Erythroid response to lenalidomide (LEN) + recombinant erythropoietin (EPO) and endogenous serum EPO concentration in MDS cytokine-failures

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7031 Background: LEN promotes erythropoiesis in a subset of lower risk MDS pts who fail EPO treatment (tx) [N Eng J Med 2005;352:549]. We reported that LEN acts to relieve suppression of the EPO-R signal in non-del(5q) MDS progenitors. We hypothesized that erythroid response (HI-E) to LEN is influenced by endogenous EPO level and can be augmented by combined tx (CT) with EPO in pts with low serum EPO (sEPO) concentration. To evaluate the potential benefit of CT, the effect of sEPO level, and the effects of LEN pharmacokinetics (PK) on cytopenias, we performed a two-stage PK and efficacy study. Methods: Eligible pts had transfusion-dependent (TD), Low/Int-1 IPSS MDS who failed prior treatment with EPO. In the 1st stage pts received LEN monotherapy (MT) at 10mg/d [n=25] or 15mg/d [n=15]. Single dose [n=12] and steady state [n=24] PK were evaluated on days -7 and +14 at the 10mg LEN dose. After 16 wks of MT, erythroid non-responders (NR) and minor (MiE) responders (IWG 2000) were offered CT with epoetin alpha 40,000U/wk for 8 wks. Results: Among 39 pts, median age is 72 years; 7 pts had del(5q). HI-E response to LEN-MT was 36% (n=14) [10mg, 36%; 15mg, 36%] with 13 major (Ma) [del(5q), n=6] and 1 MiE. 18 pts received CT at wk16 with 5(28%) HI-E (3Ma, 2MiE) [10mg, 10%; 15 mg, 50%]. Mean baseline sEPO was higher in HI-E responders vs. NR to LEN-MT [1177 vs.530 mU/ml], whereas in CT responders, mean wk 16 sEPO was lower [339 vs. 1116 mU/ml]. Similarly, HI-E response rate to CT was higher in pts with sEPO <500 mU/ml (4/12, 33% vs. 1/6, 17%). LEN AUC was higher in pts with reduced creatinine clearance (30–49 mL/min, n=2: 955+49; vs. >50 mL/min, n=22: 558±166). There was no difference in AUC or Cmax by magnitude of change in ANC or platelet count in the first month of tx. However, mean AUC inversely correlated with time to >50% reduction in platelet count (ANOVA, P = 0.04). Conclusions: These data suggest that HI-E response to LEN in TD-cytokine failures is sEPO-dependent, yielding a higher response rate to LEN-MT in pts with appropriate sEPO elevation, whereas addition of EPO may improve response in pts with low EPO production. The benefit of CT with LEN+EPO will be investigated in a phase III intergroup study (E2905) in pts who failed primary EPO tx or have a poor cytokine response profile. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene Celgene, Pharmion Celgene Pharmion