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Olverembatinib and high-dose methotrexate in acute lymphoblastic leukemia: delayed methotrexate clearance and
Ji-Xin Tian1, Ying-Xi Liao1, Xiao-Xu Wang1
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Abstract:
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.
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