Gilteritinib as a New Option for the Treatment of Relapsed/Refractory Acute Myeloid Leukemias with FLT3 Gene Mutation: A Literature Review and Three Case Reports

AA Shatilova1, IG Budaeva2, IE Prokop’ev2, YuV Mirolyubova1, DV Ryzhkova2, KV Bogdanov1, TS Nikulina2, AV Petrov2, TV Chitanava1, DV Motorin1, EN Tochenaya2, AI Reshetova1, SV Efremova2, EK Antonov1, VV Ivanov1, AV Petukhov1, YuA Alekseeva1, EG Lomaia1, LL Girshova1

1 Center for Personalized Medicine, VA Almazov National Medical Research Center, 2 Akkuratova ul., Saint Petersburg, Russian Federation, 197341

2 VA Almazov National Medical Research Center, 2 Akkuratova ul., Saint Petersburg, Russian Federation, 197341

For correspondence: Aleksina Alekseevna Shatilova, 2 Akkuratova ul., Saint Petersburg, Russian Federation, 197341; Tel.: +7(911)476-35-58; e-mail: alexina-96@list.ru

For citation: Shatilova AA, Budaeva IG, Prokop’ev IE, et al. Gilteritinib as a New Option for the Treatment of Relapsed/Refractory Acute Myeloid Leukemias with FLT3 Gene Mutation: A Literature Review and Three Case Reports. Clinical oncohematology. 2023;16(1):69–79. (In Russ).

DOI: 10.21320/2500-2139-2023-16-1-69-79


ABSTRACT

Acute myeloid leukemias (AML) are the most ubiquitous of all adult leukemias. The prognosis of the disease depends on its genetic profile. The mutation in FLT3 gene, which codes FMS-like tyrosine kinase 3, is observed in 1/3 of patients and is responsible for a high rate of relapses. The prognosis of relapsed/refractory FLT3-positive AML is extremely poor. The standard intensive therapy rarely yields long-term responses. The new first- and second-generation FLT3 tyrosine kinase inhibitors enriched treatment opportunities for patients with this mutation. Gilteritinib, a potent second-generation FLT3-ITD/TKD inhibitor, is a new effective and well tolerated drug for the treatment of relapsed/refractory FLT3-positive AML. Due to its efficacy, low toxicity, and good manageability, this drug can be administered to all patients, including the elderly or those with severe comorbidities and complications of previous therapy. Besides, this drug can be used in outpatient units. The present paper contains three case reports dealing with different clinical situations in patients with FLT3-positive AML treated with gilteritinib in real-world clinical practice.

Keywords: acute myeloid leukemias, FLT3, gilteritinib.

