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Background: For many inborn errors of metabolism (IEM), allogeneic hematopoietic stem cell transplantation (HSCT) is the only cure., Methods: We report the outcome in 160 patients with inherited diseases, who were treated with HSCT in 3 decades. Median age was 3 years (range 0.1-63). Grafts were from matched related donors (MRDs, 56), matched unrelated donors (MUDs, 66), or HLA-mismatched donors (38)., Results: Graft failure (GF) occurred in 26 patients (16%), severe acute graft-versus-host disease (GVHD) in 9 (6%), and chronic GVHD in 23 (12%). Ten-year survival was 64% before the year 2000 and 86% after that (P = 0.01). Ten-year survival for MRD grafts was 90%, as opposed to 79% for MUD grafts and 56% for HLA-mismatched grafts (P = 0.03). In multivariate analysis, GF was associated with having an HLA-mismatched donor (P < 0.05) or MUD (P = 0.015) and with reduced-intensity conditioning (P < 0.01). Death was associated with year of transplant (P = 0.015), having an HLA-mismatched donor (P < 0.001), and being a male recipient from an immune female donor (P = 0.05)., Conclusions: The outcome after HSCT for IEM depends on HLA match, year and immune female donor.

Human TCRαβ(+) CD4(-)CD8(-) double-negative (DN) T cells represent a minor subset in peripheral blood, yet are important in infectious diseases and autoimmune responses. We examined the frequency of DN T cells in 17 patients after allogeneic hematopoietic stem cell transplantation (aHSCT) at 1, 2, 3, 6, and 12 months post-aHSCT and show that these cells increase early after aHSCT and decrease with time after aHSCT. DN T cells reside in the terminally differentiated effector (CD45RA(+)CCR7(-)) T-cell population and are polyclonal, determined by T-cell receptor Vβ CDR3 analysis. Gene expression analysis of ex vivo sorted DN T cells showed a distinct set of gene expression, including interleukin-8, as compared with CD4(+) or CD8(+) T cells. DN T cells contributed to MHC class I-restricted EBV-directed immune responses, defined by antigen-specific cytokine production and by detection of HLA-A*02:01-restricted EBV BMLF-1 (GLCTLVAML), LMP-2A (CLGGLLTMV), and HLA-A*24:02-restricted EBV BRLF-1 (DYCNVLNKEF) and EBNA3 (RYSIFFDY)-specific T cells. We created retroviral-transfected Jurkat cell lines with a Melan-A/MART-1-specific TCR(+) and the CD8α chain to study TCR(+) DN T cells in response to their nominal MHC class I/peptide ligand. We show that DN T cells exhibit increased TCRζ chain phosphorylation as compared with the TCR(+)CD8(+) transgenic T-cell line. DN T cells contribute to antigen-specific T-cell responses and represent an effector T-cell population that may be explored in immunotherapeutic approaches against viral infections or transformed cells.

Background: Umbilical cord blood transplantation (UCBT) is increasingly used and produces similar results to matched unrelated donor transplantation., Methods: We performed a retrospective single-center analysis of 50 umbilical cord blood transplantations UCBTs performed from 2001 to 2010, including 37 single and 13 double umbilical cord blood transplantations UCBTs., Results: The rate of engraftment of neutrophils was 88% at a median time of 29 days (range, 3-79). Complete donor chimerism (DC) within the CD19, CD3, and CD33 cell lineages was seen in 74%, 72%, and 76% of the patients, respectively. DC was associated with acute graft-versus-host disease (GVHD) grades II to IV for the CD3 cell lineage (P=0.01) and, in multivariate analysis, with total body irradiation for all lineages (P<0.01). Overall survival (OS) at 1 and 5 years was 55% and 43%. Nonmalignant diseases were associated with better 5-year OS (72%) than malignancies (28%; P=0.026). In multivariate analysis, a negative correlation was seen between OS and age (hazard ratio [HR], 1.04; 95% confidence interval [95% CI], 1.02-1.06; P<0.001), acute GVHD grades III and IV (HR, 3.43; 95% CI, 1.95-6.02; P<0.001), and mesenchymal stem cell treatment (HR, 2.66; 95% CI, 1.11-6.35; P=0.027). Transplant-related mortality at 100 days and 1 year was 16% and 30%. The incidence of acute GVHD grades II to IV was 34%. Acute GVHD grades III and IV was associated with ABO incompatibility (HR, 2.61; P=0.05) and myeloablative conditioning (HR, 4.17; P=0.047)., Conclusions: The outcome in patients with nonmalignant diseases was acceptable, but transplant-related mortality in the whole group remains high. A significantly higher rate of DC was associated with total body irradiation-based conditioning and with acute GVHD grades II and IV.

