The Changing Patterns of Graft Failure in MPS1H, Hurler Syndrome: A Review of 30-Years Experience

Introduction: Hurler syndrome (HS), the most severe phenotype of mucopolysaccharidosis type I, is characterized by α-L-iduronidase (IDUA) deficiency. Without therapy, most affected children die of cardiac complications in the first decade. Haematopoietic stem cell transplantation (HSCT) is the standard of care in children with HS as it is the only therapy that can arrest disease progression. One of the challenges in HSCT for HS is graft failure. Here, we examined the evolving pattern of graft failure over the past three decades.

Methods: Retrospective review of all children with HS undergoing first HSCT at the Royal Manchester Children's Hospital or the University of Minnesota Children's Hospital over a thirty-four-year period (1983 - 2016). The diagnosis of HS was confirmed by an increase in urinary GAG excretion, a deficiency or absence of IDUA in peripheral blood leukocytes, and the clinical phenotype. A full-intensity Busulfan-based myeloablative conditioning regimen (MAC) with pharmacokinetic-guided dosing was started from 2004 (post Bu-pK era). Conditioning regimen used prior to Bu-pK era was variable. Graft failure was classified into 4 types: 1. Primary aplasia, (no neutrophil engraftment by Day +42) 2. Primary autologous reconstitution (neutrophil engrafted by Day +42 but with <20% donor-derived hematopoiesis) 3. Secondary aplasia (cytopenia following neutrophil engraftment and fully donor-derived hematopoiesis) 4. Secondary autologous reconstitution (falling donor chimerism <20% following neutrophil engraftment and adequate donor-derived hematopoeisis)

Results: A total of 240 children with HS were enrolled (131 pre-Bu-pK; 109 post-Bu-pK). The median age at HSCT was 16.3 months (range 4.9-72.2 months) in pre-Bu-pK era and 14.0 months (range 3.8-65.1 months) in post-Bu-pK era (p = 0.002) ). In pre-Bu-pK era, the graft source was predominately marrow/peripheral blood (n=109, 83.2%). The use of cord blood (CB) increased from 16.8% (n=22) in pre-Bu-pk era to 63.3% (n=69) in post-Bu-pK era (p<0.001). The 5-year overall survival (OS) improved from 60.8% to 85.2% (p<0.001) while the 5-year event-free survival increased from 41.2% to 76.3% (p<0.01) in the modern era. The proportion of patients with graft failure reduced significantly from 37.2% (49/113 patients) in pre-Bu-pK era to 10.1% (11/109 patients) in post-Bu-pK era (p<0.001). Of the 49 patients with graft failure in pre-Bu-pK era, 1 had primary aplasia, 19 had primary autologous reconstitution and 28 had secondary autologous reconstitution. In the post-Bu-pk era, all the graft failure occurred in CB recipients (10 had a busulfan based MAC; 1 had a non-MAC). Of these 11 patients, 7 patients had aplasia while 4 had autologous marrow reconstitution. On univariate analysis, neither pre-transplant factors (age and sex) nor transplant factors (graft-recipient HLA disparity, total nucleated cell dose, CD34+ cell dose, graft-recipient ABO compatibility, conditioning regimen, type of serotherapy and GVHD prophylaxis regimen) were correlated with graft failure in CB recipients receiving busulfan-based MAC in the post-Bu-pK era. Of 60 patients with graft failure, 48 (39 pre-Bu-pK; 9 post-Bu-pK) had a second transplant. Of the 39 patients undergoing second transplant in the early era, 13 died and 5 had repeat graft failure. Three patients underwent third transplant and all died of transplant-related complications (1 GVHD, 2 infection). Of the 9 patients undergoing second transplant in the modern era, 8 are alive and engrafted; the sole death was from adenoviral infection. For all patients undergoing second HSCT, the estimated 5-year OS 70.1% (pre-Bu-pK 66.7% vs. post-Bu-pK 85.7%, p=0.235). Of the 85 patients who were "alive-and-engrafted" after first transplant in post-Bu-pK era, 68 (80%) had full-donor chimerism while 17 (20%) had mixed-donor chimerism. CB was significantly associated with a higher rate of full-donor chimerism (p=0.01) among engrafted survivors.

Conclusions: The transplant outcomes have improved. All deaths due to infection, graft failure and pulmonary failure have significantly reduced a better transplant care. The pattern of graft failure has changed from primarily marrow reconstitution likely secondary to inadequate myelosuppression in pre-Bu-pk era, to graft rejection likely secondary to inadequate immunosuppression in post-Bu-pk era.