Midostaurin: A New Oral Agent Targeting FMS‐Like Tyrosine Kinase 3‐Mutant Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML), a clonal hematologic malignancy that results in bone marrow failure, is the most common acute leukemia in adults (median age of diagnosis 67 yrs), and treatment options, especially in the elderly population, are limited. Induction chemotherapy with 7 + 3, the combination of continuous-infusion cytarabine and intermittent dosing of an anthracycline administered over 7 and 3 days, respectively, has remained the standard of care since its introduction in 1973 in the United States. Midostaurin is a first-generation FMS-like tyrosine kinase 3 (FLT3) inhibitor (TKI) that was approved by the U.S. Food and Drug Administration in April 2017 for the treatment of FLT3-mutant AML. We performed a search of the PubMed database (January 1990-January 2017) to review pertinent clinical trials of midostaurin. Phase I, II, and III trials reported in English evaluating the safety and efficacy of midostaurin in patients with AML or myelodysplastic syndrome were included. The ClinicalTrials.gov database was also searched for ongoing trials. In the only phase III trial that has been conducted to date, midostaurin demonstrated significant improvement compared with placebo in overall and event-free survival in patients aged 18-59 years with newly diagnosed FLT3-mutant AML treated with standard induction chemotherapy. The median overall survival for patients randomized to the midostaurin group was 74.7 months versus 25.6 months in the placebo group (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.63-0.96, p=0.009). Median event-free survival was 8.2 months with midostaurin compared with 3.0 months with placebo (HR 0.78, 95% CI 0.66-0.93, p=0.002). In addition to being evaluated in combination with conventional chemotherapy, midostaurin has been studied as monotherapy, in combination with the hypomethylating agents azacitidine and decitabine, and as single-agent maintenance. Studies evaluating midostaurin in the maintenance setting after allogeneic stem cell transplantation are underway. Midostaurin is the first oral multitargeted TKI to improve overall survival in patients with FLT3-mutant AML and represents an important addition to the limited armamentarium against AML.

Advances in treatment formulations for acute myeloid leukemia

“…However, specific AML therapies are mostly oral treatments, although the new schedules developed for patients with AML are also affected by adverse effects and drug resistance. Tyrosine kinase inhibitors are associated with digestive adverse effects (vomiting, nausea, diarrhea, and heartburn), various types of skin rash, headaches, muscle cramps, heart dysfunction, hepatic impairments, pulmonary toxicities, or cardiotoxicities [40][41][42].…”

The role of FLT3 inhibitors as maintenance therapy following hematopoietic stem cell transplant

“…Midostaurin is also an orally bioavailable multikinase inhibitor with activity against FLT3, VEGF, PDGFR and c-KIT [31] . As monotherapy, Midostaurin had high response rates of up to 70% in patients with FLT3+ AML, but a poor rate of CR (0–5%) was seen [3] , [11] , [12] .…”

Novel Isoquinolinamine and Isoindoloquinazolinone Compounds Exhibit Antiproliferative Activity in Acute Lymphoblastic Leukemia Cells

“…A large number of FDA-approved kinase inhibitors such as Gefitinib (Kazandjian et al ., 2016), Idelalisib (Miller et al ., 2015) and Midostaurin (Stansfield and Pollyea, 2017) are characterized by quinolone, quinazolinones or indole backbones (Fig. 1).…”