Phase I Study of the Combination of 5-Azacitidine Sequentially with High-Dose Lenalidomide in Higher-Risk Myelodysplastic Syndrome (MDS) and Acute Myelogenous Leukemia (AML)

Abstract 2613

The hypomethylating agents are standard of care in patients with higher risk MDS and used frequently in older AML. A number of strategies, including combination approaches, are being developed to improve results of single agent hypomethylating agent. For instance the combination of 5-azacitidine and lenalidomide (LEN) has been shown to be safe and active in a phase I trial (Sekeres JCO 2010; 28:2253–8). Recently the use of high dose LEN (50 mg orally daily) has been reported to have significant activity in older AML (Vij Blood. 2011;117:1828–33). We hypothesized that sequential combination of 5-azacitidine followed by LEN could be safe and active in patients with higher risk MDS and AML. To test this concept, we developed a phase I/II protocol of such combination. Here, we present results from the completed phase I portion of the study. Patients with refractory or relapsed AML and MDS (bone marrow blasts more than 10%) of any age or untreated patients older than 60 years with AML or MDS who refused or were not eligible for frontline therapy were eligible. Adequate performance status, liver function and renal function were requiered. All study participants were registered into RevAssist® program. Females of childbearing potential were required to have a negative pregnancy test. 5-azacitidine was administered at 75 mg/m² IV daily for 1 to 5 day on a 28 day cycle. LEN was administered on day 6 for 5 or 10 days. The phase I portion of the study design followed a classic “3+3” design and only LEN was dose escalated. 28 patients were registered in the study. The following doses of LEN were used: 10 (N=5), 15 (N=3), 20 (N=3), 25 (N=3), 50 (N=4), 75 mg (N=3) orally for 5 days and 75 for 10 days (N=7). Median age was 65 (range 31 to 79); 19 patients had AML and 9 had MDS or CMML. Median baseline WBC was 1.95 K/μL (range 0.1 to 19.1), median platelet count 68 K/μL (4 to 328), median bone marrow blasts 23% (range 11% to 84%), 8 had diploid cytogenetics and 20 others including 5q- (8 patients), monosomy 5 (5 patients) and monosomy 7(7 patients), del 17 (4 patients), t(9:11)(2 patients) and t(3;5)(2 patients). FLT-3 and N-RAS mutations were seen in 2 patients each and NPM-1 mutation in 1 patient. 22 patients had received prior therapy. A total of 88 cycles of therapy have been administered with a median of 1.5 cycles (range 1 to 10). No dose limiting toxicity was documented and the maximal tolerated dose was therefore not reached. At the 75 mg × 10 days dose, one patient died unexpectedly and subsequently 6 additional patients were treated with no additional severe toxicities observed. Common non-hematological toxicities were fatigue, loss of appetite, constipation, skin rash, fevers and weight loss. Of 6 patients that had not received prior therapy, 5 were evaluable for response and 3 (60%) achieved a complete response at doses of 25 and 50 mg of LEN. No response was observed in previously treated patients but 9 (47%) had stable disease. In conclusion, the combination of 5-azacitidine with high dose LEN up to 75 mg orally × 10 days is safe in patients with AML/MDS. The study continues now in a phase II extension of N=40 patients with LEN at a dose of 50 mg daily × 10 days.