A phase 1 trial of romidepsin, azacitidine, dexamethasone and lenalidomide in relapsed or refractory T-cell lymphoma.

Targeted therapies can induce responses in patients with relapsed/refractory T-cell lymphoma (r/r TCL) but are not curative. Genetic mutations associated with epigenetic and transcriptional dysregulation are common in many TCL subtypes, and drugs that modulate the epigenome and that target transcriptional regulators have synergistic activity in TCL. We hypothesized that fixed duration treatment with multi-agent combinations of these drugs could produce deep responses leading to durable remissions. In a phase 1 trial, we tested escalating doses of lenalidomide added to romidepsin, azacitidine and dexamethasone (RAdR) in patients with r/r TCL. The primary objective was to identify the maximum tolerated dose (MTD) of lenalidomide that could safely be used in RAdR. Secondary endpoints included response rate, survival and markers of immune activation. Twenty-six patients enrolled and 21 were evaluable for response. Adverse events were predominantly gastrointestinal and hematologic. Grade 3-4 thrombocytopenia and neutropenia occurred in 19% and 21% of cycles. The MTD of lenalidomide was 20 mg. Amongst the nine patients treated at the MTD the objective response rate was 89% and complete response rate 22%. At 1-year, the estimated rate of PFS was 14% and overall survival was 66%. Cell line models of anaplastic large cell lymphoma were interrogated to explore the activity of drug combinations in responding genetic subtypes. RAdR demonstrated activity in patients with highly refractory TCL but did not induce durable responses. This novel combination effectively bridged some patients with refractory TCL to consolidation such as allogeneic transplantation. (NCT04447027).