Efficacy and safety of CPX-351 in high-risk Acute Myeloid Leukemia

Abstract Introduction: CPX-351 is a dual liposomal drug (daunorubicin and cytarabine) approved for the treatment of high-risk acute myeloid leukemia (AML), following the results of the pivotal trial. This study showed significant longer survival in patients aged 60-75 years treated with CPX-351 compared to 7+3 with therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC) with similar safety profile and clear benefit for patients proceeding to allogeneic stem cell transplant (SCT). Since then, several real-world studies (RW) from different countries, confirmed the efficacy observed in the phase 3 and generating important insights into the use of CPX-351. Additionally, they have addressed important data not included in the pivotal study such as its use in younger patients, measurable residual disease (MRD) or response according to molecular alterations in myelodysplasia-related genes (MRg) included in the current classifications. Our aim is to analyze the the efficacy of CPX-351 in a real-life setting, evaluating the impact of MRD in a broader population of high-risk-AML. Methods: Retrospective, observational, multicenter study of newly diagnosed high-risk AML (t-AML and AML-MRC) treated with CPX-351 in 21 Spanish centers (May 2018 to July 2025). For this purpose, we collected data from medical records of AML patients treated with CPX-351 and investigated efficacy outcomes derived from the follow-up analysis between clinical parameters:overall survival (OS) and ORR(complete remission (CR) or CR with incomplete hematology recovery (CRi)) and [1] age ( ≤ 60 y) [2] MRD, assesed by multiparametric flow cytometry (*negative: below the threshold of 10 –3) [3] cytogenetic and molecular alterations [4], consolidation with SCT. The study was approved by Ethics Committee of the Coordinating Center. Statistical analysis was performed using SPSS v. 26. Results: A total of 219 patients with high-risk-AML treated with CPX-351 were included. Median age was 65y (range 20-78), 53 (24.2%) were younger than 60y and 135 (61,6%) were male. Median bone marrow blast at diagnosis was 30% (IQR 21-53.5). Among 195 patients with cytogenetics available:74 (33.8%) was normal, 87(39.7%) showed myelodysplasia-related cytogenetic (CM) with53 (60.9%) complex karyotype and 34 (15%) presented other alterations. Molecular profile was available in 188: 99 (52.7%) showed MRg and 40 (21.3 %) were TP53 mutated. ELN2022 risk stratification was: 12 (5.5%) favorable, 33 (15.1%) intermediate and 174 (79.5%) adverse. Among 193 patients evaluable for response, the overall response rate (ORR) was 63.7%, with 86.1% responders after 1 st cycle and MRD negative in 58% of responders. Consolidation (at least 1 cycle, 1-3) was given to 73 patients. A total of 100 (45.6%) patients underwent SCT. Early mortality at 30 and 60 days was 1.4% and 6.1% respectively. With a median follow-up time (IQR) of 8.6 months, the 1-y OS and relapse free survival (RFS) were 56.5% and 59.8%, respectively. Response to CPX-351 induction was statistically associated with better 1-y OS (68 vs 43.9%), regardless the number of induction cycles (1 cycle 68 vs 2 cycles 69%). End of induction MRD negativity was associated with a trend towards better 1y-OS (73.8 vs 60.4%, p=0.09). TP53 muation, del17p and CM were associated with end-of-induction MRD positivity. SCT was also associated with better 1-y OS (79.6% vs 35.8%). We found no difference in terms of OS regarding age(<60 66.5 vs >60 53.3%, p=0.1). Despite the lack of differences in response between younger and older in terms of ORR(64% vs 78%) or MRD response(67 vs 52%), there is a significant difference (p<0.05) in reaching SCT between both groups: 38 (71.7% vs 37.3%). Presence of del17p or TP53 mutation were predictive of worse 1y-OS (16.7 vs 62.4%; 34.2 vs 61.6%, respectively), load of TP53 disfunction was predictive of worse OS(no hit 64.1%, single hit 40.8%, double hit 14%). Efficacy of CPX-351 was not affected by mutations in MRg vs not mutated (57.9% vs 53.4%). No differences were found in ORR or OS based on whether AML was defined by cytogenetic alterations and/or prior MDS(58.6%) or solely the presence of MRg (64%) (p=0.14). Regarding safety profile, a 44 % of patients experienced mucositis, most of them low grade (1-2) in 97.9%. Conclusions: Our preliminary results support the previous evidence that CPX-351 improves overall survival in high-risk AML regardless of patients age and with acceptable safety profile.