Prognostic Significance of Mutations In Isocitrate Dehydrogenase (IDH) Enzyme Isoforms 1 and 2 and Single Nucleotide Polymorphisms (SNP) In IDH1, In Patients with Acute Myeloid Leukemia Treated with High Dose Cytarabine and Idarubicin Induction
Authors: Ravandi Farhad , Patel Keyur P. , Luthra Rajyalakshmi , Faderl Stefan , Konopleva Marina , Kadia Tapan , Brandt Mark , Pierce Sherry , Kornblau Steven M. , Garcia-Manero Guillermo , Cortes Jorge E. , Kantarjian Hagop 
Published: October 2019

Abstract
Abstract 2706

Background
IDH1 and IDH2 gene mutations have been identified as novel, recurring molecular aberrations among patients with normal karyotype acute myeloid leukemia (AML). The potential impact of these mutations as well as an IDH1 single nucleotide polymorphism (SNP) on the outcome of the patients is being actively investigated.

Materials and Methods
Among 358 patients with AML treated from October 2004 to February 2010 on 4 consecutive protocols using high dose ara-C plus idarubicin induction therapy (IA alone, IA plus tipifarnib [IAT], IA plus sorafenib [IAS], and IA plus vorinostat [IAV]), pre-treatment samples were available for 170 patients [median age 53 years, (range, 17 – 73); 96% ≤ 65 years] for testing for IDH1R132, IDH2R172 and IDH2R140 mutations. All patients received an induction course of therapy followed by up to 5 reduced-dose consolidation cycles followed by maintenance therapy with T, S, or V for up to a year; patients treated with IA had no maintenance. We examined whether presence of mutations in either gene or the codon 105 SNP in IDH1 was associated with pre-treatment characteristics or outcome. We also sought whether treatment with any of the 4 regimens had an impact on the outcome of patients with IDH aberrations.

Results
Overall, IDH1 and IDH2 mutations were present in 12 (7%) and 24 (14%) patients, respectively, and IDH1G105 SNP in 24 (14%). Overall, 52 (30%) patients had IDH gene aberrations; 2 patients had concomitant IDH1R132 mutation and IDH1G105 SNP, 3 patients had IDH2R140 mutation and IDH1G105 SNP, 1 patient IDH2R172 mutation and IDH1G105 SNP, and 1 patient had IDH1R132 mutation, IDH1G105 SNP, and IDH2R140 mutation. There was a strong association with normal karyotype with 11 of 12 (92%) of IDH1 mutated, 18 of 24 (75%) of IDH2 mutated, and 18 of 24 (75%) of IDH1 SNP being diploid. There was no association between any of the aberrations and patient age, sex, therapy-related vs. de novo AML, presenting WBC, peripheral blood blasts, or FAB subtype. IDH1 mutation was associated with a higher presenting platelet count (median 99 vs. 50 × 109/L in IDH1 wild-type [WT], p<0.05) and IDH1 SNP with a higher platelet count (median 68 vs. 46 × 109/L in IDH1WT, p<0.04) and a lower bone marrow blast percentage (median 39% vs. 54% in IDH1WT, p<0.03). 12 of 52 patients with IDH aberrations also had FLT3-ITD compared to 22 of 128 patients with IDH-WT (p=NS). There was no association with achievement of complete response (CR), remission duration, overall and event-free survival and any the IDH aberrations. Furthermore, there was no association with a higher CR rate or survival among any of the 4 different regimens for the 52 patients with aberrant IDH gene.

Conclusions
IDH aberrations including mutations and SNP occur in about 30% of younger patients with AML, mostly with diploid karyotype. IDH1 mutations and SNP are associated with a higher presenting platelet count and SNP with lower bone marrow blasts. Using high-dose ara-C based induction regimens, we did not detect an association with outcome for any of the aberrations.

Disclosures:
No relevant conflicts of interest to declare.