FLT3 is a member of the class III receptor tyrosine kinase family that exerts a key role in the proliferation and differentiation of hematopoietic progenitor cells. FLT3 inhibitors have dramatically altered the prognosis of the FLT3 mutant AML.
Acute myeloid leukemia (AML) is the most common type of leukemia in adults [1][2]. It is a heterogeneous group of hematological malignancies characterized by the clonal proliferation of immature myeloid cells in the bone marrow [1]. In its most recent classification, the World Health Organization identified AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related myeloid neoplasms, and AML not otherwise specified [3]. The incidence increases with age, with 50% of the patients being older than 60 years old. Treatment of AML for younger and fit patients usually relies on chemotherapy. For older patients, the new standard of treatment is a combination of hypomethylating agents and venetoclax. In younger patients, the first round of chemotherapy usually yields a complete remission rate of 60 to 70%. The success of the AML treatment is mostly dependent on recurrent cytogenetic and genetic alterations. The 2017 European Leukemia Net classification has divided AML patients into three prognosis groups based on their oncogenetic characteristics [4].
FLT3
FLT3 are oncogenic and show transformation activity in cells. Before the rise of small molecule inhibitors, FLT3-mutated AML was associated with a poor prognosis with a high relapse risk [7][8][9] even after allogeneic hematopoietic stem cell transplantation (aHSCT) [10]. Many studies have now reported a link between the rate of ITD allelic ratio and prognosis, with a ratio higher than 0.5 associated with a higher risk of treatment failure and relapse [11]. The prognostic impact of
FLT3
Table 1). These differences partly explain the drugs’ side effects and efficacy. Current FLT3 inhibitors are usually divided between first- (Sorafenib, Midostaurin, and Lestaurtinib) and second-generation TKIs (gilteritinib, quizartinib, crenolanib). Next-generation TKIs have fewer off-target effects leading to fewer and less severe side effects and a higher FLT3 specificity [13][14]. Most common side effects now include cytopenias and gastrointestinal effects such as nausea and vomiting. These toxicities are easily manageable through transfusions, antibiotic courses, and antiemetics. A brief overview of the different developmental phase of the
FLT3
Table 1.
Agent | Type |
---|---|
Second generation, type I | |
Table 4.
Reference | Drug | Study Design | N | Type of FLT3 Mut | Response | Survival | ||
---|---|---|---|---|---|---|---|---|
Ravandi et al. [38] | Sorafenib + Azacitidine | Phase II | 43 | FLT3-ITD (93%) | CR 16% | Median OS 6.2 months | ||
Ohanian et al. [39] | Sorafenib + Azacitidine | Phase I/II | 27 | FLT3-ITD (100%) | CR 26% | Median OS 8.3 months | ||
Williams et al. [40] | Midostaurin + Decitabine | Phase I | 16 | FLT3-ITD (13%) | CHR 26% | |||
120 mg once a day | FLT3-ITD, FLT3-TKD, LTK, ALK, AXL | |||||||
Crenolanib | ||||||||
Strati et al. [41] | Midostaurin + Azacitidine | Phase I/II | 54 | FLT3-ITD (68%), TKD (6%) | ORR 26% | Second generation, type I | 100 mg TID | |
Swaminathan et al. [ | FLT3-ITD, FLT3-TKD, PDGFRβ |
Table 2.
Indication | Dose | Target |
---|
Agent | Trial |
---|
Sorafenib | First generation, type I | 400 mg BID | FLT3-ITD, RAF, VEGFR1/2/3, PDGFRβ, KIT, RET |
Salvage monotherapy | Midostaurin | Phase I, phase II | |||||||
Midostaurin | First generation, type I | 50 mg BID | FLT3-ITD, FLT3-TKD, PKC, SYK, FLK-1, AKT, PKA, KIT, FGR, SRC, PDGFRα/β, VEGFR1/2 | ||||||
Quizartinib | Phase II, phase III | Quizartinib | Second generation, type II | 60 mg once a day | FLT3-ITD, KIT, PDGFR | ||||
Gilteritinib | |||||||||
Gilteritinib | Phase II, phase III | ||||||||
Crenolanib | Phase II | ||||||||
Combination with intensive chemotherapy (newly diagnosed) | Midostaurin | 42 | Phase III | ||||||
] | Quizartinib + Azacitidine/LDAC | Phase I/II | 73 | Phase I: FLT3-ITD and WT, Phase II: FLT3-ITD only | Q + A: CR 22% Q + LDAC: CR 8% |
Q + A: median OS 13.4 monthsQ + LDAC Median OS: 6.7 months |
Quizartinib | Cortes et al. | Phase I, Phase III (ongoing) |
[26] | Quizartinib | Phase 3 | 367 | R/R AML | FLT3-ITD | OS | OS Quizartinib > OS salvage chemotherapy (p = 0.02) | Nausea, prolonged QT interval, vomiting, dysgueusi | |
Wang et al. [43] | Gilteritinib + Azacitidine vs. Azacitidine alone | Phase III | 136 | FLT3-mutated AML | Trial halted (did not meet endpoint) | Gilteritinib | Phase III (ongoing) | ||
Perl et al. [32] | Gilteritinib | Phase 1/2 | 252 | R/R AML | FLT3 mut and WT | Tolerability, safety, pharmacokinetics | N/A | Crenolanib | Phase III (ongoing) |
Infections/Anemia/thrombopenia | |||||||||
Perl et al. [33] | Gilteritinib | Phase 3 | 371 | R/R AML | FLT3-ITD and TKD | Combination with demethylating agents | Sorafenib | Retrospective study | |
Midostaurin | Phase II study | ||||||||
Quizartinib | Phase I/II | ||||||||
Gilteritinib | Phase III (failed) | ||||||||
Crenolanib | Preclinical | ||||||||
Posttransplantation maintenance | Sorafenib | Phase II, phase III | |||||||
Midostaurin | Phase III (failed) | ||||||||
Quizartinib | Phase III (ongoing) | ||||||||
Gilteritinib | Phase III (ongoing) | ||||||||
Crenolanib | Phase III (ongoing) |
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