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

Abstract

Background: The high prognostic value of minimal residual disease (MRD) assessment in Acute Myeloid Leukemia patients (AML) undergoing intensive induction therapy has been confirmed by several studies. The most widely adopted 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, mostly younger patients receiving a conventional 3+7 induction are included in clinical studies evaluating MRD in AML. As a consequence, secondary AML, evolving from a previous myelodisplastic syndrome (s-AML) or therapy-related AML (t-AML), which usually affect elderly AML patients are usually under-represented in those trials. Recently, CPX-351 was approved for the treatment of s-AML and t-AML, following the positive results of the Phase III trial by Lancet et al. However, as MRD was not assessed in this trial, only a limited ammount of data are available on the kinetics and the prognostic value of MRD in elderly s- AML and t-AML patients receiving CPX-351 induction. Aims: In order to assess the prognostic value and to define the best time points for MRD assessment, MFC-based and WT1 based MRD was evaluated in a cohort of elderly s-AML or t-AML patients receiving CPX-351 induction. Timepoints for assessment were after induction (TP1), after first consolidation (TP2) and at the end of treatment (TP3). As a comparison, we also evaluated MRD in a cohort of elderly s-AML and t-AML patients who received an age-adjusted fludarabine-containing regimen (FLAI3). MRD analysis in this cohort was performed with the same methodics and at the same timepoints. 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 first induction cycle, 95 patients (59%) achieved CR. Patients treated with CPX-351 had a significantly higher CR rate, if compared to patients receiving FLAI (40/50, 80% and 55/101, 54.5%, respectively, p<0.05). Adding GO to FLAI did not increase CR rate. Overall, in the two cohorts, an MRD negative CR was achieved in 51 (53.7%) and 53 responding patients (55.8%) assessed with MFC or WT1-based methods, respectively. The probability of achieving MFC MRD negativity was significantly higher among patients treated with CPX-351, when compared to patients receiving FLAI with or without GO (MFC MRD negativity rate of 26/40, 65% and 25/55, 45%, respectively, p<0.05). In both cohort, the most informative timepoint in terms of survival prediciton was after first cycle (TP1). WT1-based MRD assessment led to superimposable results. In multivariate analysis, MRD was significantly correlated with an higher probability of longer 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). Allogeneic stem cell transplantation consolidation (HSCT) was also significantly correlated with longer OS in both treatment groups (p<0.05). Notably, 12/40 (30%) CR patients treated with CPX 351 underwent HSCT, whereas only 8 CR patients proceeded to HSCT in the FLAI group (15%) Conclusions: MRD assessment has a strong prognostic value also in the context of elderly s-AML and t-AML patients. WT1-based and MFC-based MRD assessment lead to similar conclusions thus allowing to obtain MRD data from virtually all AML patients treated in the selected time period. Overall, CPX-351 resulted in higher CR rate with deeper MRD responses, if compared to FLAI3. This increased efficacy translated in a significantly higher number of elderly AML patients proceeding to HSCT in CR, which is the only curative approach in this particular AML setting.