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

Abstract

Background. Intrathecal chemotherapy, radiation therapy, and systemic chemotherapy are used for both prophylaxis and treatment of central nervous system (CNS) disease in hematologic malignancies. Twenty‐three cases of myelopathy that occurred in patients who received intensive CNS‐directed therapy were evaluated to identify the determinants of this severe CNS toxicity. Methods. Nine cases treated by the authors and 14 collected from the literature are discussed. Twelve had Burkitt's leukemia/lymphoma. Patient ages ranged from 3 to 30 years (median, 15 years). The dose intensity of CNS‐directed therapies, including intrathecal cytosine arabinoside (ara‐C), intrathecal methotrexate (MTX), systemic high dose (HD) MTX, systemic HD ara‐C, systemic thiotepa, and CNS radiation, was evaluated by the determination of single drug doses and cumulative total drug or irradiation doses over elapsed treatment durations. Results. Central nervous system treatment was prophylactic in 10 cases; active CNS disease was being treated in 13 cases. One patient received only intrathecal ara‐C before toxicity occurred; others received intrathecal ara‐C and varying combinations of intrathecal MTX, HD ara‐C, HD MTX, CNS radiation, and systemic thiotepa. Eight patients died of toxicity, of whom 6 had autopsy‐proven cord necrosis; 3 were ventilator‐dependent; 10 had persistent paraplegia or paraparesis; and 2 recovered completely. Conclusion. Both highly intensive, short CNS treatment sequences and lower intensity, long term cumulative treatments may result in this rare but severe myelopathy. The cause is multifactorial, with systemic chemotherapy, intrathecal chemotherapy, and radiation therapy contributing to toxicity. Multiple intrathecal ara‐C and/or MTX doses given at frequent (daily) intervals should be avoided. Concurrent intrathecal ara‐C and systemic HD ara‐C also appear to be especially toxic. Intrathecal hydrocortisone given with intrathecal ara‐C does not protect against myelopathy. Multiple, frequently spaced courses of CNS‐directed therapies must be avoided, especially in patients who have received prior CNS radiation.

Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children

“…Furthermore, the review of 12 other cases of the literature does not allow firm conclusions concerning cumulative compared with a dose-toxic threshold with Cyt. 39 In the study by Watterson et al, 40 on 23 patients with hematologic malignancies (n ¼ 17), or solid tumors (n ¼ 6) receiving an intensive CNS prophylactic (13 had CNS involvement), three received only Cyt IT before developing myelopathy. Pui et al 41 have shown that therapeutic escalation by TIT in ALL significantly reduces the risk of CSF relapse (165 patients, estimated risk 1.2%).…”

Radiation myelitis following allogeneic stem cell transplantation and consolidation radiotherapy for non-Hodgkin's lymphoma

“…24 However, such risk is limited to 5% if systemic methotrexate is not administered. 25 Although spinal myelopathy has been observed following intrathecal methotrexate and/or cytarabine with craniospinal irradiation in children, 26 this experience is very limited and no formal association has been rigorously established. The use of intrathecal therapy in patients at risk for CNS relapse following transplant improves freedom from disease relapse within the neuroaxis 27 and is standard practice for high risk patients.…”

Motor nervous system impairment persists in long‐term survivors of childhood acute lymphoblastic leukemia

“…1,4 Vincristine, which has been one of the basic elements in the treatment of leukemia and other malignancies since it first was introduced in 1962, is known to cause impaired motor function as a symptom of peripheral neuropathy during treatment. 5 The clinical signs of nerve injury are depression of deep tendon reflexes, motor weakness and clumsiness, and sensory involvement.…”