Patients with AML with an IDH2 R172K mutation have improved overall survival with venetoclax + azacitidine as compared to those with IDH2 R140Q mutations Free

Introduction: Mutations in the Kreb's cycle enzyme isocitrate dehydrogenase 2 (IDH2) and its homolog, isocitrate dehydrogenase 1 (IDH1) are observed in 20% of patients with acute myeloid leukemia (AML). Mutations in IDH2 primarily occur in two distinct hotspots: IDH2 arginine 140 mutated to glutamine (R140Q) and IDH2 arginine 172 mutated to lysine (R172K). These two mutated forms of IDH2 generate unique subtypes of leukemia when introduced into mouse hematopoietic stem cells (Fortin et al PNAS 2023). Furthermore, clinical data have shown that the two mutations are mutually exclusive and have distinct co-mutation profiles suggesting they represent two distinct forms of leukemia (Middeke et al Blood 2022). A recent retrospective study described that AML patients with IDH2 R172K mutations have slower blast clearance in response to intensive induction chemotherapy regimens (Salman et al Blood Advances 2025). The differential response of AML with distinct IDH2 mutations to lower intensity regimens, specifically, venetoclax+azacitidine (ven/aza), has not been studied.

Results: We analyzed a retrospective sequential cohort of 43 newly-diagnosed AML patients with IDH2 mutations treated with ven/aza at the University of Colorado Cancer Center from 2012 to 2025. 31/43 (72%) had IDH2 R140Q mutations and 12/43 (28%) patients had IDH2 R172K mutations, reflecting mutation frequencies previously documented in the literature. Patients with R172K were significantly younger (57 vs 75, p= 0.003). There were no significant differences in ELN risk categories between the two groups. Consistent with prior studies, when looking at next generation sequencing data, the two IDH2 mutations were mutually exclusive (pair-wise Fisher's exact test p<0.05). Furthermore, the genes that were co-mutated differed between the leukemias with the different IDH2 mutations. In our cohort, R140Q IDH2 mutations were enriched for co-occurring NPM1 and FLT3-ITD mutations (which were rarely observed in R172K IDH2 AML). In contrast, R172K IDH2 mutations more frequently co-occurred with DNMT3A mutations.

In our cohort, we found that patients with R172K mutations had longer overall survival when compared to patients with R140Q mutations: 2 year R172K OS 81% (95% CI 61-100) vs R140Q 40% (26-63), long-rank p-value 0.028. This survival difference remained when controlling for patients with co-occurring NPM1 (p=0.03) and FLT3 (p=0.028) mutations. The survival difference was also maintained, though was no longer statistically significant, when patients were stratified by age of diagnosis (>70, p=0.17; or <70, p=0.25). When controlling for transplant status, the survival difference was maintained among patients who received a stem cell transplant (SCT) (log-rank p=0.14), but lost when comparing patients that did not receive a SCT (p=0.54). Investigating this further, we found that patients with R172K mutations received a SCT earlier in their disease course (R172K time to transplant 86 days, inter-quartile range (IQR) 71-124, versus R140Q time to SCT 200 days, IQR 111-280, Wilcoxon p-value 0.0077). Median cumulative incidence of SCT in the R172K cohort was 103 days vs not-reached in the R140Q cohort (Gray's test p=0.013). Consistent with this difference, we found that among transplanted patients, those with R172K mutations achieved MRD negativity within 3 cycles of ven/aza 75% of the time vs 68% of the time with R140Q mutations.

Conclusion: Our results support prior evidence that the two predominant IDH2 mutations are biologically distinct; furthermore, we show they have a differential impact on outcomes with ven/aza. In contrast to recent findings with response to intensive chemotherapy, in our cohort, patients with R172K IDH2 mutations responded more quickly to ven/aza, had deeper responses, and were more likely to proceed to SCT. This result contrasts with a recent study showing patients with IDH2 R172K mutations had no difference in OS when treated with intensive chemotherapy (Salman et al Blood Advances 2025), suggesting an important difference compared with ven/aza in patients with IDH2 R172K mutations. Our study illustrates that there can be important, clinically relevant differences between AML with mutations within the same gene, particularly IDH2, when analyzed by specific therapies administered.