A Phase II Multicenter Study of Lenalidomide in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma (cHL): Preliminary Results

Background: Relapsed or refractory cHL remains a clinical challenge with limited effective treatments after high dose therapy with autologous stem cell rescue (ASCT). Lenalidomide (Revlimid®) is an approved anti-neoplastic therapy for multiple myeloma and myelodysplastic syndrome. In ongoing investigations, it has a manageable toxicity profile and promising clinical activity in a number of B cell malignancies. Multiple potential mechanisms of action for lenalidomide have been identified including direct effects on tumor cells, alteration of the tumor microenvironment, anti-angiogenic properties, modification of cytokine profiles, and immune (T and NK) cell modulation. Since these effects have the potential to alter factors involved in cHL pathogenesis, we postulated that lenalidomide may have clinical activity in relapsed/refractory cHL. Methods: Relapsed or refractory cHL patients who previously underwent (or were not candidates for) ASCT, were enrolled in a prospective, multi-center Phase II study of single agent lenalidomide. The treatment regimen was 25 mg/day of lenalidomide on days 1–21 of a 28-day cycle, and dose reductions were allowed for hematologic and non-hematologic toxicity. Treatment continued until progressive disease or an unacceptable adverse event at the lowest allowed dose of lenalidomide (5 mg/day). The primary endpoint was overall response rate (CR + PR) defined by the 2007 revised IWG criteria after ≥2 lenalidomide cycles, and cytostatic response rate (CR + PR + stable disease > 6 months). All radiographic measurements were performed blinded by image response assessment team (IRAT) review (M.J.S.). Here, we report the results of a planned analysis of the first stage (n=15) of a two stage design (total planned accrual of n=35 evaluable patients). Results: Median age at treatment was 36 (range 25–63) years with 8 females. Median number of prior therapies was 4 (range 2–6), and 13 patients had received a prior stem cell transplant (12 ASCT, 1 ASCT and allogeneic). Eleven patients (73%) had not responded to their last prior therapy, and the median time from last prior therapy to enrollment on this study was 3 (range 1–66) months. Median time of follow-up from enrollment on this study was 6 (range 2–10) months. Of the 15 enrolled patients, 3 were removed from the study prior to receiving 2 cycles of lenalidomide due to: elevated bilirubin and transaminases (n=1), desquamating rash (n=1), and rapid disease progression during cycle 1 (n=1). For the 12 evaluable patients, we observed 1 complete remission, 3 partial remissions, and 3 stable disease > 6 months for an overall response rate (CR + PR) of 4/12 (33%) and an overall cytostatic response rate (CR + PR + SD > 6 months) of 7/12 (58%). The complete remission was observed after 2 cycles, and partial remissions were observed after 2 (n=2) or 6 (n=1) cycles of lenalidomide. Notably, 6/7 (86%) lenalidomide responders (CR + PR + SD > 6 months) had failed to respond to their last prior therapy before enrollment. In general, the treatment was well tolerated, and the most common grade 3/4 adverse events included neutropenia (47%), leukopenia (33%), thrombocytopenia (27%), and anemia (20%). The lenalidomide dose was reduced in 4 patients for cytopenias (n=2), rash (n=1), and fatigue (n=1). Conclusions: Single agent lenalidomide therapy has sufficient evidence of activity to warrant second-stage evaluation in a larger cohort of patients with relapsed or refractory cHL, to define ORR, PFS, and the adverse event profile with prolonged therapy.