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

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.