Real-World Analysis of CPX-351 Induction in Acute Myeloid Leukemia-Myelodysplasia Related (AML-MR): An Updated Analysis from the Marrow Consortium
Authors: Peters Daniel T , Nicolet Deedra , Madanat Yazan F , Gonzalez-Lugo Jesus D , Ambinder Alexander J. , Chan Onyee , Hochman Michael Jamie , Al Ali Najla H. , Klein Victoria , Mrózek Krzysztof , Lin Tara L. , Mims Alice , Foucar Charles , Zeidner Joshua F 
Published: December 2024

Background: Liposomal cytarabine/daunorubicin (CPX-351) is a standard frontline treatment for adult patients (pts) with AML-MR. However, the pivotal trial leading to FDA-approval of CPX-351 enrolled pts aged ≥60 years (y) with: 1) therapy-related AML (t-AML), 2) AML with antecedent myelodysplastic neoplasm (MDS) or chronic myelomonocytic leukemia (CMML), and 3) AML-MR defined by cytogenetics (AML-MRC) based on 2016 WHO criteria. Updated WHO and International Consensus Classification (ICC) guidelines now incorporate MDS-related mutations into the criteria for AML-MR. Thus, there is limited data on the role of CPX-351 in younger pts (&lt;60 y) and/or those with MDS-related gene mutations.
Methods: We retrospectively analyzed clinical and molecular characteristics of pts with AML-MR (based on 2022 WHO/ICC criteria) treated with frontline CPX-351 as part of the Myeloid Malignancy Association on Rapid Research Outcomes Working Group (MARROW) Consortium. Pts were divided into two age groups: &lt;60y and ≥60y. Further analyses were conducted using four subgroups: 1) AML-MR by cytogenetics (AML-MRc), 2) AML-MR by molecular mutations (AML-MRm), 3) AML with antecedent myelodysplastic syndrome or chronic myelomonocytic leukemia (MDS/CMML), and 4) treatment-related AML (t-AML). Pts with internal tandem duplications of FLT3 were excluded. Rates of composite complete remission (CRc: CR + CRi + CRh), complete remission (CR), disease-free survival (DFS), and overall survival (OS) were compared between the groups.
Results: Overall, 267 pts were treated with CPX-351. The median age was 63y (range, 21-78); median age was 55y and 67y in the younger (n=96) and older cohort (n=171), respectively. The older cohort was predominantly male (72%) whereas more female pts were in the younger cohort (54%). The majority of younger and older groups were White (75% vs 87%) followed by Black patients in 18% vs 7%, respectively. Clinical characteristics at diagnosis were similar in both age groups, including median hemoglobin (8.1 vs 8.7g/dL), platelets (46 vs 50 x 109/L), WBC count (3.4 vs 4.4 x 109/L), and bone marrow blast percent (32 vs 30.5%). By the 2022 European LeukemiaNet risk classification, most pts (with complete classification data; n=180) were categorized in the adverse-risk group (n=147, 82%) with a higher percentage in the younger cohort (n=39; 89%).
Within the entire cohort, 58% (n=156) had AML-MRc, 40% had AML-MRm (n=107), 39% had antecedent MDS/CMML (n=105), and 18% had t-AML (n=49). Forty-three (17%) pts had TP53 mutation (TP53m). When comparing younger and older age groups, there were differences in proportion of AML-MR subgroups: AML-MRc (66.7 vs 53.8%; p=0.057), AML-MRm (30.2 vs 45.6%; p=0.029), antecedent MDS/CMML (32.3 vs 43.3%; p=0.081), t-AML (26 vs 14%; p=0.018). AML-MRm identified were ASXL1 (28%), RUNX1 (28%), SRSF2 (28%), STAG2 (21%), U2AF1 (20%), BCOR (18%), SF3B1 (14%), EZH2 (11%), ZRSR2 (4%). Mutation percentages were similar between younger and older age groups, though with numerical difference noted in ASXL1 (n=4 vs 25; 14 vs 32%; p=0.08).
Overall, the cCR and CR rates were 58% and 36%, respectively; median OS was 1.3 years. Partitioning by age did not demonstrate a significant difference in cCR (54% vs 60%; p=0.36) or CR (36% vs 38%) between younger and older groups, respectively. By excluding TP53m, response rates were improved in both age groups: cCR (56% vs 65%; p=0.24), CR (35% vs 41%; p=0.46), but there was still no difference between age groups. Further, there was no significant difference in cCR between age groups when analyzed by AML-MR subgroup: AML-MRc (50 vs 61%; p=0.34) , AML-MRm (62 vs 64%; p=0.82), antecedent CMML/MDS (48% vs 52%; p=0.81), or t-AML (72 vs 61%; p=0.54). Median OS among AML-MR subgroups divided by &lt;60y and ≥60y showed the longest OS in younger pts with AML-MRm only: AML-MRc (0.90 vs 1.66y; p=0.39), AML-MRm (3.17 vs 1.63y; p=0.14), antecedent CMML/MDS (0.89 vs 1.13y; p=0.86), and t-AML (1.88 vs 1.27y; p=0.66).
Conclusions: This real-world analysis demonstrates no significant difference in outcomes between younger and older age groups treated with frontline CPX-351 for AML-MR. AML-MRm was more common in older pts in this study, yet younger pts with AML-MRm appeared to have the best overall survival outcomes with CPX-351. Further research is needed to validate these results and explore the subgroups of pts with AML-MR that may derive most benefit from CPX-351.