Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome.

BACKGROUND: Allogeneic hematopoietic stem-cell transplantation is the standard of care for Hurler syndrome (mucopolysaccharidosis type I, Hurler variant [MPSIH]). However, this treatment is only partially curative and is associated with complications. METHODS: We are conducting an ongoing study involving eight children with MPSIH. At enrollment, the children lacked a suitable allogeneic donor and had a Developmental Quotient or Intelligence Quotient score above 70 (i.e., none had moderate or severe cognitive impairment). The children received autologous hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with an α-L-iduronidase (IDUA)-encoding lentiviral vector after myeloablative conditioning. Safety and correction of blood IDUA activity up to supraphysiologic levels were the primary end points. Clearance of lysosomal storage material as well as skeletal and neurophysiological development were assessed as secondary and exploratory end points. The planned duration of the study is 5 years. RESULTS: We now report interim results. The children's mean (±SD) age at the time of HSPC gene therapy was 1.9±0.5 years. At a median follow-up of 2.10 years, the procedure had a safety profile similar to that known for autologous hematopoietic stem-cell transplantation. All the patients showed prompt and sustained engraftment of gene-corrected cells and had supraphysiologic blood IDUA activity within a month, which was maintained up to the latest follow-up. Urinary glycosaminoglycan (GAG) excretion decreased steeply, reaching normal levels at 12 months in four of five patients who could be evaluated. Previously undetectable levels of IDUA activity in the cerebrospinal fluid became detectable after gene therapy and were associated with local clearance of GAGs. Patients showed stable cognitive performance, stable motor skills corresponding to continued motor development, improved or stable findings on magnetic resonance imaging of the brain and spine, reduced joint stiffness, and normal growth in line with World Health Organization growth charts. CONCLUSIONS: The delivery of HSPC gene therapy in patients with MPSIH resulted in extensive metabolic correction in peripheral tissues and the central nervous system. (Funded by Fondazione Telethon and others; ClinicalTrials.gov number, NCT03488394; EudraCT number, 2017-002430-23.).

Evidence of Treatment Benefits in Patients with Mucopolysaccharidosis Type I-Hurler in Long-term Follow-up Using a New Magnetic Resonance Imaging Scoring System.

We developed a brain and spine magnetic resonance scoring system based on a magnetic resonance assessment of 9 patients with mucopolysaccharidosis type I-Hurler who underwent hematopoietic stem-cell transplantation. The score is reliable and correlates with long-term clinical and cognitive outcome in patients with mucopolysaccharidosis type I-Hurler.

Hepatic focal nodular hyperplasia after pediatric hematopoietic stem cell transplantation: The impact of hormonal replacement therapy and iron overload.

BACKGROUND: The advent of techniques for the assessment of iron overload (liver T2*-MRI) has led to the awareness that focal nodular hyperplasia (FNH) represents a possible incidental finding after hematopoietic stem cell transplantation (HSCT), though its pathogenesis is still unclear. METHODS: We performed a retrospective analysis of the liver T2*-MRI scans performed between 2013 and 2018 in a single pediatric HSCT Unit and recorded the number of patients with FNH (group A). Patients incidentally diagnosed with FNH at imaging performed for different clinical indications were included in group B. RESULTS: Nine of 105 (8.6%) patients from group A were diagnosed with FNH. Group B included three patients. Overall, 12 patients were diagnosed 4.4 ± 3.1 years after HSCT. At univariate analysis, female gender (odds ratio [OR] 3.77, P = .03), moderate-to-severe iron overload (OR 6.97, P = .01), and hormone replacement therapy (HRT) administered for at least 6 months (OR 18.20, P = .0002) exposed patients to a higher risk of developing FNH. The detrimental effect of HRT was significant also at multivariate analysis (OR 7.93, P = .024). MRI-T2* values in affected patients were statistically lower than healthy controls (P < .001). CONCLUSIONS: We confirm the high incidence of FNH among transplanted pediatric patients and demonstrate the potential pathogenic role of HRT and iron overload.

Outcomes of Children with Hemophagocytic Lymphohistiocytosis Given Allogeneic Hematopoietic Stem Cell Transplantation in Italy.

