Sequential Azacitidine and High-Dose Lenalidomide for Relapsed and Refractory High-Risk MDS and AML: Interim Analysis of a Phase 2 Study

Introduction: Relapsed/refractory high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have a dismal prognosis with few conventional treatment options. Intensive therapies are often intolerable or ineffective. Previously, Pollyea et al reported a phase 1/2 study for elderly, newly diagnosed AML patients (pts) who were administered sequential azacitidine with high-dose lenalidomide; the maximum tolerated dose of lenalidomide was 50 mg for 21 days of a 6-week cycle, and the ORR was 40% with a 28% CR/CRi rate (Leukemia 2012 893 and Haematologica 2013 591). Based on the efficacy and tolerability of this regimen, we designed a single-center phase 2 study for high-risk MDS and AML pts with relapsed/refractory disease.

Methods: The primary objective was to evaluate the efficacy of this regimen in this population. Secondary objectives included safety, response duration, progression-free survival/overall survival, the number of eligible pts able to proceed to transplantation, and correlative outcomes. The schema involved azacitidine 75 mg/m² d1-7 followed by lenalidomide 50 mg d8-28; d29-42 was a recovery period for a total 42-day cycle. Cycles could be repeated indefinitely in the absence of excessive toxicity or disease progression. Pts were ≥18 with relapsed/refractory high-risk MDS or AML. The study was designed to maximize inclusion to approximate a real-world clinical population, but pts with extensive organ dysfunction or hyperproliferative disease that was not controllable with hydroxyurea were excluded. Using a Simon two-stage minimax design, 37 pts are required to double the null hypothesis, a 15% CR/CRi rate. At least 2 of the first 18 pts must achieve a CR/CRi to justify proceeding to the second stage of the study; interim results are presented here.

Results: Nineteen pts have been enrolled as of July 1 2014, with a median follow-up of 78 days. 16 are evaluable; 3 did not complete a full cycle, the protocol-defined minimum to be evaluable, due to disease progression. The median age was 73 (18-86). 16 were male; 16 had AML and 3 had high-risk MDS. The median number of prior therapies was 1 (range 1-5). All MDS patients had failed a hypomethylator. Three had relapsed after allogeneic stem cell transplantation. Using European LeukemiaNet cytogenetic and molecular prognostic data, 1 pt was considered favorable, 2 were intermediate-1, 4 were intermediate-2 and 12 were adverse. Five had a monosomal karyotype; 1 had a del(5q) as part of a complex karyotype. The median number of cycles received was 1 (0-4).

Adverse events (AEs) were reported according to the NCI CTCAE v4.0. There were 114 independent possibly related AEs; the most common AEs (>25% of pts) were constipation (9/19, 47%), anemia (7/19, 37%), diarrhea (7/19, 37%), dizziness (7/19, 37%), abdominal pain (6/19, 32%), hypoxia (6/19, 32%), injection site reactions (6/19, 32%), anorexia (6/19, 32%), pruritus (6/19, 32%), pneumonia (5/19, 26%), nausea (5/19, 26%), thrombocytopenia (5/19, 26%) and hypotension (5/19, 26%). The possibly related ≥ grade 3 AEs (reported as total number of events) were: thrombocytopenia (n=9), febrile neutropenia (n=6), anemia (n=6), leukopenia (n=4), neutropenia (n=4), weakness (n=4), renal insufficiency (n=1) and pruritus (n=1). Three pts required a 50% dose reduction of lenalidomide for renal insufficiency (n=1), rash/GVHD flare (n=1) and fatigue (n=1), and 8 held lenalidomide for at least 2 days during at least 1 treatment cycle.

The ORR was 50% (8/16) for evaluable patients and 42% (8/19) for all patients. 43% (7/16) of evaluable patients had a CR/CRi (n=2 CR, including 1 complete cytogenetic remission, n=5 CRi). There was 1 PR. 2/3 high-risk MDS patients responded (both CRi). The median time to achieve best response was 1.5 months. Lower baseline bone marrow blasts were predictive of response. Median OS was 91 days; 569 days for responders and 71 days for non-responders. 12 pts died; 1 was treatment related (renal failure) and 11 were disease related. Early death rate (death in the first 30 days) was 17% (2/12). 2/6 pts felt to be eligible for a stem cell transplantation were able to use this regimen as a bridge to this therapy.

Conclusions: The requisite number of responders to proceed to the second phase of the study was reached. Sequential azacitidine and high-dose lenalidomide has activity in relapsed/refractory AML and high-risk MDS; updated clinical results and correlative studies will be presented.