HMA/Ven Treatment Modifications and Associated Outcomes in IDH-Mutant AML
Authors: Chin Kuo-Kai , Derkach Andriy , Famulare Christopher , Gupta Gaurav , Borge Prabhakar , Geyer Mark Blaine , Goldberg Aaron D. , Haque Tamanna , Park Jae H. , Roeker Lindsey , Tallman Martin S. , Stahl Maximilian , Stein Eytan M. 
Published: December 2024

Introduction: The combination of a hypomethylating agent (HMA) and venetoclax (VEN) is frequently used in induction chemotherapy-ineligible patients with isocitrate dehydrogenase-mutated (IDHm) acute myeloid leukemia (AML). While this combination is associated with high response and survival rates, the frequency and impact of treatment modifications are not well known.

Objective: To characterize treatment modifications for IDHm AML patients treated with HMA/VEN and associated outcomes.

Methods: With approval of the Institutional Review Board, we conducted a single-center retrospective study of all IDHm AML patients who received HMA/VEN from 1/1/2018 to 6/30/2023. Patients with newly diagnosed (ND) and relapsed/refractory (R/R) AML were reviewed for demographics and clinical characteristics. European LeukemiaNet 2022 guidelines were used to risk stratify and to adjudicate responses. Measurable residual disease (MRD) status was based on multiparameter flow cytometry at a cut-off of 10-4. We tracked overall survival (OS) and event-free survival (EFS, defined as survival in the absence of disease progression, relapse, treatment discontinuation, or death). Toxicities were defined by Common Terminology Criteria for Adverse Events (CTCAE) 5.0. Finally, treatment modifications (e.g. VEN days and cycle length) were annotated by chart review. Cycle length was defined as the time between the start of a cycle of HMA/VEN and start of the next cycle or EFS event. Categorical variables were compared using Fisher's exact test. For continuous data, student's t-tests and Mann-Whitney tests were used. Kaplan-Meier methodology was used for survival statistics.

Results: We identified 89 patients, 49 with newly diagnosed (ND) AML and 40 with relapsed/refractory (R/R) AML. Twenty-nine patients had IDH1m AML, and 60 had IDH2m AML. CR/CRi rates were 76% for ND and 55% for R/R, with median overall survival (mOS) of 29.2 months (95% CI 17.0, NR) for ND and 17.1 months (17.0, NR) for R/R. Amongst ND patients, 39% achieved MRD-negativity (n=19), whereas 33% (n=13) of R/R patients did so. No significant differences in CR/CRi rate, MRD-negativity rate, or mOS were noted between the IDH1m and IDH2m groups.

Looking at treatment cycle characteristics, patients received a median of 2 HMA/VEN cycles (range 1-22). The median VEN days per cycle was 22 and the median cycle length per patient was 7.6 weeks. The most common reason for an extended cycle was cytopenia (66% of treatment holds). HMA/VEN responders (that achieved CR/CRi) received more VEN days in their non-CR cycles days (median 28 days vs 20 days, p &lt; 0.001) compared to non-responders but had similar cycle lengths (median 7 weeks vs 7.1 weeks, p = 0.76). Because multiple patients who received fewer VEN days did so due to early mortality events, we added a 3-month landmark to avoid immortal time bias, excluding 10 patients. With this approach, there was no significant difference in OS for patients that averaged different VEN days (≤14 days: n=11, mOS not reached; 15-21 days: n= 26, mOS 21.8 months; 22-28 days: n=42, mOS 28.0 months, p = 0.52). Similarly, there was no significant difference in OS for patients that averaged different cycle lengths (&lt;6 weeks: n=25, mOS 21.7 months; 6-8 weeks: n=26, mOS not reached; &gt;8 weeks n=28, mOS 21.8 months, p = 0.9). Focusing on cycles after CR/CRi, there was also no difference in OS when comparing different VEN days (≤14 days: n=14, mOS 21.8 months; &gt;14 days: n=20, mOS 30.6 mo, p = 0.65) or cycle length (≤7 weeks, n=17, mOS 30.6 months, &gt;7 weeks, n=17, mOS 32.7 months, p = 0.84). Toxicities significantly decreased after CR/CRi but were considerable before and after CR/CRi. Even after CR/CRi, grade 3 neutropenia (85%), thrombocytopenia (39%), and anemia (25%), as well as ED visits or unplanned hospitalizations (24%), occurred in a large portion of cycles.

Conclusions: HMA/VEN is an efficacious treatment regimen for IDHm AML and treatment modifications, especially those after CR/CRi, do not appear to compromise long-term survival outcomes. However, toxicities associated with treatment are common with surprising persistence after achieving complete remission and despite treatment modifications. Finding an approach that can achieve high response rates and deep remissions without leading to long-term toxicities, such as an induction-like approach with HMA/VEN based therapy with IVO maintenance, will be paramount for future studies.