Prognostic Relevance of Minimal Residual Disease in Therapy Related and Secondary Acute Myeloid Leukemia Receiving CPX-351 or Fludarabine-Based Induction

Background: Minimal residual disease (MRD) assessment retains high prognostic value in Acute Myeloid Leukemia patients (AML) undergoing intensive induction therapy. Widely available MRD techniques include multicolor flow cytometry (MFC), RT-PCR for recurrent genetic lesion and, for patients lacking specific markers, RT-PCR for the pan- leukemic marker WT1. However, most of the data on the prognostic value of MRD come from trials including younger patients treated with conventional 3 + 7 regimen. Furthermore, AML arising from a previous myelodisplastic syndrome (s-AML) and therapy-related AML (t-AML) are usually under-represented in trial involving younger patients. Few data are, therefore, available on the kinetics and the prognostic value of MRD in elderly s- AML and t-AML patients; especially in the context of more modern frontline treatment such as CPX-351. Aims: We evaluated MRD in a cohort of elderly s-AML or t-AML patients receiving induction therapy either with an age-adjusted fludarabine-containing regimen (FLAI3) or CPX-351, in order to compare the probability of achieving MRD negativity, to assess the prognostic value of MRD and to define the best time-points for MRD assessments. Methods: A total of 151 elderly (>60 year, median age 68, range 60-77) patients were analyzed in this study. Patients were treated between January 2005 and January 2020 in our Center, either with CPX-351 (n=50) or fludarabine- high dose cytarabine-idarubicin (FLAI), with (n=72) or without (n =29) gemtuzumab-ozogamicin (GO). MRD was analyzed in all patients achieving hematological complete remission (CR) with both MFC and WT1 expression levels. All patients were affected by s-AML or t-AML, defined according to the WHO 2016 criteria. Results: After induction, CR was achieved in 95 patients (59%). CR rate was 40/50 in patients treated with CPX-351 (80)% significantly higher when compared to patients receiving FLAI (55/101, 54.5%, p<0.05). The addition of GO to FLAI did not increase CR rate. Among CR patients, a total of 51 (53.7%) and 53 patients (55.8%) achieved MRD negativity, with MFC or WT1-based methods, respectively. MFC MRD negativity probability was higher among patients receiving CPX-351 as induction therapy (MFC MRD negativity rate of 26/40, 65% and 25/55, 45% in CR patients who received CPX-351 or FLAI, respectively, p<0.05). Adding GO to FLAI did not improve MRD negativity probability. The most informative timepoint was after first cycle. WT1-based MRD assessment led to similar results. In multivariate analysis, MRD showed significant prognostic value for Overall Survival (OS) in all treatment group (2-year OS of 34% and 77% in patients with or without residual MFC MRD after induction, respectively, p<0.05). Similarly, consolidation with allogeneic stem cell transplantation (HSCT) was correlated with higher OS. Notably, 12/40 (30%) CR patients treated with CPX 351 underwent HSCT. Summary/Conclusion: In conclusion MRD assessment retains a strong prognostic value also in s-AML and t-AML patients. The evaluation of MRD with both methods lead to similar conclusions and allowed us to obtain MRD data from virtually all AML patients treated in the selected time period. CPX-351 treatment resulted in higher CR rate with deeper MRD responses, if compared to FLAI3 and allowed a significant number of elderly AML patients to proceed to HSCT.