Background: Allogeneic hematopoietic stem cell transplantation (ASCT) is a possible cure for many inherited disorders., Methods: We report 20 years of experience in 71 patients. The disorders include 7 immunodeficiencies, 21 hematological disorders, 13 histiocytic disorders, 9 mucopolysaccharoidoses, 7 metachromatic leukodystrophies (MLD), 3 adrenoleukodystrophies (ALD), 2 adrenomyeloneuropathy (AMN), 6 patients with Gaucher's disease, 1 Sandhoff's disease, and 2 patients with aspartylglucosaminuria. Their median age was 4 (0-39) years. The donors were 29 HLA-identical related, 27 matched unrelated (MUD) and 15 HLA mismatches., Results: In recipients of HLA-identical sibling grafts, none developed acute GVHD grades II-IV as against 22% in all others. The overall cumulative incidence of chronic GVHD was 17%. The 5-year survival rates were 93%, 84%, and 46% in recipients of grafts from HLA-identical siblings, MUD and HLA-mismatches, respectively. The overall 10-year survival rate was 69%. All of the surviving patients with immunodeficiencies and hemoglobinopathies are well. Four patients with Hurler's disease are also well, apart from skeletal problems. Five patients with Gaucher's disease are between 14 and 22 years after the transplant. Two infants with MLD deteriorated, a girl with the juvenile form has stable disease and one woman with the adult form has improved. Among four survivors with ALD/AMN, three are well and one has dementia. Two patients with aspartylglucosaminuria have stable disease., Conclusion: In patients with inborn errors of metabolism, ASCT gives a high survival rate using HLA-matched donors. Beneficial effects are seen in those who are transplanted early.

Background: Aspartylglucosaminuria is a rare, inherited lysosomal disease characterized by a slowly progressive mental retardation and coarse facial and body features. With the intent to provide the deficient enzyme aspartylglucosaminidase, allogeneic stem-cell transplantation (ASCT) has been attempted. Only a few cases of transplants have been reported., Methods: Two siblings with aspartylglucosaminuria underwent allogeneic bone marrow transplants using unrelated human leukocyte antigen-A, -B, and DR identical donors at ages 10 years 5 months and 5 years 10 months, respectively. They were followed during 5 years with biochemical, neuroradiologic, neuropsychologic, and clinical investigations., Results: During 5 years follow-up, no neuropsychologic or clinical deterioration was noted in the children. A stable expression of aspartylglucosaminidase was found during the whole follow-up period. The spinal fluid concentration of Tau-protein, a marker of neuronal and axonal degeneration and damage, peaked at approximately 12 months after bone-marrow transplantation and then declined to almost normal levels after 5 years. By magnetic resonance imaging (MRI), an improvement of myelination in the youngest sibling and an arrest of demyelination in the older one were observed., Conclusion: The importance of long-term follow-up of children after ASCT in this rare, very slowly progressive lysosomal disease must be emphasized. We report that none of the children had lost any capabilities since the transplantation; moreover, an improvement is shown in biochemical markers and MRI white-matter signals, suggesting a beneficial effect.

