Real World Evidence of Efficacy of CPX-351 in Secondary Acute Myeloid Leukemia Defined According to Who 2022 Classification
Authors: Riva Carola , Minetto Paola , Chies Maria , Vernarecci Chiara , Zecchetti Giada , Maio Elena , Azzanelli Ylenia , Colombo Nicoletta , Rosellini Sara , Parodi Alessia , Tedone Elisabetta , Carminati Enrico , Puglisi Francesco , Nurra Clara , Fugazza Giuseppina , Nozza Paolo , Cea Michele , Lemoli Roberto Massimo , Guolo Fabio 
Published: December 2024

Background and aims:
Advances in understanding of Acute Myeloid Leukemia (AML) ontogeny are leading to a switch from a clinical to a molecular definition of secondary AML (s-AML). This is reflected by the WHO 2022 classification, where s-AML is hierarchically defined by 1. the presence of myelodysplasia (MDS) related gene mutations, 2. MDS related cytogenetic aberrations if no MDS-gene mutations are found and 3. clinically, if an antecedent history of MDS is present, recognizing three distinct s-AML categories.
The WHO 2022 definition of s-AML is thus significantly different from the previous 2016 edition, where s-AML were defined either by the presence of MDS-related cytogenetic aberration, by a history of a previous chemo-radiotherapy for unrelated neoplasm (t-AML), by a history of MDS, or by the presence of morphological marrow dysplasia.
CPX-351, compared to conventional 3+7, proved to be more effective as frontline treatment for s-AML patients. Consequently, the drug is currently approved by FDA and EMA for fit s-AML patients defined by the WHO 2016 classification, which did not consider MDS related gene mutations.
While representing a more accurate tool for s-AML classification, the implication of the WHO 2022 classification on treatment choice remains unclear, since conflicting data about the efficacy of CPX-351 in s-AML defined according the new classification are available.
The aim of this study was to compare the outcome of a cohort of elderly s-AML patients receiving CPX-351 treatment, stratified according to both 2016 and 2022 WHO classification, in order to confirm the efficacy of the drug in the molecularly-defined s-AML subgroup.
Methods:
Next-generation sequencing (NGS) was performed at diagnosis utilizing the Myeloid Solution panel by SOPHiA Genetics, encompassing 34 critical gene mutations. Samples were processed on an Illumina MiSeq platform, and analysis was performed using SOPHiA DDM® Software.
AML with MDS-related gene mutations was defined according to WHO 2022, and included mutations in ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2.
Minimal Residual disease (MRD) analysis was conducted in all CR patients using multicolour flow cytometry (MFC), with a 0.1% threshold.
Results:
A total of 85 patients (median age 69, range 37-77) affected by s-AML defined by former WHO 2016 classification and treated with CPX-351 in our Centre were included.
Following WHO 2016 classification, 21 patients (25%) had t-AML, 55 (64%) had s-AML with MDS-related cytogenetics and 9 (11%) had s-AML defined by morphological criteria alone. According to WHO 2022, 69 patients (82%) had s-AML with MDS-related genetic aberration, 13 patients (15%) had s-AML with MDS-related cytogenetic aberrations whereas 3 patients had a previous history of MDS only (3%).
ELN 2022 risk score was favourable, intermediate or unfavourable in 3 (3%), 28 (33%) and 54 (64%) patients, respectively.
After induction, 66 patients (78%) achieved complete remission (CR), whereas early death rate was 3/85 (3.8%). Among 66 CR patients, MRD was negative in 48 (72%). Both CR rate and MRD negativity were not affected by s-AML subcategory, either according to WHO 2016 or 2022, nor by ELN risk score.
After a median follow-up of 42.1 months (CI 95% 31-62 months), median OS was 19 months (CI 95% 15.89-20.69) and 2-year OS was 40.2%.
Survival was not affected by s-AML subcategory, regardless if WHO 2016 or 2022 was adopted, nor by ELN risk score. Specifically, when classifying patients according to WHO 2022, median OS was 21 and 18 months in patients with or without s-AML defined by the presence of MDS-related genes mutations (p&lt;0.05).
A total of 23 patients underwent allogeneic stem cell transplantation (HSCT) in first CR, 14 of them (61%) with MRD negative status. Median OS was not reached in HSCT patients. Receiving HSCT was the only independent factor related to a longer overall survival, both in univariate and multivariate analysis (p&lt;0.05). Survival among HSCT was not influenced by the presence of MDS-related gene mutations (p=n.s.).
Conclusion
Our data show that CPX-351 has high activity in s-AML, defined according to WHO 2022. Patients with MDS-related gene mutations had a superimposable outcome to the other patients, with overall high CR rate, allowing a significant proportion of patients to receive HSCT with negative MRD. Those data therefore suggest that CPX-351 is a reasonable option also for patients with genetically defined s-AML.