Page 90 - Haematologica-5

Haematologica 2018 Volume 103(5):822-829
1Hematology Laboratory, Biology and Pathology Center, CHRU of Lille; 2INSERM, UMR-S 1172, Cancer Research Institute of Lille; 3University of Lille, F-59000; 4Hematology Department, Saint-Louis Hospital, AP-HP, Paris; 5EA3518, Institut Universitaire d’Hématologie (IUH), University 7 Paris Diderot; 6Circulating Biomarkers Laboratory, Curie Institute, Paris; 7Acute Leukemia French Association (ALFA) coordination, Saint-Louis Hospital, AP-HP, Paris; 8Hematology Department, Versailles Hospital, Le Chesnay; 9Hematology Department, Lyon Sud Hospital, Pierre Benite and 10Cytogenetic Laboratory, Versailles Hospital, Le Chesnay, France
Ferrata Storti Foundation
Acute Myeloid Leukemia
Clinical relevance of IDH1/2 mutant allele burden during follow-up in acute myeloid leukemia. A study by the French ALFA group
Yann Ferret,1,2,3 Nicolas Boissel,4,5 Nathalie Helevaut,1 Jordan Madic,6 Olivier Nibourel,1,2,3 Alice Marceau-Renaut,1,2,3 Maxime Bucci,1 Sandrine Geffroy,1 Karine Celli-Lebras,7 Sylvie Castaigne,8 Xavier Thomas,9 Christine Terré,10 Hervé Dombret,4,5 Claude Preudhomme1,2,3 and Aline Renneville1,2,3
ABSTRACT
Assessment of minimal residual disease has emerged as a powerful prognostic factor in acute myeloid leukemia. In this study, we investigated the potential of IDH1/2 mutations as targets for min- imal residual disease assessment in acute myeloid leukemia, since these mutations collectively occur in 15-20% of cases of acute myeloid leukemia and now represent druggable targets. We employed droplet digital polymerase chain reaction assays to quantify IDH1R132, IDH2R140, and IDH2R172 mutations on genomic DNA in 322 samples from 103 adult patients with primary IDH1/2 mutant acute myeloid leukemia and enrolled on Acute Leukemia French Association (ALFA) - 0701 or -0702 clinical trials. The median IDH1/2 mutant allele fraction in bone marrow samples was 42.3% (range, 8.2 - 49.9%) at diagnosis of acute myeloid leukemia, and below the detection limit of 0.2% (range, <0.2 - 39.3%) in complete remission after induction therapy. In univariate analysis, the presence of a normal karyotype, a NPM1 mutation, and an IDH1/2 mutant allele fraction <0.2% in bone marrow after induction therapy were statistically significant predictors of longer disease-free sur- vival. In multivariate analysis, these three variables remained significantly predictive of disease-free survival. In 7/103 (7%) patients, IDH1/2 muta- tions persisted at high levels in complete remission, consistent with the presence of an IDH1/2 mutation in pre-leukemic hematopoietic stem cells. Five out of these seven patients subsequently relapsed or progressed toward myelodysplastic syndrome, suggesting that patients carrying the IDH1/2 mutation in a pre-leukemic clone may be at high risk of hemato- logic evolution.
Introduction
Assessment of minimal residual disease (MRD) has emerged as a powerful prog- nostic factor in acute myeloid leukemia (AML).1–6 Many studies have shown that MRD detection using multiparameter flow cytometry or real-time quantitative polymerase chain reaction (qPCR) provides powerful independent prognostic infor- mation in AML.7,8 Chimeric fusion genes, such as PML-RARA, CBFB-MYH11 or RUNX1-RUNX1T1, NPM1 mutations, as well as WT1 expression are well-estab- lished molecular markers for MRD monitoring in AML. However, sensitive and leukemia-specific MRD markers are lacking in approximately 40% of AML patients. This prompted us to investigate the potential of other recurrent molecular
Correspondence:
aline.renneville@gmail.com
Received: October 29, 2017. Accepted: February 16, 2018. Pre-published: February 22, 2018.
doi:10.3324/haematol.2017.183525
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/5/822
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