Tyrosine Kinase Inhibitor Targeting KIT Research Articles

Avapritinib is effective for treatment of minimal residual disease in acute myeloid leukemia with t (8;21) and kit mutation failing to immunotherapy after allogeneic hematopoietic stem cell transplantation.

In patients with t(8;21) acute myeloid leukemia (AML) with recurrent measurable residual disease (MRD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), pre-emptive interferon-α therapy and donor lymphocyte infusion are noneffective in 30%-50% of patients. Avapritinib is a novel tyrosine kinase inhibitor targeting KIT mutations. We retrospectively report about 20 patients with t(8;21) AML and KIT mutations treated with avapritinib after allo-HSCT with MRD and most failing to respond to immunotherapy. Reduction of RUNX1-RUNX1T1 after 1 month of treatment was ≥1 log in 12 patients (60%), which became negative in 4 patients (20%). In 13 patients who received avapritinib for ≥3 months, the reduction was ≥1 log in all patients, which became negative in 7 patients (53.8%). The median follow-up time was 5.5 (2.0-10.0) months from avapritinib initiation to the last follow-up. Three patients underwent hematologic relapse and survived. Among all 20 patients, RUNX1-RUNX1T1 transcripts turned negative in 9 patients (45%). The efficacy did not differ significantly between D816 and non-D816 KIT mutation groups. The main adverse effect was hematological toxicity, which could generally be tolerated. In summary, avapritinib was effective for MRD treatment in patients with t(8;21) AML with KIT mutations failing to respond to immunotherapy after allo-HSCT.

Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT

BackgroundThe stem cell factor receptor, KIT, is a target for the treatment of cancer, mastocytosis, and inflammatory diseases. Here, we characterise the in vitro and in vivo profiles of masitinib (AB1010), a novel phenylaminothiazole-type tyrosine kinase inhibitor that targets KIT.Methodology/Principal Findings In vitro, masitinib had greater activity and selectivity against KIT than imatinib, inhibiting recombinant human wild-type KIT with an half inhibitory concentration (IC50) of 200±40 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC50 of 150±80 nM in Ba/F3 cells expressing human or mouse wild-type KIT. Masitinib also potently inhibited recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, masitinib demonstrated weak inhibition of ABL and c-Fms and was inactive against a variety of other tyrosine and serine/threonine kinases. This highly selective nature of masitinib suggests that it will exhibit a better safety profile than other tyrosine kinase inhibitors; indeed, masitinib-induced cardiotoxicity or genotoxicity has not been observed in animal studies. Molecular modelling and kinetic analysis suggest a different mode of binding than imatinib, and masitinib more strongly inhibited degranulation, cytokine production, and bone marrow mast cell migration than imatinib. Furthermore, masitinib potently inhibited human and murine KIT with activating mutations in the juxtamembrane domain. In vivo, masitinib blocked tumour growth in mice with subcutaneous grafts of Ba/F3 cells expressing a juxtamembrane KIT mutant.ConclusionsMasitinib is a potent and selective tyrosine kinase inhibitor targeting KIT that is active, orally bioavailable in vivo, and has low toxicity.