Results of Haematopoietic Stem Cell Transplantation (HSCT) for Hurler’s Syndrome: European Experience 1994–2004.
Authors: Boelens Jaap Jan , Wynn R. , O’Mearra A. , Veys P. , Cavazzana-Calvo M. , Wulffraat N. 
Published: April 2020

Abstract
Worldwide more than 400 patients with Hurler’s syndrome (HS), characterized by severe neurodegeneration, cardiac disease, skeletal abnormalities and death in early childhood, have undergone allogeneic-HSCT since 1980. Although, long term follow up of successfully transplanted children is very encouraging, the engraftment and survival results are very variable between the various studies, ranging from less than 25% up to more than 85%. We retrospectively analyzed the results of 146 patients transplanted in Europe from 1994–2004, to assess: 1) the effect of conditioning regimen and grafts (-manipulation) used on the “alive and engrafted” rate and 2) the transplantation-related morbidity/mortality.
HSCT with a family donor was performed in 52 patients. An unrelated donor was used in 94 patients. The majority of patients received marrow (n=103). The rest received cordblood (n=23) or peripheral blood (n=20). Twenty-eight patients received a T-cell depleted (TCD) graft. Conditioning regimens used were grouped as follows: busulfan-cyclofosfamide 200mg/kg (n=68), busulfan- with high dose cyclofosfamide (either 240mg/kg or 260mg/kg; n=41), fludarabine-based myelo-ablative (n=19) and reduced intensity conditioning regimens (RIC: n=18). Fourteen patients received dose-adjusted busulfan. Engrafted was defined as a donor chimerism of more than 10%, and an alpha-L-iduronidase level of more than the lower limit of normal for the heterozygote individuals (&gt;4.5 nmol/hr/mg).
The “alive and engrafted” rate after first transplantation and overall “alive and engrafted” rate after one to three transplantations was 83/146 (57%) and 111/146 (76%), respectively. The median follow up was 39 mth (5–120mths). Multivariate analysis (confounders: age, sex, heterozygote donor, unrelated donor, stem cell source, HLA-disparity, conditioning regimen, TCD and busulfan targeting) on the primary endpoint “alive and engrafted” showed that RIC (RR 13,4: 2,6–67,1) and TCD (RR 5,7: 1,14–28,4) are individual risk factor for graft failure. Busulfan targeting suggests to be an individual protective factor (RR 0,27; 0,04–1,8); 12/14 (86%) were “alive and engrafted” after 1st HSCT. Thirthy three patients received a 2nd graft, of whom 26/33 (82%) are alive and engrafted: 16/21 using the same, 10/12 using a different donor, and 16/19 after myeloabaltive, 10/14 after RIC. Two of the 3rd HSCTs were successful. After 1st HSCT moderate to severe aGvHD (grade ≥2) occurred in 23/146 (16%) patients. Extensive cGvHD was seen in 2/114 (1.4%) patients, only. IPS/DAH was seen in 4/134 (2.3%) patients and VOD in 12/134 (9%) patients. Main cause of death (n=28) was infectious (n=15: mainly viral). Other causes of death: GvHD (n=3), Cardiac ECI (n=2), VOD (n=2), DAH (n=1), unknown (n=1), Hurler (n=4). The majority of the “alive and engrafted” patients have a donor chimerism of &gt;95% (91/111; 82%), 11/111 (9,9%) between 75–95%, 6/111 (5,4%) between 50–75% and 3/111 (2.7%) between 10–50%.
In summary, no stem cell source (BM, cordblood and PBSC) is superior and no conditioning regimen used is superior. RIC and TCD results in inferior engraftment rates. Second HSCTs are successful in more than 80%. Relatively low morbidity rates are seen. The engraftment of HSCT for HS can be optimized by avoiding T-cell depletion, RIC and probably by busulfan-targeting.