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Dasatinib Active Against Ph+ Leukemia With CNS Involvement

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NEW YORK (Reuters Health) Sept 05 - Dasatinib, a second-generation dual-specific BCR-ABL kinase inhibitor, penetrates the blood-brain barrier and has promising therapeutic potential for Philadelphia chromosome-positive leukemia that has spread to the CNS, researchers report in the August 15 issue of the journal Blood.

While imatinib has proven to be an effective agent against Ph+ leukemia, up to 20% of imatinib-treated patients will develop CNS relapses, note Dr. Kimmo Porkka from Biomedicum Helsinki, Finland, and colleagues. Many Ph+ leukemia cases with CNS involvement are seen, "despite complete responses in peripheral blood and bone marrow, and are attributable to poor penetration of imatinib into the cerebrospinal fluid with inadequate concentrations for kinase inhibition," the investigators point out.

Dr. Porkka and colleagues have observed in a mouse model of intracranial Ph+ leukemia that dasatinib increased survival whereas imatinib failed to inhibit intracranial tumor growth, an observation seen in other preclinical and clinical studies, they note. Moreover, with continued dasatinib administration, "stabilization and regression of CNS disease was achieved."

Dasatinib also showed substantial activity in 11 adult and pediatric patients with CNS Ph+ leukemia. "Clinically meaningful responses were achieved with dasatinib even as monotherapy and were maintained for more than or equal to 6 months in 45% of patients," Dr. Porkka and colleagues report.

In three additional patients, isolated CNS relapse occurred during dasatinib treatment; in two of them, the cause was expansion of a BCR-ABL-mutated dasatinib-resistant clone. "This suggests a strong selection pressure exerted by dasatinib and thus access of the drug into the CSF," the researchers note.

"Dasatinib," they conclude, "may prove to be a valuable alternative to imatinib and an addendum to conventional cytotoxic therapy for Ph+ CNS leukemia. Prospective, controlled studies are warranted to more fully determine treatment responses and characterize drug tolerability and safety in this patient population."

Blood 2008;112:1005-1012.