Prognostic Factors and Response Duration in 419 MDS Treated with Erythropoietin±GCSF: The GFM Experience.

Background: EPO and its derivative darbepoietin alfa (DAR) are important treatments of anemia in lower risk MDS. Prognostic factors of response and of its duration have been recently updated (

Patients: 419 MDS pts were treated with EPO (≥30000UI/wk for at least 12 wks) or DAR (300μg/wk)± GCSF in 25 GFM centers between 1998 and 2006 (160 prospectively analyzed in 3 consecutive trials, and 259 retrospectively analyzed). Median follow-up was 54 months, median age: 73.5 years. WHO classification: RA (14%), RCMD (16%), 5q- syndrome (4%), RARS (21%) RCMD-RS (13%), RAEB-1 (22%), RAEB-2 (6%), and also 4%CMML (FAB); karyotype: 64% FAV, 16% INT, and 4% UNFAV (16% failure or not done). IPSS: 34% LOW, 40% INT-1, 8% INT-2, 2% HIGH (16% unavailable). 185, 126, 80 and 28 pts received EPO alone (alfa or beta), DAR, EPO+G and DAR+G respectively. Median pre-treatment EPO level was 76 UI/l (only 7% pts>500 UI/l). All pts had Hb<10g/dl and 54% required RBC transfusions (including 36% with >2 RBC units/month).

Results: 63% pts responded (IWG criteria: 43%HI-E major and 20% HI-E minor), including 57%, 63%, 57%, 66%, 63% with EPO alfa alone, beta alone, EPO+G, DAR alone, DAR+G response (p=ns). Median response duration was 20 mos (range 3–74 mos), 25 and 14 mos for major and minor responses (p= 0.001). Relapse was associated with treatment discontinuation (45%), progression to higher grade MDS (12%) or AML (13%), but without evident cause in 30% cases. In univariate analysis, significantly higher response rates were observed in pts with <10% blasts (p= 0.002), low and INT-1 IPSS score (p=0.001), transfusion <2 RBC units/month (p<0.0001), EPO level<200UI/l (p<0.0001) whereas no significant difference in response rate were seen between RA (69%,) RCMD (72%), RARS (59%), RCMD-RS (71%), RAEB-1 (60%) and 5q- syndrome (52%), and between cytogenetic groups. The response rate in RARS and RCMD-RS was similar with EPO or DAR alone (62.5%), and EPO or DAR+G (60%). In multivariate analysis, EPO <200UI/l (p=0.008), transfusion requirement (p<0.0001) and IPSS (p=0.047) remained predictive factors of response. Longer response duration was significantly associated with blasts<10% (20 mos vs 8 mos for blasts>10%, p=0.007), major response (vs minor), IPSS low-INT-1 (median 22 mos vs 8 mos for INT-2/HIGH, p=0.001) and in pts with absence of multilineage dysplasia (24 mos vs 16 mos, p=0.01). In multivariate analysis, blasts <10% and major response remained predictive factors of longer response.

Conclusions:

1. EPO level <200UI/l, RBC transfusions <2 units/month were confirmed as major prognostic factors of response to EPO±G.

2. Good response rates were seen in RAEB-1, and with EPO alone, in RARS and RCMD-RS.

3. Multilineage dysplasia was not associated with lower response rates, but with shorter response duration.

4. Other prognostic factors of shorter response duration were minor response (vs major), and blasts >10%.

A case control study with pts of the International MDS risk Analysis Workshop, who received RBC transfusion alone, is in progress to evaluate the impact of EPO treatment on leukemia-free survival and overall survival, and its results will be presented.