Final Results From the Phase 2 Continuation Study of the Lenalidomide and Azacitidine Combination in Patients with Higher-Risk Myelodysplastic Syndromes (MDS)

Lenalidomide (LEN) and azacitidine (AZA) have activity in lower- and higher-risk MDS patients (pts), where both microenvironment and cell regulatory mechanisms play a role. The LEN/AZA combination was well-tolerated in the Phase 1 study (Sekeres JCO 2010) that established Phase 2 dosing, with an overall response rate (ORR) of 67%.

The primary objectives for this multicenter, Phase 2 trial were to determine the efficacy and safety of combination therapy, with AZA 75mg/m² daily × 5 days, and LEN 10mg daily × 21 days of a 28-day cycle (maximum of 7 cycles), in pts with higher-risk MDS (IPSS score ≥1.5, or World Health Organization (WHO) classification with ≥5% myeloblasts) not previously treated with AZA or LEN. Adverse Events (AEs) were assessed per NCI CTC v.3.0, with median decrease in absolute neutrophil count (ANC) or platelets (plt) calculated for the first 8 weeks of therapy. Subjects were enrolled to the Phase 1 study from 5/05 through 5/08, and to the Phase 2 continuation from 3/09 through 4/11, with results reported through 7/11. Bone marrow biopsies were performed after the 4^th and 7^th cycles, and pts could continue on AZA monotherapy off-study. Responses were assessed per modified International Working Group criteria as complete or partial response (CR, PR), or hematologic improvement (HI), and validated centrally. Time to progression was from date of CR, and overall survival (OS) from date of study enrollment.

A total of 36 pts were enrolled at 3 centers (18 Phase 1, 18 Phase 2); median age was 68 years (range 47–78), 13 pts (36%) were female, median interval from diagnosis was 8 weeks (range, 2–106), and median follow-up was 15 months (range 2–60). Prior MDS therapies included growth factors (19%), immunosuppressants (14%), and chemotherapy (17%). Median baseline hemoglobin was 9.7 g/dL, platelet count 65 k/uL, neutrophil count 840 k/uL, erythropoietin level 108 MIU/mL, and bone marrow blast percentage was 11%. IPSS categories were Int-1 (5 pts), Int-2 (20 pts), and High (11 pts); 8 pts had RAEB-1, 21 had RAEB-2, and 3 had CMML. Only 1 pt had a chromosome 5q deletion. Pts received a median of 5 cycles of therapy on-study. Grade 3/4 non-hematologic AEs (related or unrelated) included cardiac (11%), febrile neutropenia (31%), other infection (8%), pulmonary (11%), vascular access-related thrombosis (6%), CNS hemorrhage (6%), or other (11%). Three pts (8%) died while on-study. 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%). Median decrease from baseline in ANC was 35% and in plts was 18%. Of 35 patients evaluable, the ORR was 71%: 14 pts (40%) had a CR and 11 (31%) had HI, of whom 3 had bi- or tri-lineage HI. Median time to response was 3 months (range, 1–7). Three patients had progressive disease while on-study. Among pts achieving a CR, 7 (50%) continue to receive therapy; median age was 68 years (range, 50–76); IPSS was Int-1 (n=3), Int-2 (n=9), and High (n=2); WHO was RAEB-1 (n=5) and RAEB-2 (n=9); cytogenetic profiles were: 9 (64%) normal; 1 (7%) del (5q); 1 (7%) +8, 1 (7%) −7, 1 (7%) complex, and 1 (7%) unknown; median CR duration at last study assessment was 16 months (range, 3–36) and median OS at last assessment among CR pts was 27 months (range, 7–55). Seven CR pts (50%) evolved to AML a median of 20 months from achieving CR (range, 9–31); 10 (71%) remain alive at last study assessment.

The LEN/AZA combination is well-tolerated and highly active in treating higher-risk MDS. The ORR seen in the Phase 1 study was supported by Phase 2 data, with good OS, even among progressing pts. Subsequent randomized studies will compare the LEN/AZA combination to AZA monotherapy and other AZA-based combinations.

Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau. Off Label Use: Use of lenalidomide, wapproved for lower-risk del(5q), will be discussed in higher-risk patients with MDS. Komrokji:Celgene: Honoraria, Research Funding, Speakers Bureau. Lancet:Celgene: Research Funding. List:Celgene: Consultancy. Maciejewski:Celgene: Membership on an entity's Board of Directors or advisory committees.