Patterns of molecular response to and relapse after combination of sorafenib, idarubicin, and cytarabine in patients with FLT3 mutant acute myeloid leukemia

Aref Al-Kali, Jorge Cortes, Stefan Faderl, Dan Jones, Caroline Abril, Sherry Pierce, Mark Brandt, Hagop Kantarjian, Farhad Ravandi

Research output: Contribution to journalArticle

Abstract

Background: FMS-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase involved in hematopoietic progenitor cell development. Mutations of FLT3 have been reported in about a third of patients with acute myeloid leukemia (AML), and inhibitors of FLT3 are of clinical interest. Sorafenib is an orally active multikinase inhibitor with potent activity against FLT3 and the Raf/ERK/MEK kinase pathway. Methods: We studied the patterns of molecular response and relapse in 18 patients with mutated FLT3 treated with the combination of sorafenib, idarubicin, and cytarabine. Results: The median follow-up was 9 months. Sixteen patients achieved complete remission (CR), and the other 2 patients achieved CR but lacked platelet recovery for an overall response rate of 100%. Ten patients had their FLT3-mutated clone eradicated, with 6 patients who showed some residual FLT3-mutated cells, and 2 patients who showed persistent FLT3-mutated cells. The elimination of FLT3-mutated population at the time of morphologic CR, however, was not predictive of relapse. After a median follow-up of 9 months (range, 1-16 months), 10 (55%) patients had relapsed, with a median CR duration of 8.8 months (range, 1-9.5 months). By DNA sequencing, there was no evidence of an acquired FLT3 point mutation at the time of relapse in 7 patients tested, which suggested the presence of other mechanisms of sorafenib resistance. Conclusion: Sorafenib, combined with chemotherapy, is effective in attaining CR, but relapses still occur.

Original languageEnglish (US)
Pages (from-to)361-366
Number of pages6
JournalClinical Lymphoma, Myeloma and Leukemia
Volume11
Issue number4
DOIs
StatePublished - Aug 2011
Externally publishedYes

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Idarubicin
Cytarabine
Acute Myeloid Leukemia
Protein-Tyrosine Kinases
Recurrence
sorafenib
MAP Kinase Kinase Kinases
MAP Kinase Signaling System
Receptor Protein-Tyrosine Kinases
Hematopoietic Stem Cells
DNA Sequence Analysis
Point Mutation
Blood Platelets
Clone Cells

Keywords

  • Acute Myeloid Leukemia AML
  • FLT3 mutation
  • Sorafenib

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Patterns of molecular response to and relapse after combination of sorafenib, idarubicin, and cytarabine in patients with FLT3 mutant acute myeloid leukemia. / Al-Kali, Aref; Cortes, Jorge; Faderl, Stefan; Jones, Dan; Abril, Caroline; Pierce, Sherry; Brandt, Mark; Kantarjian, Hagop; Ravandi, Farhad.

In: Clinical Lymphoma, Myeloma and Leukemia, Vol. 11, No. 4, 08.2011, p. 361-366.

Research output: Contribution to journalArticle

Al-Kali, Aref ; Cortes, Jorge ; Faderl, Stefan ; Jones, Dan ; Abril, Caroline ; Pierce, Sherry ; Brandt, Mark ; Kantarjian, Hagop ; Ravandi, Farhad. / Patterns of molecular response to and relapse after combination of sorafenib, idarubicin, and cytarabine in patients with FLT3 mutant acute myeloid leukemia. In: Clinical Lymphoma, Myeloma and Leukemia. 2011 ; Vol. 11, No. 4. pp. 361-366.
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T1 - Patterns of molecular response to and relapse after combination of sorafenib, idarubicin, and cytarabine in patients with FLT3 mutant acute myeloid leukemia

AU - Al-Kali, Aref

AU - Cortes, Jorge

AU - Faderl, Stefan

AU - Jones, Dan

AU - Abril, Caroline

AU - Pierce, Sherry

AU - Brandt, Mark

AU - Kantarjian, Hagop

AU - Ravandi, Farhad

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N2 - Background: FMS-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase involved in hematopoietic progenitor cell development. Mutations of FLT3 have been reported in about a third of patients with acute myeloid leukemia (AML), and inhibitors of FLT3 are of clinical interest. Sorafenib is an orally active multikinase inhibitor with potent activity against FLT3 and the Raf/ERK/MEK kinase pathway. Methods: We studied the patterns of molecular response and relapse in 18 patients with mutated FLT3 treated with the combination of sorafenib, idarubicin, and cytarabine. Results: The median follow-up was 9 months. Sixteen patients achieved complete remission (CR), and the other 2 patients achieved CR but lacked platelet recovery for an overall response rate of 100%. Ten patients had their FLT3-mutated clone eradicated, with 6 patients who showed some residual FLT3-mutated cells, and 2 patients who showed persistent FLT3-mutated cells. The elimination of FLT3-mutated population at the time of morphologic CR, however, was not predictive of relapse. After a median follow-up of 9 months (range, 1-16 months), 10 (55%) patients had relapsed, with a median CR duration of 8.8 months (range, 1-9.5 months). By DNA sequencing, there was no evidence of an acquired FLT3 point mutation at the time of relapse in 7 patients tested, which suggested the presence of other mechanisms of sorafenib resistance. Conclusion: Sorafenib, combined with chemotherapy, is effective in attaining CR, but relapses still occur.

AB - Background: FMS-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase involved in hematopoietic progenitor cell development. Mutations of FLT3 have been reported in about a third of patients with acute myeloid leukemia (AML), and inhibitors of FLT3 are of clinical interest. Sorafenib is an orally active multikinase inhibitor with potent activity against FLT3 and the Raf/ERK/MEK kinase pathway. Methods: We studied the patterns of molecular response and relapse in 18 patients with mutated FLT3 treated with the combination of sorafenib, idarubicin, and cytarabine. Results: The median follow-up was 9 months. Sixteen patients achieved complete remission (CR), and the other 2 patients achieved CR but lacked platelet recovery for an overall response rate of 100%. Ten patients had their FLT3-mutated clone eradicated, with 6 patients who showed some residual FLT3-mutated cells, and 2 patients who showed persistent FLT3-mutated cells. The elimination of FLT3-mutated population at the time of morphologic CR, however, was not predictive of relapse. After a median follow-up of 9 months (range, 1-16 months), 10 (55%) patients had relapsed, with a median CR duration of 8.8 months (range, 1-9.5 months). By DNA sequencing, there was no evidence of an acquired FLT3 point mutation at the time of relapse in 7 patients tested, which suggested the presence of other mechanisms of sorafenib resistance. Conclusion: Sorafenib, combined with chemotherapy, is effective in attaining CR, but relapses still occur.

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