PS1336 DISCREPANCE OF ALLELIC BURDEN CHANGES AND CLINICAL RESPONSE IN PATIENTS WITH HIGHER RISK MYELODYSPLASTIC SYNDROME TREATED WITH HYPOMETHYLATING AGENTS

Abstract

Background:Hypomethylating agents (HMAs) such as azacitidine (AZA) and decitabine (DEC) are used to treat higher risk myelodysplastic syndrome (HR‐MDS). However, underlying genetics and allelic burden change after HMAs needs to be clarified.Aims:This study investigated the effects of alleleic burden changes on the clinical outcomes after treatment with HMAs.Methods:This study included bone marrow samples from 64 patients (34 AZA and 30 DEC) taken at diagnosis and follow‐up after median 4 cycles. Targeted deep sequencing on a custom myeloid gene panel of 84 genes (Agilent SureSelect) was performed on trios of T‐cell, pre‐HMA, and post‐HMA samples on 64 HR‐MDS patients.Results:At diagnosis, we detected 135 mutations from 54 patients. Most frequently mutated genes were TP53 (n = 9), DNMT3A (n = 7), ASXL1 (n = 7), DDX41 (n = 7) and U2AF1 (n = 6). HMAs were administered median 4 cycles (range 1–14). At follow‐up, allelic burdens were decreased from median 13.7% (range 1.5–87.7) to 1.7% (range 0.0–49.4%), where from median 9.9% to 0.8% in AZA group (p < 0.001) and from median 17.8% to 6.7% in DEC group (p = 0.005). CR/mCR rate were higher in patients with allelic burden reduction <2% (n = 26/43, 60%) than those without (24%, n = 5/21), but not significantly different (p = 0.765). With median follow‐up duration of 19.3 months (range 0.2–99.6 months), 2‐year overall survival (OS) rates were 54.6 ± 8.1% and 44.8 ± 11.3% in patients with and without allelic burden reduction, respectively (p = 0.907). The presence of TP53 mutations did not affect the achievement of CR/mCR (p = 0.379). However, the presence of TP53 mutations were associated with inferior OS rates: 2‐year OS rates of 56.5 ± 7.2% and 22.2 ± 13.9% (p = 0.001). In the multivariate analysis, IPSS high (HR 5.34) and the presence of TP53 mutations (HR 3.42) affected adversely on OS, while the achievement of CR/mCR (HR 0.23) and the performance of allogeneic transplantation (HR 0.33) were favorable factors for OS.Summary/Conclusion:This study showed that allelic burden is decreased after treatment with both azacitidine and decitabine in HR‐MDS patients. However, the allelic burden reduction is independent to the achievement of CR and OS. The presence of TP53 mutation remained independent prognostic factor in HR‐MDS patients treated with HMAs, even with decreased allelic burden.