Acute myeloid leukemia

DNMT3A mutant transcript levels persist in remission and do not predict outcome in patients with acute myeloid leukemia

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We investigated the prognostic impact of minimal residual disease (MRD) monitoring in acute myeloid leukemia patients harboring DNA methyltransferase 3A-R882H/-R882C mutations (DNMT3Amut). MRD was determined by real-time quantitative PCR (RQ-PCR) in 1494 samples of 181 DNMT3Amut patients. At the time of diagnosis, DNMT3Amut transcript levels did not correlate with presenting clinical characteristics and concurrent gene mutations as well as the survival end points. In Cox regression analyses, bone marrow (BM) DNMT3Amut transcript levels (log10-transformed continuous variable) were not associated with the rate of relapse or death. DNMT3Amut transcript levels were significantly higher in BM than in blood after induction I (P=0.01), induction II (P=0.05), consolidation I (P=0.004) and consolidation II (P=0.008). With regard to the clinically relevant MRD time points, after two cycles of induction and at the end of therapy, DNMT3Amut transcript levels had no impact on the end point remission duration and overall survival. Of note, only a minority of the patients achieved RQ-PCR negativity, whereas most had constantly high DNMT3Amut transcript levels, a finding which is consistent with the persistence of clonal hematopoiesis in hematological remission.

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This work was supported in part by grants 01GI9981 and 01KG0605 from the German Bundesministerium für Bildung und Forschung (BMBF), grant 109675 from the Deutsche Krebshilfe and the Sonderforschungsbereich (SFB) 1074 funded by the Deutsche Forschungsgemeinschaft (SFB 1074, projects B3 and B4). VG is a grant recipient of the Else-Kröner-Forschungskolleg; LB and MH are Heisenberg Professors of the Deutsche Forschungsgemeinschaft (DFG, BU 1339/3-1 and HE 5240-6-1). AMLSG treatment trials were in part supported by Pfizer and Amgen. We are grateful to all members of the German-Austrian AML Study Group (AMLSG) for their participation in this study and providing patient samples; a list of participating institutions and investigators is provided in the Supplementary Appendix.

Author contributions

VIG, DW, RFS, KD and HD designed the research; VIG, PP, AK, SK, AC, JK and SKS performed experiments; VIG, VT, PP, AK, SK, AC, JK, SKS and KD analyzed the results; DW and RFS performed statistical analyses; DK, HAH, ISW, GH, AK, MR, KG, TK, WF, MW, LB, VT, BS, FT, MH, AG, RFS, HD and KD accrued patients and provided material; VIG, DW, HD and KD wrote the paper.

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Correspondence to K Döhner.

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The authors declare no conflict of interest.

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Presented in abstract form at the 57th Annual Meeting of the American Society of Hematology, Orlando, FL, USA on 6 December 2015.

Supplementary Information accompanies this paper on the Leukemia website

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