Journal article
TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes
The New England journal of medicine, Vol.375(21), pp.2023-2036
11/24/2016
DOI: 10.1056/NEJMoa1605949
PMCID: PMC5217532
PMID: 27959731
Abstract
The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear.
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.
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.
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. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).
Details
- Title: Subtitle
- TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes
- Creators
- John S Welch - Washington University in St. LouisAllegra A Petti - University of ChicagoChristopher A Miller - Massachusetts General HospitalCatrina C Fronick - Washington University in St. LouisMichelle O'Laughlin - Washington University in St. LouisRobert S Fulton - Washington University in St. LouisRichard K Wilson - Washington University in St. LouisJack D Baty - Washington University in St. LouisEric J Duncavage - Washington University in St. LouisBevan Tandon - Washington University in St. LouisYi-Shan Lee - Washington University in St. LouisLukas D Wartman - Washington University in St. LouisGeoffrey L Uy - Washington University in St. LouisArmin Ghobadi - Washington University in St. LouisMichael H Tomasson - Washington University in St. LouisIskra Pusic - Washington University in St. LouisRizwan Romee - Washington University in St. LouisTodd A Fehniger - Washington University in St. LouisKeith E Stockerl-Goldstein - Washington University in St. LouisRavi Vij - Washington University in St. LouisStephen T Oh - Washington University in St. LouisCamille N Abboud - Washington University in St. LouisAmanda F Cashen - Washington University in St. LouisMark A Schroeder - Washington University in St. LouisMeagan A Jacoby - Washington University in St. LouisSharon E Heath - Washington University in St. LouisKierstin Luber - Washington University in St. LouisMegan R Janke - Washington University in St. LouisAndrew Hantel - University of ChicagoNiloufer Khan - University of ChicagoMadina J Sukhanova - University of ChicagoRandall W Knoebel - University of ChicagoWendy Stock - University of ChicagoTimothy A Graubert - Harvard UniversityMatthew J Walter - Washington University in St. LouisPeter Westervelt - Washington University in St. LouisDaniel C Link - Washington University in St. LouisJohn F DiPersio - Washington University in St. LouisTimothy J Ley - Washington University in St. Louis
- Resource Type
- Journal article
- Publication Details
- The New England journal of medicine, Vol.375(21), pp.2023-2036
- DOI
- 10.1056/NEJMoa1605949
- PMID
- 27959731
- PMCID
- PMC5217532
- ISSN
- 0028-4793
- eISSN
- 1533-4406
- Grant note
- R01 HL128447 / NHLBI NIH HHS R35 CA197561 / NCI NIH HHS P01 CA101937 / NCI NIH HHS P50 CA171963 / NCI NIH HHS K12 CA167540 / NCI NIH HHS K08 CA166229 / NCI NIH HHS
- Language
- English
- Date published
- 11/24/2016
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Health and Human Physiology; Internal Medicine
- Record Identifier
- 9984359564102771
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