Background: Unrelated donor umbilical cord blood transplantation (UCBT) is beneficial in the treatment of very young babies with early infantile, lysosomal storage diseases and hemoglobinopathies, diagnosed in utero or in the neonatal period.

Methods: Over the past 9 years, we have treated 18 neonates (≤3 months of age at transplant) with Krabbe disease (n=11) metachromatic leukodystrophy (n=1), Tay Sachs disease (n=1), Hurler syndrome (n=2), Hunter syndrome (n=2), and Beta-Thalassemia Major (n=1) with UCBT after myeloablative conditioning therapy with Busulfan, Cyclophosphamide and ATG. All babies received cyclosporine + methylprednisolone (n=16) or cyclosporine + cellcept (n=2) for 9 months post transplant for prophylaxis against GvHD. Engraftment, acute and chronic GvHD, survival, treatment related mortality, and deaths were scored.

Results: Eighteen babies were transplanted and 17 were evaluable for engraftment, GvHD, and survival. One baby died before engraftment of pulmonary hypertension day 15 post transplant. The cumulative incidence of overall survival was 94.4% (95% CI 83.9%–100.0%), 88.9 (95% CI 74.4%–100.0%) and 77.8% (95% CI 53.8%–100.0%) at 1, 2, and 5 years, respectively. In these infants receiving very high cell doses from their UCB graft (median total nucleated cell dose of 18.71x107/kg), neutrophil engraftment with an ANC >500/uL occurred at a median of 19 days with a cumulative incidence of engraftment of 94.1% (95%CI 77.9%–100.0%) by 42 days. Platelet engraftment (platelet count of 50K/uL untransfused) occurred in a median of 56 days with a cumulative incidence of engraftment of 94.1% (95%CI 77.8%–100.0%) at 6 months post transplant. Grade I-II acute GvHD occurred in 15/18 infants while one infant developed grade III acute GvHD of skin and gut. The cumulative incidence of grade II-III acute GvHD by day +100 was 29.4% (95%CI 6.9%–51.9%). Nine of seventeen evaluable patients developed cGvHD manifesting as autoimmune cytopenias with a cumulative incidence of 41.2% (95%CI 16.9%–65.5%) and 52.9% (95%CI 28.0–77.8%) at 1 and 2 years, respectively. In six patients, cGvHD presented as autoimmune cytopenia de novo. No graft factors were identified as being significant to development of cGvHD. All patients responded to treatment with methylprednisolone, azithroprine +/− rituximab. One patient required splenectomy. In contrast, the incidence of cGvHD in a group of otherwise similar older patients was 14.7%.

Conclusion: We report an unexpected and high incidence of cGvHD manifesting primarily as autoimmune hemolytic anemia with other cytopenias, post UCBT in a population of very young babies. We hypothesize that post transplant immunosuppression interferes with the normal development of the immune system in the first year of life creating immune dysregulation and graft directed cell destruction. After lytic agents to stabilize disease, removal of chronic immunosuppressive therapy appears to facilitate recovery. Alternative strategies to prevent GvHD should be considered for this unique patient population.

Author notes

Disclosure: No relevant conflicts of interest to declare.