Efficacy of Recombinant Erythropoietin + 13-cis Retinoic Acid + Dihydroxylated Vitamin D3 in the Treatment of Anemia of Low-Intermediate Risk Myelodysplastic Syndrome Patients.
Authors: Ferrero Dario , Dellacasa Chiara , Darbesio Antonella , Bertini Marilena , Pregno Patrizia , Boccadoro Mario 
Published: April 2020

Abstract
Human recombinant erythropoietin (rEPO) improved anemia, in most of casistics, in about 30–35% of myelodysplastic syndrome (MDS) patients without BM blast excess. More recent sudies, employing either higher rEPO doses (70–80.000 U/week) or combinations of rEPO + G-CSF or all trans retinoic acid reported erythroid responses in 40–50% of patients. However, responses were quite less frequent in transfusion-dependent patients. On the basis of a previous our study (D. Ferrero et al.: Leuk Res1996; 20: 867–876; Blood1999; 94 suppl.1: 307) reporting more than 50% transfusion reduction in 30% of MDS patients treated with a combination of 13-cis retinoic acid (RA) + dihydroxylated vitamin D3 (D3), we employed in a new protocol the same combination of differentiating agents + rEPO. Thirty-two MDS patients, 19 males and 13 females, with a median age of 74.5 (46–90) entered the sudy. Diagnosis, according to W.H.O. classification was RA in 10, RARS in 3, RCMD in 7, 5q- syndrome in 2, RAEB1 in 10. IPSS score, available in 21, was: low risk in 4, intermediate-1 risk in 14, intermediate-2 risk in 3. Cytogenetic abnormalities were evidenced in 7/21 patients. Twenty-two/32 patients were transfusion- dependent with a median requirement of 2 U/month (1 – 7). All patients received a combination of RA (20 – 40 mg/day) + D3 (1 microgram/day) + human rEPO (either alpha or beta epoetin), starting from 30–40,000 U/week up to 70 – 80,000 U/week (median maximal dose: 70,000 U). Six/10 RAEB1 patients also received intermittent courses of low-dose 6-thioguanine and 2 patients received G-CSF for coexisting severe neutropenia. Erythroid responses were scored as major in the case of 100% reduction in transfusion requirements or greater than 2 g/dl increase in Hb level in untransfused patients, minor in the case of at least 50% reduction in transfusion requirements or 1–2 g/dl increase in Hb level without transfusions. Erytroid responses (13 major, 7 minor) were detected in 20/32 (62.5%) patients, without significant differences between patients without blast excess (14/22: 63.6% responsive) and RAEB1 patients (6/10: 60% responsive). Responses were observed in 13/22 (59%) transfusion-dependent and in 7/10 (70%) untransfused patients. EPO serum level were tested in 19 patients: 15 had values below 200 U/l and 12 of them (80%) responded, 4 had values greater than 200 U/l and no one of them responded. Median response duration was 9 months (2 – 27+) and 35% of responses are projected to be maintained at 15 – 27 months. Median survival was 12.5 months (6.5 – 25+) in RAEB1 patients, unreached (52% projected alive at 4 years) in patients without blast excess. Therapy was well tolerated, with only mild RA- induced mucosal dryness. In conclusion, our combination of rEPO + differentiating agents seems to be more effective than either treatment alone in ameliorating anemia of MDS patients, particularly in transfusion- dependent patients. However, the efficacy is probably low in patients with very high serum EPO levels.