Background: The aim of this study was to investigate the relationship between cytomegalovirus (CMV) and extensive chronic graft-versus-host disease (GvHD) after allogeneic stem-cell transplantation (SCT)., Methods: Two hundred sixty-two consecutive patients undergoing conventional SCT with human leukocyte antigen-identical sibling donors, given cyclosporine A and methotrexate as GvHD prophylaxis and surviving more than 3 months after SCT, were retrospectively analyzed. Most patients received transplants because of a hematologic malignancy (n=226), but 36 patients with nonmalignant disorders were included in the analysis. Ninety-nine patients were monitored for CMV infection with rapid virus isolation and 163 patients by either a pp65 antigenemia test (n=5) or a qualitative polymerase chain reaction (PCR) assay for CMV-DNA (n=158)., Results: One hundred thirty (50%) of the patients developed chronic GvHD, of whom 17 (6.5%) developed extensive chronic GvHD. Risk factors for development of extensive chronic GvHD were determined by multivariate logistic regression. The strategy of PCR-based monitoring for CMV-DNA, giving preemptive antiviral therapy on demand, significantly decreased the risk for developing extensive chronic GvHD (odds ratio=0.32, P =0.03). No other factors tested, including recipient and donor age and sex, source of graft, cell dose, and acute GvHD, had any significant effect on the development of extensive chronic GvHD., Conclusions: We conclude that the risk for extensive chronic GvHD in this homogenous group of patients was reduced by the use of PCR-based preemptive therapy.

Background: The aim of the present investigation was to evaluate whether the subjective symptoms of dry mouth in long-term-surviving pediatric bone marrow transplant (BMT) patients are associated with low unstimulated salivary secretion rates (USSR) and with stimulated whole salivary secretion rates (SSSR)., Methods: Fifty-three patients surviving > or =2 years after pediatric allogeneic BMT were included. USSR, SSSR, and the change in salivary secretion rates since the previous year were estimated. A questionnaire regarding subjective symptoms of xerostomia was answered., Results: The mean USSR and SSSR were 0.24+/-0.17 and 0.90 +/- 0.58 ml/min, respectively. Salivary gland dysfunction, defined as USSR < or =0.1 ml/min or SSSR < or =0.5 ml/min, was present in 35% of the patients. Seventy-nine percent of the patients expressed one or more symptom of dry mouth, and 49% gave at least two answers indicating dry mouth. The number of complaints increased with age at examination (P<0.05). Both USSR (P<0.01) and SSSR (P<0.01) were inversely correlated to the total number of complaints of xerostomia. A reduction in SSSR compared with the year before was correlated to two or more complaints of xerostomia (P<0.01). The presence of dry mouth at night or on awakening was indicative of both low USSR (P<0.01) and SSSR (P<0.001). Patients reporting dryness during the day had significantly lower SSSR (P<0.05)., Conclusion: The expression of subjective complaints of xerostomia among long-term surviving pediatric BMT patients is correlated to salivary gland dysfunction and age. It is very important to identify these patients with salivary gland dysfunction to relieve their symptoms and prevent secondary complications.

Background: Several preventive strategies against cytomegalovirus (CMV) disease have been developed during the last decade. These have frequently been used in combination, and it has been difficult to identify each strategy's contribution., Methods: Risk factors for CMV disease, death in CMV disease and transplant-related mortality were analyzed in 584 patients, who underwent a total of 594 allogeneic bone marrow transplants., Results: The overall probability of CMV disease was 8.9%. No seronegative patient who had a seronegative marrow donor developed CMV disease. The corresponding probabilities for seronegative patients with seropositive donors, seropositive patients with seronegative donors, and seropositive patients with seropositive donors were 5.4%, 13.7%, and 11.7%, respectively. In multivariate Cox models, the use of preemptive antiviral therapy and being CMV-seronegative reduced the risk for CMV disease, CMV-associated death, and transplant-related mortality (TRM). Patients who received unrelated or mismatched family donor transplants had increased risks for CMV disease, CMV-associated death, and TRM. Older age was a significant risk factor for CMV disease and TRM. A total of 258 patients who were monitored by polymerase chain reaction for CMV DNA were analyzed separately to assess whether addition of another CMV preventive strategy could give benefit. Patients who received mismatched or unrelated donor transplants had increased risk for CMV disease, death in CMV disease, and TRM. High-dose acyclovir prophylaxis or addition of intravenous immune globulin had no influence., Conclusions: Preemptive therapy based on polymerase chain reaction for CMV DNA was associated with reduced risks for CMV disease, CMV-associated death, and TRM, whereas other prophylactic modalities did not give additional benefit.

