Phase 2 clinical trial of intrathecal topotecan in children with refractory leptomeningeal leukemia: A Children's Oncology Group trial (P9962)

Abstract

Purpose We performed a phase 2 study in children with recurrent or refractory leptomeningeal leukemia to determine the objective response rate after treatment with intrathecal topotecan. Patients and Methods Patients received age-adjusted intrathecal topotecan (0.4 mg/dose for patients > 3 years of age) administered twice weekly (every 3 to 4 days) for six weeks during induction, weekly for 4 weeks during consolidation, and twice monthly for 4 months and then monthly thereafter during maintenance. Results Twenty-two patients enrolled in the study, of whom 20 were eligible and assessable for toxicity and 16 were assessable for response. Of 16 patients, 6 (38%) had a complete response, 8 (50%) had stable disease, and 2 (13%) had progressive disease. The median EFS time (95% CI) was 3.1 (1.6 – 10.3) months and the median overall survival time (95% CI) was 18.0 (7.3 – 38.3) months. Eight patients (40%) experienced grade 3 or 4 adverse events. There were no grade 4 neurological events (Table III). Four patients experienced a total of 6 grade 3 neurological events including an olfactory seizure, a headache, transient grade 3 speech impairment, muscle weakness, motor neuropathy, and ataxia. Headache was the most common grade ≤ 2 neurologic event and two patients developed grade ≤ 2 arachnoiditis. Conclusion Intrathecal administration of topotecan was tolerable on this dose and schedule. The majority of adverse events were mild to moderate, reversible side effects. Complete central nervous system remissions were achieved in a subset of children with recurrent or refractory CNS leukemia.

Topoisomerase 1 inhibition reversibly impairs synaptic function

“…Furthermore, TOP1 cleavage complexes and DNA damage accumulate in mouse models of the neurodegenerative syndromes ataxia telangiectasia and spinocerebellar ataxia with axonal neuropathy (51). Cancer patients (including children) treated with topotecan report memory impairment and confusion suggestive of deficits in synaptic function and neurotransmission (52)(53)(54). Thus, transient TOP1 inhibition has the potential to impair brain function reversibly, whereas a persistent change in TOP1 activity has the potential to disrupt neurodevelopment and promote neurodegeneration.…”

Correlating Pathology With the Clinical Symptoms of Methotrexate-induced Leukoencephalopathy in a Child With Relapsed T-cell Acute Lymphoblastic Leukemia

“…Only 1 complication of leukoencephalopathy was reported, although the study size was small. 20 Our patient did receive IT topotecan to prevent relapse without effect. It did not, however, exacerbate her CNS symptoms.…”

Combined high‐dose intra‐arterial and intrathecal chemotherapy for the treatment of a case of extraocular retinoblastoma

“…Finally, as previously published, we highlight the activity and safety of intrathecal topotecan for high‐risk retinoblastoma with CSF involvement included in this multimodality treatment . We selected intrathecal topotecan based on its activity in retinoblastoma and previous reports for intrathecal use …”

“…IAC alone would not be effective for the control of leptomeningeal dissemination, which is usually present in these cases. Intrathecal or ideally intraventricular chemotherapy would lead to pharmacologically active drug concentrations in the cerebrospinal fluid (CSF) and because of its low toxicity profile it may be administered concomitant to IAC …”