Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I Versus Type II FLT3 Inhibitors

Overview

Journal Blood Cancer Discov

Specialties Hematology
Oncology

Date 2021 Mar 8

PMID 33681815

Citations 45

Authors

Ahmad S Alotaibi

Musa Yilmaz

Rashmi Kanagal-Shamanna

Sanam Loghavi

Tapan M Kadia

Courtney D DiNardo

Gautam Borthakur

Marina Konopleva

Sherry A Pierce

Sa A Wang

Guilin Tang

Veronica Guerra

Bachar Samra

Naveen Pemmaraju

Elias Jabbour

Nicholas J Short

Ghayas C Issa

Maro Ohanian

Guillermo Garcia-Manero

Kapil N Bhalla

Keyur P Patel

Koichi Takahashi

Michael Andreeff

Jorge E Cortes

Hagop M Kantarjian

Farhad Ravandi

Naval Daver

Affiliations

Soon will be listed here.

Abstract

Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with -mutated AML treated with FLT3i-based therapies (secondary resistance cohort), and pretreatment bone marrow samples from patients with no response to FLT3i-based therapies (primary resistance cohort). Targeted next generation sequencing at relapse identified emergent mutations involving on-target , epigenetic modifiers, pathway, and less frequently , and . and D835 mutations emerged most commonly following type I and type II FLT3i-based therapies, respectively. Patients with emergent mutations at relapse had inferior overall survival compared with those without emergent mutations. Among pretreatment mutated patients, pretreatment cohort level variant allelic frequencies for were higher in non-responders, particularly with type I FLT3i-based therapies, suggesting a potential role in primary resistance as well. These data demonstrate distinct pathways of resistance in -mutated AML treated with type I versus II FLT3i.

Citing Articles

Precision Medicine in Myeloid Neoplasia: Challenges and Opportunities.

Hochman M, Muniz J, Papadantonakis N J Pers Med. 2025; 15(2).

PMID: 39997326 PMC: 11856194. DOI: 10.3390/jpm15020049.

Advances and Challenges in Quizartinib-Based FLT3 Inhibition for Acute Myeloid Leukemia: Mechanisms of Resistance and Prospective Combination Therapies.

Bruzzese A, Martino E, Labanca C, Mendicino F, Lucia E, Olivito V Eur J Haematol. 2025; 114(4):584-595.

PMID: 39763167 PMC: 11880963. DOI: 10.1111/ejh.14383.

Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia.

Sonowal H, Rice W, Bejar R, Bejar R, Byun J, Jung S Cancer Res Commun. 2024; 5(1):74-83.

PMID: 39665627 PMC: 11725774. DOI: 10.1158/2767-9764.CRC-24-0258.

Acute myeloid leukemia management and research in 2025.

Kantarjian H, DiNardo C, Kadia T, Daver N, Altman J, Stein E CA Cancer J Clin. 2024; 75(1):46-67.

PMID: 39656142 PMC: 11745214. DOI: 10.3322/caac.21873.

A Combinatorial Functional Precision Medicine Platform for Rapid Therapeutic Response Prediction in AML.

Sahib N, Mohamed J, Rashid M, Jayalakshmi , Lin Y, Chee Y Cancer Med. 2024; 13(22):e70401.

PMID: 39560206 PMC: 11574777. DOI: 10.1002/cam4.70401.

References

Perl A, Altman J, Cortes J, Smith C, Litzow M, Baer M . 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):1061-1075. PMC: 5572576. DOI: 10.1016/S1470-2045(17)30416-3. View

Daver N, Cortes J, Ravandi F, Patel K, Burger J, Konopleva M . Secondary mutations as mediators of resistance to targeted therapy in leukemia. Blood. 2015; 125(21):3236-45. PMC: 4440880. DOI: 10.1182/blood-2014-10-605808. View

Smith C, Paguirigan A, Jeschke G, Lin K, Massi E, Tarver T . Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis. Blood. 2017; 130(1):48-58. PMC: 5501146. DOI: 10.1182/blood-2016-04-711820. View

Warren M, Luthra R, Yin C, Ravandi F, Cortes J, Kantarjian H . Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients. Mod Pathol. 2012; 25(10):1405-12. DOI: 10.1038/modpathol.2012.88. View

Smith C, Wang Q, Chin C, Salerno S, Damon L, Levis M . Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature. 2012; 485(7397):260-3. PMC: 3390926. DOI: 10.1038/nature11016. View

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

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

Cortes J, Perl A, Dohner H, Kantarjian H, Martinelli G, Kovacsovics T . 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(7):889-903. PMC: 8152787. DOI: 10.1016/S1470-2045(18)30240-7. View

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

10.

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

11.

McMahon C, Ferng T, Canaani J, Wang E, Morrissette J, Eastburn D . Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia. Cancer Discov. 2019; 9(8):1050-1063. DOI: 10.1158/2159-8290.CD-18-1453. View

12.

Luthra R, Patel K, Reddy N, Haghshenas V, Routbort M, Harmon M . Next-generation sequencing-based multigene mutational screening for acute myeloid leukemia using MiSeq: applicability for diagnostics and disease monitoring. Haematologica. 2013; 99(3):465-73. PMC: 3943309. DOI: 10.3324/haematol.2013.093765. View

13.

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

14.

Swords R, Freeman C, Giles F . Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia. Leukemia. 2012; 26(10):2176-85. DOI: 10.1038/leu.2012.114. View