Is There a Role for ATRA in Combination to EPO in Lower Risk Myelodysplastic Syndrome? Preliminary Results of a Phase II Study.
Authors: Ades L. , Mohamed H. , Vassilief D. , Berger E. , Slama B. , Vey N. , Delarue R. , Beyne-Rauzy O. , Guerci A. , Cheze S. , Thomas X. , Stamatoullas A. , Gardembas M. , Bauduer F. , Kolb A. , Chaury M.C. , Legros L. , Damaj G. , Hamza F. , Vaultier S. , Dreyfus F. , Fenaux P. 
Published: April 2020

Abstract
Recombinant EPO, when used alone at 60 000 UI/ w, improves anemia in 25 to 30 % of low risk MDS, mainly when serum EPO level is low, and is ineffective on other cytopenias. A previous study (Blood2002,99:1578) suggested that the addition of ATRA to EPO could increase the response rate on anemia, and also improve neutrophils and platelets in some MDS. We report preliminary results of a phase II study of EPO beta and ATRA in lower risk MDS, stratified on serum EPO level, previous results with EPO alone and presence of cytopenias other than anemia.
Trial design: Inclusion criteria were
MDS with &lt; 10 % marrow blasts anemia requiring transfusions or Hb&lt;10g/dl, or Hb&lt;12g/dl and another cytopenia (neutrophils &lt;1500/mm3 or platelets&lt;50000/mm3) exclusion of other causes of anemia.
Patients with EPO level &lt;500 UI/l, previously untreated with EPO and with anemia alone (arm A) were treated with EPO beta alone (20000 UIx3/week). Patients with EPO level &gt;500 UI/l, or unsuccessfully treated by EPO alone or with cytopenia(s) other than anemia (arm B) received the same EPO regimen plus ATRA (45 mg/m2/day, 1 week on, 1 week off). ATRA was escalated to 80 mg/m2/d in case of failure. Responses were evaluated every 12 weeks, based on IWG criteria.
Patients: Between Nov 2004 and June 2005, the 99 initially planned pts were included; 48 of them already had a follow up greater than 12 weeks and were evaluable for response (reference date: June 15th, 2005). 14 pts entered arm A, 9 of them had erythroid response (HI-E, major in 7, minor in 2), and this arm will not be further analysed here. 37 patients entered arm B (3 of them after failure of arm A), due to previous failure of EPO alone (n=16), EPO &gt; 500 UI/l (n=12) thrombocytopenia or neutropenia in the absence of the 2 other criteria (n=9). Arm B pts included 23 Males and 14 females, median age 70, 9 RA, 13 RARS, 15 RAEB1; Karyotype was normal in 20 pts, abnormal in 15 pts including 3 pts with del (5q), and a failure in 2 pts. IPSS was low (7pts,), int-1 (20 pts), int-2 (8 pts) and undetermined (2 pts).
Treatment results in arm B: 17 (46 %) pts had HI-E after 12 weeks of EPO beta+ATRA, including HI-E major (n=7) and HI-E minor (n=10). 8 of the minor and non responders received 12 further weeks of EPO+ ATRA at 80 mg/m2/d but without improvement. HI-E occurred in 4/12 (33%,) pts with EPO &gt;500 UI/l (all minor responses), 8/16 (50%) pts having failed EPO alone (2 major, 6 minor responses), 5/9 (55 %) pts enrolled in arm B due to neutropenia and/or thrombocytopenia (all major responses). Only 2 of the 19 pts with neutrophils&lt; 1500/mm3 had HI-N (1 major, 1 minor), and none of the 9 pts with platelets&lt;50000/mm3 had HI-P. No major side effects of treatment were observed. Baseline EPO level had significant prognostic value for erythroid response in arm B.
Conclusion: Our preliminary findings suggest that the addition of ATRA to EPO improves the erythroid response in about one half of lower risk MDS patients unresponsive to EPO alone, and yields erythroid response in one third of pts with high EPO levels, but most erythroid responses in those 2 patient groups have been minor so far. This combination had very limited effects on neutropenia and thrombocytopenia in MDS. Updated results will be presented.