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

Abstract

Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with FLT3-mutated acute myeloid leukemia (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 (NGS) at relapse identified emergent mutations involving on-target FLT3, epigenetic modifiers, RAS/MAPK pathway, and less frequently WT1 and TP53. RAS/MAPK and FLT3-D835 mutations emerged most commonly following type I and II FLT3i-based therapies, respectively. Patients with emergent mutations at relapse had inferior overall survival compared with those without emergent mutations. Among pretreatment RAS-mutated patients, pretreatment cohort-level variant allelic frequencies for RAS were higher in nonresponders, particularly with type I FLT3i-based therapies, suggesting a potential role in primary resistance as well. These data demonstrate distinct pathways of resistance in FLT3-mutated AML treated with type I versus II FLT3i. Significance: Sequential NGS-based mutational analysis at relapse after FLT3i-based therapies showed distinct pathways of secondary resistance between type I and II FLT3i. FLT3 mutations may be lost at relapse after FLT3i-based therapies. Pretreatment RAS/MAPK mutations may also be associated with primary resistance in patients treated with type I FLT3i. See related commentary by Shastri et al., p. 113.

Acute myeloid leukemia: Treatment and research outlook for 2021 and the MD Anderson approach

“…Third-generation compounds (FT10101, crenolanib) are under development potentially to overcome these and other mechanisms of resistance, such as the emergence of MAPK-pathway mutations (eg, RAS, RAF, PTPN11, NF1). 144 Combination therapy of FLT3 inhibitors with agents that induce apoptosis may enhance cytotoxicity against FLT3-mutated and wild-type clones and potentially delay or prevent resistance to FLT3 inhibitor-based therapies. Preclinical data indicated strong synergism between venetoclax and FLT3 inhibitors.…”

“…Certain activating point mutations (such as FLT3‐ ITD F691L ) are resistant to current FLT3 inhibitors. Third‐generation compounds (FT10101, crenolanib) are under development potentially to overcome these and other mechanisms of resistance, such as the emergence of MAPK‐pathway mutations (eg, RAS, RAF, PTPN11, NF1) 144 …”

FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

“…Secondary resistance to FLT3i could be either on-target (changes in the FLT3) or off-target (constitutive activation of non-FLT3-dependent oncogenic pathways). The on-target mechanism of resistance includes emergence of secondary TKD mutations in patients treated with type II inhibitors like quizartinib or sorafenib 69 , 70 . Type I FLT3i’s like gilteritinib are less prone to develop secondary mutations in the TKD, although the gatekeeper F691M can confer resistance to gilteritinib 71 .…”

“…Type I FLT3i’s like gilteritinib are less prone to develop secondary mutations in the TKD, although the gatekeeper F691M can confer resistance to gilteritinib 71 . Off-target resistance includes clonal evolution during FLT3i therapy even when FLT3 -ITD mut clone is lost 70 . In a study that identified molecular mechanisms of resistance to gilteritinib, 32% of patients had emergent mutations in the RAS/MAPK pathway ( K/NRAS ), and 5% had emergent BCR/ABL1 fusions 71 .…”

Genomic Abnormalities as Biomarkers and Therapeutic Targets in Acute Myeloid Leukemia

“…Mutations of the FLT3-TKD D835 or I836 amino acid were shown to be the main FLT3 mutations associated with resistance to class II FLT3 inhibitors [88]. The available data suggests that nearly one third of patients who developed resistance to FLT3 inhibition have these mutations in FLT3 at the time of relapse [85,88,89]. A recent investigation of 67 FLT3-ITD+ AML patients who were treated with class I or II inhibitors demonstrated that more than half of the patients had detectable mutations at relapse, from which 26% had mutations in the TKD of FLT3 (D835).…”