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Quizartinib elicits differential responses that correlate with karyotype and genotype of the leukemic clone

Leukemia volume 30, pages 1422–1425 (2016)Cite this article

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Fms-like tyrosine kinase 3 (FLT3) is one of the most commonly mutated genes in acute myeloid leukemia (AML) and as such has been a highly studied therapeutic target in the field. Indeed, highly potent FLT3 inhibitors such as quizartinib (AC220) have generated substantial antileukemic clinical effects among relapsed/refractory AML patients with FLT3-internal tandem duplication (ITD) mutations, as well as a smaller number of patients without documented FLT3 mutation.1 Importantly, nearly 70% of quizartinib-treated FLT3-ITD+ patients show objective antileukemic responses per the modified International Working Group response criteria,2 many of which allowed subsequent allogeneic hematopoietic cell transplantation and prolonged survival in some.3

Although initially FLT3 inhibition was believed to act on myeloblasts primarily via direct cytotoxicity,4 recent data suggest that in some AML patients FLT3 inhibition causes terminal differentiation of FLT3-ITD+ blasts.5, 6 As FLT3 inhibition is a major area of ongoing preclinical and clinical investigation in the field of AML, we sought to define predictors of differentiation and cytotoxic effects of quizartinib therapy at a molecular and genetic level. We retrospectively performed an independent analysis of all marrow studies from the 21 patients treated with quizartinib at our center on a recent phase 2 clinical trial. Here we confirm that FLT3 inhibition by quizartinib generates potent antileukemic effects manifesting as two major patterns of drug response, namely differentiation and cytotoxic responses. We also provide evidence that cooperating mutations modify clinical response to FLT3 kinase inhibition.

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Acknowledgements

This study was supported by the National Institutes of Health, the National Cancer Institute (NCI; grant 1K23CA141054 to AEP) and the Leukemia and Lymphoma Society (NPS, CCS and AEP). NPS was supported by a grant from the National Cancer Institute (1R01 CA166616-01) and MC is supported by R21CA198621 also from the NCI. We thank Cezary Swider, PhD for technical expertise and assistance with cell processing.

Author contributions

GEN designed research, collected data, performed research, performed histopathologic analysis of clinical samples and wrote the paper; JC analyzed data and wrote the paper; DR collected data; JDM and CDW performed research NPS and CCS performed research; AB performed histopathologic analysis of clinical samples; MC and AEP designed research, analyzed data and wrote the paper. All authors provided critical review of the paper and approved the submission.

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Author notes

  1. G E Nybakken and J Canaani: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Kaiser Permanente Santa Clara, CA, USA

    G E Nybakken

  2. Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, USA

    J Canaani, M Carroll & A E Perl

  3. Department of Pathology, Rowan University, Glassboro, NJ, USA

    D Roy

  4. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

    J D Morrissette, C D Watt & A Bagg

  5. Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA

    N P Shah & C C Smith

  6. Philadelphia Veterans Hospital, Philadelphia, PA, USA

    M Carroll

Authors
  1. G E Nybakken
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  2. J Canaani
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  3. D Roy
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  7. C C Smith
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  8. A Bagg
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  10. A E Perl
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Corresponding author

Correspondence to A E Perl.

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Competing interests

AEP has served as a consultant to Ambit Biosciences, Astellas Pharmaceuticals and Arog Pharmaceuticals. CCS received clinical trial grant funding from Astellas. The remaining authors declare no conflict of interest.

Additional information

Results were presented in part at the 54th annual meeting of the American Society of Hematology meeting.

Supplementary Information accompanies this paper on the Leukemia website

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Nybakken, G., Canaani, J., Roy, D. et al. Quizartinib elicits differential responses that correlate with karyotype and genotype of the leukemic clone. Leukemia 30, 1422–1425 (2016). https://doi.org/10.1038/leu.2015.320

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