Arsenic trioxide entered cerebrospinal fluid with the help of mannitol overwhelm the meningeal relapse of acute promyelocytic leukemia

Central nervous system (CNS) relapse of acute promyeloytic leukemia (APL) is increasingly reported after treatment with arsenic trioxide (As₂O₃),1 the optimal therapy for this case remains unclear. As₂O₃ highly effective on APL marrow relapse, but its efficacy in CNS relapse is undefined. Recent researches showed that little As₂O₃ passed through the blood-brain-barrier (BBB) with general intravenous infusion.2,3 which limited its use in CNS relapse of APL (CNSAPL). After discovered the different tolarance between APL blasts and human cortex neuron to As₂O₃ in vitro,4,5 and primarily cleared the safe range of As₂O₃ concentration in CNS,5–7 we created a non-invasive method to help As₂O₃ enter into CNS,8 which indicated that 20% mannitol intravenous bolus at the speed of 0.2 ± 0.5 mL/s opened BBB temporarily . Can this method increase arsenic concentration to therapeutic and safe level in CNS? Can As₂O₃ be used to prevent and treat CNSAPL? The treatment of a patient with isolated meningle APL relapse and chemotherapy resistance gave us the unique opportunity of documenting CNS penetration of As₂O₃ helped by mannitol intravenous bolus, which included 125 ml of 20% mannitol bolus through medial cubital vein with the speed of 12 ± 30 mL/min, and followed with 250 mL mixed liquor (including 20% mannitol and As₂O₃ 0.08 mg/kg/d) intravenous infusion with the speed of 6 mL/min, subsequently followed by As₂O₃ 0.08 mg/kg/d + 5% glucose 250 mL infusion with the speed of 0.5 mL/min, the total dosage of As₂O₃ is also 0.16 mg/kg/d.

A 34-year-old woman developed APL eight years ago, experienced two times of marrow relapse and one time of CNS relapse, and achieved complete remission after treated with As₂O₃ (0.16 mg/kg/d) general intravenous infusion and ATRA oral, supplemented by mitoxantrone for leukocytosis and intrathecal methotrexate (12 mg/dose) and cytarabine (50 mg/dose). The CSF was gradually normalized (CR3).Three months after CR3, the patient represent a heavy headache, the number of blasts in CSF was 1500/L, and the intracranial pressure was 2.8 kPa. Head magnetic resonance imaging (MRI) scan showed no local lesion. Marrow examination was normal. After accepted six-days As₂O₃ general intravenous and two times of intrathecal methotrexate (12 mg/dose) and cytarabine (50 mg/dose), her symptoms and signs were not improved, and the intracranial pressure reached to 3.6 kPa, the number of APL blasts in CSF increased to 2050/L. It was clear that chemotherapy resistance occurred. We gave her the mannitol assisted As₂O₃ penetration therapy after obtained an informed consent. Spinal fluid was collected by lumber pouncture at the 30 min after As₂O₃ infusion finished every three-day. Arsenic levels in CSF were monitored dynamically by atomic fluorescence method. The apoptosis rates and CD33/CD11b ratios of APL blasts were assayed by flow cytometry. The morphologic and agarose gel electrophoresis were used to evaluated apoptosis.