R2: Preliminary Results of a Phase II Study of Lenalidomide and Rituximab in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma (NHL).

Abstract

1679 Poster Board I-705 Background Lenalidomide (Revlimid®) is a potent immunomodulatory agent that has recently demonstrated clinical activity in the treatment of relapsed/refractory Multiple Myeloma and low- and int-1 risk Myelodysplastic syndromes with the del (5q) mutation. Laboratory data has shown that lenalidomide enhances T- and NK-cell mediated immune synapse formation and ADCC, and it exerts antiproliferative activity. In relapsed/refractory (R/R) NHL lenalidomide treatment achieved modest responses, although duration of response was >16.5 months (Witzig et al JCO, in press). Synergistic activity between lenalidomide and rituximab has been reported in lymphoma cell and animal models. Here we assess safety and efficacy of the lenalidomide and rituximab combination (R2) in patients with R/R indolent NHL. Methods Eligible patients had relapsed/refractory indolent NHL with measurable disease, ≥1 prior therapy, and ECOG PS 0-2. Oral lenalidomide was administered once daily on days 1-21 of a 28-day cycle, and was continued until disease progression. Rituximab 375mg/m2 IV was initiated on day 15 of cycle 1, and repeated weekly for a total of 4 doses; if after cycle 2 patient had less than a complete response (CR), 4 additional doses could be administered at discretion of the treating physician. After Gr. 3 tumor lysis syndrome (TLS) developed in 2 of the first 4 patients, the protocol was amended to reduce lenalidomide starting dose from 25 mg to 20mg daily, and TLS prophylaxis was provided with allopurinol in subsequently enrolled patients. Response and progression were evaluated according to IWG criteria (Cheson et al 1999). Results Of 15 patients currently enrolled on study, 14 received >2 cycles of R2, and 12 are evaluable for response. Median age for evaluable patients is 60 yrs (range: 50-91), 5 pts are female, and histologies include FL (n=9), SLL (n=1), and marginal zone lymphoma (n=2). Median time from diagnosis to treatment on study was 7.5 years (3.3-19), median number of prior therapies was 4 (range:1-11), and 9 patients were considered heavily pretreated (defined as ≥ 3 prior courses of therapy). All patients received prior rituximab, 6 patients had rituximab-resistant disease (defined as no response or relapse ' 6 months after initiating rituximab), and 5 patients had received prior radioimmunotherapy. Of 12 evaluable patients, 10 (83.3%) responded to R2, including 5 patients (41%) with a CR and 4 patients (33%) with a PR. Responses occurred in 4 of 6 patients (66%) with rituximab refractory disease, and in 7 of 9 (77%) heavily pretreated patients. Of 9 patients with R/R FL, 5 (55%) achieved a CR and 3 (33%) had a PR in response to R2, for an 88% ORR. At a median follow-up of 12 months, the median progression free survival has not been reached. Most common grade 3/4 adverse events were fatigue (2/12, 16%), neutropenia (3/12, 25%), lymphopenia (4/12, 33%), and hyponatremia (2/12, 16%). After prophylaxis was initiated, TLS was not observed at the 20 mg dose level. Conclusion This is the first study to demonstrate that the R2 combination is generally well tolerated and active in patients with R/R indolent NHL. Clinical activity was particularly noted among patients with R/R FL, who achieved 88% OR and 55% CR rate. The tolerability profile of R2 was consistent with other studies of each agent individually in the R/R setting. TLS prophylaxis and monitoring is recommended, particularly during initial cycles of treatment. These data support further evaluation of the potential clinical synergy between rituximab and lenalidomide in larger studies of FL and in earlier lines of therapy. Disclosures Off Label Use: Lenalidomide for treatment of non-hodgkin's lymphoma. Tuscano:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

How we manage follicular lymphoma

“…89 After promising single-agent activity was seen particularly in patients with refractoriness to prior therapies, 90 lenalidomide was combined with rituximab and achieved high response rates in first-line therapy. 91,92 An international prospective randomized phase III trial (RELEVANCE) currently compares the so-called R 2 combination of lenalidomide and rituximab against conventional R-chemotherapies, both arms being followed by a respective maintenance in remission.…”

Single‐agent lenalidomide is active in patients with relapsed or refractory aggressive non‐Hodgkin lymphoma who received prior stem cell transplantation

“…Combination studies have shown additional benefits in the post‐transplantation setting for aggressive NHL. Preclinical studies have demonstrated synergistic activity between lenalidomide and rituximab (Hernandez‐Ilizaliturri et al , ; Reddy et al , ; Wu et al , ), and emerging clinical data support the potential combination of lenalidomide with a rituximab‐containing regimen in NHL (Dutia et al , ; Czuczman & Rummel, ; Nowakowski et al , ). There is a recent report of a phase II study of 45 patients with newly diagnosed CD20+ DLBCL or FL grade 3 who received standard dose R‐CHOP21 with oral lenalidomide 25 mg/d (days 1–10), which demonstrated an ORR of 98–83% CR (Nowakowski et al , ).…”

Report on the 56th ASH Annual Meeting, San Francisco,

“…Lenalidomide (phase 3 combination trials with monoclonal antibody and chemoimmunotherapy) is used as immunomodulatory drugs [ 18 ]. The immune checkpoint inhibitors used are ipilimumab (CTLA-4 inhibitor, phase I completed and combination trial considered) [ 19 ], pidilizumab, nivolumab, MK-3475 (PD-1 inhibitors, phase 2 single agent and combination trials) [ 20 ].…”