A Phase II Multicenter Study of 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. 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 hypothesized that lenalidomide may have clinical activity in cHL.

N=38 rel/ref cHL patients (pts) who previously underwent (or were not candidates for) ASCT were enrolled from October 2007 to May 2009 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. 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 34 (range 25-63) years with 23 females. Median number of prior therapies was 4 (range 2-9). 33 pts had received a prior stem cell transplant (29 ASCT, 1 syngeneic, 3 both ASCT and allogeneic). 22 pts (58%) 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 12 (range 3-22) months. Of the 38 enrolled pts, 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). Median number of lenalidomide cycles administered per patient was 4 (range 2-22). For the 35 evaluable pts, we observed 1 CR, 5 PR, and 6 SD > 6 months for an overall response rate of 17% (6/35) and an overall cytostatic response rate of 34% (12/35). Median duration of CR/PR was 4.5 (range 2-10) months. The CR was observed after 2 cycles, and PRs were observed after 2 (n=2), 4 (n=1), 6 (n=1), and 18 (n=1) cycles of lenalidomide. Currently, lenalidomide treatment continues in 5 pts with SD (n=4, at ≥3, ≥7, ≥9, ≥15 cycles) or PR (n=1, ≥22 cycles). Of note, 8/12 (67%) lenalidomide responders 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 were neutropenia (40%), anemia (24%), leukopenia (21%), and thrombocytopenia (16%). The lenalidomide dose was reduced in 6 pts for cytopenias (n=2), fatigue (n=2), ALT/AST (n=1), and neuropathy (n=1), and discontinued in 4 pts for rash (n=2), elevated bilirubin/transaminases (n=1), and cytopenias (n=1). For pts with dose reduction, the lenalidomide doses ranged from 20 mg to 5 mg. No tumor lysis syndrome or documented tumor flare reactions were observed.

Single agent lenalidomide therapy has preliminary evidence of activity in pts with rel/ref cHL, including pts progressing after ASCT. Continuous daily dosing of lenalidomide is currently being evaluated in an effort to maximize single agent efficacy, and exploration of lenalidomide combinations with other active agents in rel/ref cHL is warranted.

Fehniger:Celgene: research funding solely to support this clinical trial. Off Label Use: The use of Lenalidomide in relapsed or refractory Hodgkin lymphoma. Bartlett:Celgene: research funding solely to support this clinical trial.