Autologous stem cell transplantation versus consolidation chemotherapy as post-remission treatment in newly diagnosed favorable and intermediate risk patients with AML: A comparative analysis of HOVON-SAKK-Nordic trials

Abstract Introduction High-dose chemotherapy followed by autologous stem cell transplantation (auto-HCT) or consolidation chemotherapy (CT) are post-remission therapy options for patients with acute myeloid leukemia (AML) who achieve complete remission (CR). Currently, these treatments are recommended as post-remission therapy for patients with favorable or intermediate European LeukemiaNet (ELN) 2022 risk AML who are in a measurable residual disease (MRD) negative CR. Our aim was to compare outcomes of auto-HCT versus CT in a recently treated HOVON-SAKK-Nordic cohort. Methods Newly diagnosed AML patients aged 18-65 years with ELN 2022 favorable or intermediate risk, treated with two cycles of intensive 7+3 induction chemotherapy in two recent HOVON-SAKK-Nordic clinical trials (HOVON-SAKK-Nordic 102/30-09 and 132/30-13) were included. Following CR achievement, patients received either busulfan (3.2 mg/kg IV or equivalent for 4 days) and cyclophosphamide (60 mg/kg for 2 days) (Bu/Cy) followed by auto-HCT, or CT consisting of mitoxantrone (10 mg/m²/day) and etoposide (100 mg/m²/day) for 5 days, according to protocol. Study endpoints included relapse-free survival (RFS), measured from the date of start of post-remission treatment until relapse or death, whichever occurred first, and overall survival (OS), calculated from start of post-remission treatment until death. A Cox proportional hazards regression model was developed, stratified by trial number and adjusted for age, number of induction cycles to CR, ELN 2022 risk group, white blood cell (WBC) count at diagnosis, and MRD status. MRD was measured after the second induction cycle with flow cytometry and/or qPCR for NPM1. Safety and toxicity of auto-HCT and CT were assessed by comparing days to neutrophil (>0.5×109/L) and platelet recovery (>50×109/L), duration of hospitalization, and frequency of grade 3-5 adverse events (AEs). Results Among 1,005 ELN 2022 favorable and intermediate risk AML patients treated in the two trials, 224 received auto-HCT and 199 received CT as post-remission treatment. Baseline characteristics were not significantly different between the two groups, except for WBC count (>20×109/L: 47% vs 31% for auto-HCT vs CT, respectively, p<0.001). The median follow-up was 99 months (interquartile range: 85-119). RFS and OS were similar among patients treated with auto-HCT compared with CT (5-year RFS: 60±3% vs 56±4%, p=0.70; 5-year OS: 72±3% vs 71±3%, p=0.76). In multivariable analysis, auto-HCT showed similar outcomes to CT: RFS hazard ratio (HR) 0.80 (95% CI: 0.56–1.13, p=0.20) and OS HR 0.91 (95% CI: 0.60–1.37, p=0.64) for auto-HCT compared with CT. Median days to absolute neutrophil count recovery were 13 vs 39 (<0.001) and median days to platelet recovery were 42 vs 57 (p<0.001) for auto-HCT and CT, respectively. Median hospitalization duration was shorter for the auto-HCT at 23 days vs 29 days for CT (p<0.001). The most prevalent grade 3-5 AE was febrile neutropenia occurring in 37% of patients receiving auto-HCT and 33% in patients undergoing CT (p=0.41). Oral mucositis was more frequent in the auto-HCT cohort (12%) compared with the CT cohort (5%, p=0.01), while pneumonia was more frequent in the CT cohort (8%) compared with the auto-HCT cohort (3%, p=0.048). Other grade 3–5 AEs were generally balanced between the two cohorts. Focusing on favorable risk patients with an MRD negative CR (n=162), the two post-remission strategies had comparable outcomes with regards to RFS (5-year 69±5% vs 62±6%, p=0.89) and OS (5-year 79±4% vs 75±5%, p=0.68) for auto-HCT vs CT, respectively. Similarly, no difference was observed between the two modalities in intermediate risk MRD negative patients (n=68; 5-year RFS 53±8% vs 39±10%, p=0.38; 5-year OS 71±7% vs 59±10%, p=0.22) for auto-HCT vs CT. Adjustment for covariates yielded similar results between auto-HCT and CT for RFS (favorable MRD-negative patients: HR 0.76, 95%CI: 0.38-1.53, p=0.45; intermediate MRD-negative patients: HR 0.88, 95%CI: 0.45-1.73, p=0.71; respectively) and OS (favorable MRD-negative patients: HR 0.81, 95%CI: 0.35-1.87, p=0.62; intermediate MRD-negative patients: HR 0.67, 95%CI: 0.29-1.55, p=0.35; respectively).Conclusions Treatment with Bu/Cy followed by auto-HCT is associated with similar RFS and OS in favorable and intermediate risk AML patients compared to CT when MRD guided treatment is used. CT was associated with longer durations for hematologic recovery and hospitalization.