Search

Background Infections are a major concern for immunocompromised children. We investigated whether non-pharmaceutical interventions (NPIs) implemented in the general population during the coronavirus disease 2019 (COVID-19) pandemic in Germany had an impact on frequency, type and severity of infections in these patients. Patients and methods We analyzed all admissions to the clinic of pediatric hematology, oncology and stem cell transplantation (SCT) with (suspected) infection or fever of unknown origin (FUO) from 2018 to 2021. Results We compared a 27-month period before NPIs (Pre-COVID: 01/2018–03/2020; 1041 cases) with a 12-month period with underlying NPIs (COVID: 04/2020–03/2021; 420 cases). During the COVID period the number of in-patient stays with FUO or infections decreased (38,6 cases/month vs. 35,0 cases/month), the median duration of hospital stays was longer (8 d (CI95: 7–8 d) vs. 9 d (CI95: 8–10 d) P=0,02)), the mean number of antibiotics per case increased (2,1 (CI95: 2,0–2,2) vs. 2,5 (CI95: 2,3–2,7); P=0,003)) and a substantial reduction of viral respiratory and gastrointestinal infections per case was seen (0,24 vs. 0,13; P Conclusions Introduction of NPIs in the general population during the COVID-pandemic substantially reduced viral respiratory and gastrointestinal infections in immunocompromised patients, while severe (bacterial) infections were not prevented.

Transplantation of allogeneic hematopoietic stem cells represents an established treatment for children with high-risk leukemia. However, steroid-refractory chronic graft-versus-host disease (SR-cGvHD) represents a severe life-threatening complication, for which there is no standard therapy. After failing several lines of immunosuppressive and biological treatment, we applied an immunoablative therapy with re-transplantation of purified CD34+ donor stem cells to reset the aberrant immune system. Two pediatric patients, who had been transplanted for high-risk acute lymphoblastic leukemia, underwent the procedure. Interestingly, enough stem cells could be mobilized, harvested, and purified to be used as grafts more than one year after allogeneic transplantation under intensive immunosuppressive therapy and ongoing SR-cGvHD. With a follow-up of 8 and 22 months, respectively, both patients are without immunosuppressive therapy and do not show signs of active disease. Regeneration of skin manifestations started promptly, other damaged organs did not progress and continue to show recovery from severe fibrotic transformation. Bone marrow function is robust and T cell receptor repertoires showed polyclonal immune reconstitution. In conclusion, stem cell harvest and re-transplantation of human CD34+-selected allogeneic stem cells is possible and represents a new therapeutic option in SR-cGvHD by resetting a profoundly disturbed immune network.

Almost 2 years into the pandemic and with vaccination of children significantly lagging behind adults, long-term pediatric humoral immune responses to SARS-CoV-2 are understudied. The C19.CHILD Hamburg (COVID-19 Child Health Investigation of Latent Disease) Study is a prospective cohort study designed to identify and follow up children and their household contacts infected in the early 2020 first wave of SARS-CoV-2. We screened 6113 children P = 0.047). Most importantly, children showed sustained seroconversion up to 9 months PSO, and serum antibody concentrations persistently surpassed adult levels (ratio serum IgG spike children vs. adults 90 days PSO 1.75, P P = 0.01; 270 days 1.54, P = 0.001). In a low-incidence setting, SARS-CoV-2 infection and humoral immune response present distinct patterns in children including higher antibody levels, and lower seroprevalence in families with pediatric index cases. Children show long-term SARS-CoV-2 antibody responses. These findings are relevant to novel variants with increased disease burden in children, as well as for the planning of age-appropriate vaccination strategies.

Background Mucolipidosis type II (MLII) is an ultra-rare lysosomal storage disorder caused by defective lysosomal enzyme trafficking. Clinical hallmarks are craniofacial dysmorphia, cardiorespiratory dysfunction, hepatosplenomegaly, skeletal deformities and neurocognitive retardation. Death usually occurs in the first decade of life and no cure exists. Hematopoietic stem cell transplantation (HSCT) has been performed in few MLII patients, but comprehensive follow-up data are extremely scarce. Methods MLII diagnosis was confirmed in a female three-month-old patient with the mutations c.2213C > A and c.2220_2221dup in the GNPTAB gene. At nine months of age, the patient received HSCT from a 9/10 human leukocyte antigen (HLA)-matched unrelated donor. Results HSCT resulted in a sustained reduction of lysosomal storage und bone metabolism markers. At six years of age, the patient showed normal cardiac function, partial respiratory insufficiency and moderate hepatomegaly, whereas skeletal manifestations had progressed. However, the patient could walk and maintained an overall good quality of life. Neurocognitive testing revealed a developmental quotient of 36%. The patient died at 6.6 years of age following a human metapneumovirus (hMPV) pneumonia. Conclusions The exact benefit remains unclear as current literature vastly lacks comparable data on MLII natural history patients. In order to evaluate experimental therapies, in-depth prospective studies and registries of untreated MLII patients are indispensable., Graphical abstract Unlabelled Image

