Romidepsin, Azacitidine, Dexamethasone, and Lenalidomide (RAdR) for Relapsed/Refractory T-Cell Lymphoma

Mature T-cell lymphomas (TCL) are a heterogeneous group of diseases with a poor prognosis, particularly in the relapsed/refractory (r/r) setting. Drugs targeting epigenetic regulation and immunomodulation such as romidepsin, azacitidine and lenalidomide have single agent activity against r/r TCL with objective response rates (ORR) and complete response rates (CR) around 30% and 10%. Lenalidomide and romidepsin have each been combined with azacitidine showing improved rates of CR, but extended treatment schedules add toxicity. We hypothesized that cyclic, time-limited administration of a multi-targeted combination regimen would induce durable remissions.

We tested escalating doses of lenalidomide (5 to 20mg) with fixed doses of romidepsin, azacitidine and dexamethasone. Eligible patients were ≥18 years old with r/r TCL and had received at least 1 prior line of therapy (must have included brentuximab vedotin if anaplastic large cell lymphoma [ALCL] or CD30+ mycosis fungoides [MF]). Prior allogeneic transplantation was allowed. Patients first received a 7-day course of lenalidomide for correlative research followed by up to six 28-day cycles of romidepsin (12mg/m²; days 1 and 10), azacitidine (300mg; days 1-10), dexamethasone (40mg; days 1 and 10), and lenalidomide (5-20mg; days 1-10) without maintenance. The primary objective was to test the overall safety of the regimen and the primary endpoint was the maximum tolerated dose (MTD) of lenalidomide. A 3+3 design was used with an additional 9 patients treated at the MTD. Survival was estimated using the Kaplan-Meier method; patients were censored at time of allogeneic transplantation (SCT). The study was supported by the Intramural Research Program of the NIH and was registered at Clinicaltrials.gov (NCT04447027).

Twenty-six patients with r/r TCL were enrolled during 2020-2024. The median age was 61 years (range, 28-80) and 23% were ≥70 years old. Eighteen (69%) were male, 42% were black, 31% white, 15% Asian and 12% Hispanic. Nodal TCL subtypes were the most common (62%) including peripheral T-cell lymphoma not otherwise specified (31%; PTCL, NOS) and angioimmunoblastic (19%). Six (23%) had MF and four (15%) had adult T-cell leukemia/lymphoma. Median prior lines of therapy were 2 (range, 1-8), 31% had received ≥4 prior lines and 2 patients had received prior SCT.

Two dose-limiting toxicities were observed, grade 4 thrombocytopenia at dose level 1 and grade 3 abdominal pain at dose level 2; the MTD of lenalidomide was determined to be 20mg. Grade ≥3 non-hematologic adverse events (AE) included hypokalemia (12%), kidney injury, adrenal insufficiency, fatigue, anorexia, weight loss and infection (all, 8%). Grade ≥3 neutropenia, thrombocytopenia and anemia occurred in 17%, 15% and 13% of cycles.

The median number of cycles were 4 (range, 1-6), eight (31%) completed the planned 6 cycles of treatment. Ten (38%) discontinued for progression, 23% due to toxicity (four due to thrombocytopenia, one each due to abdominal pain and anxiety) and 8% due to patient/provider preference. Seven (27%) patients required dose reduction.

One patient withdrew during the lenalidomide lead-in and was not included in the efficacy analyses. In patients who received RAdR (N=25) the ORR was 56%, 95% CI (34.9% - 75.6%) and CR 12%, 95% CI (2.5% - 31.2%). After a median follow up of 18.2 months, 1-year progression-free survival (PFS) was 14.9%, 95% CI (5.4% - 41.1%) and 1-year overall survival (OS) was 63.3%, 95% CI (45.8% - 87.4%). Two patients (PTCL, NOS and MF) remain in remission off therapy after more than 36 months of follow up without consolidation. All 5 patients who received consolidative SCT are alive at 19-39 months of follow up.

In patients with nodal TCL (N=16) the ORR was 63%, 95% CI (35.4% - 84.8%) and CR 19%, 95% CI (4.0% - 45.6%). 1-year PFS was 16.9%, 95% CI (5.0% - 57.4%) and 1-year OS was 70.3%, 95% CI (49.5% - 99.8%). In patients treated at the MTD (N=9: 5 PTCL, NOS, 2 ALCL, ALK- and 2 MF) the ORR was 89%, 95% CI (51.8% - 99.7%) and CR 22%, 95% CI (2.8% - 60.0%). 1-year PFS was 11.1%, 95% CI (1.8% - 70.5%) and 1-year OS was 71.4%, 95% CI (44.7% - 100%).

Multiagent targeted therapy with RAdR is safe in r/r TCL and induces a high rate of response, particularly at the MTD, but durable complete responses are uncommon without consolidation. The four-drug regimen is active across the diverse spectrum of TCL subtypes and may be an effective therapeutic bridge to transplantation.