Efficacy and safety of quizartinib in Japanese patients with FLT3-ITD positive relapsed or refractory acute myeloid leukemia in an open-label, phase 2 study


FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations in patients with acute myeloid leukemia (AML) are associated with early relapse and poor survival. This multicenter, single-arm, two-stage phase 2 study (NCT02984995) was conducted to evaluate the efficacy and safety of quizartinib hydrochloride (initial dose 20/30 mg/day), an oral, highly potent, selective FLT3 inhibitor in Japanese patients (median age 65 years) with FLT3-ITD positive relapsed/refractory (R/R) AML. The composite complete remission (CRc) rate (primary endpoint) was 53.8% (90% confidence interval 36.2–70.8%) for evaluable patients in the efficacy analysis set. The median duration of CRc and overall survival was 16.1 weeks and 34.1 weeks, respectively. The most frequent treatment-emergent adverse events (TEAEs) were febrile neutropenia (43.2%), platelet count decreased (37.8%), and QT prolonged (35.1%). Two (5.4%) patients experienced TEAEs associated with treatment discontinuation. All serious TEAEs (45.9%), except febrile neutropenia (16.2%), were reported in ≤ 2 patients. The incidence of QTcF 451–480 ms and 481–500 ms was 37.8% and 2.7%, respectively. No QTcF > 500 ms, events of torsade de pointes or arrhythmia with clinical symptoms were reported. Quizartinib monotherapy was well tolerated and resulted in clinically meaningful reductions in blast count in Japanese patients with FLT3-ITD R/R AML.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2


  1. 1.

    O’Donnell MR, Tallman MS, Abboud CN, Altman JK, Appelbaum FR, Arber DA, et al. Acute myeloid leukemia, version 3.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2017;15:926–57.

  2. 2.

    Niino M, Matsuda T. Type distribution of myeloid leukemia from Cancer Incidence in Five Continents vol. X. Jpn J Clin Oncol. 2016;46:394.

  3. 3.

    Ohtake S, Miyawaki S, Kiyoi H, Miyazaki Y, Okumura H, Matsuda S, et al. Randomized trial of response-oriented individualized versus fixed-schedule induction chemotherapy with idarubicin and cytarabine in adult acute myeloid leukemia: the JALSG AML95 study. Int J Hematol. 2010;91:276–83.

  4. 4.

    Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood. 1999;93:3074–80.

  5. 5.

    Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100:1532–42.

  6. 6.

    Kihara R, Nagata Y, Kiyoi H, Kato T, Yamamoto E, Suzuki K, et al. Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. Leukemia. 2014;28:1586–95.

  7. 7.

    Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Hematol Am Soc Hematol Educ Program. 2013;2013:220–6.

  8. 8.

    Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

  9. 9.

    Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98:1752–9.

  10. 10.

    Ravandi F, Kantarjian H, Faderl S, Garcia-Manero G, O’Brien S, Koller C, et al. Outcome of patients with FLT3-mutated acute myeloid leukemia in first relapse. Leuk Res. 2010;34:752–6.

  11. 11.

    Tallman MS. New strategies for the treatment of acute myeloid leukemia including antibodies and other novel agents. Hematology Am Soc Hematol Educ Program. 2005;2005:143–50.

  12. 12.

    Mori M, Kaneko N, Ueno Y, Yamada M, Tanaka R, Saito R, et al. Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Invest New Drugs. 2017;35:556–65.

  13. 13.

    Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009;114:2984–92.

  14. 14.

    Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013;31:3681–7.

  15. 15.

    Cortes J, Perl AE, Döhner H, Kantarjian H, Martinelli G, Kovacsovics T, et al. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2018;19:889–903.

  16. 16.

    Cortes JE, Tallman MS, Schiller GJ, Trone D, Gammon G, Goldberg SL, et al. Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML. Blood. 2018;132:598–607.

  17. 17.

    Cortes J, Khaled S, Martinelli G, Perl A, Ganguly S, Russell N, et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019;20:984–97.

  18. 18.

    Phase 1 Study of Quizartinib [Available at:] Accessed August 21, 2018.

  19. 19.

    Mander AP, Thompson SG. Two-stage designs optimal under the alternative hypothesis for phase II cancer clinical trials. Contemp Clin Trials. 2010;31:572–8.

  20. 20.

    Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics No. 1. Ordinance No. 28 (27 Mar 1997) Ministry of Health, Labour and Welfare, Japan; 1997 [Available at:] Accessed November 8, 2018.

  21. 21.

    Ethical Guidelines for Human Genome/Gene Analysis Research (established on 29 Mar 2001, fully rev. on 28 Dec 2004, partially rev. on 29 Jun 2005, partially rev. on 1 Dec 2008, fully rev. on 8 Feb 2013). Ministry of Education, Culture, Sports, Science and Technology; Ministry of Health, Labour and Welfare; Ministry of Economy, Trade and Industry; Japan; 2001 [Available at:] Accessed November 8, 2018.

  22. 22.

    Ethical Guidelines for Clinical Studies (established on 30 Jul 2003, fully rev. on 28 Dec 2004, fully rev. on 31 Jul 2008): Ministry of Health, Labour and Welfare, Japan; 2003 [Available at:] Accessed November 8, 2018 [In Japanese].

  23. 23.

    Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21:4642–9.

  24. 24.

    Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0: Japan Clinical Tumor Research Group; 2009 [Available at:] Accessed November 8, 2018.

  25. 25.

    Agarwal SK, Mangal N, Menon RM, Freise KJ, Salem AH. Response rates as predictors of overall survival: a meta-analysis of acute myeloid leukemia trials. J Cancer. 2017;8:1562–7.

  26. 26.

    Shah SS, Kantarjian HM, Ravandi F, O’Brien S, Garcia-Manero G, Andreeff M, et al. Survival outcomes in relapsed/refractory acute myeloid leukemia patients who achieve less-than-complete response after salvage therapy. Blood. 2013;122:2654.

  27. 27.

    Forman SJ, Rowe JM. The myth of the second remission of acute leukemia in the adult. Blood. 2013;121:1077–82.

Download references


The main data of this manuscript were previously presented at the 80th Annual Meeting of the Japanese Society of Hematology (October 12–14, 2018, Osaka, Japan). This study was sponsored by Daiichi Sankyo Co., Ltd. Medical writing and editorial assistance was provided by Dr. Deepali Garg, MBBS, PGDHA, of Cactus Communications and was funded by Daiichi Sankyo Co., Ltd.

Author information

Correspondence to Takeshi Takahashi.

Ethics declarations

Conflict of interest

KU has received honoraria and lecture fees from Novartis and research funding from Fujimoto, Astellas, Otsuka, Sumitomo Dainippon, Kyowa Hakko Kirin, GlaxoSmithKline, Sanofi, Shire, SymBio, Celgene, Daiichi Sankyo, Boehringer Ingelheim, Pfizer, and Janssen, and speakers bureau from Novartis, Ono, Takeda, Chugai, Nippon Shinyaku, Mochida, MSD, Celgene, Sumitomo Dainippon, and Pfizer. MM, SO, and TTg are employees of Daiichi Sankyo. SS was an employee of Daiichi Sankyo at the time of this study. TT, KM, HO, TS, and RI have no conflicts of interest to declare.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Fig. 1 Kaplan–Meier curve for event-free survival (efficacy analysis set). Patients without a documented best response of CRc were excluded from the analyses. CIs were calculated based on the method proposed by Brookmeyer and Crowley. CI, confidence interval; CRc, composite complete remission; EFS, event-free survival (TIFF 695 kb)

Supplementary Fig. 2 Kaplan–Meier curve for leukemia-free survival (efficacy analysis set). The analyses for LFS were conditional on the patients having a documented best response of CRc. Patients without a documented best response of CRc were excluded from the analyses. CIs were calculated based on the method proposed by Brookmeyer and Crowley. CI, confidence interval; CRc, composite complete remission; NE, not evaluated; LFS, leukemia-free survival (TIFF 662 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Takahashi, T., Usuki, K., Matsue, K. et al. Efficacy and safety of quizartinib in Japanese patients with FLT3-ITD positive relapsed or refractory acute myeloid leukemia in an open-label, phase 2 study. Int J Hematol 110, 665–674 (2019) doi:10.1007/s12185-019-02727-6

Download citation


  • Acute myeloid leukemia
  • FLT3 inhibitor
  • FLT3-ITD mutation
  • Quizartinib
  • Relapsed or refractory acute myeloid leukemia