Background: A 2.5-year-old boy received a cadaveric orthotopic liver transplant for acute liver failure due to non-A, non-B, non-C hepatitis. After transplantation, he developed thrombocytopenia and neutropenia and subsequently severe aplastic anemia. The patient also suffered from recurrent cytomegalovirus (CMV) viremia, treated with foscarnet and ganciclovir., Methods: For treatment of his aplastic anemia, the patient underwent an allogeneic bone marrow transplantation from his HLA-identical sister after conditioning with cyclophosphamide at 200 mg/kg and antithymocyte globulin at 3 mg/kg for 5 days. Prophylactic acyclovir was given because of ongoing CMV viremia at the time of bone marrow transplantation., Results: The transplant course was uneventful, with rapid engraftment. There were no signs of liver dysfunction, graft-versus-host disease, or reactivation of CMV. The patient is in excellent health, with normal liver and bone marrow function 3 years after bone marrow transplantation., Conclusion: This case report shows that allogeneic bone marrow transplantation is feasible and well tolerated in a patient with severe aplastic anemia after liver transplantation for acute fulminant viral hepatitis.

Ten allogeneic bone marrow transplant (BMT) recipients with hepatic venoocclusive disease (VOD) were treated with recombinant human tissue plasminogen activator (rt-PA). Two of them subsequently underwent orthotopic liver transplantation (OLT). One additional patient with VOD underwent OLT without prior rt-PA treatment. Treatment with rt-PA was started a median of 14 (1--35) days after BMT. The dose of rt-PA given to adults was 10-50 mg i.v. and that given to children was 3-10 mg i.v. Treatment was given for 2-4 days. In three patients, the dose was administered over a longer period or it was repeated. Four patients responded to rt-PA therapy and six did not. Eight patients suffered from hemorrhages, one intracranial and three gastrointestinal. Four patients required blood transfusions. Four had minor subcutaneous hemorrhages and/or epistaxis. One patient died of intracranial hemorrhage and five from hepatic and/or multiorgan failure. Two patients treated with rt-PA, 10 mg/day for 4 days, are alive; one is alive and well 3 months after BMT, the other has relapsed after 7 months. The three patients undergoing OLT died of chronic hepatic failure, cerebral edema, and pneumonia. Our experience suggests that rt-PA should not be administered in high doses and that the treatment should not be given over a longer period, because of the risk of severe hemorrhages.

Forty-five recipients of bone marrow from HLA-identical siblings were given intravenous immune globulin (IVIG) 0.5 g/kg once a week during the first 3 months after transplantation. Fifty-three consecutive previously transplanted HLA-identical siblings were included as controls. Only patients who were cytomegalovirus (CMV) seropositive or had a CMV-seropositive donor were included. There were no major differences in patient characteristics between the two groups. However, more patients in the IVIG group received individualized graft-versus-host disease (GVHD) prophylaxis with less cyclosporine (P < 0.01), more controls received liposomal amphotericin B (P = 0.01), and more patients in the IVIG group received low-dose heparin as prophylaxis against veno-occlusive disease of the liver (P < 0.001). Median follow-up was 21 months in the IVIG group and 47 months in the control group. There were no differences between the groups with regard to time to engraftment, hospitalization time, or days with fever. No differences between the IVIG group and control group were detected in the incidence of acute GVHD grade II-IV (17% vs. 23%) or chronic GVHD (30% vs. 42%). The incidence of bacterial septicemias (53% vs. 63%) and invasive fungal infections (9% vs. 6%) was unaffected by IVIG treatment. The incidence of symptomatic CMV infection was the same in the two groups (14% vs. 16%). One control patient died of CMV interstitial pneumonitis, and 1 patient from each group died from viral interstitial pneumonitis of other origin. The incidence of veno-occlusive disease (VOD) was 16% in the IVIG group versus 6% in the controls (P = NS). Fatal VOD occurred in 11% of the IVIG group compared with none of the controls (P = 0.02). Other transplant-related complications did not differ between the two groups. Two-year survival was 62% in the IVIG group and 60% in the controls (P = NS). No significant beneficial effect was seen with IVIG, which may increase mortality in VOD. The use of high dose IVIG as prophylaxis in marrow transplant recipients is questioned.