A Phase 2 Multicenter Study of Continuous Dose Lenalidomide in Relapsed or Refractory Classical Hodgkin Lymphoma

Relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) remains a clinical challenge with limited effective treatments after high dose therapy with autologous stem cell transplantation (ASCT). Lenalidomide (Revlimid®) is an approved anti-neoplastic therapy for multiple myeloma and myelodysplastic syndrome with del(5q). In ongoing investigations it has a manageable toxicity profile and promising clinical activity in a number of B cell malignancies. We previously reported a study of single agent lenalidomide administered at 25 mg on days 1–21 of a 28 day cycle (Fehniger et al., Blood 118:5119, 2011, n=38), that showed a 19% objective response rate and a 33% cytostatic response rate, with a subsets of patients (pts) obtaining prolonged benefit from lenalidomide therapy. We hypothesized that clinical efficacy may be improved by using a continuous dosing schedule.

42 rel/ref cHL pts who previously underwent (or were not candidates for) ASCT were enrolled in a prospective, multi-center, phase 2 study of continuous dose, single agent lenalidomide. The treatment regimen for this cohort was 25 mg/day of lenalidomide on days 1–28 of a 28 day cycle. Treatment continued until progressive disease or an unacceptable adverse event at the lowest allowed dose (5 mg) of lenalidomide. The primary endpoint was overall response rate [complete remission (CR) + partial remission (PR)] as defined by the 2007 revised IWG criteria, and cytostatic response defined as CR + PR + stable disease (SD) > 6 months.

Median age at treatment was 38 (range 20–83) years. Median number of prior therapies was 3 (range 1–15). 31 pts (74%) had received a prior stem cell transplant (26 ASCT, 2 allogeneic, 3 both ASCT and allogeneic). 18 pts (43%) had not responded to their last prior therapy, and the median time from last prior therapy to enrollment on this study was 4 (range 1–126) months. Median time of follow-up from enrollment on this study was 15 (range 2–35) months. Of the 42 enrolled pts, 5 were removed from the study prior to receiving 2 cycles of lenalidomide due to cytopenias (n=2), venous thrombosis (n=1), increased ALT/AST (n=1), and withdrawal of consent (n=1) and were not evaluable for response. Median number of lenalidomide cycles administered per patient was 4 (range 2 to >24). For the 37 evaluable pts, we observed 3 CRs, 8 PRs, and 2 SD > 6 months for an overall response rate (CR + PR) of 30% (12/37) and an overall cytostatic response rate (CR + PR + SD > 6 months) of 35% (14/37). For patients that responded, the median time to treatment failure was 8.2 (range 4 to > 24) months. All 3 CRs were observed after 2 cycles, and PRs were observed after 2 (n=5), 4 (n=1), 7 (n=1), and 15 (n=1) cycles of lenalidomide. Currently, lenalidomide treatment continues in 2 patients with PR (at ≥21 and '24 cycles). In general, the treatment was well tolerated, and the most common (> 10%) grade 3–4 adverse events were neutropenia (48%), leukopenia (29%), thrombocytopenia (26%), and anemia (12%). Using this continuous dosing regimen, the lenalidomide dose was reduced in 4 pts for cytopenias (n=3), skin ulceration (n=1), and discontinued in 8 pts for vertigo (n=1), myelodysplasia (n=1), pregnancy (n=1), rash (n=1), and cytopenias (n=4). For pts with dose reduction, the lenalidomide doses ranged from 20 mg to 5 mg. These results suggest a modest increase in the number of patients that required lenalidomide discontinuation due to toxicity (9.5% prior to cycle 2, 19% after cycle 2) with continuous dose lenalidomide initiated at 25 mg/day, compared with to the previous interrupted dose phase 2 study cohort with lenalidomide dosing on day 1–21 of a 28 day cycle (5.3% prior to cycle 2, 10.5% after cycle 2) patients.

Compared with interrupted dose lenalidomide, continuous dose lenalidomide therapy has similar activity in pts with rel/ref cHL, with modest increases in therapy discontinuations and dose reductions. Exploration of lenalidomide combinations with other active agents in rel/ref cHL is warranted.

Fehniger:Celgene: Research Funding. Off Label Use: This is a clinical trial of lenalidomide in relapsed/refractory classical Hodgkin lymphoma, which constitutes off-label drug use. Goy:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Carson:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.