Arsenic Trioxide Entered Cerebrospinal Fluid with the Help of Mannitol Overwhelm the Meningeal Relapse of Acute Promyelocytic Leukemia.

Background and objective Central nervous system (CNS) relapse of acute promyeloytic leukemia (APL) is increasingly reported after treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (As₂O₃), the optimal therapy for these cases remains unclear. As₂O₃ highly effective in APL marrow relapse, but its efficacy in APL CNS relapse is undefined. Recent researches showed that little As₂O₃ could pass through the intact blood- brain-barrier (BBB), which limits its use in prevention and treatment of central nervous system acute promyelocytic leukaemia (CNSAPL). After discovered the different tolarance between NB4 cell line and human cortex neuron to As₂O₃in vitro, and primarily cleared the safe range of As₂O₃ level in central nervous system (CNS), we created a non-invasive method to help As₂O₃ enter into CNS effectively.

Methods Five volunteers with isolated meningle APL relapse received the new As₂O₃ regimen (mannitol helped As₂O₃ penetration) after accepted the conventional treatment: As₂O₃ 0.16mg/kg/d diluted with 5%glucose 250ml common speed intravenous infusion with intensive intrathecal chemotherapy (MTX 12mg/dose + cytarabine 50mg / dose + Dexamethasone 10mg/dose) and showed chemotherapy resistance. The new regimen included 125ml of 20% mannitol bolus through medial cubital vein with the speed of 12„d`30ml / min, followed by As₂O₃ 0.08mg/kg/d diluted with 250ml-20% mannitol intravenous infusion with the speed of 6ml /min, and then followed by As₂O₃ 0.08mg/kg/d diluted with 5%glucose 250ml intravenous infusion with the speed of 0.5ml/min, meanwhile, associated with intensive intrathecal chemotherapy. The elemental arsenic levels in CSF and plasma during the new regimen performance were dynamic monitored with atomic fluorescence, and the differentiation and apoptosis of the blast cells in CSF were detected with flow cytometry assay.

Results The elemental arsenic level in the CSF treated with mannitol helped As₂O₃ penetration was fluctuated between 0.04 mg /L (0.2 micromol /L) and 0.05mg / L(0.25 micromol /L), which was much higher than that with common speed As₂O₃ intravenous infusion, and reached to the As₂O₃ effectively therapeutic level. The blast cells in CSF showed significant differentiation and apoptosis after treated with mannitol helped As₂O₃ penetration. Three of the five patients obtained complete remission, two of them reached partial remission.

Conclusions The new regimen of mannitol helped As₂O₃ penetration promoted the entrance of elemental arsenic to CNS, which might be benefit to prevent and cure CNS APL, especially to chemotherapy resistant CNS APL.