Emergence of BCR–ABL1 Fusion in AML Post–FLT3 Inhibitor-Based Therapy: A Potentially Targetable Mechanism of Resistance – A Case Series

Despite the promising result with FLT3 inhibitors in AML, the emergence of resistance poses a significant challenge, leading to a shorter response duration and inferior survival. This is frequently driven by on-target or parallel prosurvival mutations. The emergence of BCR–ABL1 as a mechanism of possible clonal evolution in relapsed AML has rarely been reported. Here we report our experience with three patients who had emergent BCR–ABL1 fusion at relapse after FLT3 inhibitors–based therapies. The first patient was refractory to multiple lines of therapies, including FLT3 inhibitors–based therapy. Patients 2 and 3 showed some response to combined FLT3-inhibitor and BCR–ABL targeted therapy (gilteritinib and ponatinib). The availability of effective targeted therapies for BCR–ABL1 makes this an important aberration to proactively identify and possibly target at relapse post–FLT3-inhibitor therapies.


INTRODUCTION
The development of multiple small-molecule kinase inhibitors targeting FLT3 has improved the outcome of FLT3-mutated acute myeloid leukemia (AML) (1). Despite high response rates with FLT3 inhibitor-based therapies, the emergence of new mutations frequently drives resistance, and resulting in short durations of response and survival (2)(3)(4)(5). These emergent mutations may involve the activating loop or gatekeeper residues of the FLT3 (on target resistance) (2,3,5) or genes regulating parallel prosurvival signaling pathways such as PI3K/AKT and RAS/MAPK (off-target resistance) (4,5). Herein, we report the cases of three patients who relapsed following an FLT3 inhibitor-based therapy, with an emergent BCR-ABL1 fusion, rendering a potentially targetable mechanism of resistance.

Patient 1
A 33-year-old woman was diagnosed with AML with a normal karyotype (no molecular testing done locally at baseline). She received 7 + 3 induction without a response and was reinduced with fludarabine and cytarabine (FLAG) with complete remission (CR), followed by four cycles of high-dose cytarabine (HiDAC) consolidation. She relapsed 5 months after the last consolidation and was referred to our institution following an unsuccessful salvage attempt with FLAG.
The Philadelphia chromosome, t(9,22) (q34,q11.2), results in a BCR-ABL1 fusion gene, encoding a constitutively active oncogenic tyrosine kinase. The incidence of the Ph chromosome in de novo AML ranges from 0.5 to 3% (8). Acquisition of BCR-ABL1 as a secondary abnormality and a mechanism of possible clonal evolution in relapsed AML has rarely been reported postchemotherapy treatment (9) and now post-FLT3 inhibitor-based therapy (5,10).
Although rare (3-5%), identification of BCR-ABL1 fusion at relapse has clinical significance as it is a targetable mutation. In this report, patients 2 and 3 were refractory to FLT3 inhibitor-based therapies, but eventually responded to combined FLT3-inhibitor and BCR-ABL targeted therapy (gilteritinib and ponatinib). Patient 1 remained refractory to multiple conventional salvage chemotherapy plus FLT3inhibitor regimens, possibly in some part due to BCR-ABLmediated resistance to FLT3 inhibitor-based therapies. Ponatinib is a potent kinase inhibitor with pan-BCR-ABL1 inhibitor activity and strong FLT3-inhibitor activity. Smith et al. (11) demonstrated in vitro activity of ponatinib against FLT3-ITD and F691 gatekeeper mutation. Gilteritinib is a selective FLT3 inhibitor with potent activity against FLT3-ITD, as well as TKD mutations, although 5 (12.2%) of 42 patients acquired F691 gatekeeper mutations at relapse post-gilteritinib therapy (5). Combinatorial or sequential use of gilteritinib and ponatinib to overcome each individual drug resistance could be of interest for prospective evaluation, especially in FLT3-mutated patients with detectable subclonal acquisition of BCR-ABL1 fusion. Combining these two potent FLT 3 inhibitors should ideally be performed under clinical investigation/trial setting, with close monitoring and caution for myelosuppression, ideally in large leukemia centers with significant expertise. An increased understanding of the mechanisms of FLT3-inhibitor resistance may help identify and target known druggable pathways of resistance to overcome primary and secondary resistance in clinical practice.

DATA AVAILABILITY STATEMENT
All datasets generated in this study are included in the article/supplementary material.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by the Institutional Review Board (IRB), MD Anderson Cancer Center (MDACC) IRB protocol DR09-0223 and PA12-0395. The patients/participants provided their written informed consent to participate in this study.

AUTHOR CONTRIBUTIONS
ND, AA, and MY collected the data, conceived, designed, and wrote the manuscript. SL, KP, BT, and GT analyzed and reported the molecular and cytogenetics data. CD, GB, TK, NP, GI, MK, NS, and FR treated the patients, read, revised, and approved the final manuscript. All authors contributed to the article and approved the submitted version.

ACKNOWLEDGMENTS
Special thanks to Jordan Pietz, MA, CMI for his assistance in creating the visual artwork. All copyrights to the visual artwork are retained by MD Anderson Cancer Center.