The Impact of Molecular and Cytogenetic Clonal Evolution on Survival in Relapsed/Refractory AML

Abstract

Background: Clonal diversity and evolution in acute myeloid leukemia (AML) are consequences of disease progression and play a pivotal role in the development of drug resistance and refractoriness to therapy. Much work has been done with characterizing clonal architecture in bulk tumors samples or single-cell DNA sequencing, but real-world data observing the impact of clonal evolution and responses to therapy remains scarce in the relapsed and refractory settings. Therefore, the purpose of this study was to analyze the impact of observed clonal evolution on survival.Patients & Methods: We retrospectively analyzed 81 patients with AML with relapsed or refractory disease from June 2018 to December 2020. Cytogenetic and molecular data were obtained at the time of diagnosis and the time of primary induction failure or relapse, when available. We identified a total of 24 patients that demonstrated evidence of clonal evolution following induction or salvage therapy. Baseline patient demographics were obtained, including cytogenetic risk and next-generation sequencing molecular profiling at diagnosis and throughout treatment alongside dates and types of induction regimens. We compared the survival of those with evidence of clonal evolution to matched groups without. The groups with and without clonal evolution were compared for baseline statistical differences using an unpaired t-test with Welch's correction and Kaplan-Meier survival analyses were computed and compared with log-rank tests using GraphPad Prism. The event for calculating the overall survival was the date of death with patients otherwise censored at the date of last contact.Results: Of the 24 patients with evidence of clonal evolution, we detected that evolution occurred in four (16.7%) patients at the time of primary induction failure (refractory to first induction), 19 (70.8%) at the time of first relapse, and 3 (12.5%) at the time of second relapse. The median age of patients with clonal evolution was 63 years (range: 23 - 74) with 17 (70.8%) males and 7 (29.2%) females. The most commonly occurring mutations were NPM1 (25.0%), FLT3-ITD (20.8%), and TP53 (20.8%). At the time of initial diagnosis, cytogenetic risk was favorable in one (4.2%), intermediate in 7 (29.2%), and adverse in 16 (66.7%). The majority (79.2%) of patients underwent first induction with 7+3 and 8 (33.3%) patients underwent allogenic SCT. At the time of clonal evolution and ignoring the adverse prognosis associated with relapse, one patient with favorable cytogenetics remained favorable, only one (14.3%) patient with intermediate cytogenetics shifted to adverse, and one (6.3%) patient in the adverse category shifted to intermediate by ELN criteria. Three (12.5%) patients out of 24 acquired FLT3-ITD and three (12.5%) acquired an additional cooperating mutation (NRAS, KRAS, or KIT) for a total of 25.0% acquiring a signaling pathway mutation. Out of 10 patients with either mutated TP53 or MLL, three (27.3%) acquired a cooperating mutation in FLT3 or RAS. We then compared the clonal evolution cohort with the 57 remaining relapsed/refractory patients without evidence of clonal evolution. There was no difference between the groups with respect to baseline characteristics, including age (p = 0.989), ECOG status at diagnosis (p = 0.4689), Charlson Comorbidity Index (CCI) score (p = 0.6454), or prior SCT (p = >0.999). The median overall survival (OS) of the clonal evolution group was 227 days and compared to 382 days in the non-evolution cohort (p = 0.843).Conclusion: We did not detect a significant OS difference between those with clonal evolution and those without. Independent of the adverse prognosis associated with relapsed or refractory disease, cytogenetic risk category appeared to remain the same with clonal evolution. Common trends during clonal evolution included acquisition of one or several cooperating mutations in FLT3 or RAS, both with and without the presence of mutated TP53 and MLL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.