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Background: Pediatric patients with Philadelphia chromosome positive (Ph+) or ABL-class fusion positive acute lymphoblastic leukemia (ALL) are currently treated with the tyrosine kinase inhibitor (TKI) imatinib added to a chemotherapy backbone that also contains several courses of high-dose methotrexate (HDMTX). A limited number of case studies suggested delayed MTX clearance in patients concomitantly using HDMTX and imatinib. Methods: MTX clearance and serum creatinine in 24 newly diagnosed Ph+/ABL-class fusion positive pediatric ALL patients treated with imatinib (imatinib group) were compared with 281 randomly selected age-matched Ph-negative pediatric ALL patients treated without TKI (control group), receiving in total 61 and 897 HDMTX courses, respectively. Results: Mild to severe delayed MTX clearance (MTX level at T48 hours>0.4 µM) was more frequently found in the imatinib group than in the control group in all courses (55.7% vs 41.1% p = 0.036). After the first HDMTX course, 12.5% (n = 3) of the imatinib group presented with a severe delayed MTX clearance (T48 > 5 µM) versus 2.3% in the control group (p = 0.039). In two (8.3%) of these patients in the imatinib group, this was accompanied by increased creatinine, therefore meeting the criteria for Delayed MTX Elimination (DME). In the control group 12/281 (4.3%) patients presented with DME. Glucarpidase was administered in 2 (8.3%) vs 4 (1.4%) patients in the imatinib group and control group, respectively. Conclusion: Imatinib increased the risk of delayed MTX clearance in newly diagnosed pediatric Ph+ chromosome or ABL-class fusion positive ALL patients. We therefore recommend stringent supportive care measures and for patients with severe delayed MTX clearance resulting in severe toxicities temporary discontinuation of imatinib or a lower dose of MTX during the next HDMTX courses.