Sorafenib treatment of FLT3-ITD + acute myeloid leukemia: Favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation

Cheuk Him Man, Tsz Kan Fung, Christa Ho, Heron H C Han, Howard C H Chow, Chun Hang Ma, William W L Choi, Si Lok, Alice M S Cheung, Connie Eaves, Yok Lam Kwong, Anskar Y H Leung

Research output: Journal article publicationJournal articleAcademic researchpeer-review

185 Citations (Scopus)

Abstract

Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% of acute myeloid leukemias (AMLs) and confers a poor prognosis. Thirteen relapsed or chemo-refractory FLT3-ITD + AML patients were treated with sorafenib (200-400 mg twice daily). Twelve patients showed clearance or near clearance of bone marrow myeloblasts after 27 (range 21-84) days with evidence of differentiation of leukemia cells. The sorafenib response was lost in most patients after 72 (range 54-287) days but the FLT3 and downstream effectors remained suppressed. Gene expression profiling showed that leukemia cells that have become sorafenib resistant expressed several genes including ALDH1A1, JAK3, and MMP15, whose functions were unknown in AML. Nonobese diabetic/severe combined immunodeficiency mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations, and might provide important leads to further improvement of treatment outcome with FLT3 inhibitors.
Original languageEnglish
Pages (from-to)5133-5143
Number of pages11
JournalBlood
Volume119
Issue number22
DOIs
Publication statusPublished - 5 Jun 2012
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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