Survival benefit and immune-related toxicities after hematopoietic stem cell transplantation in Krabbe disease: a systematic review and meta-analysis.

Background: Krabbe disease is a rare, rapidly progressive leukodystrophy with high early mortality. Hematopoietic stem cell transplantation (HSCT) is the main disease-modifying intervention used in clinical practice and may act through donor-derived myeloid and immune-cell replacement, enzymatic cross-correction, and immunomodulation. However, its benefits and immune-related toxicities remain incompletely quantified. Methods: We conducted a systematic review and meta-analysis of studies reporting HSCT outcomes in genetically or enzymatically confirmed Krabbe disease. The primary outcome was overall survival (OS). Secondary outcomes included 5-year OS, transplant-related mortality (TRM), acute and chronic graft-versus-host disease (aGVHD and cGVHD), neurological stability, and MRI stability. For OS, publication bias or small-study effects were assessed using funnel-plot inspection and Egger's regression test. Exploratory univariable meta-regression examined total study sample size, publication year, and Newcastle-Ottawa Scale (NOS) score, and robustness was assessed using leave-one-out sensitivity analysis. Results: Fifteen studies involving 141 patients were included. Pooled OS after HSCT was 84% (95% CI, 75%-93%), 5-year OS was 80% (69%-92%), and TRM was 7% (1%-13%). The pooled incidences of aGVHD and cGVHD were 53% (16%-90%) and 25% (0%-53%), respectively. Neurological stability was reported in only four studies including 15 patients (77%; 31%-100%), and MRI stability in four studies including 32 patients (49%; 7%-90%); both estimates showed substantial heterogeneity and wide confidence intervals. Subgroup analyses by disease-onset age, pre-transplant symptom status, and age at HSCT showed no statistically significant OS differences. Egger's test detected no significant funnel-plot asymmetry (P = 0.569). Leave-one-out estimates ranged from 82% to 86%. Meta-regression showed inverse associations of reported OS with total study sample size and NOS score (both P < 0.001), whereas publication year was not significant (P = 0.118). Conclusion: HSCT is associated with favorable survival and relatively low pooled TRM in selected patients with Krabbe disease. However, survival should not be interpreted as preservation of neurological function, because neurological, MRI, and GVHD outcomes were reported in few studies and patients and remained heterogeneous and imprecisely estimated. These findings require cautious interpretation but provide clinically useful benchmark data for counseling and comparison with emerging cellular and gene-based therapies. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261285624.