Excessive spinal cord toxicity from intensive central nervous system-directed therapies

Area of Science:

• Neuro-oncology
• Hematology
• Pharmacology

Background:

• Central nervous system (CNS) disease in hematologic malignancies is managed with intrathecal chemotherapy, radiation therapy, and systemic chemotherapy.
• This study evaluates 23 cases of myelopathy following intensive CNS-directed therapy to identify causes of severe CNS toxicity.

Observation:

• Myelopathy occurred in patients receiving various combinations of intrathecal cytosine arabinoside (ara-C), intrathecal methotrexate (MTX), high-dose (HD) systemic MTX, HD systemic ara-C, systemic thiotepa, and CNS radiation.
• Treatment was prophylactic in 10 cases and for active CNS disease in 13 cases.
• Outcomes included death (8 patients), autopsy-proven cord necrosis (6 patients), ventilator dependence (3 patients), persistent paraplegia/paraparesis (10 patients), and complete recovery (2 patients).

Findings:

• Both intensive, short-term and lower-intensity, long-term cumulative CNS-directed therapies can lead to severe myelopathy.
• Myelopathy is multifactorial, involving systemic chemotherapy, intrathecal chemotherapy, and radiation therapy.
• Specific toxic combinations include frequent daily intrathecal ara-C and/or MTX, and concurrent intrathecal ara-C with systemic HD ara-C.

Implications:

• Frequent intrathecal chemotherapy administration, especially in patients with prior CNS radiation, should be avoided.
• Concurrent intrathecal and systemic high-dose ara-C is particularly toxic and should be used with extreme caution.
• Careful regimen design is essential to mitigate the risk of severe CNS toxicity in patients with hematologic malignancies.