Gilteritinib use in the treatment of relapsed or refractory acute myeloid leukemia with a FLT3 mutation

2020 ◽  
Author(s):  
Octavio Ballesta-López ◽  
Antonio Solana-Altabella ◽  
Juan Eduardo Megías-Vericat ◽  
David Martínez-Cuadrón ◽  
Pau Montesinos
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Salvage Chemotherapy ◽  
Mechanisms Of Resistance ◽  
Flt3 Inhibitor ◽  
Refractory Acute Myeloid Leukemia ◽  
Dose Reductions ◽  
Acute Myeloid

The prognosis of patients with relapsed or refractory acute myeloid leukemia (R/R AML) is dismal with salvage standard approaches, and mutations of FMS-like tyrosine kinase 3 ( FLT3) gene, occurring in around 30% of AML patients may confer even poorer outcomes. Several targeted tyrosine kinase inhibitors have been developed to improve FLT3-mutated AML patient´s survival. Gilteritinib, a highly specific second-generation class I oral FLT3 inhibitor, has demonstrated superiority to salvage chemotherapy (SC) in R/R FLT3 mutated AML based on significantly longer OS in the gilteritinib arm than in the SC arm. Gilteritinib is generally well tolerated, but some clinically relevant adverse events should be monitored, especially myelosuppression, QTc prolongation and differentiation syndrome, usually manageable (dose reductions, interruption or discontinuation) and reversible. We discuss clinical development, efficacy, safety and mechanisms of resistance of gilteritinib in the treatment of R/R patients with FLT3 mutated AML.

FLT3 as a therapeutic target in AML: still challenging after all these years

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5089-5102 ◽  
Author(s):  
Thomas Kindler ◽  
Daniel B. Lipka ◽  
Thomas Fischer
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Genetic Alterations ◽  
Molecular Target ◽  
Lessons Learned ◽  
Laboratory Studies ◽  
Flt3 Inhibitor ◽  
Acute Myeloid

Abstract Mutations within the FMS-like tyrosine kinase 3 (FLT3) gene on chromosome 13q12 have been detected in up to 35% of acute myeloid leukemia (AML) patients and represent one of the most frequently identified genetic alterations in AML. Over the last years, FLT3 has emerged as a promising molecular target in therapy of AML. Here, we review results of clinical trials and of correlative laboratory studies using small molecule FLT3 tyrosine kinase inhibitors (TKIs) in AML patients. We also review mechanisms of primary and secondary drug resistance to FLT3-TKI, and from the data currently available we summarize lessons learned from FLT3-TKI monotherapy. Finally, for using FLT3 as a molecular target, we discuss novel strategies to overcome treatment failure and to improve FLT3 inhibitor therapy.

scholarly journals A phase 1/2 study of the oral FLT3 inhibitor pexidartinib in relapsed/refractory FLT3-ITD–mutant acute myeloid leukemia

2020 ◽  
Vol 4 (8) ◽  
pp. 1711-1721 ◽  
Author(s):  
Catherine C. Smith ◽  
Mark J. Levis ◽  
Olga Frankfurt ◽  
John M. Pagel ◽  
Gail J. Roboz ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Drug Exposure ◽  
Kinase Inhibitors ◽  
Response Rate ◽  
Phase 1 ◽  
Complete Response ◽  
Flt3 Inhibitor ◽  
Acute Myeloid

Abstract FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitors (TKIs) have activity in acute myeloid leukemia (AML) patients with FLT3 internal tandem duplication (ITD) mutations, but efficacy is limited by resistance-conferring kinase domain mutations. This phase 1/2 study evaluated the safety, tolerability, and efficacy of the oral FLT3 inhibitor PLX3397 (pexidartinib), which has activity against the FLT3 TKI–resistant F691L gatekeeper mutation in relapsed/refractory FLT3-ITD–mutant AML. Ninety patients were treated: 34 in dose escalation (part 1) and 56 in dose expansion (part 2). Doses of 800 to 5000 mg per day in divided doses were tested. No maximally tolerated dose was reached. Plasma inhibitory assay demonstrated that patients dosed with ≥3000 mg had sufficient levels of active drug in their trough plasma samples to achieve 95% inhibition of FLT3 phosphorylation in an FLT3-ITD AML cell line. Based on a plateau in drug exposure, the 3000-mg dose was chosen as the recommended phase 2 dose. The most frequently reported treatment-emergent adverse events were diarrhea (50%), fatigue (47%), and nausea (46%). Based on modified response criteria, the overall response rate to pexidartinib among all patients was 21%. Twenty-three percent of patients treated at ≥2000 mg responded. The overall composite complete response rate for the study was 11%. Six patients were successfully bridged to transplantation. Median overall survival (OS) of patients treated in dose expansion was 112 days (90% confidence interval [CI], 77-150 days), and median OS of responders with complete remission with or without recovery of blood counts was 265 days (90% CI, 170-422 days). This trial was registered at www.clinicaltrials.gov as #NCT01349049.

scholarly journals Gilteritinib in the treatment of relapsed and refractory acute myeloid leukemia with a FLT3 mutation

2020 ◽  
Vol 11 ◽  
pp. 204062072093061
Author(s):  
Serena Chew ◽  
Melissa C. Mackey ◽  
Elias Jabbour
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Clonal Evolution ◽  
Response To Therapy ◽  
Activating Mutations ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a malignancy of uncontrolled proliferation of immature myeloid blasts characterized by clonal evolution and genetic heterogeneity. FMS-like tyrosine kinase 3 (FLT3) mutations occur in up to a third of AML cases and are associated with highly proliferative disease, shorter duration of remission, and increased rates of disease relapse. The known impact of activating mutations in FLT3 in AML on disease pathogenesis, prognosis, and response to therapy has led to the development of tyrosine kinase inhibitors targeting FLT3. Gilteritinib is a potent, second generation inhibitor of both FLT3 and AXL, designed to address the limitations of other FLT3 inhibitors, particularly in targeting mechanisms of resistance to other drugs. In this review, we present comprehensive data on recent and ongoing studies evaluating the role of gilteritinib in the relapsed and refractory FLT3 mutated AML setting.

Quizartinib in the treatment of FLT3-internal-tandem duplication-positive acute myeloid leukemia

2019 ◽  
Vol 15 (34) ◽  
pp. 3885-3894 ◽  
Author(s):  
Shilpa Paul ◽  
Adam J DiPippo ◽  
Farhad Ravandi ◽  
Tapan M Kadia
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Tyrosine Kinase Domain ◽  
Missense Mutations ◽  
Internal Tandem Duplication ◽  
Acute Myeloid

FLT3 mutations, characterized by an internal-tandem duplication or missense mutations in the tyrosine kinase domain, are observed in a third of patients with newly diagnosed acute myeloid leukemia. FLT3-ITD mutations are associated with high relapse rates and short overall survival with conventional chemotherapy. Several tyrosine kinase inhibitors targeting FLT3 have been developed in an effort to improve survival and therapeutic options. This review focuses on quizartinib, a second-generation FLT3 inhibitor that has demonstrated efficacy and safety as a single agent and in combination with chemotherapy. We discuss its clinical development as well as its place in the treatment of FLT3-mutated acute myeloid leukemia among the other FLT3 inhibtors currently available and its mechanisms of resistance.

Sign in / Sign up

Export Citation Format

Share Document