We report on 109 patients with hemophagocytic lymphohistiocytosis (HLH) undergoing 126 procedures of allogeneic hematopoietic stem cell transplantation (HSCT) between 2000 and 2014 in centers associated with the Italian Pediatric Hematology Oncology Association. Genetic diagnosis was FHL2 (32%), FHL3 (33%), or other defined disorders known to cause HLH (15%); in the remaining patients no genetic abnormality was found. Donor for first transplant was an HLA-matched sibling for 25 patients (23%), an unrelated donor for 73 (67%), and an HLA-partially matched family donor for 11 children (10%). Conditioning regimen was busulfan-based for 61 patients (56%), treosulfan-based for 21 (20%), and fludarabine-based for 26 children (24%). The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 71% and 60%, respectively. Twenty-six patients (24%) died due to transplant-related causes, whereas 14 (13%) and 10 (9%) patients experienced graft rejection and/or relapse, respectively. Twelve of 14 children given a second HSCT after graft failure/relapse are alive and disease-free. Use of HLA-partially matched family donors was associated with higher risk of graft failure and thus with lower EFS (but not with lower OS) in multivariable analysis. Active disease at transplantation did not significantly affect prognosis. These data confirm that HSCT can cure most HLH patients, active disease not precluding successful transplantation. Because in HLH patients HLA-haploidentical HSCT performed through CD34+ cell positive selection was found to be associated with poor sustained engraftment of donor cells, innovative approaches able to guarantee a more robust engraftment are warranted in patients given this type of allograft.

Efficacy of two different doses of rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease in children with haematological malignancies transplanted from an unrelated donor: a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Although rabbit anti-T-lymphocyte globulin (ATLG) is largely used for the prevention of immune-mediated complications in patients given allogeneic haemopoietic stem-cell transplantation (HSCT) from an unrelated donor, the optimum dose of this drug in children is still undefined. We aimed to test whether a higher dose of ATLG was superior to a lower dose for prevention of grade II-IV acute graft-versus-host disease (GVHD). METHODS: We conducted a multicentre, randomised, open-label, phase 3 trial in seven Italian centres comparing two different doses of ATLG (30 mg/kg vs 15 mg/kg, given intravenously over 3 days, from day -4 to -2) in children (aged 0-18 years) with haematological malignancies transplanted from an unrelated donor, selected using high-resolution typing for HLA-class I/II loci. All patients received a myeloablative regimen and cyclosporine-A plus short-term methotrexate as post-transplantation GVHD prophylaxis. Patients were randomly assigned (1:1) to either of the two groups and were stratified by the degree of HLA-compatibility with their donor, the source of haemopoietic stem cells used (bone marrow vs peripheral blood stem cells), and the disease risk category. The randomisation was open label; all investigators were aware of the treatment allocation. The primary endpoint of the study was 100-day cumulative incidence of grade II-IV acute GVHD. Statistical analyses were done according to the per-protocol principle. Other outcomes included cumulative incidence of chronic GVHD, non-relapse mortality, disease recurrence, and probability of overall survival and event-free survival. This study was registered with ClinicalTrials.gov, number NCT00934557. FINDINGS: Between Jan 15, 2008, and Sept 25, 2012, 89 patients were randomly assigned to the 30 mg/kg ATLG group and 91 to the 15 mg/kg ATLG group; 84 patients in the 30 mg/kg ATLG group and 88 in the 15 mg/kg ATLG group were included in the analysis. The median follow-up for the whole study population was 3·4 years (IQR 1·7-5·1). The 100-day cumulative incidence of grade II-IV acute GVHD was 36% (95% CI 28-48) in the 15 mg/kg ATLG group and 29% (20-40) in the 30 mg/kg ATLG group (hazard ratio [HR] 0·74, 95% CI 0·44-1·25; p=0·26). The cumulative incidence of non-relapse mortality was 9% (5-18) in the 15 mg/kg ATLG group and 19% (12-30) in the 30 mg/kg ATLG group (HR 2·08, 0·89-4·96; p=0·092). Cumulative incidence of disease recurrence was 15% (12-24): 14% (8-23) in the 15 mg/kg ATLG group versus 20% (13-31) in the 30 mg/kg ATLG group (HR 1·54, 0·74-3·21; p=0·25). The 5-year overall survival probability was 70% (62-77) for the whole study population: 78% (69-87) in the 15 mg/kg ATLG group versus 62% (50-73) in the 30 mg/kg ATLG group (HR 1·80, 1·01-3·20; p=0·045). The 5-year event-free survival was 77% for children in the 15 mg/kg ATLG group versus 61% in the 30 mg/kg ATLG group (HR 1·87, 1·07-3·28; p=0·028). INTERPRETATION: Children with haematological malignancies transplanted from unrelated donors selected through high-resolution HLA-typing benefit from the use of a 15 mg/kg ATLG dose in comparison with a 30 mg/kg ATLG dose. ATLG at 15 mg/kg should thus be regarded as the standard serotherapy regimen for unrelated donor allogeneic HSCT in this patient population. Future randomised studies will continue to aim to optimise patient outcome and strategies to prevent acute GVHD occurrence. FUNDING: Fresenius/Neovii Biotech.

