Kronos Bio, Inc. is presenting preclinical data that demonstrate anti-leukemic activity of the investigational spleen tyrosine kinase (SYK) inhibitor, lanraplenib, in combination with multiple targeted agents in patient-derived cell isolates and cell lines at the 64th American Society of Hematology (ASH) Annual Meeting & Exposition in New Orleans. The data are being shared as part of a poster presentation. Lanraplenib is a next-generation SYK inhibitor that is currently being evaluated in combination with gilteritinib in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia (AML) in a Phase 1b/2 study.

The company anticipates sharing initial data from the lanraplenib/gilteritinib trial, along with the recommended Phase 2 dose (RP2D), in the fourth quarter of 2023 or first quarter of 2024. Researchers evaluated lanraplenib and a second SYK inhibitor, entospletinib, which the company has discontinued developing, in combination with a menin inhibitor (SNDX5613), in two cell lines with FLT3 internal tandem duplication/MLL rearrangement. Synergistic anti-proliferative effects were observed across a broad range of concentrations.

The combination triggered differentiation and apoptosis, suggesting a more complete blockade of the HOXA9/MEIS1 transcriptional program through synergistic inhibition by orthogonal mechanisms. Additionally, the researchers evaluated synergistic activity of lanraplenib with the FLT3 inhibitor, gilteritinib, and BCL2 inhibitor, venetoclax, in patient-derived AML isolates. This analysis found synergistic anti-proliferative activity for both combinations. Patient-derived xenograft (PDX) studies also demonstrated deeper reductions in leukemic burden in the peripheral blood and bone marrow after 28 days of treatment with lanraplenib and gilteritinib.

In a follow-up PDX study with an optimized regimen, the combination significantly extended overall survival compared to either single agent. Kronos Bio also presented two posters at the meeting focused on increasing the understanding of measurable residual disease (MRD) negative CR as a surrogate endpoint in AML trials. One poster analyzed MRD and survival data from 1,128 patients with NPM1-mutated AML in three cooperative group trials, confirming that achieving MRD negative CR predicts better overall and event-free survival.

A second poster described the development of a next generation sequencing-based assay for measuring MRD and compared the performance of this assay against the gold standard RT-qPCR based method.