TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Abstract

BACKGROUND The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. METHODS We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols. RESULTS Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles. CONCLUSIONS Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine.

Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation

“…DAC might also be an alternative for AML patients with high blast counts or rapid disease kinetics at relapse. In addition, it was recently shown that patients exhibiting a TP53 mutation had an extraordinary high response rate to DAC [63]. Although this observation needs to be confirmed prospectively, it might be worth to consider DAC in this molecularly defined patient group.…”

Meta-analysis of studies with genome sequencing in myelodysplastic syndrome treated with hypomethylating agents

“…Mutations in the TET2, DNMT3A, TP53 genes were reported to be associated with a high probability of response to HMA [13,14,15]. At the same time, mutations in the EZH2 and TP53 genes are associated with a lower level of overall survival [11,13]. However these findings are not confirmed in the other studies [11,15].…”

“…At the same time, mutations in the EZH2 and TP53 genes are associated with a lower level of overall survival [11,13]. However these findings are not confirmed in the other studies [11,15]. Thus it is crucial to understand the reasons behind the variability of results.…”

“…In this study we summarized the results of 12 studies with whole exome/genome sequencing in MDS [10,11,[13][14][15][16][17][18][19][20][21][22].…”

“…Genes involved in both methylation and other metabolic pathways are often mutated with MDS [11]. At the moment, a number of works have been published that analyze the mutational status of the main genes involved in the pathogenesis of MDS and their predictive value in the context of response to therapy and overall survival.…”