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Acute Myeloid Leukemia
Persistent IDH1/2 mutations in remission can predict relapse in patients with acute myeloid leukemia
Chi Young Ok,1 Sanam Loghavi,1 Dawen Sui,2 Peng Wei,2 Rashmi Kanagal- Shamanna,1 C. Cameron Yin,1 Zhuang Zuo,1 Mark J. Routbort,1 Guilin Tang,1 Zhenya Tang,1 Jeffrey L. Jorgensen,1 Rajyalakshmi Luthra,1 Farhad Ravandi,3 Hagop M. Kantarjian,3 Courtney D. DiNardo,3 L. Jeffrey Medeiros,1 Sa A. Wang1 and Keyur P. Patel1
1Department of Hematopathology, 2Department of Biostatistics and 3Department
of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
ABSTRACT
Persistence of IDH1 or IDH2 mutations in remission bone marrow specimens of patients with acute myeloid leukemia has been observed, but the clinical impact of these mutations is not well known. In this study, we evaluated 80 acute myeloid leukemia patients with known IDH1 R132 or IDH2 R140/R172 mutations and assessed their bone marrow at the time of remission to determine the potential impact of persistent IDH1/2 mutations. Approximately 40% of acute myeloid leukemia patients given standard treatment in this cohort had persistent mutations in IDH1/2. Patients with an IDH1/2 mutation had an increased risk of relapse after 1 year of follow-up compared to patients without a detectable IDH1/2 mutation (59% versus 24%; P<0.01). However, a persistent mutation was not associated with a shorter time to relapse. High IDH1/2 mutation burden (mutant allelic fre- quency ≥10%) did not correlate with relapse rate (77% versus 86% for patients with a low burden, i.e., mutant allelic frequency <10%; P=0.66). Persistent mutations were also observed in NPM1, DNMT3A and FLT3 during remission, but IDH1/2 mutations remained significant in predict- ing relapse by multivariate analysis. Flow cytometry was comparable and complementary to next-generation sequencing-based assay for pre- dicting relapse. Monitoring for persistent IDH1/2 mutations in patients with acute myeloid leukemia in remission can provide information that could be used to justify early interventions, with the hope of facilitating longer remissions and better outcomes in these patients.
Introduction
Acute myeloid leukemia (AML), defined as more than 20% of myeloblasts in blood and/or bone marrow, is heterogeneous and complex at the genomic level. Data from The Cancer Genome Atlas show that many genes are recurrently mutat- ed in patients with AML, including NPM1, FLT3, DNMT3A, IDH1/2, and KRAS/NRAS.1 IDH1 and IDH2 mutations are found in 6-16% and 8-19% of AML patients, respectively.2-7 Collectively, IDH1/2 mutations are observed in 16-20% of AML patients and are enriched (25-30%) in cases of AML with a normal karyotype.6,8,9 IDH1/2 mutations are acquired early in the natural history of AML and can be present in the founding clone.10 There are known mutational hot spots in these genes: codon 132 (Arg) in IDH1 and codons 140 (Arg) and 172 (Arg) in IDH2. IDH2 R140 mutations occur more commonly than R172 mutations in AML.5 IDH1 and IDH2 mutations can also infrequently occur together at presentation.11 The presence of an IDH1/2 mutation alone is not sufficient for the development of AML.12 IDH2 mutations can be associated with clonal hematopoiesis of indetermi- nate potential (CHIP) in the older population.13 Moreover, IDH1/2 mutations occur
Ferrata Storti Foundation
Haematologica 2019 Volume 104(2):305-311
Correspondence:
cok@mdanderson.org or KPPatel@mdanderson.org
Received: February 12, 2018. Accepted: August 24, 2018. Pre-published: August 31, 2018.
doi:10.3324/haematol.2018.191148
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/2/305
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