Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML

Abstract

The pathophysiology of IDH mutations in tumorigenesis is increasingly described, yet the prognostic significance of IDH1 and IDH2 mutations in AML remains controversial. The primary objective of this study was to define the natural history and prognosis of patients with AML and IDH1 or IDH2 mutations and provide historical survival expectations. A total of 826 patients treated from 2010 to 2014 at a single institution were evaluated, including 167 patients (20%) with AML and IDH1 or IDH2 mutations. Median age was 62 years (range 18–92). There were 59 IDH1-R132, 83 IDH2-R140, and 23 IDH2-R172 mutations. Clinicopathologic characteristics associated with IDH-mutations included older age, less frequent therapy-related status, and increased incidence of intermediate-risk cytogenetics, FLT3-ITD mutations, and NPM1 mutations. Remission rates (CR/CRi) by AML treatment status were: induction, 68%; Salvage-1 (S1), 42%; and Salvage-2 and beyond (S2+), 27%. No difference in response was identified by IDH mutation status. Similarly, overall survival (OS) was not dependent on IDH status within any cohort. The median OS was 15.4 months in induction, 8.7 months in S1, and 4.8 months in S2+. This analysis defines the clinical outcome associated with IDH-mutations in both the front-line and salvage AML treatment settings, and confirms that response rate and OS for both IDH-mutated and IDH wild-type AML patients is comparable. This provides contemporary data to be used for comparison with results of novel investigational (e.g., selective IDH inhibitor) strategies.

Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia

“…Previous studies of IDH1 mutations on outcome after IC have reported either no impact on or an increased rate of disease recurrence. [37][38][39] Therefore, our data demonstrating a reduced risk of relapse after allo-SCT in patients with an IDH1 mutation raise the possibility that the genetic factors determining outcome after IC may differ from those determining relapse after allo-SCT.…”

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

“…IDH1/2 mutations can be identified in approximately 20% of patients with AML and approximately 5% of patients with MDS (37,38), and can contribute to leukemia via a block in hematopoietic cell differentiation (16,17,23,24,39). We have discovered AG-221, an oral, selective, first-in-class inhibitor of the mutant IDH2 enzyme.…”

Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group

“…12 From September 2012 on, NPM1 and FLT3 testing was performed within our panel-based, next-generation sequencing hematologic malignancy platform, as previously described. 13 FLT3 AML cases for which NPM1 mutation analysis was not performed, and vice versa, were excluded. Minimal residual disease elimination status, assessed by clearance of NPM1, 14 was also collected.…”

“…Because transplantation strategies may have influenced outcomes, RFS was evaluated after censoring at the time of transplant and showed a trend toward superior survival in the FLT3-TKD Figure 2). Eight patients proceeded to transplant after achieving their first CR; there was no difference in pretransplant .84 9 (7)(8)(9)(10)(11)(12)(13)(14) . .98…”