A Phase II Study Of The Combination Of Azacitidine and Lenalidomide In Patients (pts) With Higher Risk Myelodysplastic Syndromes (MDS)

Several combination strategies with hypomethylating agents are being developed to improve the results of single agent azacitidine in front line higher risk MDS. An example is the combination of azacitidine and lenalidomide (Sekeres Blood 2012) that in pilot studies has resulted in significant activity in this patient population. At this point, the optimal dose and sequence of these agents is not known. We performed a phase I trial of the sequential combination of azacitidine followed by lenalidomide in MDS and AML (ASH 2011 abstract 2613). In this study the optimal dose and schedule of these two agents was defined as azacitidine 75 mg/m² IV on days 1 to 5 followed by lenalidomide 25 mg for 5 days on days 6 to 10 every 28 days. This dose and schedule was subsequently studied in pilot phase II study of patients with higher risk MDS with predefined stopping rules, results of which are shown here. Previously untreated patients with MDS, or AML by WHO criteria, with bone marrow blasts from 10% to 30%, or INT-1 or above MDS, were eligible. Other criteria included adequate performance status, renal and hepatic functions. All patients were registered in the RevAssist Program. Bone marrow aspirates were performed at baseline and on course 1 day 28 and every 1 to 3 cycles of therapy thereafter. The study had 2 stopping rules (SR): for response and toxicity. The response SR targeted an ORR (CR/CRp) of 30%. CR is defined as blasts less than 5%, ANC over 10³ ku/L and a platelet count over 100 x 10³ ku/L. CRp is as CR but with platelets between 30 to 100 x 10³ ku/L. Patients were treated in cohorts of 10 patients for a maximal of 40 patients. The study would stop early if 0 responses were observed in the first 10 patients, less than 4 in the first 20 or less than 6 in the first 30. For toxicity (grade III, IV), the study will stop early if 5 out 10, 9/20, 12/30 experienced toxicity. We treated 40 patients in this phase II study therefore not meeting either the SR for toxicity or response. The median age was 66 years (range 38-85). Median percentage of blasts was 14 (range 4 to 40). Fifty % of patients had higher-risk disease, 5 (12%) int-1 and 14 (37%) int-2. Cytogenetics were analyzed in 37 patients: 7 (18%) pts were diploid, 18 (48%) had complex cytogenetics, 4 (10%) isolated deletion 7 and the others miscellaneous including +8. The median WBC at initiation of therapy was 2.6 (range 1-32). In total, 9 pts achieved CR (22%), and 5 CRp (12%) for an ORR 34%. Two additional patients achieved hematological improvement and 7 (17%) marrow CR (defined as blasts less than 5% but not accounted here for ORR). The median number of cycles is +4 (range 1-+12) and still ongoing. No drug related induction mortality was documented. No drug related grade III o IV toxicity was observed. The most common toxicities being fatigue, constipation, rash, nausea, all grade 1 to 2. With a median follow up of 6 months, the median overall survival of the study group has not been reached and median CRD was has not been reached. In conclusion, the combination of azacitidine and sequential lenalidomide is well tolerated and providing a response rate over expectation.