Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia

Lynn Quek, Paul Ferguson, Marlen Metzner, Ikhlaaq Ahmed, Alison Kennedy, Catherine Garnett, Sally Jeffries, Claudia Walter, Kim Piechocki, Adele Timbs, Robert Danby, Manoj Raghavan, Andrew Peniket, Mike Griffiths, Andrew Bacon, Janice Ward, Keith Wheatley, Paresh Vyas, Charles Craddock

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Abstract

Disease relapse is the major cause of treatment failure after allogeneic stem cell transplantation (allo-SCT) in acute myeloid leukemia (AML). To identify AML-associated genes prognostic of AML relapse post–allo-SCT, we resequenced 35 genes in 113 adults at diagnosis, 49 of whom relapsed. Two hundred sixty-two mutations were detected in 102/113 (90%) patients. An increased risk of relapse was observed in patients with mutations in WT1 (P = .018), DNMT3A (P = .045), FLT3 ITD (P = .071), and TP53 (P = .06), whereas mutations in IDH1 were associated with a reduced risk of disease relapse (P = .018). In 29 patients, we additionally compared mutational profiles in bone marrow at diagnosis and relapse to study changes in clonal structure at relapse. In 13/29 patients, mutational profiles altered at relapse. In 9 patients, mutations present at relapse were not detected at diagnosis. In 15 patients, additional available pre–allo-SCT samples demonstrated that mutations identified posttransplant but not at diagnosis were detectable immediately prior to transplant in 2 of 15 patients. Taken together, these observations, if confirmed in larger studies, have the potential to inform the design of novel strategies to reduce posttransplant relapse highlighting the potential importance of post–allo-SCT interventions with a broad antitumor specificity in contrast to targeted therapies based on mutational profile at diagnosis.
Original languageEnglish
Pages (from-to)193-204
Number of pages12
JournalBlood Advances
Volume1
Issue number3
Early online date14 Dec 2016
DOIs
Publication statusPublished - 27 Dec 2016

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