Comparison of consecutive versus alternate day schedules of high-dose cytarabine consolidation chemotherapy in Acute Myeloid Leukemia: Single-center randomized controlled trial from India

Abstract

Abstract INTRODUCTION The treatment strategy of patients with Acute myeloid leukaemia (AML) includes induction chemotherapy which is to achieve remission and consolidation. High-dose cytarabine (HiDAC) is considered the standard consolidation therapy in patients achieving complete remission (CR), the standard dosage & schedule of administration being 1.5-3 g/m2/dose q12 hourly on days 1, 3, and 5 (HiDAC-135). However, the schedule of HiDAC administration on three consecutive days, i.e. days 1, 2&3 (HiDAC-123), could be a viable option, especially in low-middle-income countries, where longer duration of hospital stay is associated with higher treatment costs & lower inpatient bed turnover rate, thus adversely affecting treatment compliance in AML patients. To the best of our knowledge, there are no randomized controlled study reported from India to compare treatment outcomes between the two dosing schedules of HiDAC. AIMS & OBJECTIVES To compare the effects of two different schedules of administration of HiDAC, namely consecutive (HiDAC-123) versus alternative day (HiDAC-135) schedule, in terms of treatment outcome and adverse events (AE) in AML patients who achieved complete remission and were eligible for intensive consolidation chemotherapy. METHOD The trial was registered in the Clinical Trial Registry of India (CTRI/2025/02/081494) & institutional ethics committee approval was obtained before recruitment of patients. Eligible patients were randomized to receive high-dose cytarabine chemotherapy according to one of the two dosing schedules: HiDAC-123 or HiDAC-135. The dose of Cytarabine was 1.5 g/m2 administered q12 hourly by intravenous infusion over 3 hours in accordance with the assigned treatment arm. Prophylactic granulocyte colony stimulating factor(G-CSF) was started 24 hours after last dose of Cytarabine in all patients, and they were closely monitored for cytopenias and other treatment-related adverse events, with documentation of duration & grade of neutropenia & thrombocytopenia. Supportive care, including antibiotics and transfusion of blood products, was provided as clinically indicated. Daily complete blood counts (CBC) were obtained to assess for hematologic recovery. Prophylactic platelet transfusion was used to maintain platelet count > 10 x 109/L. RESULTS Total 59 patients were treated between January 2024& June 2025;31 patients receiving HiDAC-123 & 28 patients received HiDAC-135 regimen. The mean age of patients in study was 30.74 Years;37(12.88) years in HiDAC-123 group& 29(14.42) years in HiDAC-135 group. Male: female ratio was 1.4:1. The baseline characteristics were comparable in the 2 treatment groups. Based on ELN 2022 risk stratification,47.4% of patients had favorable-risk AML,13.5% intermediate-risk, and 38.9% adverse-risk AML. The median time to neutrophil recovery was significantly reduced in HiDAC-123 group compared to HiDAC-135 group [13.87 (1.80)days versus 17.46(3.01)days; p < 0.001]. Median time to platelet recovery was also significantly reduced in HiDAC-123 group compared to HiDAC-135 group [13.58(1.84) days vs 18.04(3.77) days;(p < 0.001). All patients experienced grade 4 neutropenia; however, there was no significant difference in the incidence of grade 3/4 febrile neutropenia between the 2 groups. The median number of platelets transfused was lower in HiDAC-123 group [8(6,11.5) units] compared to HiDAC-135 group[11(8,13) units), but the difference was not statistically significant(p=0.09). The mean number of G-CSF doses administered was significantly lower in HiDAC-123 group compared to HiDAC-135 group [9.32(2.05)] vs. 18.5(2.92) ;(p < 0.001). The HiDAC-123 schedule was associated with shorter mean duration of hospitalization [14.52(2.37)days vs. 18.5(2.92) days; p <0.001]. There was no statistically significant difference in red blood cell transfusion requirement between the two groups. The commonest non-hematologic adverse events observed in both arms was nausea (grade 1-2). There was no incidence of grade 3-4 non-hematological AE, & no treatment-related mortality in the study. CONCLUSION In our single-institution experience, the condensed consecutive-day schedule of high-dose cytarabine (HiDAC-123) was associated with more rapid hematologic recovery, reduced number of GCSF doses and duration of hospital stay compared to the alternate-day HiDAC-135 regimen. These findings suggest that HiDAC-123 may be a more favorable schedule in terms of tolerability and resource utilization.