Severe central nervous system toxicity after fludarabine, thiotepa and melphalan conditioning for allogeneic stem cell transplantation
Neurological complications (NC) are a known but heterogeneous risk after allogeneic stem cell transplantation (allo-SCT). Although the exact incidence remains poorly defined, we observed an unexpectedly high rate of severe central nervous system (CNS) events after conditioning with fludarabine, thiotepa and melphalan (Flu-Thio-Mel). This raised concern for potential regimen-related toxicity. We therefore aimed to systematically characterize neurotoxicity after Flu-Thio-Mel-based allo-SCT, identify possible risk factors, and compare outcomes with a cohort receiving fludarabine and busulfan (Flu-Bu).
This retrospective single-center study included all 55 adult patients who received allo-SCT conditioning with anti-thymocyte globulin (ATG)-Fresenius and Flu-Thio-Mel between 2019 and 2024. All new, recurring or worsening NC within one year post-SCT were reviewed for type, location, severity, etiology, and outcome. CNS toxicity was defined as NC involving the CNS in which toxicity by the conditioning was deemed the most probable cause by neurologists. In a comparator cohort, 47 patients received ATG-thymoglobulin and Flu-Bu conditioning between 2019 and 2022, with otherwise similar transplantation procedures.
Potentially toxic NC occurred in 17 patients (30.9%) in the Flu-Thio-Mel and 15 patients (31.9%) in the Flu-Bu cohort. Neuropathy was the most frequent drug-related NC in both groups (7 versus 9 cases). However, NC after Flu-Thio-Mel occurred earlier (median 46 versus 103 days post-SCT, p=0.043) and were more often fatal (5 versus 0 cases) than NC after Flu-Bu. CNS toxicity was observed in 7 Flu-Thio-Mel patients (12.7%) but in none of the Flu-Bu patients (p=0.014). The median onset of CNS toxicity was 32 days post-SCT (range: 6-139). It occurred in three distinct clinical patterns with CTCAE grades 2 through 5. 3 patients developed fatal leukoencephalopathy, 2 patients developed severe encephalomyelopathy with remaining deficits, and 2 patients developed myeloneuropathy with minimal sequelae. Patients with CNS toxicity were older (median 66 versus 54.5 years, p=0.024) and had a lower renal function (median eGFR 72.57 versus 105.13 mL/min/1.73m2, p=0.024) than those without. No association was found between CNS toxicity and sex, diagnosis, donor type, prior chemotherapy, neurological history, or graft-versus-host-disease (GVHD).
Neurotoxicity was frequently observed (31-32%) after both Flu-Thio-Mel and Flu-Bu conditioning for allo-SCT, highlighting a potential underrecognized complication. Severe and sometimes fatal CNS toxicity appeared specific to Flu-Thio-Mel conditioning. These findings suggest that standard-dose Flu-Thio-Mel may be contra-indicated in older patients and those with even mild renal impairment, and underscore the need for awareness and prospective studies.