Acquired WT1 mutations contribute to relapse of NPM1-mutated acute myeloid leukemia following allogeneic hematopoietic stem cell transplant

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Abstract

The role of WT1 protein in hematopoiesis and leukemogenesisis incompletely elucidated. WT1 overexpression is common in acute myeloid leukemia (AML); however, WT1 mutations occur in only about 10% of cases, with increasing incidence in the setting of relapse. In this study, we investigated the clinical and molecular characteristics of WT1 mutations in NPM1-mutated AML, to enhance our understanding of the biology and potential therapeutic implications of WT1 mutations. Our study cohort included 67 patients with NPM1 mutated AML and a median follow-up of 13.7 months. WT1 mutations were identified in 7% (n = 5) of patients at the time of initial diagnosis. WT1 mutant clones were presumed to be present as co-dominant clones in 3/5 and in subclonal populations in 2/5 cases based on variant allelic frequency (VAF) when compared with NPM1 mutation VAF. All WT1 mutations became undetectable at time of MRD-negative (NPM1-wild type) remission. None of these patients experienced relapse at the time of last follow-up (median, 15 months; range, 4.5–20.2 months). A total of 15/67 (22%) patients relapsed; among these patient, four (27%) relapsed with WT1 mutant AML. Three of four patients had undergone allogeneic hematopoietic stem cell transplantation (HSCT). None of these patients had detectable WT1 mutations at the time of initial diagnosis. WT1 mutations were presumed clonal in two cases and subclonal in the other two cases, based on VAF. Our results indicate that WT1 mutations contribute to relapse in NPM1 mutated AML, especially in the setting of HSCT. These findings suggest that emerging WT1 mutations may serve as a conduit for relapse in NPM1-mutated AML, and that sequential molecular profiling to evaluate potential emergent WT1 mutations during surveillance and particularly at relapse likely has prognostic value in patients with NPM1 mutated AML.

Original languageEnglish (US)
Pages (from-to)370-376
Number of pages7
JournalBone marrow transplantation
Volume57
Issue number3
DOIs
StatePublished - Mar 2022

ASJC Scopus subject areas

  • Hematology
  • Transplantation

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