Received: September 16, 2022

Accepted: December 12, 2022

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REFERENCES

  1. Shallis RM, Wang R, Davidoff A, et al. Epidemiology of acute myeloid leukemia: Recent progress and enduring challenges. Blood Rev. 2019;36:70–87. doi: 10.1016/j.blre.2019.04.005.
  2. American Cancer Society. Key Statistics for Acute Myeloid Leukemia (AML). Available from: https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html. (accessed 30.09.2022).
  3. Loowenberg B, Rowe JM. Introduction to the review series on advances in acute myeloid leukemia (AML). Blood. 2016;127(1):1. doi: 10.1182/blood-2015-10-662684.
  4. Fathi AT, Chen YB. The role of FLT3 inhibitors in the treatment of FLT3-mutated acute myeloid leukemia. Eur J Haematol. 2017;98(4):330–6. doi: 10.1111/ejh.12841.
  5. Kazi JU, Ronnstrand L. FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications. Physiol Rev. 2019;99(3):1433–66. doi: 10.1152/physrev.00029.2018.
  6. Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the FLT3 gene found in acute myeloid leukemia. Leukemia. 1996;10(12):1911–8.
  7. Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079–89. doi: 10.1056/NEJMoa1112304.
  8. Yanada M, Matsuo K, Suzuki T, et al. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 2005;19(8):1345–9. doi: 10.1038/sj.leu.2403838.
  9. Gale RE, Green C, Allen C, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood. 2008;111(5):2776–84. doi: 10.1182/blood-2007-08-109090.
  10. Choi EJ, Lee JH, Lee JH, et al. Comparison of anthracyclines used for induction chemotherapy in patients with FLT3-ITD-mutated acute myeloid leukemia. Leuk Res. 2018;68:51–6. doi: 10.1016/j.leukres.2018.03.006.
  11. Brunet S, Labopin M, Esteve J, et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol. 2012;30(7):735–41. doi: 10.1200/JCO.2011.36.9868.
  12. Chew S, Mackey MC, Jabbour E. Gilteritinib in the treatment of relapsed and refractory acute myeloid leukemia with a FLT3 mutation. Ther Adv Hematol. 2020;11:2040620720930614. doi: 10.1177/2040620720930614.
  13. Kennedy VE, Smith CC. FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies. Front Oncol. 2020;10:612880. doi: 10.3389/fonc.2020.612880.
  14. Short NJ, Kantarjian H, Ravandi F, Daver N. Emerging treatment paradigms with FLT3 inhibitors in acute myeloid leukemia. Ther Adv Hematol. 2019;10:2040620719827310. doi: 10.1177/2040620719827310.
  15. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017;377(5):454–64. doi: 10.1056/NEJMoa1614359.
  16. Ueno Y, Kaneko N, Saito R, et al. ASP2215, a novel FLT3/AXL inhibitor: Preclinical evaluation in combination with cytarabine and anthracycline in acute myeloid leukemia (AML). J Clin Oncol. 2014;32(15_suppl):7070. doi: 10.1200/jco.2014.32.15_suppl.7070.
  17. NCCN Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia. Version 2.2022. Available from: https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. (accessed 20.06.2022).
  18. Ксоспата® (инструкция по медицинскому применению). Доступно по: https://grls.rosminzdrav.ru/InstrImg/2021/11/24/1475865/fab432db-24de-4e64–89bb-170602489d9f.pdf. Ссылка активна на 30.09.2022.
    [Xospata® (package insert). Available from: https://grls.rosminzdrav.ru/InstrImg/2021/11/24/1475865/fab432db-24de-4e64–89bb-170602489d9f.pdf. Accessed 30.09.2022. (In Russ)]
  19. Pulte ED, Norsworthy KJ, Wang Y, et al. FDA approval summary: gilteritinib for relapsed or refractory acute myeloid leukemia with a FLT3 mutation. Clin Cancer Res. 2021;27(13):3515–21. doi: 10.1158/1078-0432.CCR-20-4271.
  20. Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1–2 study. Lancet Oncol. 2017;18(8):1061–75. doi: 10.1016/S1470-2045(17)30416-3.
  21. Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1–2 study. Lancet Oncol. 2017;18(12):e711 [published correction]. Lancet Oncol. 2018;19(7):e335 [published correction]. Lancet Oncol. 2019;20(6):e293 [published correction].
  22. Perl AE, Hosono N, Montesinos P, et al. Clinical outcomes in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib. Blood Cancer J. 2022;12(5):84. doi: 10.1038/s41408-022-00677-7.
  23. Tzogani K, Roshol H, Olsen HH, et al. The European Medicines Agency Review of Gilteritinib (Xospata) for the Treatment of Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with an FLT3 Mutation. Oncologist. 2020;25(7):e1070–e1076. doi: 10.1634/theoncologist.2019-0976.
  24. Wilson AJ, O’nions J, Subhan M. Successful remission induction therapy with gilteritinib in a patient with de novo FLT3-mutated acute myeloid leukaemia and severe COVID-19. Br J Haematol. 2020;190(4):e189–e191. doi: 10.1111/bjh.16962.
  25. Bocchia M, Carella AM, Mule A, et al. Therapeutic Management of Patients with FLT3 + Acute Myeloid Leukemia: Case Reports and Focus on Gilteritinib Monotherapy. Pharmgenomics Pers Med. 2022;15:393–407. doi: 10.2147/PGPM.S346688.
  26. Gilteritinib Plus Azacitidine Combination Shows Promise in Newly Diagnosed FLT3-Mutated AML. 2021;26(Suppl 1):S10. doi: 10.1002/onco.13652.
  27. Wang ES, Montesinos P, Minden MD, et al. Phase 3 Trial of Gilteritinib Plus Azacitidine Vs Azacitidine for Newly Diagnosed FLT3mut+ AML Ineligible for Intensive Chemotherapy. Blood. 2022;27;140(17):1845–57. doi: 10.1182/blood.2021014586.
  28. Short NJ, DiNardo CD, Daver N, et al. A Triplet Combination of Azacitidine, Venetoclax and Gilteritinib for Patients with FLT3-Mutated Acute Myeloid Leukemia: Results from a Phase I/II Study. Blood; 2021:138(Suppl 1):696. doi: 10.1182/blood-2021-153571.