Phase II Study of Sequential Infusion of Donor Lymphocyte Infusion and Cytokine-Induced Killer Cells for Patients Relapsed after Allogeneic Hematopoietic Stem Cell Transplantation.

Seventy-four patients who relapsed after allogeneic stem cell transplantation were enrolled in a phase IIA study and treated with the sequential infusion of donor lymphocyte infusion (DLI) followed by cytokine-induced killer (CIK) cells. Seventy-three patients were available for the intention to treat analysis. At least 1 infusion of CIK cells was given to 59 patients, whereas 43 patients received the complete cell therapy planned (58%). Overall, 12 patients (16%) developed acute graft-versus-host disease (aGVHD) of grades I to II in 7 cases and grades III to IV in 5). In 8 of 12 cases, aGVHD developed during DLI treatment, leading to interruption of the cellular program in 3 patients, whereas in the remaining 5 cases aGVHD was controlled by steroids treatment, thus allowing the subsequent planned administration of CIK cells. Chronic GVHD (cGVHD) was observed in 11 patients (15%). A complete response was observed in 19 (26%), partial response in 3 (4%), stable disease in 8 (11%), early death in 2 (3%), and disease progression in 41 (56%). At 1 and 3 years, rates of progression-free survival were 31% and 29%, whereas rates of overall survival were 51% and 40%, respectively. By multivariate analysis, the type of relapse, the presence of cGVHD, and a short (<6 months) time from allogeneic hematopoietic stem cell transplantation to relapse were the significant predictors of survival. In conclusion, a low incidence of GVHD is observed after the sequential administration of DLI and CIK cells, and disease control can be achieved mostly after a cytogenetic or molecular relapse.

Multiparametric Whole Blood Dissection: A one-shot comprehensive picture of the human hematopoietic system.

Human hematopoiesis is a complex and dynamic system where morphologically and functionally diverse mature cell types are generated and maintained throughout life by bone marrow (BM) Hematopoietic Stem/Progenitor Cells (HSPC). Congenital and acquired hematopoietic disorders are often diagnosed through the detection of aberrant frequency or composition of hematopoietic cell populations. We here describe a novel protocol, called "Whole Blood Dissection" (WBD), capable of analyzing in a single test-tube, hematopoietic progenitors and all major mature cell lineages composing either BM or peripheral blood (PB) through a multiparametric flow-cytometry analysis. WBD allows unambiguously identifying in the same tube up to 23 different blood cell types including HSPC subtypes and all the major myeloid and lymphoid lineage compartments at different stages of maturation, through a combination of 17 surface and 1 viability cell markers. We assessed the efficacy of WBD by analyzing BM and PB samples from adult (n = 8) and pediatric (n = 9) healthy donors highlighting age-related shift in cell composition. We also tested the capability of WBD on detecting aberrant hematopoietic cell composition in clinical samples of patients with primary immunodeficiency or leukemia unveiling expected and novel hematopoietic unbalances. Overall, WBD allows unambiguously identifying >99% of the cell subpopulations composing a blood sample in a reproducible, standardized, cost-, and time-efficient manner. This tool has a wide range of potential pre-clinical and clinical applications going from the characterization of hematopoietic disorders to the monitoring of hematopoietic reconstitution in patients after transplant or gene therapy. © 2017 The Authors. Cytometry Part A Published by Wiley Periodicals, Inc. on behalf of ISAC.

Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study.

Mucopolysaccharidosis type I-Hurler syndrome (MPS-IH) is a lysosomal storage disease characterized by multisystem morbidity and death in early childhood. Although hematopoietic cell transplantation (HCT) has been performed in these patients for more than 30 years, large studies on the long-term outcome of patients with MPS-IH after HCT are lacking. The goal of this international study was to identify predictors of the long-term outcome of patients with MPS-IH after successful HCT. Two hundred seventeen patients with MPS-IH successfully engrafted with a median follow-up age of 9.2 years were included in this retrospective analysis. Primary endpoints were neurodevelopmental outcomes and growth. Secondary endpoints included neurologic, orthopedic, cardiac, respiratory, ophthalmologic, audiologic, and endocrinologic outcomes. Considerable residual disease burden was observed in the majority of the transplanted patients with MPS-IH, with high variability between patients. Preservation of cognitive function at HCT and a younger age at transplantation were major predictors for superior cognitive development posttransplant. A normal α-l-iduronidase enzyme level obtained post-HCT was another highly significant predictor for superior long-term outcome in most organ systems. The long-term prognosis of patients with MPS-IH receiving HCT can be improved by reducing the age at HCT through earlier diagnosis, as well as using exclusively noncarrier donors and achieving complete donor chimerism.

Should Posterior Reversible Encephalopathy Syndrome Be Mainly Considered an Epileptic Disorder? Results of a Sequential Neurophysiological Study in a Pediatric Cohort.

Despite a wide number of studies trying to define clinical, physiopathological, and neuroradiological features of posterior reversible encephalopathy syndrome (PRES), the true nature of symptoms is still not fully understood. We studied a standard cohort of 24 pediatric patients, affected by hemato-oncological diseases, with a neuroradiological diagnosis consistent with PRES identified from 2006 to 2013. Ten of them developed PRES after hematopoietic stem cell transplantation. We analyzed the sequence of clinical, radiological, and electrophysiological data. In all the patients who were recorded at the onset of the first symptoms, electroencephalograms showed focal nonconvulsive seizures or status epilepticus (SE). We found a sensitivity of 100% for electroencephalogram (EEG) with a good correlation between clinical signs and the localization of seizures, whereas computed tomography scans showed a sensitivity of 50% only. Following prompt treatment, intensive care unit admission rate was only 8%. PRES is a multifactorial neurologic event with focal nonconvulsive seizures or SE as the main feature in pediatric patients. Clinical manifestations are epileptic in nature, and prompt EEG recording is useful for diagnosis and supports an earlier treatment, potentially preventing the appearance of complications such as generalized seizures or refractory SE.

Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy.

Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10-41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors. Overall, 9 of 24 patients (37.5%) were alive at last follow-up with a median follow-up of these surviving patients of 1430 days. Deaths were attributed to transplant in nine (including two after a second transplant due to graft failure), and to mitochondrial neurogastrointestinal encephalomyopathy in six patients. Thymidine phosphorylase activity rose from undetectable to normal levels (median 697 nmol/h/mg protein, range 262-1285) in all survivors. Seven patients (29%) who were engrafted and living more than 2 years after transplantation, showed improvement of body mass index, gastrointestinal manifestations, and peripheral neuropathy. Univariate statistical analysis demonstrated that survival was associated with two defined pre-transplant characteristics: human leukocyte antigen match (10/10 versus <10/10) and disease characteristics (liver disease, history of gastrointestinal pseudo-obstruction or both). Allogeneic haematopoietic stem cell transplantation can restore thymidine phosphorylase enzyme function in patients with mitochondrial neurogastrointestinal encephalomyopathy and improve clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy in the long term. Allogeneic haematopoietic stem cell transplantation should be considered for selected patients with an optimal donor.

Tigecycline Lock Therapy for Catheter-Related Bloodstream Infection Caused by KPC-Producing Klebsiella pneumoniae in Two Pediatric Hematological Patients.

