Gilteritinib Affects the Selection of Dominant Clones in Clonal Hematopoiesis: Sequential Genetic Analysis of an FLT3-ITD Positive AML Patient with Long-Term Gilteritinib Therapy

Abstract

We performed sequential molecular analyses of a 75-year-old woman with de novo FLT3-ITD positive acute myeloid leukemia (AML) who had received gilteritinib therapy for 43 months. At the time of diagnosis, her karyotype was normal; however, FLT3-ITD, NPM1, DNMT3A, and IDH2 mutations were detected. She received induction therapy with daunorubicin and cytarabine and achieved hematological complete remission (HCR). After attaining HCR, she underwent consolidation therapy with azacytidine or cytarabine, aclarubicin, and granulocyte-colony stimulating factor. However, AML relapsed eight months after the first HCR. FLT3-ITD and NPM1 mutations were persistently positive, and the patient received gilteritinib therapy. Although the FLT3-ITD clone was not detected during gilteritinib treatment, a clone harboring monosomy 7 and CBL mutations emerged. Bone marrow examinations at 15, 24, and 32 months after gilteritinib treatment revealed multi-lineage blood cell dysplasia without an increase in myeloblasts. After 33 months of treatment, gilteritinib was discontinued for two months because to ileus development, and the FLT3-ITD clone was detected again. Gilteritinib treatment was restarted, and FLT3-ITD became negative. Our analysis demonstrated that: (1) hematopoiesis derived from gilteritinib-resistant clones was generated by long-term gilteritinib treatment, and (2) FLT3-ITD clones regained clonal dominance in the absence of FLT3 inhibition. These findings suggest that gilteritinib affects the selection of dominant clones during clonal hematopoiesis.

Keywords:

• gilteritinib
• FLT3-ITD
• CBL
• monosomy 7
• clonal hematopoiesis

Consent to Participate

The patient’s daughter provided informed consent to publish the patient’s case details and any accompanying images.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Akihiko Gotoh reports grants, personal fees from Eisai, grants, personal fees from Ono Pharmaceutical, grants, personal fees from Taiho Pharmaceutical, grants, personal fees from Takeda Pharmaceutical, grants, personal fees from Nippon Shinyaku, grants, personal fees from Chugai Pharmaceutical, grants from MSD, grants, personal fees from Otsuka Pharmaceutical, grants, personal fees from Sumitomo Pharma, grants from Bayer, grants, personal fees from Daiichi Sankyo, grants, personal fees from Nihon Pharmaceutical, personal fees from Novartis Pharma, personal fees from Alexion Pharmaceuticals, personal fees from Kyowa Kirin, personal fees from Janssen, personal fees from Pfizer Japan, personal fees from Sanofi, personal fees from PharmaEssentia Japan, outside the submitted work. Yosuke Minami received research funding from Ono, and Honoraria from Bristol-Myers Squibb, Novartis, and Pfizer. Yuka Harada reports grants from JSPS KAKENHI Grant, grants from Clinical Research Fund of Tokyo Metropolitan Government, during the conduct of the study. Part of the NGS assay was supported by a National Cancer Research and Development Expenses Grant. The authors report no other conflicts of interest in this work.