Comparing Outcomes between CPX-351 and Fludarabine-Based Induction in Secondary Acute Myeloid Leukemia in the Real-World Setting: The Prognostic Role of Measurable Residual Disease

BACKGROUND: Secondary Acute Myeloid Leukemia (s-AML) arising from a preceding hematologic disorder (MRC-AML) or developing after prior cytotoxic therapy (t-AML) are characterized by a high frequency of high-risk cytogenetic and molecular aberrations, leading to poor complete remission (CR) rates and overall survival (OS). Performing allogeneic hematopoietic stem cell transplantation (HSCT) in first CR, especially with negative Minimal Residual Disease (MRD), enhances the chance of cure, however, MRD negativity is hardly achieved with conventional treatments. Recently CPX-351 showed better results compared to conventional treatments in elderly s-AML patients. In the UK NCRI AML19 trial CPX-351 and FLAG-IDA had similar results in high-risk AML with subgroup analysis revealing better OS with CPX-351 in patients with MDS-related gene mutations. AIMS: This study aimed to compare the probability of achieving MRD negativity and its prognostic relevance in a cohort of patient affected by s-AML receiving an induction therapy with CPX-351 or a fludarabine, high dose cytarabine, idarubicin age-adjusted regimen (FLAI). METHODS: One hundred-eighty three elderly patients (median age 69, range 60-77) were diagnosed with s- AML, according to WHO 2016 classification. Patients treated after January 2019 (n=82) received CPX-351 according to EMA approval, while patients treated before January (n=101) received an fludarabine-high dose cytarabine-idarubicin age adjusted regimen. MRD analysis was conducted in all CR patients using multicolor flow cytometry (MFC), with a 0.1% threshold. Among patients receiving CPX-351, 20 were diagnosed with t-AML (24%) and 62 with MRC-AML (76%). The majority (77/82, 94%) had MDS-defining cytogenetic and/or molecular abnormalities. A complex karyotype was found in 38 patients (46%) and TP53 mutation in 22 (27%). In the FLAI arm, 18 (18%) had t-AML and 83 (83%) had MRC-AML. ELN 2017 risk was favorable (8%, n=7 and 11% n=11), intermediate (39%, n=32 and 49% n=49) and unfavorable (53%, n=43 and41%, n=41) in CPX arm and FLAI arm, respectively. RESULTS: After first cycle, CR was achieved in a total 119 patients (65%). CR rate was 64/82 in patients treated with CPX-351 (78%), significantly higher when compared to patients receiving FLAI (55/101, 54.5%, p<0.05). Thirty-day mortality was 3/82 (3.6%) and 8/101 (8%) in CPX-351 and FLAI treated patients, respectively. Severe mucositis was observed in 1 (1%) and 8 (8%) patients in the CPX and FLAI arm, respectively (p<0.05). In the CPX-351 arm, CR rate was not affected by karyotype, ELN risk, age, previous HMA treatment or WHO classification, whereas in the FLAI arm it was lower among ELN 2017 high risk patients (p<0.05). In the whole cohort, among CR patients, a total of 65 (54.6%) achieved MFC MRD negativity. MFC MRD negativity probability was higher among patients receiving CPX-351 as induction therapy (MFC MRD negative CR rate of 40/64, 62.5% and 25/55, 45% in patients who received CPX-351 or FLAI, respectively, p<0.05). Among CPX-351 treated patients, MFC-MRD negativity was not affected by any of the analyzed variables. In the FLAI cohort, MFC-MRD negativity rate was significantly lower among ELN 2017 unfavorable risk patients (p<0.05). After a median follow-up of 20.7 months (Cl 95% 16.49-26.37) for CPX-351 treated patients and 58 months (Cl 95% 34.97-72.98) for FLAI treated patients, median OS in the whole cohort was 13.4 months (Cl 95% 8.04-16.97) with better OS in CPX arm compared to patients receiving FLAI (median OS 17.7 vs 11.2 months, respectively, p<0.05). Multivariate OS analysis showed that MRD was the strongest prognostic factor for OS, completely independent of treatment received (2-year OS of 35% and 79% in patients with or without residual MFC MRD after induction, p<0.05). In a landmark analysis including CR patients alive at day 30, HSCT consolidation was the strongest predictor of survival. Notably, 21/64 (32.8%) CR patients treated with CPX351 underwent HSCT, compared to 5/55 (9%) CR patients treated with FLAI. SUMMARY/CONCLUSION: In our S-AML cohort, CPX-351 showed superior outcomes if compared to FLAI, this can be explained by the enhanced anti-leukemic activity who increases the likelihood of achieving MRD negativity, as well as its better tolerability, allowing a higher number of patients to proceeded to HSCT and consequently improving long-term OS.