Safety and Efficacy of Enzyme Replacement Therapy (ERT) in Combination with Haematopoietic Stem Cell Transplantation (HSCT) for Hurler’s Syndrome: European Experience 2003–2005.

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, graft-failure, mortality and morbidity can limit its success. Although ERT (laronidase) is available for HS, a HSCT is still needed to abort severe neurodegeneration. We analyzed 21 patients who underwent a HSCT with ERT in Europe between 12/2003 to 4/2005, to assess:

1. the effect of ERT on the “alive and engrafted” rate and

2. the transplantation-related morbidity/mortality.

Twenty-one patients received ERT (100 U/kg weekly) from diagnosis until approximately 7 weeks (range 0–20 wks) after successful HSCT. Clinical condition was, except for 1 patient, moderate/good before start of ERT. Thirty-one HSCTs were performed in these patients: 8 patients received a 2nd graft because of graft-failure of whom 2 received a 3th graft. For the first HSCT, 8 patients received full-graft marrow or PBSC, the others T-cell depleted (marrow/PBSC: n=3) or cordblood (n=10). Sixteen unrelated donors and 5 family donors (4sibs/1haplo) were used. Conditioning regimens used were conventional myeloablative (n=17) or treosulfan / fludarabine (n=4). Engrafted was defined as a donor chimerism of more than 10%, and an alpha-L-iduronidase level >LLN for heterozygote individuals (>4.5 nmol/hr/mg). Effect of ERT on the “alive and engrafted” rate was analysed in a multivariate analysis with a historic (transplanted 1994–2004) control group (n=148).

Clinical condition before HSCT was good for all patients. The “alive and engrafted” rate after first HSCT and overall “alive and engrafted” rate after one to three HSCTs was 12/21 (57%) and 17/21 (81%), respectively. The median follow up was 8 mth (3–17mths). Two patients died: 1 after 2nd and 1 after 3th HSCT. HSCTs with full-graft were successful in 5/8, and for TCD 0/3 and cordblood 8/10. Five of 8 patients receiving a 2nd graft are alive and engrafted and 1/2 after 3rd graft. Multivariate analysis (confounders: age, sex, heterozygote donor, unrelated donor, stem cell source, HLA-disparity, conditioning regimen, T-cell depletion and busulfan-targeting) on the primary endpoint “alive and engrafted” showed that ERT doesn’t significantly influence the primary endpoint (RR 0,54: 0,15–2). After 1^st HSCT moderate to severe aGvHD (grade ≥2) occurred in 1/21 (4,8%) patients. Extensive cGvHD wasn’t seen. IPS/DAH was seen in 1/21 (4,8%) and VOD in 2/21 (9,6%) patients. Cause of death was extensive cGvHD after 3rd and candida sepsis after 2d HSCT. The majority of the overall “alive and engrafted” patients are having a donor chimerism of >95% (15/17), 2 patients are mixed chimeric (75–95%). ERT-infusion-related toxicity was limited to mild reactions.

In patients with HS, ERT with HSCT is well tolerated, with low morbidity rates, but had no effect (neither positive nor negative) on the engraftment in this group. Specifically for patients in a poor clinical condition preHSCT, ERT might be of advantage. A prospective study is needed to determine the longer term outcome of ERT on HSCT outcomes.