Blast clearance dynamics and time to response across IDH1- and IDH2-mutated AML

Abstract Background: Isocitrate dehydrogenase (IDH) mutations are frequently implicated in the development of acute myeloid leukemia (AML). In a recent study (Salman MY, Blood Adv 2025), it was reported that IDH2 mutation subtypes, R140 and R172, may respond differently to intensive chemotherapy. In this study, we evaluated mid-cycle and end-of-cycle bone marrow blast responses in AML patients with IDH2 R140, IDH2 R172, and IDH1 R132 mutations, aiming to determine whether these subtypes exhibit different response dynamics. Methods: We reviewed the charts of AML patients diagnosed at Mayo Clinic, Rochester, between the years 2016 - 2023 that had available next generation sequencing (NGS) data. Institutional review board approval was obtained. All data were recorded at the time of AML diagnosis. Patients without molecular data or not treated with intensive chemotherapy (7+3 or CPX-351) were excluded from this study. Bone marrow blast percentages were assessed at mid-induction (days 14-21) and end of cycle (counts recovery). Blast clearance dynamics and complete remission rates were compared across IDH mutation subgroups and correlated with outcomes. GraphPad Prism 10.0.0 was used for statistical analysis. Results: Out of 381 AML patients, 31 had IDH2 mutations (23 with R140 and 8 with R172), and 8 had IDH1 mutations (all R132). Among patients with IDH2 mutations, those with R172 had numerically higher median mid-cycle bone marrow blast percentage compared to R140 (10% vs. 4%, p = 0.37). There was no significant difference in mid-cycle blast percentages between patients with IDH1 and IDH2 mutations (4.5% vs. 4%, p = 0.8). At mid-cycle, 68% of patients with IDH2 R140 had blast counts 5%, compared to 38% of those with IDH2 R172, suggesting a trend for faster mid-cycle clearance in the R140 group, though not statistically significant (OR 3.57, p = 0.2). In a broader comparison, 60% of IDH2-mutated patients and 50% of IDH1-mutated patients achieved blast clearance (blasts 5%) at mid-cycle, though not statistically significant (p = 0.7). At the end of the induction, patients with IDH2 R140 had significantly lower median bone marrow blast percentages compared to those with R172mutations (2% vs. 4%, p = 0.01). Similarly, patients with IDH1 mutations showed low blast counts compared to the IDH2 group (1.5% vs. 3%, p = 0.1). A higher proportion of IDH2 R140 patients achieved blast clearance compared to those with R172 mutations (100% vs. 75%, p = 0.06), while proportion of patients who achieved blast clearance were similar between IDH1 and IDH2 patients (87.5% vs 93.1%, P = 0.5). Analysis of overall complete remission rates (including both complete remission CR and CR with incomplete hematologic recovery CRi) within the IDH2-mutated group showed a higher rate in patients with the R140 mutation compared to those with R172 (87% vs. 75%), though the difference was not statistically significant (p = 0.5). When comparing IDH1- and IDH2-mutated patients, overall complete remission rates were 75% and 84%, respectively, with no significant difference observed (p = 0.6). Kaplan–Meier analysis of time to end-of-induction blast clearance revealed no statistically significant difference between IDH2 R140 and R172 patients (median time to clearance: 31 vs. 37 days, p = 0.3). Similarly, no difference was observed between IDH1 and IDH2-mutated patients (33 vs. 31 days, p = 0.9). Overall survival analyses showed no significant difference between IDH2 R140 and R172 groups (median 66.8 months vs not reached, P = 0.4). Likewise, no difference was observed between IDH1 and IDH2 patients (44.4 months vs not reached, P = 0.7), indicating similar overall survival across mutation subtypes. Conclusion: IDH2-R140 was associated with more effective blast cytoreduction following intensive induction compared to IDH2-R172. Although not statistically significant, IDH2 R172consistently showed trends toward higher blast percentages, delayed response, and lower overall complete remission rates. These findings align with the recent study reporting significantly slower blast reduction and delayed response in R172-mutated AML. Also, no significant differences were found between IDH1- and IDH2-mutated patients in terms of response kinetics or overall survival. Together, these findings highlight potential biological differences among IDH mutation subtypes that may impact treatment response and require further investigation in larger prospective cohorts.