TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes.

N Engl J Med. 2016 Nov 24;375(21):2023-2036.


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.


Welch JS1, Petti AA1, Miller CA1, Fronick CC1, O'Laughlin M1, Fulton RS1, Wilson RK1, Baty JD1, Duncavage EJ1, Tandon B1, Lee YS1, Wartman LD1, Uy GL1, Ghobadi A1, Tomasson MH1, Pusic I1, Romee R1, Fehniger TA1, Stockerl-Goldstein KE1, Vij R1, Oh ST1, Abboud CN1, Cashen AF1, Schroeder MA1, Jacoby MA1, Heath SE1, Luber K1, Janke MR1, Hantel A1, Khan N1, Sukhanova MJ1, Knoebel RW1, Stock W1, Graubert TA1, Walter MJ1, Westervelt P1, Link DC1, DiPersio JF1, Ley TJ1.