Outcomes of Newly Diagnosed Acute Myeloid Leukemia Patients between 65-75 Years and Treated with Intensive Induction Chemotherapy Versus Hypomethylating Agents and Venetoclax: A Propensity Score Adjusted Cohort Study

Background: The application of intensive induction chemotherapy (Ind-CTX) is the standard of care for treatment in fit patients diagnosed with acute myeloid leukemia (AML). Nevertheless, it is associated with remarkable toxicity in elderly and unfit patients. In 2018, venetoclax in combination with hypomethylating agents (VEN+HMA) was approved for the treatment of AML in unfit patients or patients ≥ 75 years. Since then, there has been a trend to use VEN+HMA in older patients but less than 75 years old. It is unknown if HMA+VEN is superior to Ind-CTX in patients between ages 65-75 years old.

Methods: We conducted a retrospective cohort study at a single center to compare treatment outcomes in patients diagnosed with AML between the ages of 65 and 75 and treated with VEN+HMA or 7+3 (i.e., 7 days of cytarabine; 100 mg/m2 per day by continuous infusion and 3 days of an anthracycline) +/- midostaurin or gemtuzumab ozogamicin. Acute promyelocytic leukemia was excluded. Key outcomes included overall survival (OS), event-free survival (EFS), and clinical response rates. Data collected involved age, gender, ethnicity, comorbidities, AML subtypes, cytogenetics, BCR::ABL1 and FLT3 status, mutational profiles (via next-generation sequencing), ECOG performance status, treatment history, and follow-up. Responses to first-line treatment were categorized as composite complete response (CCR) (complete response [CR] or complete response with incomplete count recovery [CRi]) and minimal residual disease (MRD) assessed by flow cytometry (MRD-FC) or real-time PCR. EFS was defined from the start of therapy to refractoriness, progression, or death; OS was from therapy initiation to death. Survival probabilities were evaluated using the Kaplan-Meier method, with differences assessed by the log-rank test. Multivariable regression and propensity score (PS) analysis were used to adjust for confounders, including comorbidities.

Results: From May 2017 to September 2023, 730 AML patients were managed at the Cleveland Clinic Foundation. 92 patients received Ind-CTX and 61 received VEN+HMA. 49 patients (53%) received 7+3 (daunorubicin) in the Ind-CTX group and 58 (95%) received VEN+ Azacitidine in the VEN+HMA group. The median ages were 69 years (IQR 66.8-72) for Ind-CTX and 70 years (IQR 67-74) for HMA-VEN (P>0.05). Cardiovascular diseases were present in 15% of the Ind-CTX group compared to 28% in the HMA-VEN group (P=0.06). High-risk cytogenetics per ELN2022 were seen in 26% of the Ind-CTX and 42% in the VEN-HMA group (P=0.03). There was no difference in other baseline characteristics between comparison groups, including ejection fraction.

The CCR rate was 63% in the Ind-CTX compared to 52% in the VEN+HMA group). In the multivariable logistic regression, there was no statistically significant difference in CCR rates between Ind-CTX (reference) and VEN-HMA (odds ratio (OR): 0.62, 95%CI: 0.27-1.46, P=0.3). The median follow-up periods for OS and EFS were 34 months (range: 1.5 - 66.1) and 34 months (range: 1.51 - 66.04), with 113 deaths and 120 cases of progression or death, respectively. The PS-weighted median OS in the Ind-CTX was 16 months (95% CI: 12-25) compared to 13 (95%CI: 5.7-NC) in the VEN-HMA group. On the PS-weighted Cox proportional hazards model (CPH), there were no significant differences in OS (HR = 1.15, 95% CI: 0.68-1.96, P = 0.6) between comparison groups (reference: Ind-CTX). The PS-weighted median EFS in the Ind-CTX was 7.1 months (95% CI: 6.1-12) compared to 8.2 (95%CI: 5.6-NC) in the VEN-HMA group. On the PS-weighted CPH, there were no significant differences in EFS (HR = 0.78, 95% CI: 0.46-1.32, P = 0.4) between Ind-CTX (reference) and VEN+HMA groups.

Conclusion: In this propensity score-adjusted study, we found no remarkable differences in response rate, OS, or EFS for Ind-CTX compared to VEN+HMA in the treatments for AML patients aged 65-75. Multi-institutional collaboration and randomized clinical trials are necessary to come up with more definite answer on the optimal regimen for AML patients less than 75 years old.