Olverembatinib and high-dose methotrexate in acute lymphoblastic leukemia: delayed methotrexate clearance and increased nephrotoxicity

The novel tyrosine kinase inhibitors (TKIs), characterized by superior potency and selectivity against BCR-ABL1 kinase, are increasingly administered concomitantly with high-dose methotrexate (HD-MTX) for BCR-ABL1-positive acute lymphoblastic leukemia. However, data on TKI-MTX drug interactions remain scarce. We retrospectively analyzed 49 adults who received HD-MTX, of whom 10 were co-treated with olverembatinib and 17 with flumatinib. MTX clearance was estimated using a population pharmacokinetic model. Olverembatinib significantly reduces MTX clearance (35.1% slower than no-TKI) and elevates 48-hour serum concentration above the safety threshold in 80% of cases, resulting in a 60% incidence of ≥ grade 2 nephrotoxicity and a 70% rate of acute kidney injury (AKI)-both markedly higher than with HD-MTX alone (4.6% and 27.3%, respectively). Flumatinib likewise lowered MTX clearance and raised ≥ grade 2 nephrotoxicity to 29.4%, yet neither effect reached statistical significance. Temporary withdrawal of olverembatinib before HD-MTX infusion may prevent MTX-related nephrotoxicity.