Low Penetration of Imatinib (STI571) into the CSF Indicates the Need for Standard CSF Prophylaxis in Patients with CML Lymphoid Blast Crisis and Philadelphia Chromosome Positive ALL

Reviewer: Walter F. Sall, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: December 8, 2001

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Presenter: Jose F. Leis
Affiliation: Oregon Health & Sciences University

Background:

  • Chronic Myelogenous Leukemia (CML) and Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (PH+ ALL) are hematologic malignancies caused by the BCR-ABL gene, a constitutively active tyrosine kinase fusion protein generated by a 9:22 translocation.
  • These diseases have an extremely poor prognosis with poor response to conventional chemotherapy. Most patients progress to have extra-medullary disease, most commonly in the CNS. The Blood Brain Barrier excludes most chemotherapy agents, presumptively causing the CNS to function as a sanctuary site for disease, requiring CNS targeted therapies such as radiation or intra-thecal chemotherapy.
  • Gleevec is a powerful specific inhibitor of BCR-ABL tyrosine kinase activity, known to produce a hematologic response in the majority of these patients refractory to conventional chemotherapy. In a recent series at this institution, several patients in blast crisis CML (CML-BC) or PH+ ALL , who responded to Gleevec, sustained CNS relapse. Gleevec pharmacokinetics are analyzed for four of these patients in this study.

Materials and Methods

  • 42 patients with CML-BC or Ph+ALL were enrolled in a toxicity and efficacy trial of Gleevec. Dose ranged from 400 to 1000mg. Four weeks must have elapsed from the completion of conventional chemotherapy prior to initiating Gleevec therapy.
  • CBC was checked three times weekly and bone marrow aspirate was evaluated every month.
  • No CNS prophylaxis was used.
  • Plasma and CSF levels of Gleevec were assayed using liquid chromatography and mass spectrophotometric assay for four patients. Two patients had suffered CNS failure and two patients had not.

Results:

  • Eight of 42 patients suffered CNS relapse. Five of these had had a complete hematologic response with Gleevec therapy. Three of the relapses occurred within 4 days of the commencement of Gleevec therapy.
  • CSF Gleevec levels were found to be 74 fold lower than serum levels in the four tested patients.
  • CSF levels of Gleevec were found to be significantly below the levels required for inhibition of BCR-ABL activity.

Author's conclusions:

  • Patients with CML-BC and Ph+ALL treated with Gleevec are at high risk for CNS failure even in the setting of complete hematologic response.
  • Gleevec may not penetrate the CSF as evidenced by CSF levels 74 times lower in the CSF than in serum.
  • CSF Gleevec levels are below the threshold necessary for BCR-ABL inhibition and cell death in vitro.
  • CNS prophylaxis is indicated for all patients with CML-BC or Ph+ALL who are being treated with Gleevec.
  • Future directions for research include studying intrathecal Gleevec and/or blood brain barrier disruption.

Clinical/Scientific Implications:

Gleevec, a novel molecularly targeted leukemia therapy, has efficacy superior to conventional chemotherapy in CML-BC or Ph+ALL but has a similar lack of efficacy in CNS disease due to poor penetration of the blood brain barrier. Until a means of increasing CSF Gleevec levels is introduced, conventional CNS prophylaxis should be considered in patients receiving Gleevec for CML-BC or Ph+ALL.