GILTERITINIB (XOSPATA ®) IN TURKEY: EARLY ACCESS PROGRAM RESULTS Gilteritinib (XOSPATA ®) in Turkey

Main Article Content

Mehmet Hilmi DOGU
Ali Irfan Emre TEKGUNDUZ
Burak DEVECI
Gulten KORKMAZ
Melda COMERT
Omur Gokmen SEVINDIK
Osman YOKUS
Istemi SERIN

Keywords

Gilteritinib, acute myeloid leukemia, early access, real-life, response, prognosis

Abstract

Background: Gilteritinib (XOSPATA ®, Astellas) is a type I oral FLT3 inhibitor, a tyrosine kinase AXL inhibitor involved in both c-Kit and FMS-like tyrosine kinase 3 (FLT3) resistance. In the phase 3 ADMIRAL trial, gilteritinib was compared with the standard of care in (R/R) acute myeloid leukemia (AML) patients who harbored any FLT3 mutation and showed superior efficacy with regard to response and survival. Objectives: The purpose of this research was to investigate the real-life efficacy and safety of gilteritinib in FLT3-positive R/R AML patients who were treated as a part of an early access program that was held in Turkey starting in April 2020 (NCT03409081). Results: The research included 17 R/R AML patients who had received gilteritinib from a total of 7 centers. The most common adverse events were anemia and hypokalemia (7 patients, 41.2%). Grade 4 thrombocytopenia was observed in only one patient (5.9%), which led to permanent discontinuation of treatment. The overall response rate was 100%. Patients with peripheral edema had a 10.47 (95% CI: 1.64-66.82) times higher risk of death than those without peripheral edema (p<0.05). Conclusion: This research showed that patients with febrile neutropenia and peripheral edema were at a high risk of death when compared to patients without febrile neutropenia and peripheral edema.

Downloads

Download data is not yet available.


