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The classical treatment algorythm of idiopathic severe aplastic anemia (SAA) forsees, if a sibling donor is not available in the family, a first line option represented by immunosuppressive therapy (IST) with ATG and Cyclosporine A (CsA). IST provides a very good survival rate but a fairly high rate of failures (no response, relapse, need for transplant). This is particularly important in childhood and adolescence where faulty hematopoiesis represents a relevant limitation of quality of life. The option of haematopoietic stem cell transplantation (HSCT) from matched unrelated donor (MUD) as front line treatment with no prior failed IST, has never been investigated so far. This study provides for the first time the outcome analysis of 29 consecutive SAA patients who received an upfront unrelated donor HSCT without prior IST, in 9 UK Centres and compares each of these patient with 3 matched controls from the data base of the SAAWP of the EBMT who, in a similar time-span, underwent Matched Sibling Donor (MSD) HSCT. Twenty four patients received HLA-A,-B,-C,-DQ-,-DRB1 matched MUD HSCTs whilst 5 received single antigen/allele Mismatched Unrelated Donor (MMUD) grafts. The conditioning regimen was FCC (Fludarabine, Cyclophosphamide and Alemtuzumab) with the addition of low dose (3cGy) TBI for the MMUD HSCTs. GVHD prophylaxis was with CsA +-Mycophenolate. The primary endpoints were overall survival (OS) and event free survival (EFS). Events were death, disease recurrence, second HSCT, clinical PNH and post-transplant malignancies. Complete remission (CR) was defined as Hb > 10 g/dl, neutrophil count > 1x 109/l and platelet count > 100x109/l. The 87 (3 for each MUD/MMUD HSCT) patients from the EBMT data base who underwent MSD HSCT as first line treatment were matched to the upfront MUD/MMUD cohort by age, gender, time from diagnosis to HSCT and source of stem cells. Their median follow-up was 1.6 years (range 0.01-9.39). In the upfront MUD/MMUD cohort there were 12 males (41%) and 17 females (59%). Median age at HSCT was 8.46 years (range 1.73-19.11), 72% was aged below and 28% above 12 years; median interval from diagnosis to HSCT was 0.39 years (range 0.19-1.35) with 72 % receiving bone marrow and 28% peripheral blood stem cells. The median follow-up was 1.7 years (range 0.19-8.49). The median time to neutrophil recovery (>0.5 x 109/l) was 18 days (range 9-29) and the median time to platelet recovery (>50 x 109/l) was 19 days (range 10-40). The 100 day cumulative incidence (CI) of grade II-IV acute GVHD was 10 ± 6% ; there was only one case of grade III-IV acute GVHD (frequency of 3.5%). The 1 year CI of chronic GVHD was 19 ± 8%. There were 5/29 cases (frequency of 17,2 %), 4 in the MUD and 1 the MMUD subset. Chronic GVHD was limited in all cases and restricted to skin. There were only 2 events in this cohort; one primary graft failure following a HLA-A MMUD HSCT who has now successfully received a second HSCT and one death due to idiopathic pneumonia syndrome. No post-treatment malignancies occurred at last follow-up. The other 27 patients are in CR at last follow-up. The median interval diagnosis-neutrophil recovery was similar in MUD/MMUD (0.39 years; range 0.19-1.35) vs MSD transplants (0,31 years; range 0,1- 0,45) (p=0.93). The 2 year OS was 96%±4% in the upfront MUD/MMUD cohort vs 91%±3% of the MSD cohort (p=0.30). The 2 year EFS was 92%±5% in the upfront cohort vs 87%±4% in MSD (p=0.37) (Fig 1). The 2 year CI of rejection was 4%±4% in the MUD/MMUD vs .1%±1% in the MSD group (p=0.48). This is the first controlled study indicating that in idiopathic SAA of childhood and adolecence upfront MUD/MMUD HSCT using FCC as conditioning regimen, has similar outcome to MSD HSCT. MUD HSCT may be considered a feasible and successful treatment option when children lack a MSD and a MUD is readily available. Figure 1 Figure 1. Comparison of EFS between upfront MUD/MMUD and front-line MSD HSCT. Events were: death, disease recurrence, second HSCT, clinical PNH and post-transplant- malignancies. Table 1 EFS N events 2-yrs Pr (%) (SE) p-value MUD/MMUD 29 2 92 (5) 0.37 MSD 87 11 87 (4) Disclosures Dufour: Pfizer: Consultancy.

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 (>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 >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.

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