FLT3 inhibitors in acute myeloid leukemia

Acute myeloid leukemia ( AML ) remains a highly resistant disease to conventional chemotherapy, with a median survival of only 4 months for relapsed and/or refractory disease.

Molecular profiling by PCR and next-generation sequencing has revealed a variety of recurrent gene mutations.

New agents are rapidly emerging as targeted therapy for high-risk AML. In 1996, FMS-like tyrosine kinase 3/internal tandem duplication ( FLT3/ITD ) was first recognized as a frequently mutated gene in AML. According to 2017 ELN risk stratification, patients with FLT3/ITDhigh-positive AML are classified into adverse risk category. This mutation causes resistance to conventional chemotherapy. Although patients with AML can be cured with hematopoietic stem cell transplantation ( HSCT ), most of these patients are at high risk for relapse. Thus, the overall cure rate of AML is only 30–40%.

FLT3/ITD gene is found in approximately 30% of patients with AML with normal cytogenetics. FLT3/ITD belongs to the type III family of receptor tyrosine kinases.
The FLT3 gene is located on chromosome 13 .q12. It is expressed mainly in human hematopoietic progenitors and dendritic cells and plays key roles in leukemia cell proliferation, differentiation, and survival.
Constitutive activation of the FLT3/ITD gene triggers multiple downstream signaling cascades, such as STAT5, RAS, MEK, and PI3K/AKT pathways, and ultimately causes suppression of apoptosis and differentiation of leukemic cells, including dysregulation of leukemic cell proliferation.

Multiple FLT3 inhibitors are in clinical trials for treating patients with FLT3/ITD-mutated AML.

Second-generation FLT3 inhibitors

A) Quizartinib

Quizartinib is a selective and highly potent second-generation class III receptor TKI. Quizartinib is a potent and selective FLT3 inhibitor for AML. The Quizartinib dosage with the highest efficacy is 1 mg/kg once a day.

The optimum dosages and efficacy of Quizartinib alone and in combination with chemotherapy in patients with AML were investigated.

A phase I open-label, sequential group dose-escalation trial was the first to evaluate the safety and tolerability of Quizartinib in combination with chemotherapy in 19 patients newly diagnosed with AML. Out of 16 patients who achieved good response, 14 achieved CR and 2 achieved a morphologic leukemia-free state. There were no apparent additional signs of toxicity. The most common grade 3 or 4 adverse events were febrile neutropenia, neutropenia, thrombocytopenia, and anemia.

In another dose-escalation study, Quizartinib was used as a maintenance therapy in 13 patients with FLT3/ITD-mutated AML after allo-HSCT. Two patients treated with Quizartinib at 40 and 60 mg/day interrupted treatment because of grade 3 gastric hemorrhage and anemia. One patient relapsed. However, there was no maximum tolerated dose ( MTD ), and 60 mg daily was the highest dose studied.

Quizartinib has shown a strong activity in relapsed or refractory AML. Cortes et al. reported the results of a phase I trial of Quizartinib in relapsed or refractory AML for the first time. Out of 76 patients, 23 showed responses, with 10 achieving CR and 13 achieving PRs. The median duration of response was 13.3 weeks, and the median survival time was 14 weeks. The most common treatment-related adverse events were nausea, vomiting, and prolonged QT interval. The maximum tolerated dose ( MTD ) was 200 mg/day, and the dose-limiting toxicity was grade 3 QT prolongation.

Cortes and Levis reported that the CR rate reached 44 to 54% in their phase II study of relapsed and refractory AML. Importantly, 30- or 60-mg/day quizartinib monotherapy was reported in 76 patients with relapsed/refractory FLT3/ITD-mutated AML. Composite complete remission ( CRc ) rates of both groups were similar to those who received higher Quizartinib doses. The incidence of corrected QT interval ( QTc ) above 480 ms and 500 ms was also less common.

