P532: kinetics and prognostic value of measurable residual disease (mrd) in patients diagnosed with acute myeloid leukemia (aml) treated with venetoclax in combination with hypomethylating agents.

Background: Measurable residual disease (MRD) persistence at defined treatment time-points has an adverse clinical impact in patients diagnosed with acute myeloid leukemia treated with standard intensive chemotherapy treatment. MRD prognostic impact is uncertain among patients treated with venetoclax-based low-intensity regimes. A previous study, performed in patients included in the Viale-A trial, showed the potential prognostic value of a multiparameter flow cytometry-based MRD strategy in patients treated with venetoclax and azacytidine (Pratz KW, J Clin Oncol 2022;40:855-86). Further knowledge of MRD response as a prognostic value for outcome is warranted. Aims: Primary goals of the study were to determine the MRD response rate during treatment and its correlation with response duration and overall survival in AML patients treated with low intensity venetoclax-based regimes. Methods: We analyzed retrospectively patients diagnosed with AML and treated consecutively venetoclax plus hypomethylating agents at Hospital Clinic of Barcelona from March 2019 to February 2023. Patients included in the analysis corresponded to all patients who achieved a morphological response in bone marrow, meaning <5% blasts regardless of hematological recovery (CR/CRi/MLFS) lasting for at least 4 treatment cycles. MRD was measured following the updated ELN 2021 recommendations (Heuser M, et al. Blood 2021), using qRT-PCR base for patients with NPM1 mutated AML, and an eight-color MFC panel for the rest of the patients. Patients who underwent an allogeneic stem cell hematopoietic transplantation were excluded from this study (n=5). MRD accumulative response rate was calculated after cycle 2, 4 and 6. Impact of MRD results on LFS and OS was calculated with both a corresponding landmark analysis and considering MRD response as a time-dependent variable using the Mantel-Byar test. Results: Twenty-nine patients were included. Baseline characteristics are displayed in table 1. Median age in all patients was 75 years (range 49-87), 72% of them treated as frontline therapy, with 66% presenting an adverse risk genetic category. 2, 3 and 4 patients harbored high-risk mutations in FLT3-ITD, N/KRAS, and TP53. Median follow-up was 13.3 months. MRD response rate along treatment was 72% (21/29). In NPM1mut patients, 5/7 (71%) achieved a MRD response at any point (qRT-PCR base). MRD response rate at 2, 4 and 6 cycles were 34% (10/29), 65% (18/29) and 69%(16/23). Median time to achieve a MRD response was 2.5 months (range 1-10). Median overall survival (mOS) and leukemia-free survival (mLFS) were 21.7 (range 18.9-NR) and 18.9 months (range 13.3-NR). MRD response impact was analyzed using landmarks after C2, C4, and C6 and treating MRD clearance as a time-dependent variable. MRD response after C2 showed a trend for longer mOS (NR vs. 19m, p=0.1; Figure 2A) and LFS (21.7m vs. 13.3m, p=0.1) with a similar trend for mOS performing a Mantel-Byar test at the same time-point. (p = 0.09, range 8.95-NR vs. range 18.95-NR; Figure 2B) Summary/Conclusion: In AML patients treated with VenHMA, morphological response is achieved usually during the first two treatment cycles. Despite this fact, deeper MRD response is observed in most patients during subsequent treatment. Interestingly, MRD clearance showed a trend to an improved survival. The high MRD-clearance rate observed in this non-curative setting suggests that the current threshold definition is not discriminative enough to identify minor subsets with long-lasting responses from patients with shorter responses.Keywords: Acute myeloid leukemia, Outcome measurement, Measurable residual disease, Venetoclax