High Response Rate and Improved Exercise Capacity and Quality of Life with a New Regimen of Darbepoetin Alfa (DAR) +/−G-CSF in Lower-Risk MDS : a Phase II Study.
Authors: Kelaidi Charikleia , Beyne-Rauzy Odile , Braun Thorsten , Cougoul Pierre , Ades Lionel , Pillard Fabien , Lamberto Christine , Jernival Tony , Mortera Edith , Guerci Agnes , Choufi B. , Stamatoullas Aspasia , Slama Borhane , De Renzis Benoît , Ame S. , Ghandi Damaj , Boyer Françoise , Chaury Marie-Pierre , Legros Laurence , Cheze Stéphane , Testu Anna , Gyan Emmanuel , Bene Marie C , Rose Christian , Dreyfus Francois , Fenaux Pierre 
Published: October 2019

Abstract
Abstract 3812
Poster Board III-748
Background. DAR is a hyperglycosylated erythroblastic stimulating agent (ESA) with prolonged half life. Previous studies have shown high erythroid response rates with DAR +/− G-CSF in anemia of lower risk MDS (Mannone et al, Br J Haem 2006) with improvement in quality of life (QoL) (Greenberg et al, Blood 2009). In addition, treatment with ESAs in lower risk MDS does not increase progression to AML and may improve survival (Park, Grabar, Kelaidi et al, Blood 2008; Jadersten et al, JCO 2008). To better document the clinical relevance of erythroid response in those pts, we explored whether physical performance was also improved, using a new regimen of DAR+/− G-CSF. Patients and methods. In this phase II study (clinicaltrials.gov n° NCT00443339), low and int-1 MDS pts with anemia and endogenous EPO level <500 IU/L received DAR 500μg once every 2 weeks for 12 weeks. G-CSF could be added in the absence of response at week 12, and response reevaluated at week 24. Responders at week 12 or 24 could continue treatment. Some of the recruiting centers accepted to participate in an additional part of the study that included for patients (pts) at treatment onset, and at weeks 12 and 24 (i) Six minute Walk Test (6-min WT), a standardized test to evaluate global exercise capacity (distance walked in 6 minutes) (ii) In pts with no history of cardiac ischemia or heart failure and that could physicaly perform the test: peak oxygen consumption (VO2peak) evaluation on ergocycle, the reference method to assess physical performance (Albouaini et al, Heart 2007) (iii) QoL using SF-36 and FACT-AN tests.

Results
99 pts were included by 17 centers. Median age was 72 (41-88), M/F 56/43, WHO distribution: RA 27%, RCMD 17%, RARS 41%, RAEB-1 15%. Karyotype was favorable in 80%, intermediate in 20%. IPSS was low in 60%, int-1 in 40%. Median Hb was 92 g/L and 30% of the pts were RBC transfusion dependent (median 2 RBC units/month). Median endogenous EPO level was 60 IU/L. At the date of analysis, 77 and 65 pts were evaluable at weeks 12 and 24, respectively. Erythroid response rate at 12 weeks (according to IWG 2006 criteria) was 53% and reached 65% (after addition of G-CSF) at 24 weeks. Multivariate analysis for predicting response revealed that endogenous EPO level <100 IU but not IPSS or transfusion dependence, was significantly associated with response (RR 78% vs. 52% for EPO<100 vs. >100 IU/L, resp, P=0.04). 48 of the pts evaluated for response belonged to the 6 centers that participated in the QoL and exercise capacity part of the trial. All had the 6-min WT and QoL, and VO2peak evaluation could be assessed in 20 of them. Mean VO2peak was 1067 mL/min before treatment and 1157 mL/min at week 24 (p=0.15). Mean 6-min WT was 382 m at onset and 418 m at week 24 (p=0.06). A significant improvement in VO2 and 6-min WT at week 24 (vs baseline) was observed in 60% (p=0.058) and 70% (p=0.052) of responders compared to 0% and 19% of non responders, resp. Significant improvement of exercise capacity was associated with achievement of Hb level >110g/L. QoL tests were also improved in responders at week 24 compared to non responders at week 24 (p=0.04). No severe adverse events of treatment were reported.

Conclusion
This regimen of DAR every 2 weeks yielded high response rates. An objective improvement in exercise testing with treatment was seen in 60 to 70% of responders, depending on the test used. This finding, and the QoL improvement also observed in responders, confirm the clinical relevance of anemia correction in that elderly population with lower-risk MDS.

Disclosures:
Off Label Use: Darbepoetin, off-label use in anemia related with lower-risk myelodysplastic syndromes.