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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 LEN1EPO.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)1 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(2L11LE),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(RR5 1.7,p5 0.043,chi2 test),and TI in 9(14.1%)versus 16(24.6%)pts(RR51.7,p5 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(p5 0.03),and TI in 9(18.4%)versus 16(32.0%)pts(RR5 1.7,p50.12).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(p50.034).Conclusions: LEN 1 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.