Prognostic Factors and Response Duration in 419 MDS Treated with Erythropoietin±GCSF: The GFM Experience.
Authors: Park S. , Kelaidi C. , Grabar S. , Beyne-Rauzy O. , Cheze S. , Bardet V. , Escoffre-Barbe M. , Ravoet C. , Ferrant A. , Vey N. , Dombret H. , Mahe B. , Mannone L. , Legros L. , Aljassem L. , Stamatoullas A. , Vassilief D. , Quarre M.C. , Ades L. , Andrieux V. , Giraudier S. , de Botton S. , Casadevall N. , Fenaux P. , Dreyfus F. 
Published: October 2019

Abstract
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 (Blood, 2005, 106, 803–11) and we reanalyzed them in a large series of patients (pts) treated in France and Belgium.
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:
EPO level <200UI/l, RBC transfusions <2 units/month were confirmed as major prognostic factors of response to EPO±G. Good response rates were seen in RAEB-1, and with EPO alone, in RARS and RCMD-RS. Multilineage dysplasia was not associated with lower response rates, but with shorter response duration. 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.