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Clinical outcomes and characteristics of patients with TP53-mutated acute myeloid leukemia or myelodysplastic syndromes: a single center experience.

ABSTRACT: Mutations in the tumor suppressor gene TP53 are detected in 5-10% of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes. TP53 mutations have been associated with complex karyotypes, therapy-related malignancies, lower response rates to cytotoxic chemotherapy, and an overall adverse prognosis. In this single-center retrospective study, we analyzed the clinicopathologic characteristics and outcomes of 83 patients with TP53-mutated myeloid malignancies treated at Yale Cancer Center between 9/2015 and 5/2019. Complex karyotypes (n = 75; 90%) and therapy-related malignancies (n = 32; 39%) were common. Median overall survival (OS) was 7.6 months. Intensive chemotherapy did not improve OS compared to lower-intensity treatment for AML patients. Patients who underwent allogeneic hematopoietic stem cell transplant (alloHSCT) had a significantly longer median OS, despite relatively limited follow-up. In conclusion, our data confirm the limited efficacy of intensive chemotherapy approaches for TP53-mutated patients with myeloid neoplasms and suggest that a minority of patients achieve long-term survival with alloHSCT.

SUBMITTER: Bewersdorf JP

PROVIDER: S-EPMC7603787 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear.MethodsWe 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.ResultsOf 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.ConclusionsPatients 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. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).

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Clinical outcomes and characteristics of patients with TP53-mutated acute myeloid leukemia or myelodysplastic syndromes: a single center experience.

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