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1994 IDH Mutations Identify a Subgroup of NPM1 Patients with a More Favorable Prognosis. a Retrospective Multicenter Study of the Filo Group

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster II
Hematology Disease Topics & Pathways:
AML, Diseases, Myeloid Malignancies
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Sylvain Garciaz1*, Marie Anne Hospital2*, Colombe Saillard, MD3*, Yosr Hicheri4*, Evelyne D'Incan2*, Jerome Rey2*, Catherine Lacombe5*, Arnaud Pigneux, MD, PhD6*, Marie-Christine Béné, PharmSciD, PhD7*, Christian Recher, MD, PhD8, Marie-Joelle Mozziconacci9* and Norbert Vey, MD10

1Institut Paoli Calmettes, Institut Paoli-Calmettes, Marseille, France
2Onco-Hematology Department, Paoli-Calmette Cancer Institute, Marseille, France
3Institut Paoli Calmettes, Marseille, France
4Institut Paoli-Calmettes, MARSEILLE, France
5INSERM - Institut Cochin Hospital Cochin, Paris, FRA
6Hematology Clinic, Bordeaux University Hospital, Pessac, France
7Hematology laboratory, CHU, nantes, France
8Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
9Institut Paoli-Calmettes, Marseille, FRA
10Hematologie clinique, Institut Paoli Clamettes, Marseille, France

IDH mutations are strongly enriched in cytogenetically normal AML harboring NPM1 mutation (CN-NPM1mut-AML). The impact of these mutations on response to treatment is still a matter of debate. In the ELN 2017 classification, NPM1mut/FLT3-ITD allelic ratio >0.5 (FLT3-high) are considered intermediate-risk AML, whereas NPM1mut/ FLT3-ITD neg or <0.5 (FLT3-low) are low-risk. We aimed to evaluate the impact of IDH mutation in CN-NPM1mut-AML patients (pts) treated intensively. For this purpose, we retrospectively analyzed 177 CN-NPM1-AML pts from the Paoli-Calmettes Institute and from the French Innovative leukemia organization (FILO) databases who had received conventional intensive chemotherapy according to the FILO protocols (anthracycline-cytarabine based regimen for induction and High-intermediate dose cytarabine (HIDAC) for consolidation. Forty-seven (26%) AML pts had an IDH mutation -18 IDH1-R132 (10%), 27 IDH2-R140 (15%) and 2 IDH2-R172 (1%) – while 130 AML pts were IDHwt. Pts characteristics are presented in the Table.The complete response rate after one or two courses of chemotherapy (CR1) was 100% and 90% (p-value=.03) in the IDHmut and IDHwt groups, respectively. For pts in CR1, NPM1 molecular residual disease after the first consolidation (MRD2) was negative (>4 Log reduction) in 86% vs 53% of pts (p-value=.04). Nine (19%) and 24 (18%) pts received an allogeneic transplantation in CR1. The median time between CR1 and relapse was 11 months and 8 months, in IDHmut and IDHwt pts, respectively (p-value=.008). Day-100 non-relapse mortality was 8% and 12% respectively (p-value=ns). Median follow-up is 45 months (range, 2.4-115). Median EFS and OS are 21 months vs 12 months (p-value=.01) and 112 vs 23 months (p-value=.02), in the IDHmut vs IDHwt groups respectively (Figure). No survival differences were observed between IDH1mut and IDH2mut AML patients. Multivariate analyses with age>65, FLT3-high and IDHmut as covariates showed that IDHmut was independently associated with a higher EFS (HR=1.7, ranges 1.1-2.6) and OS (HR=1.7, ranges 1.1-2.7). Our results suggest that IDHmut is associated with a better response and a good disease control with high-dose chemotherapy. Nevertheless, some relapses still occur justifying the use of an IDH inhibitor combined with first-line chemotherapy or in a post-remission maintenance setting.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH