Blast Clearance Dynamics and Time to Response Across IDH1- and IDH2-Mutated AML

IDH mutations are found in 15%-20% of acute myeloid leukemia (AML). Recent evidence suggests that IDH mutation subtypes may respond differently to intensive chemotherapy. We evaluated blast clearance patterns, remission outcomes, and overall survival (OS) in AML patients with IDH2 R140, IDH2 R172, and IDH1 R132 mutations to assess differences in treatment response.

We retrospectively reviewed AML patients diagnosed at Mayo Clinic, Rochester (2016-2023) with NGS data and treated with intensive chemotherapy (7+3 or CPX-351). Bone marrow blasts were assessed at diagnosis, mid-induction, and end-of-cycle; blast clearance was defined as < 5%. Composite remission (CRc) included CR/CRi per ELN 2022. IDH2 responders were classified as early (after Cycle 1) or late (≥ 2 cycles). Blast reduction was calculated as log₁₀ (diagnosis blasts/end-induction blasts) and normalized per day. OS was measured from diagnosis.

Among 381 patients, 31 had IDH2 mutations (23 R140, 8 R172) and eight had IDH1 R132. Baseline blasts were similar. Mid-cycle blasts were lower in R140 versus R172 (4% vs. 10%), with higher clearance (68% vs. 38%). End-induction blasts were lower in R140 versus R172 (2% vs. 4%) with higher clearance (100% vs. 75%). IDH1 and IDH2 showed similar clearance patterns. Log₁₀ analyses showed deeper and faster blast reduction in R140 versus R172, with comparable kinetics between IDH1 and IDH2. OS did not differ across subtypes. Early CRc in IDH2-mutated patients was associated with numerically longer OS.

IDH2 R140 demonstrated faster blast clearance than R172, while remission and survival were similar across IDH subtypes. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.