LAUSR

Dear Editor, We present a 72-year-old patient with cardiovascular risk factors and acute Philadelphia positive B cell lymphoblastic leukemia (B-ALL) since 2017 treated with tyrosine kinase inhibitors, imatinib and dasatinib; 6 cycles of vincristine, cyclophosphamide, etoposide and velcade; and 12 monthly intrathecal (IT) methotrexate (MTX) injections of 12.5 mg with folic acid rescue. After treatment, he remained in asymptomatic remission for 1 year but then developed low back pain and mild leg weakness with hyporeflexia, down going plantar response, and spinal sensory deficit up to T12 level. MRI of the whole spine demonstrated significant degenerative changes and a subtle intramedullary nonenhancing T2-signal prolongation from D11 to conus medullaris, suggestive of a chronic IT MTX myelotoxicity (Fig. 1a, b). Cerebral MRI was noncontributory; cerebrospinal fluid (CSF) analysis yielded elevated protein, malignant lymphocytes, and positive BCRABL and B cell immunoglobulin gene rearrangement, confirming the diagnosis of a secondary leptomeningeal involvement by leukemia; and he received 50 mg IT cytosine arabinose (Ara-C) with dexamethasone PO 8 mg for 3 days without immediate complications. In 2 days, he developed severe painless flaccid paraplegia, leg areflexia, bilateral upgoing plantar response, spinal sensory deficit to T10 level, and partial urinary incontinence. Second MRI demonstrated worsening of the nonenhancing intramedullary T2prolongation with cord expansion extending from D8-D9 to conus medullaris (Fig. 1c, d), suggestive of a myelopathy progression. CSF analysis showed normal protein and glucose, 50 polymorphonuclear cells, and negative cytology, culture and negative PCR for HSV1, HSV2, EBV, CMV, enterovirus, VZV, JC-virus and HHV6. CSF oligoclonal bands were positive, and paraneoplastic panel with anti-Hu, anti-Yo, and anti-Ri was negative. Because of the subacute onset, myelitis was clinically suspected, and treatment with IV solumedrol was initiated. After a week, he regained antigravity muscle strength in the legs, but could not stand. Third MRI showed partial resolution of the MRI findings (Fig. 1e, f), and Ommaya reservoir was inserted for further administration of IT MTX, without Ara-C. The patient died from massive pulmonary emboli with cardiorespiratory failure. Intravenous or IT MTX and Ara-C are frequently used in leukemia and lymphoma for prophylaxis and treatment and are variably reported with significant neurological complications in up to 8% of patients [1]. Our patient received initially 12 monthly prophylactic IT MTX injections, but developed severe symptomatic myelopathy shortly after a single IT AraC delivered for the treatment of leptomeningeal leukemia. Known risk factors for neurological complications, including myelopathy, in IT therapy are high ITMTX dose, systemicMTX, repeated injection in less than 1 week, concurrent use of certain medications or cranial radiotherapy, active CNS disease, and MTHFR C677T polymorphism [1–3]. Although our patient had active leptomeningeal involvement at the diagnosis of myelopathy, his fulminant symptomatology was clearly time-related to the single IT Ara-C. Both IT MTX and Ara-C are implicated in chemotherapy-related myelopathy [1, 2, 4, 5], but the 12 initial preventive ITMTX injections in our patient remained symptomatically uneventful, suggesting that IT Ara-C injection for leptomeningeal leukemia is the probable trigger for his myelopathy. Furthermore, as detoxifying Ara-C enzyme, cytidine deaminase, is absent in CSF and the agent is eliminated by flow [4], prolonged exposure of the previously affected by MTX spinal cord in our patient * L. Mikhelashvili [email protected]