CPX-351 is a therapy approved for newly diagnosed (ND) therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in patients aged ≥1 year in the US and adult patients in the UK/EU. These approvals were based on the pivotal phase 3 trial of CPX-351 vs 7+3 chemotherapy in adults aged 60-75 years with high-risk/secondary AML showing significantly improved efficacy (median overall survival [OS]: 9.56 vs 5.95 months, one-sided P=0.003; complete remission [CR]/CR with incomplete platelet or neutrophil recovery [CRi]: 47.7% vs 33.3%, two-sided P=0.016) and comparable safety. Two real-world studies, V-RULES (Vyxeos Real-world US Long-term Effectiveness and Safety) and CREST-UK (CPX-351 Real-world Effectiveness and SafeTy Study; NCT05169307) were conducted in the US and UK, respectively, to collect real-world effectiveness and safety data of CPX-351. Here, we present a pooled analyses of these studies in patients aged <60 years to analyze the effectiveness and safety of CPX-351 in this age group.

V-RULES and CREST-UK are retrospective, single-arm studies that collected pseudonymized data from the medical records of patients with ND t-AML or AML-MRC who received ≥1 infusion of CPX-351 in routine practice after FDA/EU approval — V-RULES at 10 US centers (October 2017-May 2024) and CREST-UK at 15 UK centers (November 2018-March 2022). The two studies were developed and designed at different times, and, thus, some of the data collection methods differed. Response definitions differed between the two studies (defined as CR/CR with partial hematologic recovery [CRh]/CRi in V-RULES, and CR/CRi in CREST-UK) and were compared side by side in this analysis. Pooled outcomes included Kaplan-Meier (KM)-estimated OS and safety.

Overall, 134 patients aged <60 years (V-RULES, N=78; CREST-UK, N=56) received ≥1 induction of CPX-351 (1 cycle, n=114; 2 cycles, n=19; 3 cycles, n=1). Median age at AML diagnosis was 52 years (range: 18-59). The majority of patients (100/111 [90.1%]) had a known ECOG performance status of 0-1. Of patients with available cytogenetic data, 70/132 (53.0%) were classified as adverse risk per Grimwade 2010. Notably, 25/105 patients (23.8%) had mutated TP53 and 35 patients had myelodysplasia-related gene mutations. The median follow-up time was 12.1 months (interquartile range [IQR]: 5.5, 27.5). Among evaluable patients, CR/CRh/CRi was achieved by 49/75 (65.3%) in V-RULES and CR/CRi was achieved by 37/56 (66.1%) in CREST-UK. Among responders, measurable residual disease (MRD) status at best response was assessed in 50 patients (most commonly by flow cytometry [MCF]) and 22/50 (44.0%) patients were MRD-negative. Median OS was 20.0 months (95% confidence interval [CI]: 14.3, 45.4), with a KM-estimated 4-year OS of 37.2% (95% CI: 26.3, 48.1). Early mortality was 6.0% by day 30 and 11.3% by day 60. In total, 61/134 (45.5%) patients underwent hematopoietic cell transplantation (HCT) after CPX-351 treatment. Median OS post-HCT was 47.1 months (95% CI: 34.3, not estimated), with an estimated 4-year OS of 47.2% (95% CI: 26.3, 65.6). In responders, median time to neutrophil (≥500/μL) and platelet (≥50,000/μL) recovery after induction 1 was 35 days (IQR: 30, 41; n=68) and 37 days (IQR: 32, 44; n=64), respectively. Overall, 100/134 (74.6%) patients experienced grade ≥3 treatment-emergent adverse events (TEAEs). Febrile neutropenia (61/134 [45.5%]) and infection (52/134 [38.8%]) were the most common grade ≥3 TEAEs. Out of 134 patients, 47 (35.1%) patients experienced ≥1 serious TEAE.

This pooled analysis of the V-RULES and CREST-UK studies provides valuable real-world data on the effectiveness and safety of CPX-351 in adult patients aged <60 years with t-AML or AML-MRC, which is noteworthy as younger adults were not eligible for the CPX-351 phase 3 trial. We observed more favorable response, survival, and HCT outcomes in adults aged <60 years compared with the population of adults aged 60-75 years who were included in the CPX-351 phase 3 trial. Limitations of this study include its retrospective nature with clinician selected treatment in major medical centers. This retrospective real-world pooled analysis of patients treated at 25 US and UK medical centers demonstrates favorable effectiveness and acceptable tolerability of CPX-351 in younger adults with ND t-AML or AML-MRC eligible for intensive chemotherapy.

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2025
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