Effects of azacitidine in 93 patients with IDH1/2 mutated acute myeloid leukemia/myelodysplastic syndromes: a French retrospective multicenter study

Abstract

Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations in Myeloid Neoplams (MNs) exhibit DNA hypermethylation via 2-hydroxyglutarate (2HG) over-production. Clinical impact of azacitidine (AZA) remains inconsistent in IDH1/2-mutated MNs and the potential of serum 2HG as a suitable marker of response to AZA is unknown. To address these questions, we retrospectively analyzed 93 MNs patients (78 AML, 11 MDS, 4 CMML) with IDH1/2 mutations treated with AZA. After a median of 5 cycles of AZA, overall response rate was 28% (including 15% complete remission) and median OS was 12.3 months (significantly shorter in AML compared to MDS/CMML patients). In multivariate analysis of AML patients, DNMT3A mutation was associated with shorter OS while IDH1/2 mutation subtypes had no independent impact. No difference was observed in serum 2HG levels upon AZA treatment between responding and refractory patients suggesting that serum 2HG cannot be used as a surrogate marker of AZA response.

Keywords:

• Acute myeloid leukemia
• azacitidine
• IDH1
• IDH2
• 2-hydroxyglutarate

Disclosure statement

AR received research funding from Celgene. ER has served on advisory board for Celgene. CP received grants and personal fees from Celgene. RI received honoraria from Celgene. PF received honoraria and research funding from Celgene. EA is a member of Aprea. MF is a member of Celgene. LA has served on advisory board for Celgene and received research funding from Celgene, Forma therapeutics and Agios. SDB has served on advisory boards for Agios, Celgene and Forma Therapeutics and has received research funding from Agios.

The other authors (CW; RR; MD; VV; VS; SB; JD; AM; EC; MU; JR; LP; LS; JBM; FP; CQ; VPL and TB) declare no potential competing interests.

Author contributions

CW, RR, VV, MU, JR, LP, LS, JBM, FP, ER, RI, PF, TB, LA and SDB followed study participants. CW, RR, VV, MU, JR, LP, LS reported clinical data’s; VS performed cytological analysis; AR, AM, EC and CP supervised and performed molecular analysis; SB, JD and AP performed serum 2HG analysis; CW collected data and interpreted results; CW and MD performed statistical analysis; CW wrote the manuscript; SDB supervised the project; MD, VS, SB, JD, AR, JR, VPL, AP, PF, EA, MF, LA, SDB revised the manuscript. All authors approved the manuscript.