Quizartinib as a salvage chemotherapy has been administered to children with relapsed acute leukemia. The responses were evaluated in 17 patients ( 2 CR, 1 CRp, 1 CRi, 10 SD, and 3 PD ), 7 of which were FLT3/ITD-positive ( 1 CR, 1 CRp, 1 CRi, and 4 SD ). FLT3 phosphorylation in all patients was completely inhibited with Quizartinib at 60 mg/m2/day.

B) Crenolanib

Crenolanib is a potent and selective inhibitor of FLT3/WT, FLT3/ITD, FLT3-TKD, PDGFRα/β, KIT, and FLT3/D835. Crenolanib was less disruptive of erythroid colony growth, which may result in relatively less myelosuppression than that by Quizartinib.

Data from an ongoing clinical trial showed that sufficient levels of Crenolanib could inhibit both FLT3/ITD and resistant FLT3/D835 mutants in patients with AML.

In a phase II trial, the tolerability and efficacy of Crenolanib combined with standard induction chemotherapy was examined in patients with newly diagnosed FLT3 mutant AML. There were 26 patients including 19 patients with FLT3/ITD and 3 patients with FLT3/D835 mutations. Eighty-eight percent of patients achieved CR, and overall CR/CRi rate was 96%. During a median follow-up of 6 months, only 3 patients have relapsed. In the following year, the similar result was seen in Crenolanib combined with 7+3 induction and high dose cytarabine consolidation in 29 patients less than 60 years old with FLT3-mutated AML.

A head-to-head comparison with Midostaurin in combination with 7+3 was planned to further evaluate the efficacy of Crenolanib.

In addition, Crenolanib was also used in relapsed or refractory AML. Iyer et al. reported the result of 8 patients with first relapsed or primary refractory AML who received the treatment of high-dose ara-C / Mitoxantrone ( HAM ) and Crenolanib. Four patients achieved CR/CRi after 1 cycle. Only 1 patient showed a transient elevation in total bilirubin.

Maro et al. used salvage Idarubicin and high-dose ara-C and Crenolanib to treat patients with relapsed / refractory FLT3-positive AML. The ORR was 36% and median overall survival ( OS ) was 259 days. No dose-limiting toxicities ( DLT ) were observed. Grade I gastrointestinal ( GI ) toxicities including nausea, vomiting, diarrhea, and abdominal pain were the major non-hematological adverse events.

Crenolanib was administered at 200 mg/m2/day 3 times a day in another single-center phase II study in 10 patients with relapsed / refractory AML who progressed after HSCT. The ORR was 47%.

C) Gilteritinib

Gilteritinib is a novel dual FLT3/AXL inhibitor. Gilteritinib significantly reduced the colony-forming capacity of FLT3/ITD-positive leukemia cells. Gilteritinib decreases the phosphorylation levels of FLT3 and its downstream targets in cell cultures as well as in animal models. No obvious toxicity was observed.

Gilteritinib was well tolerated in 252 relapsed/refractory AML patients. The ORR was 40%, whereas the RR was 52% in FLT3-mutated patients at doses greater than or equal to 80 mg/day. More than 5% of the patients experienced serious adverse events such as fever, disease progression, neutropenia, sepsis, acute renal failure, pneumonia, pyrexia, bacteremia, and respiratory failure. Grade 3 diarrhea and transaminase elevation were limited in patients administrated at a dose of above 300 mg/day.

In another open-label, phase 1 study, gilteritinib was also shown to be well tolerated in Japanese patients with relapsed/refractory AML. The ORR in patients with mutated FLT3 and FLT/WT was 80% and 36.4%, respectively. The most common drug-related severe adverse events were thrombocytopenia and increased creatine phosphokinase.
The recommended phase II dose was 120 mg/day and MTD was 200 mg/day.

A phase III clinical trial comparing guilteritinib to a salvage chemotherapy regimen in relapsed / refractory FLT3-mutated AML patients is currently being conducted. ( Xagena )

Mei Wu et al, J Hematol Oncol 2018; 11: 133



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