ISSN (print) 1997-6933     ISSN (online) 2500-2139
Vol. 15 No. 2 (2022), MYELOID TUMORS
Vol. 15 No. 2 (2022)
MYELOID TUMORS

Efficacy and Safety of Midostaurin Combined with Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia with FLT3 Mutation

Published 01.04.2022
Sergei Nikolaevich Bondarenko
RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022
A.G. Smirnova
RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022
B.I. Ayubova
RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022
E.V. Karyagina
Municipal Hospital No. 15, 4 Avangardnaya ul., Saint Petersburg, Russian Federation, 198205
O.S. Uspenskaya
Leningrad Regional Clinical Hospital, 45 korp. 2A Lunacharskogo pr-t, Saint Petersburg, Russian Federation, 194291
Yu.S. Neredko
Stavropol Krai Clinical Oncology Dispensary, 182a Oktyabrskaya ul., Stavropol, Russian Federation, 355047
A.P. Kochergina
Krai Clinical Hospital, 1 Lyapidevskogo ul., Barnaul, Russian Federation, 656024
I.A. Samorodova
Municipal Clinical Hospital No. 31, 3 Dinamo pr-t, Saint Petersburg, Russian Federation, 197110
E.A. Pashneva
Volgograd Regional Clinical Oncology Dispensary, 78 Zemlyachki ul., Volgograd, Russian Federation, 400138
Yu.S. Chernykh
MF Vladimirskii Moscow Regional Research Clinical Institute, 61/2 Shchepkina ul., Moscow, Russian Federation, 129110
Yu.A. Dunaev
Arkhangelsk Regional Clinical Hospital, 292 Lomonosova pr-t, Arkhangelsk, Russian Federation, 163045
N.B. Esef’eva
Ulyanovsk Regional Clinical Hospital, 7 III Internatsionala ul., Ulyanovsk, Russian Federation, 432017
R.K. Il’yasov
VM Efetov Crimea Republican Clinical Oncology Dispensary, 49A Bespalova ul., Simferopol, Russian Federation, 295007
T.I. Brazhkina
Ivanovo Regional Clinical Hospital, 1 Lyubimova ul., Ivanovo, Russian Federation, 153040
I.A. Novokreshchenova
RZhD-Meditsina Clinical Hospital, 15 1-i Krasnoflotskii per., Smolensk, Russian Federation, 214025
Z.K. Simavonyan
AI Burnazyan Federal Medical Biophysical Center, 23 Marshala Novikova ul., Moscow, Russian Federation, 123098
E.I. Kuzub
Rostov State Medical University Hospital, 29 Nakhichevanskii per., Rostov-on-Don, Russian Federation, 344022
V.I. Bakhtina
Krasnoyarsk Krai Clinical Hospital, 3A Partizana Zheleznyaka ul., Krasnoyarsk, Russian Federation, 660022
T.I. Olkhovich
Krasnoyarsk Interdistrict Clinical Hospital No. 7, 4 Akademika Pavlova ul., Krasnoyarsk, Russian Federation, 660003
M.V. Burundukova
Municipal Clinical Hospital No. 2, 21 Polzunova ul., Novosibirsk, Russian Federation, 630051
E.V. Babenko
RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022
Yu.D. Oleinikova
RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022
I.M. Barkhatov
RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022
T.L. Gindina
RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022
I.S. Moiseev
RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022
A.D. Kulagin
RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022
PDF_2022-15-2-167-175 (Russian)

Keywords

acute myeloid leukemias
FLT3 mutations
targeted therapy
midostaurin

How to Cite

Bondarenko S.N., Smirnova A.G., Ayubova B.I., Karyagina E.V., Uspenskaya O.S., Neredko Y.S., Kochergina A.P., Samorodova I.A., Pashneva E.A., Chernykh Y.S., Dunaev Y.A., Esef’eva N.B., Il’yasov R.K., Brazhkina T.I., Novokreshchenova I.A., Simavonyan Z.K., Kuzub E.I., Bakhtina V.I., Olkhovich T.I., Burundukova M.V., Babenko E.V., Oleinikova Y.D., Barkhatov I.M., Gindina T.L., Moiseev I.S., Kulagin A.D. Efficacy and Safety of Midostaurin Combined with Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia with FLT3 Mutation. Clinical Oncohematology. 2022;(2):167–175. doi:10.21320/2500-2139-2022-15-2-167-175.
ACM ACS APA ABNT Chicago Harvard IEEE MLA Turabian Vancouver AMA ГОСТ

Download Citation

Endnote/Zotero/Mendeley (RIS) BibTeX

Statistics

Annotation views: 13
PDF_2022-15-2-167-175 (Russian) downloads: 4

Keywords

Abstract

Background. The detection of FLT3-ITD mutation in acute myeloid leukemia (AML) patients is associated with poor prognosis and is an indication for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the first remission. Midostaurin is the first FLT3 inhibitor approved for the treatment of AML patients with FLT3 mutation in the Russian Federation in November 2019. This study deals with the initial experiences of using midostaurin in several centers for hematology in the Russian Federation.

