Lenalidomide + Azacitidine Well Tolerated, Highly Active in Patients with Higher-Risk Myelodysplastic Syndromes

SAN DIEGO, CA—A multicenter, Phase 2 continuation trial has shown that the positive overall response rate (ORR) seen in a Phase 1 trial evaluating lenalidomide + azacitidine combination therapy is substantiated, with good overall survival (OS), even among progressing patients, in a higher-risk myelodysplastic syndromes (MDS) population. The study was presented at the 53rd American Society of Hematology Annual Meeting and Exposition.

In the continuation phase, study investigator Mikkael A. Sekeres, MD, MS, of the Leukemia Program, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, and colleagues administered azacitidine 75mg/m2 daily for five days in combination with lenalidomide 10mg given daily for 21 days of a 28-day cycle, for a maximum of seven cycles. Patients in the study had International Prognostic Scoring System scores ≥1.5 or a World Health Organization classification of ≥5% myeloblasts and were not previously treated with azacitidine or lenalidomide.

In assessing for adverse events, median decrease in absolute neutrophil count or platelets was calculated for the first eight weeks of therapy. Bone marrow biopsies were performed after the 4th and 7th cycles, and patients could continue azacitidine monotherapy off-study. The International Working Group criteria were used to gauge complete response (CR), partial response (PR), and hematologic involvement (HI). Time to progression was calculated from the date of complete response, while OS was calculated from the date of study enrollment.

A total of 36 patients were enrolled at three centers (18 in Phase 1, 18 in Phase 2). Patients received a median of five cycles of therapy on-study. Median follow-up was 15 months (range 5+–65+). Prior therapies taken by patients for MDS included growth factors (19%), immunosuppressants (14%), and chemotherapy (17%). Median baseline characteristics included: hemoglobin 9.7g/dL, platelets 65x109/L, neutrophils 840x109/L, erythropoietin level 108MIU/mL, and bone marrow blast percentage 11%. IPSS categories were intermediate (int)-1 (5 patients), int-2 (20 patients), and high (11 patients); eight patients had refractory anemia with excess blasts (RAEB)-1, 21 had RAEB-2, and three had chronic myelomonocytic leukemia. One patient had a chromosome 5q deletion.

Grade 3/4 non-hematologic adverse events included cardiac adverse events (AEs) (11%), febrile neutropenia (31%), other infection (8%), pulmonary AEs (11%), vascular access-related thrombosis (6%), CNS hemorrhage (6%), or other non-hematologic AEs (11%). Three patients died while on the study (8%). The most common Grade ≤2, non-hematologic AEs related to treatment included constipation (47%), dermatologic (rash or injection-site reaction) (44%), fatigue (39%), diarrhea (39%), nausea (19%), dizziness (19%), and dyspnea (19%). The median decrease from baseline absolute neutrophil count was 35%; the median decrease from baseline platelets was 18%.

Of 26 patients assessed, the ORR was 72%; 15 patients (42%) had a CR, 10 patients (28%) had HI, and 1 patient (3%) had BM CR. Median time to response was 3 months (range 1–7). Disease progression was observed in three patients. Of those who achieved CR, seven (50%) continue to receive therapy; median CR duration at the last assessment was 16 months (range 3–36) and median OS at that time was 27 months (range 7–55). Seven of the CR patients (50%) progressed to acute myeloid leukemia at a median of 20 months after achieving CR (range 9–31); 10 patients were alive at the last study assessment (71%).

“The combination of lenalidomide + azacitidine in patients with higher-risk myelodysplastic syndromes (MDS) is not as toxic as we thought,” Dr. Sekeres concluded. He noted that the high level of activity of lenalidomide + azacitidine combination therapy in this high-risk MDS population supports ensuing randomized studies researching the efficacy of this combination regimen against azacitidine monotherapy and other azacitidine-based courses of therapy.