Prospective Study of Avapritinib in Patients with Relapsed/Refractory or MRD-Positive Core-Binding Factor Acute Myeloid Leukemia with KIT Mutations

Core-binding factor acute myeloid leukemia (CBF-AML), which includes the recurrent genetic abnormalities RUNX1::RUNX1T1 and CBFβ::MYH11 fusions, is generally associated with a favorable prognosis. However, KIT gene mutations are a common co-occurring event in CBF-AML, and the presence of KIT mutations is associated with a poorer prognosis in these patients. Avapritinib is a tyrosine kinase inhibitor that was developed to specifically target mutations in the KIT and PDGFRA genes. While avapritinib has been approved for the treatment of gastrointestinal stromal tumors (GIST) with PDGFRA mutations and advanced systemic mastocytosis, its efficacy and safety in CBF-AML with KIT mutations have not been extensively investigated.

In this study, we evaluated the efficacy and safety of avapritinib in patients with relapsed/refractory or measurable residual disease (MRD)-positive CBF-AML harboring RUNX1::RUNX1T1 or CBFβ::MYH11 fusions. A total of 40 patients, including 24 males and 16 females, with a median age of 41 years (range, 13-77), were enrolled from two big medical centers in China. The majority of patients (33/40, 82.5%) had RUNX1::RUNX1T1 fusions, while the remaining 17.5% (7/40) had CBFβ::MYH11 fusions. In these patients, 23 (57.5%) had KIT N822 mutations, 5 (12.5%) had KIT N822 mutations, 8 (20%) had complex KIT mutations, and 4 (10%) patients had other KIT mutations. Thirteen patients had relapsed/refractory AML, and the other 27 had a positive molecular MRD of fusion genes after two consolidation treatment at least. All of the patients received avapritinib monotherapy at a dose of 100mg daily (in combination with azole antibiotics) or 200mg daily orally, with or without in combination with chemotherapy.

In the 13 relapsed/refractory AML patients, 6 had a good response to avapritinib, achieving an overall response rate（ORR) of 46.2%. Five of the 6 responding patients then underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and achieved molecular MRD-negative remission, although one patient subsequently died of pulmonary infection. Among the 27 patients with positive molecular MRD, 19 (70.4%) demonstrated a good response to avapritinib, with a reduction in molecular MRD level of at least 1 log, and 11 (40.7%) achieved molecular MRD negativity.The most common adverse event (AE) was hematological toxicity, and other AEs included facial edema, gastrointestinal reactions, rash, QT interval prolongation, and hair depigmentation.

In general, the study results suggest that avapritinib demonstrated good efficacy and safety in patients with CBF-AML harboring KIT gene mutations. These findings may support expanding the indications for this therapy in the treatment of AML.