Improved outcomes with higher cumulative doses of cytarabine consolidation in older patients with acute myeloid leukemia

Abstract

Abstract Introduction: Post-remission consolidation with intermediate to high dose cytarabine (IDAC/HIDAC) has shown to improve outcomes, compared to lower doses of cytarabine, in younger patients with acute myeloid leukemia (AML). The optimal dose and schedule of cytarabine consolidation, particularly cumulative dose, in older patients with AML remains unclear. Methods: We evaluated outcomes of older patients (≥60 years old) with AML who received cytarabine consolidation at our institution from January 2012 till December 2024. Outcomes were reviewed for patients who reached a landmark of 90 days from initial diagnosis without relapse or death to exclude patients ineligible for extended consolidation. Results: We identified 111 older patients that qualified for the 90-day landmark analysis and received cytarabine consolidation. The median follow up was 18m (range 9-166m). The median age of the cohort was 65y (range 60-75y) and majority of the patients were males (56%) and non-Hispanic Whites (NHWs) (77%). By ELN 2022 risk stratification, 33%, 27% and 40% had favorable, intermediate and adverse-risk disease. Most patients (86%) had de novo AML and all patients received induction with 7 days of cytarabine and 3 days of anthracycline (idarubicin=53%, daunorubicin=47%). Eleven patients required re-induction therapy. All patients were in first remission at the time of initiating the first cycle of cytarabine consolidation. The schedule of administrating cytarabine consolidation included consecutive dosing on days 1, 2 and 3 (condensed) in 44% of the patients and dosing on days 1, 3 and 5 (standard) in 56% of the patients. The median number of consolidation cycles administered was 2 (range 1-4) with 18%, 33%, 46% and 3% receiving 1, 2, 3 and 4 cycles, respectively. The total dose per cycle ranged from 6g/m2 (1g/m2 per dose) to 18g/m2 (3g/m2 per dose). There were 5 patients who received 3g/m2 per dose per cycle. There was one case of nephrotoxicity during cycle 1, which resolved with supportive care and the patient went on to receive subsequent cycles. There were no cases of neurotoxicity observed. The cumulative median dose from all cycles was 18g/m2 (range 6-54g/m2). A cumulative dose of <18g/m2 was considered low intensity consolidation (LIC, n=25) whereas a dose of ≥18g/m2 was considered high-intensity consolidation (HIC, n=86) based on the median cumulative dose. Overall, 41% of the patients proceeded to allogeneic hematopoietic stem cell transplantation (allo-HSCT). In patients that did not proceed to allo-HSCT, the median number of consolidation cycles administered was 3 (range 1-4) with 10%, 33%, 54% and 3% receiving 1, 2, 3 and 4 cycles, respectively. Fourteen patients (56%) in the LIC group and 47 patients (55%) in the HIC groups relapsed, respectively. The median overall survival (mOS) and relapse-free survival (mRFS) for the entire population was 25m and 19m, respectively. The mOS for LIC vs. HIC was 13m vs. 31m (p=0.02). In patients that did not proceed to allo-HSCT, the mOS for LIC vs. HIC was 7m vs. 25m (p=0.01). The mOS was not statistically different between the two intensities for patients that proceeded to allo-HSCT. The mOS for allo-HSCT vs. no allo-HSCT was 39m vs. 23m (p=0.05). The mOS for 1-2 vs. 3-4 cycles of cytarabine consolidation was 20m vs. 31m (p=0.1) in all patients and 10m vs. 26m (p=0.03) in non-transplanted patients. The mRFS for LIC vs. HIC was 10m vs. 23m (p=0.1). No associations were noted for allo-HSCT and number of cycles for RFS outcomes. In multivariable analysis, HIC (HR=0.71, 95% CI 0.51-0.82, p=0.01) and allo-HSCT (HR=0.58, 95% CI 0.44-0.79, p=0.03) had a favorable impact on OS. Conclusion: We report that cytarabine consolidation, either condensed or standard, is safe and feasible to administer in older patients with no increased risk of neuro or nephrotoxicity and a high rate of allo-HSCT. A higher cumulative dose of cytarabine consolidation was associated with improved survival outcomes, compared to a lower dose. The choice of administering HIC vs. LIC may reflect upon the physician's perception of tolerability. Nonetheless, cumulative dose of cytarabine consolidation, in addition to the dose per cycle as well as total number of cycles, should be considered in post-remission decision making. Larger studies are needed to validate the difference observed in our report.