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Neurotoxicity Following Intrathecal Chemotherapy

In a phase II study, intrathecal liposomal cytarabine was associated with unexpected neurotoxicity in some ALL patients who received concomitant high-dose intravenous methotrexate and cytarabine.

Patients with acute lymphoblastic leukemia (ALL) have substantial risk for developing leptomeningeal leukemia; thus, central nervous system (CNS) prophylaxis with intrathecal (IT) methotrexate and cytarabine is a well-established component of induction therapy. Liposomal cytarabine (DepoCyt), an FDA-approved agent for treatment of lymphomatous meningitis, is of interest for CNS prophylaxis because it is effective for treating active leptomeningeal disease and, due to its depot formulation, can be administered less frequently than standard cytarabine.

Investigators at the M.D. Anderson Cancer Center conducted a phase II study of liposomal cytarabine IT prophylaxis (3 to 6 treatments) in conjunction with the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone)/high-dose methotrexate-cytarabine regimen in adults with ALL, lymphoblastic lymphoma, or Burkitt lymphoma. Unexpected serious neurotoxicity was observed in 5 of 33 patients — in 2 during ongoing therapy and in 3 after completion of induction chemotherapy. One patient died of encephalitis, two developed cauda equina syndrome, one developed increased intracranial pressure due to pseudotumor cerebri, and one developed a seizure disorder. None of the 33 study patients developed isolated CNS relapse, although 1 of 3 patients with systemic relapse had coexisting CNS disease.

Comment: As noted by the authors, grade 3 or 4 neurotoxicity occurs in <1% of CNS prophylaxis patients who receive standard IT methotrexate, cytarabine, or combined regimens. They propose that the neurotoxicity observed in the current study is related to concomitant high-dose IV methotrexate and cytarabine. As such, these phase II results suggest that IT liposomal cytarabine should be avoided in patients who are receiving high-dose systemic regimens that penetrate the blood-brain barrier.

— Michael E. Williams, MD

Published in Journal Watch Oncology and Hematology April 30, 2007

Citation(s):

Jabbour E et al. Neurologic complications associated with intrathecal liposomal cytarabine given prophylactically in combination with high-dose methotrexate and cytarabine to patients with acute lymphocytic leukemia. Blood 2007 Apr 15; 109:3214-8.

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