Fludarabine-Associated Neurotoxicity After Hematopoietic Cell Transplantation (HCT): Clinical and Radiographic Features Predict Outcome.
Authors: Beitinjaneh Amer , McKinney Alexander , Cao Qing , Weisdorf Daniel J. 
Published: October 2019

Abstract
Abstract 2270
Poster Board II-247
Central nervous system (CNS) toxicity after HCT is an uncommon, but serious cause of transplant related mortality. Recently, toxic leukoencephalopathy is better defined using advanced MRI techniques. We reviewed all the medical records of HCT recipients (2000-2007) who received Flu-containing conditioning regimens in our institution and developed sever central nervous toxicity. We asked a specialized neuroradiologist to review their brain imagines blindly from patients' outcomes. From our database review, cases were excluded if neurologic symptoms were related to peripheral neuropathy, CNS infection, intracranial bleeding, stroke, CNS malignancy, sedative medication effect, or metabolic disturbance. We were able to identify 39 cases of sever leukoencephalopathy out of total1596 transplants and we described 3 distinct Flu-associated clinical syndromes with unique clinical and radiographic characteristics. Posterior reversible encephalopathy syndrome (PRES, n=17, 1.1%) presented with seizures, persistent headache, or visual changes along with varying compromise in mental status. Acute Toxic Leukoencephalopathy, (ATL, n=11, 0.7%) resulted mainly in cognitive dysfunction, decreased levels of consciousness, and some vision changes. A third distinct Leukoencephalopathy syndrome (LS, n=11, 0.7%) presented similarly to ATL but with less specific and chronic-appearing deep white matter changes on MRI. PRES favors the cortex/subcortical white matter (SCWM) in the early phases and ATL/LS favor the deep periventricular white matter (PVWM) in the early stages, these two entities can usually be distinguished from each other utilizing the combination of fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted images (DWI) MRI techniques (Typically diffusion is reduced in ATL and normal in PRES). Other associated features included: younger age in PRES (median 20 years vs. 55 in ATL and 42 in LS). ATL and LS can be reversible, but to a lesser degree than PRES. PRES developed later (median 77 days post HCT) compared to 30 and 31 days for ATL and LS. Patients who developed ATL had shorter overall survivals than patients with PRES and LS patients (Median overall survival was 6.9 month for PRES compared to 2 months in ATL). ATL/LS compared to PRES were more likely to present with cognitive dysfunction than seizure (refer to table). Flu-associated ATL/LS may be more common in older patients, those with renal dysfunction, prior CNS radiation or chemotherapy, and in patients received higher dose of Flu compared to PRES. Our review suggests Brian MRI with Diffusion-weighted imaging (DWI) can add considerable diagnostic and prognostic information. Prospective Flu pharmacokinetic and pharmacogenetic studies may be needed to determine the most appropriate Flu dosing to avoid neurotoxicity.
Table: Brief summary of patients' characteristics and clinical features. Different Groups Total PRES ATL LS Number 39 17 11 11 Median Age (range) 43 (3-69) 20 55 42 Total conditioning FLU (mg/m2) 200 144 200 200 Baseline Cr CL (mg/min/1.73 m2) 92 100.6 81 85.3 Previous     Flud 3 0 3 0     CNS Therapy 13 2 6 5     HCT 9 2 5 2 Presenting Symptom     Seizure 8 (21%) 7 (41%) 0 1     Confusion /cognitive 12 (30%) 2(12%) 5 (46%) 5 (46%) Median survival (days) 169 208 66 204 Death Related 13 2 7 4

Disclosures:
No relevant conflicts of interest to declare.