Aim. To analyze the initial experiences of using midostaurin at different AML stages.

Materials & Methods. The study enrolled 42 patients with newly diagnosed AML with FLT3 mutation, who were treated with midostaurin combined with chemotherapy. Allo-HSCT was performed in 11 patients.

Results. The 2-year overall survival (OS) was 51 %, and the 2-year event-free survival (EFS) was 45 %. After achieving remission, the 2-year disease-free survival (DFS) was 58 %. The 1-year DFS of allo-HSCT recipients was 86 % (95% confidence interval [95% CI] 60–100 %) vs. 66 % in patients treated with chemotherapy without allo-HSCT (95% CI 34–98 %), respectively (p = 0.5). Hyperleukocytosis at disease onset was associated with high relapse risk. Midostaurin had to be discontinued in 5 % of cases due to atrial fibrillation and QTc prolongation.

Conclusion. The present study demonstrates the safety and importance of including midostaurin in the regimens for treating AML with FLT3 mutation. Midostaurin assignment for maintenance therapy, after allo-HSCT as well as without performing it, can result in considerable improvement of OS and DFS.

PDF_2022-15-2-167-175 (Russian)

References

  1. Pemmaraju N, Kantarjian H, Ravandi F, Cortes J. FLT3 inhibitors in the treatment of acute myeloid leukemia: the start of an era? 2011;117(15):3293–304. doi: 10.1002/cncr.25908.
  2. Зайкова Е.К., Белоцерковская Е.В., Зайцев Д.В. и др. Молекулярная диагностика мутаций гена FLT3 у пациентов с острыми миелоидными лейкозами. Клиническая онкогематология. 2020;13(2):150–60. doi: 10.21320/2500-2139-2020-13-2-150-160.
  3. [Zaikova EK, Belotserkovskaya EV, Zaytsev DV, et al. Molecular Diagnosis of FLT3 Mutations in Acute Myeloid Leukemia Patients. Clinical oncohematology. 2020;13(2):150–60. doi: 10.21320/2500-2139-2020-13-2-150-160. (In Russ)]
  4. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–21. doi: 10.1056/NEJMoa1516192.
  5. Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3(9):650–65. doi: 10.1038/nrc1169.
  6. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99(12):4326–35. doi: 10.1182/blood.v99.12.4326.
  7. Кузнецова С.А., Зарубина К.И., Паровичникова Е.Н., Судариков А.Б. Определение мутаций FLT3/ITD, NPM1, CEBPA у больных ОМЛ. Гематология и трансфузиология. 2014;59(1):99.
  8. [Kuznetsova SA, Zarubina KI, Parovichnikova EN, Sudarikov AB. Detection of FLT3/ITD, NPM1, CEBPA mutations in AML patients. Gematologiya i transfuziologiya. 2014;59(1):99. (In Russ)]
  9. Whitman SP, Archer KJ, Feng L, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res. 2001;61(19):7233–9.
  10. Frohling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100(13):4372–80. doi: 10.1182/blood-2002-05-1440.
  11. Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909–18. doi: 10.1056/NEJMoa074306.
  12. Раджабова А.М., Волошин С.В., Мартынкевич И.С. и др. Роль мутаций гена FLT3 при острых миелоидных лейкозах: влияние на течение заболевания и результаты терапии. Гены и клетки. 2019;14(1):55–61. doi: 10.23868/201903007.
  13. [Radzhabova AM, Voloshin SV, Martynkevich IS, et al. Role of FLT3 gene mutations in acute myeloid leukemia: effect on course of disease and results of therapy. Geny i kletki. 2019;14(1):55–61. doi: 10.23868/201903007. (In Russ)]
  14. Kayser S, Schlenk RF, Londono MC, et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009;114(12):2386–92. doi: 10.1182/blood-2009-03-209999.
  15. Reindl C, Bagrintseva K, Vempati S, et al. Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML. Blood. 2006;107(9):3700–7. doi: 10.1182/blood-2005-06-2596.
  16. 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.
  17. 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.
  18. Voso MT, Larson RA, Jones D, et al. Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial. Blood Adv. 2020;4(19):4945–54. doi: 10.1182/bloodadvances.2020002904.
  19. Dohner K, Thiede C, Jahn N, et al. Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia. Blood. 2020;135(5):371–80. doi: 10.1182/blood.2019002697.
  20. Schlenk RF, Weber D, Fiedler W, et al. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood. 2019;133(8):840–51. doi: 10.1182/blood-2018-08-869453.
  21. Roboz GJ, Strickland SA, Litzow MR, et al. Updated safety of midostaurin plus chemotherapy in newly diagnosed FLT3 mutation-positive acute myeloid leukemia: the RADIUS-X expanded access program. Leuk Lymphoma. 2020;61(13):3146–53. doi: 10.1080/10428194.2020.1805109.
  22. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47. doi: 10.1182/blood-2016-08-733196.
Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Copyright (c) 2022 Clinical Oncohematology