French Retrospective Database Analysis of Patient Characteristics and Treatment Patterns in Patients with R/R FLT3-Mutated AML: A Registry-Based Cohort Study

Overview

Journal Oncol Ther

Specialty Oncology

Date 2023 Aug 14

PMID 37578642

Authors

Andy Garnham

Franck Bruon

Celine Berthon

Delphine Lebon

Mounika Parimi

Rosalind Polya

Kahina M Makhloufi

Marie-Helene Dramard-Goasdoue

Affiliations

Soon will be listed here.

Abstract

Introduction: There is a dearth of evidence to document treatment of FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML) in real-world settings before the introduction of FLT3 inhibitors. A retrospective cohort study was conducted to understand treatment practices prior to the availability of FLT3 inhibitors in patients with FLT3-mutated AML from two registries in France.

Methods: Patient data from January 1, 2009 to December 31, 2017 were collected from the Hauts-de-France and Midi-Pyrénées registries. Patients aged ≥ 18 years at diagnosis with FLT3-mutated AML were included. Demographic and disease characteristics of patients with FLT3-mutated AML and relapsed or refractory (R/R) FLT3-mutated AML were documented. Treatment regimens, overall survival (OS), and event-free survival were assessed in patients with R/R FLT3-mutated AML who did not participate in clinical trials.

Results: Overall, 819 and 1244 adult patients with AML from the Midi-Pyrénées and Hauts-de-France cohorts, respectively, underwent FLT3 mutation testing; 172 (21.0%) and 263 (21.1%) patients, respectively, had a FLT3 mutation. Primary R/R status was identified in 41.3% (n = 71/172) of the Midi-Pyrénées and 34.6% (n = 91/263) of the Hauts-de-France cohorts. Before R/R AML diagnosis, 82.0% and 97.5% of patients in the Midi-Pyrénées and Hauts-de-France cohorts, respectively, achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi) following induction chemotherapy; after diagnosis of R/R AML, CR/CRi rates with salvage therapy were 33.3% and 28.1%, respectively. Median OS (interquartile range) in patients receiving salvage therapy (n = 49, n = 78) was 5.2 (2.3-11.1) and 6.1 (2.5-35.2) months, in the Midi-Pyrénées and Hauts-de-France cohorts, respectively. Across both cohorts, patients with R/R FLT3-mutated AML had low rates of CR/CRi with salvage therapy and a median OS of approximately 6 months.

Conclusion: Before FLT3 inhibitor availability, real-world treatment patterns and outcomes in French patients with R/R FLT3-mutated AML were consistent with clinical trial data, highlighting a poor prognosis and unmet need for effective treatment.

References

Daver N, Schlenk R, Russell N, Levis M . Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019; 33(2):299-312. PMC: 6365380. DOI: 10.1038/s41375-018-0357-9. View

Kottaridis P, Gale R, Frew M, Harrison G, Langabeer S, BELTON A . 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.... Blood. 2001; 98(6):1752-9. DOI: 10.1182/blood.v98.6.1752. View

Short N, Rytting M, Cortes J . Acute myeloid leukaemia. Lancet. 2018; 392(10147):593-606. PMC: 10230947. DOI: 10.1016/S0140-6736(18)31041-9. View

Ferrara F, Lessi F, Vitagliano O, Birkenghi E, Rossi G . Current Therapeutic Results and Treatment Options for Older Patients with Relapsed Acute Myeloid Leukemia. Cancers (Basel). 2019; 11(2). PMC: 6406399. DOI: 10.3390/cancers11020224. View

Levis M . Midostaurin approved for FLT3-mutated AML. Blood. 2017; 129(26):3403-3406. DOI: 10.1182/blood-2017-05-782292. View

Frohling S, Scholl C, Levine R, Loriaux M, Boggon T, Bernard O . Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles. Cancer Cell. 2007; 12(6):501-13. DOI: 10.1016/j.ccr.2007.11.005. View

Zarrinkar P, Gunawardane R, Cramer M, Gardner M, Brigham D, Belli B . AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009; 114(14):2984-92. PMC: 2756206. DOI: 10.1182/blood-2009-05-222034. View

Dohner H, Weisdorf D, Bloomfield C . Acute Myeloid Leukemia. N Engl J Med. 2015; 373(12):1136-52. DOI: 10.1056/NEJMra1406184. View

Mori M, Kaneko N, Ueno Y, Yamada M, Tanaka R, Saito R . Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Invest New Drugs. 2017; 35(5):556-565. PMC: 5613053. DOI: 10.1007/s10637-017-0470-z. View

10.

Short N, Kantarjian H, Ravandi F, Daver N . Emerging treatment paradigms with FLT3 inhibitors in acute myeloid leukemia. Ther Adv Hematol. 2019; 10:2040620719827310. PMC: 6378516. DOI: 10.1177/2040620719827310. View

11.

Perl A, Martinelli G, Cortes J, Neubauer A, Berman E, Paolini S . Gilteritinib or Chemotherapy for Relapsed or Refractory -Mutated AML. N Engl J Med. 2019; 381(18):1728-1740. DOI: 10.1056/NEJMoa1902688. View

12.

Roboz G, Rosenblat T, Arellano M, Gobbi M, Altman J, Montesinos P . International randomized phase III study of elacytarabine versus investigator choice in patients with relapsed/refractory acute myeloid leukemia. J Clin Oncol. 2014; 32(18):1919-26. DOI: 10.1200/JCO.2013.52.8562. View

13.

Megias-Vericat J, Martinez-Cuadron D, Sanz M, Montesinos P . Salvage regimens using conventional chemotherapy agents for relapsed/refractory adult AML patients: a systematic literature review. Ann Hematol. 2018; 97(7):1115-1153. DOI: 10.1007/s00277-018-3304-y. View

14.

Bacher U, Haferlach C, Kern W, Haferlach T, Schnittger S . Prognostic relevance of FLT3-TKD mutations in AML: the combination matters--an analysis of 3082 patients. Blood. 2007; 111(5):2527-37. DOI: 10.1182/blood-2007-05-091215. View

15.

Cheson B, Bennett J, Kopecky K, Buchner T, Willman C, Estey E . 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(24):4642-9. DOI: 10.1200/JCO.2003.04.036. View

16.

Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T . 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. View

17.

Cortes J, Khaled S, Martinelli G, Perl A, Ganguly S, Russell N . 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(7):984-997. DOI: 10.1016/S1470-2045(19)30150-0. View

18.

Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum F, Buchner T . Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2016; 129(4):424-447. PMC: 5291965. DOI: 10.1182/blood-2016-08-733196. View

19.

Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U . 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. View

20.

Stone R, Mandrekar S, Sanford B, Laumann K, Geyer S, Bloomfield C . Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017; 377(5):454-464. PMC: 5754190. DOI: 10.1056/NEJMoa1614359. View