The Combination of Azacitidine (AZA) and Recombinant Erythropoietin (rEPO) Can Induce Rapidly Hematological Response In Intermediate-2 and High-risk MDS (including RAEB-t)

AZA, a DNA hypomethylating agent, provides 50–60% responses in higher-risk MDS after administration of 6 courses of treatment. Recent laboratory data suggests that demethylation with AZA upregulates EPO-receptor mRNA (Wallach, 2009). AZA might also affect several genes involved in cell cycle, metabolism and signal transduction which are down-regulated in bone marrow erythroid cells in MDS patients non-responsive to rEPO. There is currently insufficient data to combine AZA and rEPO in MDS patients.

We explored the safety and the efficacy of the AZA-rEPO combination in a cohort of 10 (M/F: 5/5) patients (pts) with a median age of 75(67-83) years. Diagnosis (WHO classification) was: RAEB-2: 5, CMML: 2 and RAEB-t: 3; IPSS was: int-2 in 8/10 and high in 2/10 pts. Median time from diagnosis was 6(1-31) months. 9/10 pts were transfusion dependent, 8/10 were refractory to previous rEPO administration while 2/10 pts were not treated with rEPO but their diagnostic serum EPO levels were >200 U/L. Patients were given AZA at FDA/EMEA-approved schedule (75 mg/m²/d x7d/4-weekly) initially for 5 courses and continued if response was obtained. rEPO (40,000IU/week) was given until achievement of steady Hb level >10.5 g/dL or until AZA discontinuation.

Median follow-up was 6.5(1-14) months. Patients received a median of 5 cycles (range 2–13) of AZA; 9/10 pts were treated with ≥5 courses of AZA. The median time of rEPO administration was 82(76-142) days. Best response (IWG 2006 criteria) was CR in 1/10 pts (RAEB-2: 1), marrow CR in 1/10 pts (RAEB-t: 1), and stable disease with hematological improvement (HI) in 4/10 pts (RAEB-t: 1, RAEB-2: 2, CMML: 1) leading to an overall response rate of 60%. As soon as 2 courses of AZA-rEPO were given, 5/6 responders experienced HI-erythroid response, 3/6 obtained HI-platelet response and 2/6 achieved HI-neutrophil response. Adverse events included 2 episodes of febrile neutropenia, nausea (2/10 pts), reversible renal impairment (2/10 pts) and hemorrhagic complications (3/10 patients). Currently, 9/10 patients remain alive, 1 patient experienced progression to AML and the estimated probability of 1 year-Progression Free Survival is 75%.

This study provides clinical evidence that the AZA-rEPO combination is safe and rapidly effective in higher risk MDS pts. Our results emphasize the necessity for randomized trials in order to further evaluate the AZA-rEPO combination in MDS.

No relevant conflicts of interest to declare.