Catheter-related bacteremias carry high mortality rates in hematological patients. When a multidrug-resistant microorganism is involved, the catheter should ideally be removed; however, this approach is not always possible. Tigecycline lock therapy was used in two pediatric oncohematological patients with intravascular catheter-related infection due to KPC-producing Klebsiella pneumoniae. The catheter was salvaged in both cases, and the patients were later discharged. Our experience suggests the usefulness of this approach in treating this type of infection.

Outcomes of transplantation using various hematopoietic cell sources in children with Hurler syndrome after myeloablative conditioning.

We report transplantation outcomes of 258 children with Hurler syndrome (HS) after a myeloablative conditioning regimen from 1995 to 2007. Median age at transplant was 16.7 months and median follow-up was 57 months. The cumulative incidence of neutrophil recovery at day 60 was 91%, acute graft-versus-host disease (GVHD) (grade II-IV) at day 100 was 25%, and chronic GVHD and 5 years was 16%. Overall survival and event-free survival (EFS) at 5 years were 74% and 63%, respectively. EFS after HLA-matched sibling donor (MSD) and 6/6 matched unrelated cord blood (CB) donor were similar at 81%, 66% after 10/10 HLA-matched unrelated donor (UD), and 68% after 5/6 matched CB donor. EFS was lower after transplantation in 4/6 matched unrelated CB (UCB) (57%; P = .031) and HLA-mismatched UD (41%; P = .007). Full-donor chimerism (P = .039) and normal enzyme levels (P = .007) were higher after CB transplantation (92% and 98%, respectively) compared with the other grafts sources (69% and 59%, respectively). In conclusion, results of allogeneic transplantation for HS are encouraging, with similar EFS rates after MSD, 6/6 matched UCB, 5/6 UCB, and 10/10 matched UD. The use of mismatched UD and 4/6 matched UCB was associated with lower EFS.

Autoimmune hematological diseases after allogeneic hematopoietic stem cell transplantation in children: an Italian multicenter experience.

Autoimmune hematological diseases (AHDs) may occur after allogeneic hematopoietic stem cell transplantation (HSCT), but reports on these complications in large cohorts of pediatric patients are lacking. Between 1998 and 2011, 1574 consecutive children underwent allogeneic HSCT in 9 Italian centers. Thirty-three children (2.1%) developed AHDs: 15 autoimmune hemolytic anemia (45%), 10 immune thrombocytopenia (30%), 5 Evans' syndrome (15%), 2 pure red cell aplasia (6%), and 1 immune neutropenia (3%). The 10-year cumulative incidence of AHDs was 2.5% (95% confidence interval, 1.7 to 3.6). In a multivariate analysis, the use of alternative donor and nonmalignant disease was statistically associated with AHDs. Most patients with AHDs (64%) did not respond to steroids. Sustained complete remission was achieved in 87% of cases with the anti-CD20 monoclonal antibody (rituximab). Four patients (9%) (1 autoimmune hemolytic anemia, 1 Evans' syndrome, 2 immune thrombocytopenia) died at a median of 87 days after AHD diagnosis as a direct or indirect consequence of their disorder. Our data suggest that AHDs are a relatively rare complication occurring after HSCT that usually respond to treatment with rituximab.

Treatment of graft versus host disease with mesenchymal stromal cells: a phase I study on 40 adult and pediatric patients.

This phase I multicenter study was aimed at assessing the feasibility and safety of intravenous administration of third party bone marrow-derived mesenchymal stromal cells (MSC) expanded in platelet lysate in 40 patients (15 children and 25 adults), experiencing steroid-resistant grade II to IV graft-versus-host disease (GVHD). Patients received a median of 3 MSC infusions after having failed conventional immunosuppressive therapy. A median cell dose of 1.5 × 10(6)/kg per infusion was administered. No acute toxicity was reported. Overall, 86 adverse events and serious adverse events were reported in the study, most of which (72.1%) were of infectious nature. Overall response rate, measured at 28 days after the last MSC injection, was 67.5%, with 27.5% complete response. The latter was significantly more frequent in patients exhibiting grade II GVHD as compared with higher grades (61.5% versus 11.1%, P = .002) and was borderline significant in children as compared with adults (46.7 versus 16.0%, P = .065). Overall survival at 1 and 2 years from the first MSC administration was 50.0% and 38.6%, with a median survival time of 1.1 years. In conclusion, MSC can be safely administered on top of conventional immunosuppression for steroid resistant GVHD treatment. Eudract Number 2008-007869-23, NCT01764100.