Abstract 521
PDF Downloads 584
Suppl. Files Downloads 0
HTML Downloads 151

References

1. Roboz GJ, Rosenblat T, Arellano M, Gobbi M, Altman JK, Montesinos P, O'Connell C, Solomon SR, Pigneux A, Vey N, Hills R, Jacobsen TF, Gianella-Borradori A, Foss Ø, Vetrhusand S, Giles FJ. International randomized phase III study of elacytarabine versus investigator choice in patients with relapsed/refractory acute myeloid leukemia. J Clin Oncol. 2014; 32: 1919-1926.
2. Megías-Vericat JE, Martínez-Cuadrón D, Sanz MÁ, Montesinos P. Salvage regimens us-ing conventional chemotherapy agents for relapsed/refractory adult AML patients: a sys-tematic literature review. Ann Hematol. 2018; 97: 1115-1153.
3. Ravandi F, Ritchie EK, Sayar H, Lancet JE, Craig MD, Vey N, Strickland SA, Schiller GJ, Jabbour E, Erba HP, Pigneux A, Horst HA, Recher C, Klimek VM, Cortes J, Roboz GJ, Odenike O, Thomas X, Havelange V, Maertens J, Derigs HG, Heuser M, Damon L, Powell BL, Gaidano G, Carella AM, Wei A, Hogge D, Craig AR, Fox JA, Ward R, Smith JA, Acton G, Mehta C, Stuart RK, Kantarjian HM. Vosaroxin plus cytarabine versus pla-cebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2015; 16:1025-1036.
4. Döhner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, Ebert BL, Fenaux P, Godley LA, Hasserjian RP, Larson RA, Levine RL, Miyazaki Y, Niederwieser D, Ossenkoppele G, Röllig C, Sierra J, Stein EM, Tallman MS, Tien HF, Wang J, Wierz-bowska A, Löwenberg B. Diagnosis and management of AML in adults: 2022 recommen-dations from an international expert panel on behalf of the ELN. Blood. 2022; 140: 1345-1377.
5. Kelly LM, Yu JC, Boulton CL, Apatira M, Li J, Sullivan CM, Williams I, Amaral SM, Curley DP, Duclos N, Neuberg D, Scarborough RM, Pandey A, Hollenbach S, Abe K, Lokker NA, Gilliland DG, Giese NA. CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell. 2002; 1: 421-432.
6. Hassanein M, Almahayni MH, Ahmed SO, Gaballa S, El Fakih R. FLT3 Inhibitors for Treating Acute Myeloid Leukemia. Clin Lymphoma Myeloma Leuk. 2016; 16: 543-549.
7. Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, Fox E, Ehninger G, Feldman EJ, Schiller GJ, Klimek VM, Nimer SD, Gilliland DG, Dutreix C, Huntsman-Labed A, Virkus J, Giles FJ. Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol. 2010; 28: 4339-4345.
8. Cortes J, Perl AE, Döhner H, Kantarjian H, Martinelli G, Kovacsovics T, Rousselot P, Steffen B, Dombret H, Estey E, Strickland S, Altman JK, Baldus CD, Burnett A, Krämer A, Russell N, Shah NP, Smith CC, Wang ES, Ifrah N, Gammon G, Trone D, Lazzaretto D, Levis M. 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.
9. Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Döhner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Döhner H. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017; 377: 454-464.
10. Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ. Quizar-tinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leu-kaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019; 20: 984-997.
11. Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019; 381: 1728-1740.
12. Lee LY, Hernandez D, Rajkhowa T, Smith SC, Raman JR, Nguyen B, Small D, Levis M. Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood. 2017; 129: 257-260.
13. Mori M, Kaneko N, Ueno Y, Yamada M, Tanaka R, Saito R, Shimada I, Mori K, Kuro-mitsu S. Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Invest New Drugs. 2017; 35: 556-565.
14. Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, Claxton D, Erba HP, Gill S, Goldberg S, Jurcic JG, Larson RA, Liu C, Ritchie E, Schiller G, Spira AI, Strickland SA, Tibes R, Ustun C, Wang ES, Stuart R, Röllig C, Neubauer A, Martinelli G, Bahceci E, Levis M. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute mye-loid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017; 18: 1061-1075.
15. Norman G. Likert scales, levels of measurement and the "laws" of statistics. Adv Health Sci Educ Theory Pract. 2010; 15: 625-632.
16. McMahon CM, Canaani J, Rea B, Sargent RL, Qualtieri JN, Watt CD, Morrissette JJD, Carroll M, Perl AE. Gilteritinib induces differentiation in relapsed and refractory FLT3-mutated acute myeloid leukemia. Blood Adv. 2019; 3: 1581-1585.
17. Kondo T, Onozawa M, Fujisawa S, Harada S, Ogasawara R, Izumiyama K, Saito M, Mo-rioka M, Mori A, Teshima T. Myelomonocytic differentiation of leukemic blasts accom-panied by differentiation syndrome in a case of FLT3-ITD-positive AML treated with gilteritinib. Hematology. 2021; 26: 256-260.
18. Sexauer A, Perl A, Yang X, Borowitz M, Gocke C, Rajkhowa T, Thiede C, Frattini M, Nybakken GE, Pratz K, Karp J, Smith BD, Levis M. Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITD AML. Blood. 2012; 120: 4205-4214.
19. Nybakken GE, Canaani J, Roy D, Morrissette JD, Watt CD, Shah NP, Smith CC, Bagg A, Carroll M, Perl AE. Quizartinib elicits differential responses that correlate with karyotype and genotype of the leukemic clone. Leukemia. 2016; 30: 1422-1425.
20. Kim L, Fowler B, Campbell CM, Slivnick J, Nawaz H, Kaka Y, Ruz P, Vallakati A, Bali-ga R, Vasu S, Addison D. Acute cardiotoxicity after initiation of the novel tyrosine kinase inhibitor gilteritinib for acute myeloid leukemia. Cardiooncology. 2021; 7: 36.