Differential impact of IDH1/2 mutational subclasses on outcome in adult AML: results from a large multicenter study

Abstract

Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are amongst the most frequent alterations in acute myeloid leukemia (AML) and can be found in ~20% of patients at diagnosis. Among 4930 patients (median age 56 years, interquartile range 45-66) with newly diagnosed, intensively treated AML, we have identified IDH1 mutations (mIDH1) in 423 (8.6%) and IDH2 mutations (mIDH2) in 575 (11.7%) patients. Overall, there were no differences in response rates or survival for patients with mIDH1 or mIDH2 compared to patients without mutated IDH1/2. However, distinct clinical and co-mutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with significantly increased age, lower white blood cell count (WBC), less frequent co-mutation of NPM1 and FLT3-ITD as well as lower rate of complete remissions and a trend for reduced overall survival (OS) compared to other mIDH1 variants and wtIDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC, more karyotype abnormalities, and less frequent co-mutations of NPM1 and/or FLT3-ITD. Among patients within the ELN2017 intermediate- and adverse-risk groups, RFS and OS were significantly better for patients with IDH2-R172K compared to wtIDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific co-mutation pattern and favorable outcome. In summary, the presented data from a large cohort of IDH1/2 mutant AML patients indicate novel and clinically relevant findings for the most common IDH-mutation subtypes.

Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation

“…Previous studies generated partly controversial results, either associating IDH mut with better outcome [ 8 , 13 ] and studies reporting a negative impact on outcome [ 2 , 14 , 16 ]. More recently, it was shown that IDH mutational subgroups associated with different biological features have different prognostic impact, suggesting to provide an explanation for inconsistent results concerning prognosis and survival so far [ 6 , 23 , 46 ]. To add a next level of complexity, different mutational IDH variants are associated with differential co-mutational patterns or karyotypes, incorporating prognostic value and even potentially defining distinct genomic categories in AML [ 10 , 15 , 23 , 46 – 49 ].…”

“…Still, their prognostic and predictive relevance is not fully resolved and standard AML risk stratification does not yet include IDH1 or IDH2 mutations [ 4 ]. However, there is growing evidence that IDH mutations contribute both prognostic and predictive value [ 2 , 5 , 6 ]. There have been inconsistent results regarding outcome, including complete remission (CR) rate, relapse-free survival (RFS) and overall survival (OS) depending on IDH1 and IDH2 mutational status, respectively [ 2 , 7 – 12 ].…”

Prevalence and Prognostic Role of IDH Mutations in Acute Myeloid Leukemia: Results of the GIMEMA AML1516 Protocol

“…Therefore, our data reinforce the notion that IDH1 / 2 mutational status does not impact on prognosis, in line with the reports by Di Nardo and Chotirat [ 17 , 18 ]. Accordingly, Middeke et al recently reported on the prognostic role of IDH1 / 2 mutations in the largest AML cohort treated with intensive chemotherapy [ 26 ]. They did not find any difference in response rates, nor in survival for patients carrying IDH1 / 2 mutations when compared to IDH1 / 2 -WT patients.…”

IDH2: A novel biomarker for environmental exposure in blood circulatory system disorders (Review)

“…Moreover, it has been reported that an IDH2 mutation is a marker for poor prognosis in patients with AML, and the overall survival (OS) time of the patients with wild-type IDH2 was greater than that of patients with an IDH2 mutation (45). However, another study found that patients with IDH2 R172K mutations have improved relapse-free survival (RFS) and OS times compared with patients with the wild-type (46). Therefore, this topic remains controversial, and more experimental data are needed to confirm which view is correct.…”