Minimal residual disease before and after transplantation for childhood acute lymphoblastic leukaemia: is there any room for intervention?

Eighty-two children and adolescents who underwent allogeneic transplantation for acute lymphoblastic leukaemia in remission (period 2001-2011, median follow-up 4·9 years) had been assessed for minimal residual disease (MRD) by real-time quantitative polymerase chain reaction before and at 1, 3, 6, 9 and 12 months after transplantation. Five-year event-free survival (EFS) and cumulative incidence of relapse were 77·7% [standard error (SE) 5·7] and 11·4% (SE 4·4), respectively, for patients with pre-transplant MRD <1 × 10(-4) (68%), versus 30·8% (SE 9·1; P < 0·001) and 61·5% (SE 9·5; P < 0·001), respectively, for those with MRD ≥1 × 10(-4) (32%). Pre-transplant MRD ≥1 × 10(-4) was associated with a 9·2-fold risk of relapse [95% confidence interval (CI) 3·54-23·88; P < 0·001] compared with patients with MRD <1 × 10(-4). Patients who received additional chemotherapy pre-transplant to reduce MRD had a fivefold reduction of risk of failure (hazard ratio 0·19, CI 0·05-0·70, P = 0·01). Patients who experienced MRD positivity post-transplant did not necessarily relapse (5-year EFS 40·3%, SE 9·3), but had a 2·5-fold risk of failure (CI 1·05-5·75; P = 0·04) if any MRD was detected in the first 100 d, which increased to 7·8-fold (CI 2·2-27·78; P = 0·002) if detected after 6 months. Anticipated immunosuppression-tapering according to MRD may have improved outcome, nevertheless all patients with post-transplant MRD ≥1 × 10(-3) ultimately relapsed, regardless of immunosuppression discontinuation or donor-lymphocyte-infusion. In conclusion, MRD before transplantation had the strongest impact on relapse and MRD positivity after transplantation, mostly if detected early and at low levels, did not necessarily imply relapse. Additional intensified chemotherapy and modulation of immunosuppression may reduce relapse risk and improve ultimate outcome.

Early skeletal outcomes after hematopoietic stem and progenitor cell gene therapy for Hurler syndrome.

Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem cell transplantation (HSCT). Autologous hematopoietic stem progenitor cell-gene therapy (HSPC-GT) provides superior metabolic correction in patients with MPSIH compared with HSCT; however, its ability to affect skeletal manifestations is unknown. Eight patients with MPSIH (mean age at treatment: 1.9 years) received lentiviral-based HSPC-GT in a phase 1/2 clinical trial (NCT03488394). Clinical (growth, measures of kyphosis and genu velgum), functional (motor function, joint range of motion), and radiological [acetabular index (AI), migration percentage (MP) in hip x-rays and MRIs and spine MRI score] parameters of skeletal dysplasia were evaluated at baseline and multiple time points up to 4 years after treatment. Specific skeletal measures were retrospectively compared with an external cohort of HSCT-treated patients. At a median follow-up of 3.78 years after HSPC-GT, all patients treated with HSPC-GT exhibited longitudinal growth within WHO reference ranges and a median height gain greater than that observed in patients treated with HSCT after 3-year follow-up. Patients receiving HSPC-GT experienced complete and earlier normalization of joint mobility compared with patients treated with HSCT. Mean AI and MP showed progressive decreases after HSPC-GT, suggesting a reduction in acetabular dysplasia. Typical spine alterations measured through a spine MRI score stabilized after HSPC-GT. Clinical, functional, and radiological measures suggested an early beneficial effect of HSPC-GT on MPSIH-typical skeletal features. Longer follow-up is needed to draw definitive conclusions on HSPC-GT's impact on MPSIH skeletal dysplasia.

Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial.

