Abstract
Allogeneic hematopoietic cell transplantation (HCT) continues to be standard therapy for patients with severe alpha-L-iduronidase deficiency, also termed Hurler syndrome. While many patients tolerate HCT well, in others severe toxicity is observed. An analysis was performed in 74 patients transplanted at the University of Minnesota for Hurler syndrome since 1990 in an attempt to define clinical attributes associated with a high-risk population. The stem cell source was a matched related donor for 14 (19%) of patients, while 43 patients (58%) were recipients of unrelated marrow; of these 16 were mismatched. An unrelated cord blood graft was utilized in 17 cases (23%). The preparative regimen included cyclophosphamide (Cy) and busulfan in 34 transplants (46%), while others received Cy and irradiation. The 5-year survival for all patients in this analysis was 53% (CI 41–65%). In the univariate analysis, prior cardiac complications, a history of hydrocephalus, CMV positivity, T cell depletion or choice of preparative regimen did not influence survival. A prior history of non-elective intubation also did not alter survival, nor was a history of a positive sleep study a significant factor in overall survival (40% vs. 63%; p=0.09). In contrast, the patients with a prior history of obstructive disease (reactive airway disease or bronchiolitis) had a significantly worse survival rate than those that did not (18%, CI 0–48% vs. 58%, CI 45–70%; p<0.01). Similarly, a prior history of pneumonia identified a group of patients that did poorly (survival 25% vs. 62%; p<0.01). The rate of pulmonary complications in these patients after HCT was evaluated, and 23 of all patients in the analysis (31%) required intubation. In multivariate testing, the survival of patients requiring intubation was inferior, with a relative risk of death of 4.4 (CI 2.2–9.0; p<0.01). Patients <18 months of age were less likely to require intubation than older patients (18% vs. 44%, respectively; p=0.03). Similarly, in the multiple regression analysis, patients transplanted at <2 years of age had an improved outcome; children with Hurler syndrome >2 years old had a relative risk of death of 3.0 (CI 1.2–7.4; p=0.02). Recipients of mismatched unrelated transplants also had a worse outcome in the multivariate analysis in comparison to matched related, unrelated and cord blood recipients (RR 2.9 (CI 1.2–6.8; p<0.01). Unexpectedly, the gender of Hurler patients was also correlated with outcome, as females having an increased relative risk of death (2.3; CI 1.1–5.2) compared to males (p = 0.03). While the reasons for this are unclear, it has been observed in studies on the iduronidase deficient mouse that the females had elevated levels of serum inflammatory cytokines (IL-1, IL-6 and TNF) in comparision to the males. This provides an intriguing hypothesis for the observed clinical findings - this will serve as a basis for further study. We conclude that it is possible to determine standard and high risk populations of patients with Hurler syndrome based on the pre-transplant evaluation; in children with Hurler that are <18 months of age with a negative pulmonary history, survival approaching 80% is observed. However, for patients at higher risk, alteration of the preparative regimen to reduce toxicity or prior treatment with enzyme therapy may be beneficial in achieving an improved outcome.
Renal Anemia Control in Lithuania: Influence of Local Conditions and Local Guidelines