was 53% for patients with follicular lymphoma (8/15), 60% for mantle cell lymphoma (3/5), 67% for small lymphocytic lymphoma (2/3), and 100% for marginal zone lymphoma (1/1). Seventy-five percent of patients (19/24) continued to receive treatment with lenalidomide and dexamethasone after cycle 5. The median follow-up for all enrolled patients (n = 27) was 12.2 months (range: 0.9-52.7 months) and the median PFS was 23.7 months.
Four patients discontinued therapy due to adverse events thought to be treatment related. Of these, three discontinued treatment during part 1 (myocarditis, rash, thrombocytopenia), and one discontinued treatment after the part 2 response assessment (secondary malignancy). The most common grade 3 and 4 toxicities included neutropenia (30%), leukopenia (15%), hypokalemia (15%), anemia (7%), hypophosphatemia (7%), and thrombocytopenia (7%).
In summary, treatment with lenalidomide, low-dose dexamethasone, and rituximab was shown to be effective in patients with rituximab-refractory or resistant indolent B-cell or mantle cell lymphoma. This combination, administered at different doses or on different schedules, has previously been shown to be an effective regimen for both indolent and aggressive lymphoma variants, either as initial treatment or for relapsed or refractory disease. However, what makes this trial unique is that each of the enrolled patients had demonstrated prior rituximab resistance. The current data suggest that prior and concurrent lenalidomide is effective in at least partially overcoming rituximab resistance, thereby explaining the delta in observed responses when comparing rates at the end of Part 2 with those after completion of Part 1. However, the study was not designed to prove this conclusively and it might be reasonably argued that the increment in response rates during Part 2 reflected a cumulative, delayed effect of lenalidomide alone. To address this, a prospective randomized trial of lenalidomide/dexamethasone ± late cycle rituximab would be most instructive.