Consolidation Therapy Based on Mutation Clearance in Acute Myeloid Leukemia.
In a prospective phase II study of transplant-eligible patients aged 18–60 years with intermediate-risk AML, mutation clearance after induction was used to direct HiDAC consolidation, and the 33 clearance-positive patients had longer relapse-free survival than historical HiDAC-treated controls, although the comparison did not meet the prespecified significance threshold.
Open original publication →What the AI sees
In a prospective phase II study of transplant-eligible patients aged 18–60 years with intermediate-risk AML, mutation clearance after induction was used to direct HiDAC consolidation, and the 33 clearance-positive patients had longer relapse-free survival than historical HiDAC-treated controls, although the comparison did not meet the prespecified significance threshold.
Research significance
The study provides preliminary evidence that broad leukemia-associated mutation clearance may identify patients who can achieve favorable relapse-free survival with HiDAC consolidation; it remains an inference, requiring randomized confirmation, that this strategy can safely select patients for chemotherapy rather than allogeneic transplantation.
Source abstract
BACKGROUND: Optimal consolidation therapy for patients with intermediate-risk acute myeloid leukemia (AML) in first complete remission (CR1) is controversial. Retrospective studies have suggested that the clearance of leukemia-associated mutations (LAMs) in CR1 may predict lower relapse risk and better outcomes with high-dose cytarabine (HiDAC) consolidation. We tested this hypothesis prospectively. METHODS: We performed a phase II, multicenter study of intermediate-risk, transplant-eligible, de novo AML in patients 18-60 years of age who achieved a complete remission (CR) or CR with incomplete count recovery (CRi) after induction therapy. Tumor and normal whole-exome sequencing was performed at presentation to identify somatic LAMs (median ∼30 LAMs/patient). In remission marrow samples, LAM variant allele frequencies (VAFs) were then remeasured using a VAF cutoff of less than 2.5% to define clearance. Patients who met this LAM clearance threshold received HiDAC consolidation, whereas those with persistent LAMs (VAF ≥2.5%) were recommended to undergo allogeneic hematopoietic cell transplantation. The primary endpoint compared relapse-free survival (RFS) of intermediate-risk patients with complete LAM clearance to historical cohorts with intermediate-risk AML who received HiDAC-based regimens in CR1. To account for an unplanned interim assessment, the significance threshold for the primary analysis was 0.01. RESULTS: Among 100 patients who were evaluated, intermediate-risk patients who cleared all LAMs in CR1 (n=33) had a median RFS of 33.1 months (95% confidence interval, 11.7-NA) compared to a median RFS of 11.7 months in the historical cohort (n=239; 95% confidence interval, 9.9-15.6, P=0.015). CONCLUSIONS: Among patients with intermediate-risk AML, clearance of LAMs after induction, followed by HiDAC consolidation in CR1, was associated with longer RFS compared with similarly treated historical controls. Although this result did not meet the prespecified threshold for statistical significance, the reported association sets the stage for a randomized trial to further evaluate this strategy. (ClinicalTrials.gov number, NCT02756962.).