Abstract

7002 Background: ESAs, the first line treatments of anemia in non del 5q lower risk MDS, yield only 40-50% responses. LEN gives RBC transfusion independence (TI) in about 25% of ESA resistant (or relapsing) TD lower risk MDS without del 5q (Raza, Blood, 2008), and a gene expression signature can predict response (Ebert, Plos Med 2008). We randomized in this patient population LEN alone and LEN+EPO. Methods: In this prospective multicenter open-label phase II study (NCT01718379), lower risk MDS patients without del 5q, with TD (≥4 RBC units during the previous 8 weeks (w)) with ESA resistance or relapse after a response were randomized between LEN alone, 10mg/d x 21 d/4 w (L arm) or LEN (same schedule) + EPO beta, 60 000 U/w (LE arm). The primary endpoint was erythroid response (HI-E, IWG 2006 criteria) after 4 treatment cycles. Secondary objectives included identification of biomarkers of response. Results: Between July 2010 and June 2012, 132 patients (pts, 66 / arm), median age 73 (range 46-88), M/F: 88/44 were enrolled. Median TD was 6 RBC units/8w (range 2-18). IPSS was Low in 45% and Int-1 in 55% pts. Pretreatment characteristics did not differ between the 2 groups. All but 3 pts, who withdrew consent (2L+1LE), were evaluable for response. In this ITT population, HI-E was obtained in 15 pts (23.4%) in L arm and 26 (40.0%) in LE arm (RR= 1.7, p= 0.043, chi2 test), and TI in 9 (14.1%) versus 16 (24.6%) pts (RR=1.7, p= 0.13). In the 99 pts who completed 4 treatment cycles, 41 achieved HI-E, including 15/49 (30.6%) in L arm versus 26/50 (52.0%) in LE arm (p= 0.03), and TI in 9 (18.4%) versus 16 (32.0%) pts (RR= 1.7, p=0.12). Side effects (cytopenias and 1 DVT/arm) were similar in the 2 arms. A 29-gene expression profile signature predicting HI-E to L or LE, different from that previously published, was identified and a polymorphism in the CRBN gene (Kosmider, submitted) was significantly associated with HI-E in the entire cohort (p=0.034). Conclusions: LEN + EPO yielded a significantly better erythroid response than LEN alone in lower risk MDS patients with anemia resistant to ESA alone. A gene expression signature and a CRBN gene polymorphism correlated with the erythroid response. Clinical trial information: NCT01718379.

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