A Randomized Comparison of CPX-351 and FLAG-Ida in Patients with High-Risk Acute Myeloid Leukemia (AML)/Myelodysplastic Syndrome (MDS) and MDS-Related Gene Mutations: A Subgroup Analysis of the UK NCRI AML19 Trial

Introduction: Liposomal cytarabine and daunorubicin (CPX-351) is an approved therapy for newly diagnosed therapy-related AML or AML with myelodysplasia-related changes, for which it showed improved response rate and overall survival (OS) up to 5 years compared with 7+3 chemotherapy in patients aged 60-75 years (Lancet 2018; Lancet 2021). The high-risk cohort in the UK NCRI AML19 trial (ISRCTN78449203) compared CPX-351 with FLAG-Ida in younger adults with newly diagnosed adverse cytogenetic AML or high-risk MDS (Othman 2023). The median OS in the overall population was similar between CPX-351 and FLAG‑Ida (13.3 vs 11.4 months, HR: 0.85 [95% CI: 0.6, 1.21], P=0.36), but median relapse-free survival (RFS) in patients achieving CR was longer with CPX-351 vs FLAG-Ida (22.1 vs 8.35 months, HR: 0.66 [95% CI: 0.41, 1.06], P=0.08). An exploratory subgroup analysis in patients with MDS-related gene mutations reported longer OS with CPX-351 (Othman 2023), and a further subgroup analysis showed improved outcomes with CPX-351 vs FLAG-Ida in patients with high-risk MDS (Legg 2024). Here, we performed an additional exploratory analysis of AML19 to further characterize the efficacy and safety outcomes with CPX-351 vs FLAG-Ida in patients with high-risk AML/MDS and MDS-related gene mutations.

Methods: In AML19, patients typically aged <60 years with high-risk AML/MDS were randomized 2:1 to 2 induction cycles of CPX-351 or FLAG-Ida. Older patients could enter if deemed fit by the treating physician. CPX-351 induction dose was 100 units/m² on days 1, 3, and 5 for cycle 1, and 100 units/m² on days 1 and 3 in cycle 2. Consolidation was up to 2 cycles of 65 units/m² CPX-351. FLAG-Ida consisted of fludarabine 30 mg/m² and cytarabine 2 g/m² on days 2-6 (reduced to 1 g/m² in patients >60 years), lenograstim 263 µg on days 1-7, and idarubicin 8 mg/m² on days 4-6; consolidation regimens were MACE-MiDAC. This exploratory subgroup analysis assessed outcomes in patients with MDS-related gene mutations (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2, excluding TP53) as per International Consensus Classification criteria 2022. All comparison P values are nominal.

Results: Of the AML19 cohort (N=187), 59 patients (32%) had MDS-related gene mutations; 30 were randomized to CPX-351 and 29 to FLAG-Ida. Median age (min, max) was 57.5 (40, 68) and 58 (20, 67) years, respectively. After induction cycle 1, the overall response rate (ORR, CR+CRi) was 50% vs 62% with CPX-351 vs FLAG-Ida; after cycle 2, the ORR was 69% vs 79%. Day 30 and 60 mortality rates were similar with CPX‑351 (3% and 7%, respectively) and FLAG-Ida (7% and 10%). The median OS was significantly longer with CPX-351 vs FLAG-Ida (38.4 vs 16.3 months, HR: 0.38 [95% CI: 0.19, 0.78], P=0.008). The CPX-351 arm also demonstrated longer RFS (33.1 vs 18.3 months, HR: 0.31 [95% CI: 0.11, 0.86], P=0.024) and longer event-free survival (34 vs 5.9 months, HR: 0.53 [95% CI: 0.27, 1.03], P=0.062) vs FLAG-Ida. The proportion of patients receiving transplant was numerically higher with CPX-351 (at any time, 67% vs 48%, P=0.15; in first response [CR+CRi], 75% vs 48%, P=0.07). The median OS from date of hematopoietic cell transplantation was longer with CPX-351 vs FLAG-Ida (not reached vs 18.1 months, HR: 0.3 [95% CI: 0.09, 0.96], P=0.042). There was no noticeable difference in platelet count recovery with CPX-351 vs FLAG-Ida at cycle 1 or 2, nor neutrophil count recovery at cycle 1. However, median time to neutrophil recovery was shorter with CPX-351 vs FLAG-Ida in cycle 2 (33 vs 49.5 days, P=0.0079). There was a trend toward fewer days in hospital with CPX-351 vs FLAG-Ida in cycle 2 (median 28 vs 37 days, P=0.178). Grade ≥3 adverse events (AEs) occurred in 70% and 90% of patients in the CPX-351 and FLAG-Ida arms, respectively. Rates of serious AEs were considerably lower with CPX-351 vs FLAG-Ida (10% vs 76%) due to fewer infections/sepsis, thrombocytopenia, and neutropenia with CPX-351. AEs led to death in 2 patients (7%) in the CPX-351 arm and 4 (14%) in the FLAG-Ida arm.

Conclusions: This exploratory subgroup analysis of the UK NCRI AML19 trial suggests OS and RFS are longer with CPX-351 vs FLAG-Ida in younger adults with newly diagnosed high-risk AML/MDS and MDS-related gene mutations. A more favorable toxicity profile may have resulted in higher number of patients in CPX-351 arm getting to transplant. Post-transplant OS was longer with CPX-351 compared with FLAG-Ida.