PB1731 ELEVATED FETAL HEMOGLOBIN (HBF) IN ELDERLY AML PATIENTS RECEIVING HYPOMETHYLATING AGENTS: ENHANCEMENT OF HBF INDUCTION BY RETINOIC ACID?

Abstract

Background:We recently reported elevation of fetal hemoglobin (HbF) as a potential predictor of outcome in elderly AML/MDS patients treated with DNA‐hypomethylating agents (HMA). HbF elevation prior to decitabine (DAC) treatment (Lübbert et al., Br. J. Haematol. 2017; 176:609‐617) as well as HbF induction following 2 courses of DAC treatment (Stomper et al., Haematologica 2019; 104:59‐69) were associated with superior outcome of AML/MDS patients. Interestingly, HbF elevation was shown to be associated with cytogenetic remissions and to be reversed at relapse, suggesting that HbF is preferentially induced in non‐clonal erythroid cells during HMA therapy.Preclinical work suggests that epigenetically active agents such histone deacetylase inhibitors (HDACi) can be combined with retinoic acid to induce HbF.Aims:We now investigated the effect of the add‐on drugs all‐trans retinoic acid (ATRA) and valproic acid (VPA, an HDACi) on HbF induction during DAC treatment in AML patients.Methods:The DECIDER trial addresses the effects of the add‐on of ATRA or VPA to DAC (Grishina et al., BMC Cancer 2015; 15:430). We serially studied HbF levels in 16 AML patients ≥60 years old that received >2 cycles of treatment within the DECIDER trial. Four patients received only DAC, 5 patients DAC+VPA, 5 patients DAC+ATRA, and 2 patients DAC+VPA+ATRA. HbF levels were measured in peripheral blood erythrocytes by HPLC before treatment and sequentially, i.e. after the end of each treatment course. HbF >1.0% was considered induced.Results:In this albeit small cohort, continued treatment appeared to result in variations in maximally attained levels of HbF depending on the type of drug add‐on. As to VPA, the median peak HbF level attained was 1.5% (range, 0.4 ‐ 5.0%) in 9 patients not having received VPA compared to 1.0% (range, 0.2 ‐ 4.8%) in 7 patients having received VPA. The median peak HbF level in the absence of ATRA (9 patients) was 0.8% (range, 0.2 ‐ 2.8%) compared to 2.1% (range, 0.3 ‐ 5.0 %) in 7 patients having received ATRA.Summary/Conclusion:Given that the add‐on of ATRA (but not VPA) to DAC resulted in superior outcome (Lübbert et al., ASH 2016), these preliminary results suggesting a higher induction of HbF in the presence of ATRA warrant prospective, serial HbF determinations in a planned randomized validation trial. Also, RNA‐sequencing studies in AML cell lines treated with DAC ‐/+ ATRA are addressing de‐repression of the gamma‐globin locus in vitro.