Background: Lenalidomide (LEN) and azacitidine (AZA) have demonstrated single agent activity in lower- and higher-risk MDS patients (pts). Response rates may be improved by combining LEN’s immunomodulatory, anti-angiogenic, and cytotoxic properties with AZA’s cytotoxic effects and hypomethylating activity.
Methods: The primary objective of this multicenter, Phase I trial of the Rare Diseases Clinical Research Network Bone Marrow Failure Consortium was to determine the safety of combination therapy, the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs, defined as Grade 3/4 non-hematologic toxicity per NCI CTC 3.0, or >50% prolonged decrease in absolute neutrophil count (ANC) or platelets (plt) without recovery by Day 56). Responsewas a secondary objective, using modified International Working Group response criteria. Pts with higher-risk MDS (IPSS score □1.5, or FAB or WHO classification with □5% myeloblasts) and untreated with AZA or REV were enrolled using a “3+3” dose escalation design (see Table) from 6/06 through 5/08, with results reported through 7/08. Cycles lasted 28 days, to a maximum of 7 cycles.
Results: In all, 19 pts were enrolled; 1 was excluded for a diagnosis of AML. Median age was 68 years (range 52–78), 7 pts (37%) were female, median interval from diagnosis was a median of 5 weeks (range, 2–106), and median follow-up was 5 months (range 1–13). Median baseline hemoglobin was 9.9 g/dl, platelet count 69 k/ul, neutrophil count .84 k/uL, erythropoietin level 99 MIU/ml, ferritin level 893 ng/ml, and bone marrow blast percentage was 11%. Four pts had RAEB-1, 10 had RAEB-2, and 1 had CMML; IPSS categories were Int-1 (3 pts), Int-2 (9 pts), and High (6 pts). Only 1 pt in cohort 4 had a chromosome 5q deletion. No DLTs occurred in any dosing cohort, and the MTD was not reached. Grade 3/4 non-hematologic toxicities included atrial fibrillation (1), monocular blindness (1), basal cell skin carcinoma (1), CNS hemorrhage (1), febrile neutropenia (2), shortness of breath (1), and perforated appendix (1). Median decrease in ANC was 21% and in plts was 1% (mean was 20%). Although cycle 2 was delayed for 2 patients due to neutropenia, there were no dose-reductions for toxicities. Of the 17 pts evaluable for response, the overall response rate was 71%: 7 (41%) had a complete response (CR), 1 (6%) a partial response (PR), 3 (18%) had hematologic improvement (HI), and 1 (3%) a marrow CR.
Conclusions: The combination of LEN and AZA is well-tolerated, and early results suggest efficacy superior to single agent activity in higher-risk MDS. Incorporating safety and efficacy data, the optimal dose of the combination regimen appears to be AZA 75 mg/m2 SC days 1–5 and REV 10 mg PO days 1–21. An investigation of sequential dosing of AZA followed by REV is planned.
Dosing Cohort AZA Dose Rev Dose IPSS Categories Grade 3/4 non-heme toxicities Maximum Response 1 75 mg/m2 SC days
 1-5 5 mg PO days
 1-14 1 Int-1
 2 Int-2 1 2 CR
 1 progression 2 75 mg/m2 SC days
 1-5 5 mg PO days
 1-21 2 Int-2
 1 High 2 1 CR, 1 PR, 1 HI 3 75 mg/m2 SC days
 1-5 10 mg PO days
 1-21 1 Int-2
 2 High 0 2 CR,
 1 stable disease 4 50 mg/m2 SC days
 1-5, 8-12 5 mg PO days
 1-14 1 Int-1
 2 Int-2 2 2 CR,
 1 stable disease 5 50 mg/m2 SC days
 1-5, 8-12 5 mg PO days
 1-21 2 Int-2
 1 High 2 1 HI
 1 stable disease
 1 progression 6 50 mg/m2 SC
 days 1-5, 8-12 10 mg PO
 days 1-21 1 Int-1
 1 Int-2
 1 High 2 1 HI
 1 BM CR
 1 not yet evaluable
