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Purpose <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.</p> Methods <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 + or 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.</p> Results <p>Between January 2023 and June 2025, 32 paired plasma and CSF samples were collected from ten patients (range 1–8 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: 142–249, <i>p</i> &lt; 0.001), which was even more profound for N-desmethyl-imatinib (geometric mean ratio 273, 95% CI: 218–339, <i>p</i> &lt; 0.001). 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 (<i>p</i> &lt; 0.001), resulting in stable CSF-to-plasma ratio over a median follow-up of 5.7 months (range: 0–14 months).</p> Conclusion <p>The very low CSF concentrations support the rationale for alternative TKIs with improved CNS distribution in patients at risk of CNS relapse.</p>

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Central nervous system penetration of imatinib in acute lymphoblastic leukemia: Pharmacokinetic analysis and clinical implications

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月19日

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  • Anna Sofie Buhl Rasmussen,
  • Cecilie Utke Rank,
  • Ib Jarle Christensen,
  • Allan Weimann,
  • Kasper Hansen,
  • Maria Thastrup,
  • Tianwu Yang,
  • Trine Meldgaard Lund,
  • Hilde Skuterud Wik,
  • Hartmut Vogt,
  • Ulrika Norén-Nyström,
  • Goda Vaitkeviciene,
  • Birgitte Klug Albertsen,
  • Peder Skov Wehner,
  • Bodil Als-Nielsen,
  • Christen Lykkegaard Andersen,
  • Kim Dalhoff,
  • Kjeld Schmiegelow

摘要

Purpose

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.

Methods

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 + or 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.

Results

Between January 2023 and June 2025, 32 paired plasma and CSF samples were collected from ten patients (range 1–8 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: 142–249, p < 0.001), which was even more profound for N-desmethyl-imatinib (geometric mean ratio 273, 95% CI: 218–339, p < 0.001). 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 (p < 0.001), resulting in stable CSF-to-plasma ratio over a median follow-up of 5.7 months (range: 0–14 months).

Conclusion

The very low CSF concentrations support the rationale for alternative TKIs with improved CNS distribution in patients at risk of CNS relapse.