Effective Treatment of Basophilic Leukemia of the Central Nervous System in a CML Patient with the Combination of Imatinib Mesylate and Valproic Acid.

Abstract

Imatinib is effective in all stages of CML but the level of the drug in the cerebral spinal fluid is two logs lower than in the plasma. In November, 2000 a 35 years old man in CML chronic phase was treated with interferon (10MU/day) and achieved complete hematologic remission. Two years later he progressed to myeloid blastic crisis. The patient was treated with an acute leukemia protocol (60mg/m2 daunorubicin days 1–3, 200 mg/m2 ara-C days 1–7). After hematological recovery 600 mg/day imatinib was administered continuously. 9 months later headache and vomiting indicated CNS involvement. In the CSF presence of Ph+ basophilic leukemia cells (1,27G/l) was proven by FISH. Although the patient was given intrathecal methotrexate(15mg), cytarabine(40mg) and dexamethasone(4mg), the headache was a permanent problem with persistent basophilia in the liquor. In vitro culture of his bone marrow cells at the time of the blastic phase was tested for drug sensitivity to different doses of imatinib alone or in combination with other antitumor drugs. In the in vitro growth assay 5 uM imatinib alone, 5mM valproic acid alone and 0,5uM imatinib + 5mM valproic acid together caused 15%, 33% and 80% decrease in cell survival, respectively, suggesting that combinations with valproic acid, (an anticonvulsive agent) would be more effective. Based on the results of our previous growth assay the therapy was supplemented with valproic acid (4x150mg/day). The meningeal leukemia resolved in 3 weeks and the patient had no complaint for 3 months with the same therapy.We find it noteble that basophilic CNS blast crisis was exquisitely sensitive to the administration of imatinib in combination with valproic acid, an anticonvulsive agent with antitumor activity.