Clinical and molecular response of AML harboring non-canonical FLT3 N676K driver mutations to contemporary FLT3 inhibitors

Abstract

The treatment of acute myeloid leukemia (AML) has been enhanced by the development and regulatory approval of a series of novel agents, including midostaurin and gilteritinib (FLT3 inhibitors), venetoclax (BCL2 inhibitor), ivosidenib (IDH1 inhibitor), and enasidenib (IDH2 inhibitor). A difficulty that has arisen in the era of molecular therapies, however, is determining the efficacy of these agents for patients with AML harboring atypical driver mutations. The non-canonical FLT3 p.N676K variant was initially described as an acquired resistance mechanism in patients with FLT3 internal tandem duplication (ITD) mutations who were treated with midostaurin. Clinical data from patients with the FLT3 N676K mutations are limited. Here, we detail our experience caring for nine different patients with AML harboring FLT3 N676K at the University of Chicago. Seven of nine (78%) individuals received intensive induction chemotherapy, with FLT3 inhibitors utilized in three patients upfront and five patients during subsequent lines of treatment. With the use of FLT3 inhibitors, we noted reduction, and in some instances, complete molecular suppression of detectable FLT3 N676K variant allele fraction (VAF) on NGS, underscoring the activity of FLT3 inhibitors in this population regardless of line of therapy. Individuals with FLT3 N676K-mutated AML who received FLT3 inhibitors had longer median survival (940 days) than those who did not (408 days), however, the difference was not significant likely due to small size of the study (p = 0.2). The presence of concurrent canonical FLT3 mutations was associated with loss of treatment response. In silico visualization models of the FLT3 tyrosine kinase domain in the presence of gilteritinib demonstrate that the mechanism of N676K-mediated resistance is not due to disruption of FLT3 inhibitor binding at the ATP-binding site but rather influenced by other allosteric forces on protein structure. In conclusion, this is the largest study to date demonstrating that the atypical FLT3 N676K driver mutation is sensitive to contemporary FLT3 inhibitors, such as midostaurin and gilteritinib. Our data suggest that FLT3 inhibitors should be included in both the upfront induction setting as well as in the relapsed/refractory setting for patients harboring the FLT3 N676K mutation.

Competing Interest Statement

ASA has acted as a consultant for AbbVie and Magenta Therapeutics. WS has acted as a consultant or advisor to Adaptive Biotechnologies, Jazz Pharmaceuticals, Agios, Kite, a Gilead company, Kura Oncology, GlaxoSmithKline, MorphoSys, Pfizer, Servier, has received honoraria from AbbVie, has received royalties for a chapter in UpToDate, and has received travel accommodation from Pfizer. OO has acted as a consultant for Abbvie, Impact Biomedicines, Celgene, Novartis, BMS, Taiho Pharmaceutical, CTI, Threadwell therapeutics, Bristol-Myers Squibb/Celgene, and has received research support to her institution from Celgene, Uncyte, Astex Pharmaceuticals, NS Pharma, AbbVie, Janssen Oncology, OncoTherapy Science, Agios, AstraZeneca, CTI BioPharma Corp, Kartos Therapeutics and Aprea AB. RAL has acted as a consultant or advisor to Ariad/Takeda, Celgene/BMS, CVS/Caremark, Epizyme, Immunogen, Novartis, and Servier, and has received clinical research support to his institution from Astellas, Cellectis, Daiichi Sankyo, Forty Seven/Gilead, Novartis, and Rafael Pharmaceuticals, and royalties from UpToDate. HL has acted as a consultant or advisor to Agios, Pfizer, Nkarta, CTI Biopharm, Servier, NGM Biopharma, has acted as a speaker/lecturer for SITC, CAHON, Academy for Continued Healthcare Learning, and has received research support from Miltenyi Biotec. LAG has received royalties from UptoDate, Inc. for a co-authored article on germline predisposition to hematopoietic malignancies. MJT reports grant support from AbbVie, Merck, Syndax, and TG Therapeutics and has received personal fees from AbbVie, Adaptive Biotechnologies, AstraZeneca, Celgene, Pharmacyclics, and Genentech. ASD has acted as a consultant or advisor to Jazz Pharmaceuticals and has served on a speakers bureau for Jazz Pharmaceuticals. AAP has received honoraria from AbbVie and research funding from Celgene/BMS, Pfizer and Kronos Bio. CKD has received consulting/advisory fees from Daiichi Sankyo and Sun Pharma. ASD has received fees for consulting and serving as a member of a speakers bureau for Jazz Pharmaceuticals. ED has received honoraria from AbbVie. GDW has received honoraria and has served on an advisory board for Diagnostica Stago. The remaining authors declare no relevant competing interests.

Funding Statement

This study did not receive any funding

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

University of Chicago IRB

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Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

All data produced in the present study are available upon reasonable request to the authors

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