Letter to the Editor

Ann Lab Med 2023; 43(4): 386-388

Published online July 1, 2023

Copyright © Korean Society for Laboratory Medicine.

Emergence of BCR-ABL1 (p190) in Acute Myeloid Leukemia Post-Gilteritinib Therapy

Heejeong Kim, M.D.1 , In-suk Kim, M.D., Ph.D.2 , and Hyerim Kim, M.D., Ph.D.1

1Department of Laboratory Medicine, Pusan National University School of Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan, Korea; 2Department of Laboratory Medicine, Pusan National University School of Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea

Correspondence to: Hyerim Kim, M.D., Ph.D.
Department of Laboratory Medicine, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan 49241, Korea
Tel: +82-51-240-7418, Fax: +82-51-247-6560

Received: September 18, 2022; Revised: November 25, 2022; Accepted: December 29, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Dear Editor,

AML is an aggressive clonal disease of hematopoietic stem cells. FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutation is reported in 22.2% of AML patients and is associated with early relapse and poor overall survival [1]. To improve the patient outcome of FLT3-mutated AML, numerous kinase inhibitors targeting FLT3 have been evaluated [2]. Although targeted drugs have improved the survival rate of patients with FLT3-mutated AML [3], additional mutations driving resistance have emerged, resulting in short response and survival durations [2, 4, 5]. The activation-loop or gatekeeper residues of FLT3 may be affected by these emergent mutations, although the acquisition of clones with additional mutations has been suggested as a cause of resistance in targeted therapy [6].

We describe the first case of FLT3-mutated AML with BCR-ABL1 fusion following a clinical trial with gilteritinib (ASP2215) and re-induction chemotherapy in Korea (2212-016-122). In October 2016, a 64-year-old male patient was admitted to Pusan National University Hospital, Busan, Korea, for general fatigue. The initial lab findings indicated 177×109/L white blood cell count, 143 g/L Hb, and 37×109/L platelet count. A peripheral blood smear and bone marrow (BM) aspirate showed blastic leukocytosis (blasts comprising 91% and 81%, respectively). Leukemic blasts were positive for myeloperoxidase, dimCD34, CD13, CD33, CD11c, CD14, and CD64. All detectable fusion transcripts using a commercial multiplex reverse transcription (RT-)PCR kit (HemaVision, DNA Diagnostic, Risskov, Denmark) were negative, and chromosomal analysis confirmed a normal karyotype. The FLT3-ITD mutation was detected, whereas nucleophosmin 1 (NPM1) and CCAAT/enhancer-binding protein alpha (CEBPA) mutations were not. Since AML with FLT3 mutation is not recognized as a separate entity in the 2016 WHO classification of myeloid neoplasms, the patient was diagnosed with AML, not otherwise specified, with myelomonocytic leukemia [7].

Initially, the patient received standard induction chemotherapy. At the 28th day of induction, BM aspirate/biopsy showed 10% BM blasts. Therefore, he was enrolled in a novel FLT3-inhibitor clinical study (ASP2215) and received re-induction chemotherapy. After three cycles of targeted therapy (at four months), BM aspirate/biopsy revealed hypercellularity, with ~80% blasts (Fig. 1). Cytogenetic findings demonstrated that all 20 metaphases showed positive BCR-ABL1 fusion transcripts. Philadelphia chromosome, t(9;22)(q34;q11), resulting in a BCR-ABL1 fusion gene, was validated by FISH (287/300) on a biopsy touch slide and by RT-PCR for BCR-ABL1 minor, detecting the p190 isoform (e1a2 BCR-ABL1). Therefore, a second round of re-induction chemotherapy with high-dose cytarabine and mitoxantrone was administered. Initial leukemic monoblasts (58%) reappeared on the 21st day of re-induction treatment and showed decreased positivity for minor BCR-ABL1 (one among 70 metaphases). However, after one month of re-induction therapy, BM aspirate/biopsy revealed significant proliferation of leukemic blasts (90%), prompting the decision for allogeneic stem cell transplantation (alloSCT). Unfortunately, the patient died because of an infectious complication two months after receiving the alloSCT.

Figure 1. Laboratory findings at the time of evaluation and therapy. Chromosomal testing and BME findings are indicated by red arrows. Dates are presented in the YY/MM/DD format.
*FLT3-ITD AR was calculated as the ratio of the area under the curve of mutation to wild-type alleles by fragment analysis.
Abbreviations: FLT3-ITD, FMS-like tyrosine kinase-3 internal tandem duplication; AR, allelic ratio; BM, bone marrow; BME, bone marrow examination; MTZ/AraC, mitoxantrone and cytarabine; AlloSCT, allogenic stem cell transplant.

The FLT3 inhibitor monotherapy has an insufficient effect and frequently leads to the development of drug resistance. Although it remains unclear which signaling confers resistance and whether downstream pathways are induced in refractory patients following targeted therapy, the acquisition of clones with additional mutations has been suggested as a potential resistance mechanism in targeted therapy.

In a study on 41 patients treated with gilteritinib, new mutations were found when the disease progressed [4]. The mutations associated with clinical resistance were NRAS, KRAS, and other MAPK (mitogen-activated protein kinase) pathway-activating mutations, including rare BCR-ABL1 fusions. Resistant cases of relapsed or refractory disease treated with gilteritinib have been rarely shown to harbor mutations driving the BCR-ABL1 fusion [4, 8]. To our knowledge, this is the first case of FLT3-mutated AML with a de novo Philadelphia chromosome and a minor BCR-ABL1 clone (p190 isotype) reported in Korea. At the time of initial diagnosis, next-generation sequencing for hematologic malignancies was not performed. Therefore, it is impossible to rule out that FLT3 inhibitor resistance may have developed via mechanisms other than BCR-ABL1 rearrangement.

In the current clinical case, a mutation that could cause treatment resistance during or after targeted therapy showed how gilteritinib monotherapy is limited [9]. Since resistance and relapse remain major concerns for long-term survival in FLT3-mutated AML patients who are treated with FLT3 inhibitors, molecular target therapy may require extensive monitoring and follow-up, including mutation analysis. This can improve treatment effectiveness by permitting the use of additional targeted medicines. When a patient with AML who was treated with FLT3 inhibitor therapy has a relapse with the BCR-ABL1 fusion, treatment with effective BCR-ABL1-targeted drugs may be helpful.

Kim HR collected the data and was involved in draft preparation and manuscript revision. Kim HJ was involved in draft preparation. Kim IS designed the study and reviewed the literature. All authors read the final manuscript and approved its submission.

This work was supported by a clinical research grant from Pusan National University Hospital in 2022.

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