Final Results from a Phase I Combination Study of Lenalidomide and Azacitidine in Patients with Higher-Risk Myelodysplastic Syndromes (MDS)

Abstract

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

Azacitidine induces profound genome-wide hypomethylation in primary myelodysplastic bone marrow cultures but may also reduce histone acetylation

“…Several phase I/II studies have evaluated the effect on the combination of Azacitidine and lenalidomide both in cohorts with a karyotype including del5q and mixed cytogenetic cohorts including patients without del5q. [170][171][172][173][174] The combination has shown to be feasible and with encouraging response rates exceeding the reported response rates on Azacitidine alone.…”

ASH 2010 meeting report—Top 10 clinically‐oriented abstracts in myelodysplastic syndromes (MDS)

“…Although the relatively weak HDAC inhibitor valproic acid did not improve responses to decitabine in a randomized trial of decitabine monotherapy versus combination therapy [48], ongoing trials are assessing combinations of azacitidine with vorinostat [49], a more potent HDAC inhibitor that is currently approved for treatment of patients with cutaneous T‐cell lymphoma. In addition, an azacitidine plus lenalidomide combination regimen is also moving forward, based on encouraging Phase I data from the Bone Marrow Failure Consortium [50]. However, it is discouraging that combination therapy with azacitidine and entinostat was not more efficacious than azacitidine monotherapy in the E1905 trial.…”

Safety and efficacy of azacitidine in myelodysplastic syndromes

“…In a phase I study with 18 patients, azacitidine was tested in combination with lenalidomide, which had demonstrated activity in MDS patients with 5q chromosome abnormalities. 47 The treatment regimen was well tolerated, and the overall response rate for the 17 evaluable patients was 71%, with 41% of patients achieving a complete response. This combination was well tolerated, with a significant clinical activity encouraging for further analysis.…”