Hypomethylating Agents and Venetoclax or Hypomethylating Agents Alone in Acute Myeloid Leukemia in Patients with Significant Comorbidities
Authors: Murray Graeme F , Bouligny Ian M. , Ho Thuy , Gohr Juhi F , Maher Keri 
Published: December 2024

Introduction
The Charlson Comorbidity Index (CCI) is a predictive multivariate co-morbidity index shown to predict mortality in patients with acute myeloid leukemia (AML). In our previous work, we demonstrated that a CCI of &gt; 6 was independently predictive of prognosis when treated with a hypomethylating agent (HMA) and venetoclax (3.4 months vs 8.8 months p=0.013). The aim of this study was to determine if patients with significant comorbidities (CCI&gt;6) still benefited from the addition of venetoclax to a hypomethylating agent in their first line therapy.
Methods
We analyzed 71 patients with newly diagnosed AML treated with HMA + VEN or HMA with CCI scores &gt;6 from April 12, 2013 to January 26, 2023 at VCU Massey Comprehensive Cancer Center. We retrospectively recorded baseline patient, disease, treatment characteristics, including outcomes and survival data. We used the D'Agostino & Pearson method for normality testing and the Mann-Whitney test for between-group comparisons. Categorical comparisons used Fischer's exact test. We analyzed survival by the Kaplan-Meier method with significance determined by the log-rank test. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. Toxicities were graded according to CTCAE (v5.0)
Results
We analyzed 37 (52.1%) patients treated with an HMA alone and 34 patients (47.9%) treated with both HMA + VEN in the first line setting all with CCI scores &gt;6. There were no significant differences in age, race, or sex between the two groups. ECOG scores (1 vs 2, p=0.064) and CCI scores (8 vs 8, p=0.073) trended toward being lower in the group treated with only an HMA. There was no difference in the proportion of ELN 2022 adverse-risk disease between HMA and VEN and HMA alone cohorts (56.8% vs 61.8%, p = 0.81). The majority of patients treated with a HMA alone were diagnosed before the 2020 approval of venetoclax (81.1% vs 23.5%, p&lt;0.0001). Patients treated with HMA and VEN did not appear to have a survival benefit over those treated with HMA alone (3.4 months vs 3.8 months, p=0.53). Those treated with HMA and VEN had significantly more grade 4 leukopenia, grade 3 or 4 lymphocytopenia, and grade 4 neutropenia (p&lt;0.0001; p=0.0003; p=0.0057). These patients also trended toward having more episodes of neutropenic fevers, and infections than those treated with an HMA alone (p=0.1; p=0.088).
Discussion
This study highlights that venetoclax in combination with an HMA may not provide as much benefit in overall survival in patients with significant comorbidities (CCI&gt;6) than those without. Venetoclax induced significantly more leukopenia, and possibly as a consequence of that those treated with venetoclax trended toward having more instances of neutropenic fevers and infections likely increasing hospitalizations. Further studies are needed to determine the best treatment regimen for those with AML and significant co-morbidities that will give them the best overall survival and quality of life on treatment with less adverse events.