Dorsal Column Myelopathy Following Intrathecal Chemotherapy for Leukemia

Abstract

Intrathecal (IT) methotrexate (Mtx) and/or cytarabine (AraC) improve CNS disease control in patients (pts) with hematologic malignancies. There are increasing number of case reports of irreversible, primarily dorsal column myelopathy in pts treated with IT chemotherapy. By describing the largest case series of myelopathy following IT chemotherapy, we aim to raise awareness about this devastating albeit rare complication. We retrospectively reviewed 25 pts with leukemia who developed paraplegia following IT chemotherapy between 2/2006 and 9/2021. Clinical/treatment characteristics, response, and toxicity were extracted from the medical records. Seventeen pts (68%) were male, 16 had B-cell ALL (64%), 4 had AML (16%), 2 had CML (8%), 2 had T-ALL (8%), and 1 had BPDCN (4%). The median age at diagnosis was 38 years (IQR 30-59). All pts required systemic salvage treatment after induction chemotherapy with a median number of 3 regimens received (IQR 2-5.5). In total, the median number of IT treatments was 19 per pt (IQR 14-27). Most pts (84%, n = 21) received single agent IT Mtx alternating with single agent AraC. Fifteen pts (60%) received triple IT therapy with a median of 3 treatments (IQR 0-8). Prior to the onset of myelopathy, 10 pts (40%) received allogeneic SCT and 9 pts (36%) were treated with radiation therapy. Median follow-up from diagnosis was 1.9 yrs (IQR 1.3-4.1). Myelopathy was progressive and irreversible in all pts (n = 25); 84% (n = 21) experienced sensory loss, and all pts had extremity weakness. Symptoms were ascending in 11 pts (44%) and descending in 4 pts (16%). Irreversible bowel/bladder incontinence developed in 12 pts (48%). CSF analysis at the time of symptom onset was negative for leukemia cells in most pts (n = 21, 84%) and showed malignant cells in 4 pts (16%). CSF studies showed elevated protein in 21 pts (84%). Myelin basic protein was elevated in all 13 assessed pts. On T2 weighted spinal MRI, all pts had enhancement of the dorsal columns, including 80% of pts with this dorsal column abnormality reported at the time of the study and 20% of pts (n = 5) with the dorsal enhancement noted retrospectively. Due to concern for occult disease, 20 pts (80%) received additional CNS-directed therapy after symptom onset. Twenty-two pts (88%) died at last follow-up. The time between neurological symptom onset and death was a median 3.5 months (IQR 2.6 and 5). Three pts (12%) are alive with paraplegia at a median of 4.4 years from symptom onset. Dorsal column myelopathy is a rare but devastating condition that can occur after IT chemotherapy in heavily pre-treated leukemia pts. T2 weighted spinal MRI can be helpful in the evaluation of pts that present with unexplained weakness and sensory changes. We recommend delaying additional CNS-directed therapy until work-up to rule out alternative etiologies is complete. Future strategies are desperately needed to address this irreversible treatment complication.