BACKGROUND: Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce the incidence of veno-occlusive disease in this setting. METHODS: In our phase 3 open-label, randomised controlled trial, we enrolled patients at 28 European university hospitals or academic medical centres. Eligible patients were younger than 18 years, had undergone myeloablative conditioning before allogeneic or autologous HSCT, and had one or more risk factor for veno-occlusive disease based on modified Seattle criteria. We centrally assigned eligible participants on the basis of a computer-generated randomisation sequence (1:1), stratified by centre and presence of osteopetrosis, to receive intravenous defibrotide prophylaxis (treatment group) or not (control group). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT, adjudicated by a masked, independent review committee, in eligible patients who consented to randomisation (intention-to-treat population), and was assessed with a competing risk approach. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. We assessed adverse events to 180 days after HSCT in all patients who received allocated prophylaxis. This trial is registered with ClinicalTrials.gov, number NCT00272948. FINDINGS: Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference -7·7%, 95% CI -15·3 to -0·1; Z test for competing risk analysis p=0·0488; log-rank test p=0·0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls. INTERPRETATION: Defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT. FUNDING: Gentium SpA, European Group for Blood and Marrow Transplantation.

A Hematopoietic Stem Cell Transplantation Startup in Iraqi Kurdistan: Results in Thalassemia Patients and Analysis of the Methodology.

In hemoglobinopathy-prone regions, like the Middle East, thalassemia is the most prevalent noncommunicable life-threatening disorder of children and is highly curable by hematopoietic stem cell transplantation (HSCT). Moreover, transplantation is very cost-effective, and HSCT programs can be established directly in middle-income countries (MICs) at a reduced cost while maintaining quality standards and outcomes consistent with international ones. The aim of the present study was to review and verify the efficacy of the applied methodology through the analysis of 47 consecutive matched-related HSCTs in children with thalassemia. In 2016, the first HSCT unit for adults and children with both malignant and nonmalignant diseases was developed in Iraqi Kurdistan, thanks to a capacity building project funded by the Italian Agency for Development Cooperation. Data on clinical activity were obtained from a cohort of patients treated in the newly established HSCT unit. Primary endpoints were overall survival (OS) and thalassemia-free survival (TFS). Startup of the HSCT unit was completed over a 3-year period. Assessing and meeting minimum requirements were crucial for the startup; moreover, a team of international health care professionals (HCPs), all experts in the field of HSCT, conducted the education and training phase, involving all the clinical and nonclinical professionals in the program. At a median follow-up of 2.6 years, the 3-year TFS and OS were 82.8% (SE, 5.5%) and 87.1% (SE, 4.9%), respectively. TFS and graft-versus-host-disease-free composite survival was 80.6% (SE, 5.8%). At present, the HSCT service is completely autonomous, and more than 250 transplants have been done in both adults and children. The minimal essential requirements for an HSCT startup may be affordable in many MICs. Our results for thalassemia are comparable with international data. A twinning program with an international group of experts and a capacity-building approach is crucial for the success of the program, a strategy that allows for rapid development of HSCT units.

Life satisfaction in young adults 10 or more years after hematopoietic stem cell transplantation for childhood malignant and nonmalignant diseases does not show significant impairment compared with healthy controls: a case-matched study.

Patients undergoing hematopoietic stem cell transplantation (HSCT) may experience physical and psychological deterioration that impairs their life satisfaction (LS). This study focused on LS in long-term survivors at 10 or more years after HSCT. Fifty-five patients (39 males, median age 25 years) undergoing allogeneic HSCT for childhood malignant (n = 52) or nonmalignant diseases (n = 3) were enrolled. A control group of 98 young adults (59 males, median age 24 years) was considered. A questionnaire with a modified Satisfaction Life Domain Scale was administered. We assessed such domains as education, employment, leisure time, social relationships, and perception of physical status with a 30-item questionnaire. To investigate the association between the domains and the probability of diminished LS, we performed a logistical procedure using the maximum likelihood method. Predictive factors of LS were adjusted for sociodemographic variables. In the multivariate analysis, the participant's level of LS was not significantly correlated with sociodemographic factors or with HSCT status. The same analysis showed a slight trend in favor of the control group (P = .06) for body perception. Our data suggest that the patients who undergo HSCT in childhood have no significant difference in long-term LS compared with healthy controls.