{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T01:53:09Z","timestamp":1781833989140,"version":"3.54.5"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"National Hospital"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Chemother Pharmacol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Tyrosine kinase inhibitors (TKIs) have improved outcomes in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) and are increasingly incorporated into treatment protocols of Philadelphia chromosome-like (Ph-like, ABL-class) ALL. However, central nervous system (CNS) relapse remains a significant challenge. Imatinib, a first-generation TKI, demonstrates limited CNS penetration in adults, yet data in children are sparse.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This prospective, multicenter study investigated cerebrospinal fluid (CSF) and matched plasma concentrations of imatinib and its primary bioactive metabolite (N-desmethyl-imatinib) in children and young adults with Ph\u2009+\u2009or Ph-like (ABL-class) ALL. Plasma and CSF samples were analyzed with liquid chromatography tandem mass spectrometry (LC-MS\/MS). Linear mixed-effects models were used to assess concentrations across compartments and over time.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Between January 2023 and June 2025, 32 paired plasma and CSF samples were collected from ten patients (range 1\u20138 samples\/patient; median: 3). In total, 78% of plasma imatinib concentrations were above 1,000 ng\/mL. On average, plasma imatinib concentrations were 189-fold higher than in CSF (geometric mean ratio, 95% CI: 142\u2013249,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001), which was even more profound for N-desmethyl-imatinib (geometric mean ratio 273, 95% CI: 218\u2013339,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). The highest measured CSF-imatinib concentration was 63 ng\/mL. During therapy, both plasma and CSF imatinib concentrations declined at an average of 0.32% per day (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001), resulting in stable CSF-to-plasma ratio over a median follow-up of 5.7 months (range: 0\u201314 months).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The very low CSF concentrations support the rationale for alternative TKIs with improved CNS distribution in patients at risk of CNS relapse.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00280-026-04914-9","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T01:49:53Z","timestamp":1781833793000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Central nervous system penetration of imatinib in acute lymphoblastic leukemia: Pharmacokinetic analysis and clinical implications"],"prefix":"10.1007","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4997-2914","authenticated-orcid":false,"given":"Anna Sofie Buhl","family":"Rasmussen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0578-3887","authenticated-orcid":false,"given":"Cecilie Utke","family":"Rank","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3017-7195","authenticated-orcid":false,"given":"Ib Jarle","family":"Christensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9305-171X","authenticated-orcid":false,"given":"Allan","family":"Weimann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9531-9801","authenticated-orcid":false,"given":"Kasper","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9950-5911","authenticated-orcid":false,"given":"Maria","family":"Thastrup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0856-4497","authenticated-orcid":false,"given":"Tianwu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8598-2880","authenticated-orcid":false,"given":"Trine Meldgaard","family":"Lund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1035-5521","authenticated-orcid":false,"given":"Hilde 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KS reports grants from Novo Nordisk Foundation, consulting fees from Jazz Pharmaceuticals, Servier, and SERB Pharmaceuticals, honoraria for lectures from Amgen, and stock ownership in Novo Nordisk. All other authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Scientific Ethics Committee, Capital Region of Denmark (H-22057870).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Informed consent was obtained from all patients or legal guardians.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}}],"article-number":"65"}}