Arsenic trioxide and mannitol for the treatment of acute promyelocytic leukemia relapse in the central nervous system.


Approximately 3% to 5% of patients with acute promyelocytic leukemia (APL) will have an extramedullary relapse in their lifetimes, most commonly in the central nervous system (CNS). CNS relapse can be isolated or associated with a bone marrow (BM) relapse. The most appropriate clinical management remains controversial. The major obstacle to all treatments is the need for the therapeutic drugs to penetrate the blood-brain barrier (BBB). Although arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are among the frontline medications for APL intramarrow treatment, these water-soluble medicines have limited ability to cross the BBB and cannot reach therapeutically effective levels in the cerbrospinal fluid (CSF). With regular oral doses, the ATO level in CSF has been reported to reach only 17.7% of the corresponding levels in plasma. Previously, we investigated the potential efficacy of combination therapy with mannitol and ATO using a rabbit model, and we showed that the approach caused a transient increase in the BBB permeability for ATO, thereby increasing the ATO concentration in CSF. Our experiments using human cortical neurons revealed a differential tolerance of APL blasts to different concentrations of ATO.We also identified a safe range of ATO concentrations in the human CNS. The results from these collective studies allowed an ATO concentration in CSF that was both safe and therapeutic to be achieved. Here, we describe our efforts to extend the application of our method to additional patients. This study was registered at (#ISRCTN94954912). The study protocol was reviewed and approved by the Harbin Medical University Medical Ethics Committee, and signed informed consent was obtained from all patients or their legal guardians. Seventeen CNS APL patients diagnosed between 2000 and 2010 were included in this study (10 males and 7 females, between 6 and 50 years old). Expression of the PML/RARa gene [or t(15;17)(q22;q21) transcripts] was detected in all patient CSF. For all patients, the induction treatment was started immediately on diagnosis. The daily protocol was as follows: a bolus infusion of 125mLof 20%mannitolmixed in 100 mL normal saline (NS) (for children #15 years old: 50 mL mannitol and 50 mL NS) was administered intravenously at a flow rate of 12 ;20 mL/min (;8-11 minutes total), followed by a slow intravenous infusion of 125mLof 20%mannitol plus 7.0mg/m/day ATO (for children#15 years: 50 mL mannitol and 0.16 mg/kg/day ATO) in 500 mL NS at a flow rate of 1.0 mL/min (;9-10.5 hours total). Patients were instructed to rest in bed during the entire procedure. Urine flow was measured to ensure maintenance of a rate of at least 30 to 50 mL/h. Daily infusions were continued until the patient’s CSF was found to be free of APL blasts/ promyelocytes. The level of elemental arsenic metabolites was measured in each patient’s CSF and blood samples, which had been taken immediately after every other day’s infusion. Consolidation therapy started 2weeks after the induction therapy and was repeated at 2-week intervals. A total of 3 cycles of consolidation therapy was given to all the patients who achieved normal CSF morphology with induction treatment. For each cycle of consolidation, daily ATO and mannitol infusion (administered as described for the induction treatment) continued for 14 consecutive days. Absence of PML/RARa transcripts in CSF and BM (defined as complete molecular remission [CMR]) was achieved prior to commencement of lifetime maintenance therapy. The first year after CMR, a 14-day cycle administration of ATO and mannitol was repeated at 1-month intervals. In the second year, a protocol identical to that of year 1 was instituted, but using a 3-month interval regimen. From the third year on, the protocol was administered at 6-month intervals and maintained for life. PML/RARa levels were monitored at 6-month intervals. If a relapse was identified, another cycle of remission induction was started. Clinical monitoring and supportive treatment followed our departmental guidelines. In 16 of the 17 patients examined, abnormal blasts/promyelocytes from CSF were eliminated in 18 to 32 days (median, 24 days) after the start of induction treatment. All the patients tolerated the induction well. There were no complaints of side effects associated with the use of mannitol. There were no documented cases of acute

DOI: 10.1182/blood-2014-04-568121

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