Developments in Therapeutics and Impact on AML Survival in Older Patients: A Populational Analysis

Introduction Over the last twenty years, there has been considerable progress in the domain of AML therapeutics. Starting with hypomethylating agents (HMA) in the early 2000s, decitabine and azacitidine, followed by the addition of the Bcl-2 inhibitor, venetoclax, in 2018, this progress has been especially notable for older patients (age ≥75 years) and those not qualifying for intensive chemotherapy with poor functional status,. The confirmatory phase III trial (NCT02993523) by DiNardo et. al, demonstrated that the combination of HMA and Bcl-2 inhibitor (azacitidine and venetoclax) was superior to HMA (azacitidine) alone leading to full regulatory approval in the U.S. and establishing a new standard of care in AML. Noting these impressive developments, we are interested in seeing how improvements in survival have manifested at the population level. We evaluated population-level outcomes in survival for patients ≥ 75 years old diagnosed with AML in the Surveillance, Epidemiology, and End Results (SEER) database during three distinct therapeutic eras (pre-HMA (2000-2005), HMA (2006-2017), and post-venetoclax (2018-2021). Methods: Our sample consisted of 13,004 adult patients (≥75 years) with AML diagnosed between 2000-2021 from SEER. Inclusion criteria were defined to be complete cases with ICD-O3 codes 9840,9861,9865-9867,9869,9871,9873-9874,9891,9895-9898,9910. Variables, such as age, gender, race, year of diagnosis, and income level were collected. Descriptive statistics were conducted, along with overall survival (OS) analysis via cox regression. Results: The demographic breakdown was notable for increasing minority representation (Hispanic, Asian, non-Hispanic Blacks) with each therapeutic era. Additionally, more older patients received chemotherapy with each therapeutic era. Over fifty percent of patients were treated in the 2006-2017 era and western US regions contributed more than 50% of patients in each era. Overall, patients 75 years old and higher, diagnosed in the most recent therapeutic era with venetoclax approval (2018-2021) had the best survival (HR 0.93, 95% CI 0.88-0.99, p = 0.014) compared to the previous eras 2006-2017 and 2000-2005. When examining age subgroups, patients aged 75-79, the youngest subgroup, appeared to have the best survival during the most recent therapeutic era compared to past eras (HR 0.79, 95% CI 0.73-0.87, p = <0.001), which was not seen with the older age subgroups. Overall, patients of all age subgroups treated with chemotherapy had improved outcomes compared to those not treated. Conclusion: Our population-based study demonstrates that over the last 2 decades, older AML patients are undergoing active treatment more frequently and survival outcomes have improved. This improvement corresponds to distinct eras of therapeutic developments, from the introduction of HMAs to Bcl-2 inhibitors. Improvements appear to diminish for patients greater than 79 years old. Overall, this would suggest that for future developments of AML therapeutics, it is worth to further risk-stratifying the population of older patients with AML to maximize therapeutic benefits.