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. 2014 Jul 15;120(14):2142-9.
doi: 10.1002/cncr.28705. Epub 2014 Apr 15.

Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations

Yesid Alvarado  1 , Hagop M Kantarjian, Rajyalakshmi Luthra, Farhad Ravandi, Gautam Borthakur, Guillermo Garcia-Manero, Marina Konopleva, Zeev Estrov, Michael Andreeff, Jorge E Cortes
Affiliations

Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations

Yesid Alvarado et al. Cancer. .

Abstract

Background: FLT3-internal tandem duplication (ITD) mutations are found in approximately 30% of patients with acute myeloid leukemia (AML). FLT3 inhibitors have shown clinical activity in AML with FLT3-ITD, but responses are usually short-lived.

Methods: This study examined 69 FLT3-mutated patients with AML, who were treated with different FLT3 inhibitors to analyze emergence of new mutations.

Results: At baseline, 87% of patients had an ITD mutation, 7% had a D835/I836 mutation, and 6% had combined ITD and D835/I836 mutations. Responses occurred in 32% of patients, all with FLT3-ITD; none of the patients with D835/I836 or ITD+D835/I836 responded. Mutational assessment at the time of FLT3 inhibitor discontinuation showed that 68% of patients were unchanged, 10% had become undetectable, and 22% of patients progressed from a single ITD to have combined ITD+D835/I836 mutations. In those patients with unchanged FLT3 mutation at progression, the median survival was 5 months, whereas in those with undetectable and with combined ITD+D835/I836 mutations, the median survival was 7 months, respectively.

Conclusions: These data confirm in vitro observations that a secondary tyrosine kinase domain mutation may arise after the use of FLT3 inhibitors in patients with single FLT3-ITD mutated AML, a phenomenon that is associated with resistance and a poor prognosis.

Keywords: FLT3 inhibitors; FLT3-ITD; FLT3-TKD; acute myeloid leukemia; secondary FLT3 mutations.

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Figures

Figure 1
Figure 1. Survival Curves
A: Overall Survival from beginning of treatment (Median 6 months), B: Overall Survival from FLT3 Inhibitor treatment discontinuation (Median 3 months), C: Survival Patients Transplanted (Median 7 Months), D: Survival Patients with Undetectable Mutation After Treatment (Median 7 months), E: Survival Patients with Unchanged Mutation Status (Median 5 months), F: Survival Patients Developing Both Mutations (Median 7 months).
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References

    1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010 Sep-Oct;60(5):277–300. - PubMed
    1. Lowenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235–1248. - PubMed
    1. Kantarjian H, O’Brien S, Cortes J, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer. 2006 Mar 1;106(5):1090–1098. - PubMed
    1. Estey EH. General approach to, and perspectives on clinical research in, older patients with newly diagnosed acute myeloid leukemia. Semin Hematol. 2006 Apr;43(2):89–95. - PubMed
    1. Grimwade D, Walker H, Harrison G, et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood. 2001 Sep 1;98(5):1312–1320. - PubMed

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