AML SCT-BFM 2007 was the first hematopoietic stem cell transplantation (HCT) trial in Germany to comply with the European Clinical Trials Directive, and aimed to standardize pediatric HCT for acute myeloid leukemia (AML) across centers in Germany, Austria, and the Czech Republic. Children with high-risk features and a good early response achieving a complete first remission (CR-1) and those in CR-2 after a first relapse were stratified to receive HCT from a matched donor after myeloablative conditioning consisting of busulfan, cyclophosphamide, and melphalan. Four-year EFS and OS were 61 and 70%. Cumulative incidence of relapse (CIR) was 22%. TRM was 15% and correlated with age reaching 9% (SE 3%) in children younger than 12 years and 31% (SE 9%) in older children and adolescents. Children with poorly responding primary disease or relapse were allocated to receive early HCT after a cytoreductive regimen with fludarabine, amsacrine, and cytarabine, followed by reduced intensity conditioning and prophylactic donor lymphocyte infusions. Four-year EFS and OS were 49 and 53%. CIR was 38% and TRM 11%. For patients with primary poor response disease, early use of RIC HCT followed by prophylactic DLI can induce long-term remissions in more than 50% (EFS 46% (SE 9%)).

AML SCT-BFM 2007 was the first hematopoietic stem cell transplantation (HCT) trial in Germany to comply with the European Clinical Trials Directive, and aimed to standardize pediatric HCT for acute myeloid leukemia (AML) across centers in Germany, Austria, and the Czech Republic. Children with high-risk features and a good early response achieving a complete first remission (CR-1) and those in CR-2 after a first relapse were stratified to receive HCT from a matched donor after myeloablative conditioning consisting of busulfan, cyclophosphamide, and melphalan. Four-year EFS and OS were 61 and 70%. Cumulative incidence of relapse (CIR) was 22%. TRM was 15% and correlated with age reaching 9% (SE 3%) in children younger than 12 years and 31% (SE 9%) in older children and adolescents. Children with poorly responding primary disease or relapse were allocated to receive early HCT after a cytoreductive regimen with fludarabine, amsacrine, and cytarabine, followed by reduced intensity conditioning and prophylactic donor lymphocyte infusions. Four-year EFS and OS were 49 and 53%. CIR was 38% and TRM 11%. For patients with primary poor response disease, early use of RIC HCT followed by prophylactic DLI can induce long-term remissions in more than 50% (EFS 46% (SE 9%)).

Osteonecrosis (ON) was prospectively assessed in 557 children and adolescents in the Berlin-Frankfurt-Münster Stem Cell Transplantation in children with acute lymphoblastic leukaemia 2003 trial. Median age at haematopoietic stem cell transplantation (HSCT) was 10·3 years (range 0·5-26). Cumulative incidence of symptomatic ON (sON) was 9% at 5 years (standard deviation 1%), median time from HSCT to diagnosis of sON was 12·4 months (range 1-126). Multivariate analysis identified age at HSCT [10-15 years vs.10 years: hazard ratio (HR) 3·73, P = 0·009;15 years vs.10 years: HR 5·46, P = 0·001], diagnosis of sON prior to HSCT and chronic graft-versus-host disease (yes versus no: HR 2·696, P = 0·015) as significant independent risk factors for the development of sON.

Allogeneic hematopoietic stem cell transplantation is required as rescue therapy in about 20% of pediatric patients with acute lymphoblastic leukemia. However, the relapse rates are considerable, and relapse confers a poor outcome. Early assessment of the risk of relapse is therefore of paramount importance for the development of appropriate measures. We used the EuroChimerism approach to investigate the potential impact of lineage-specific chimerism testing for relapse-risk analysis in 162 pediatric patients with acute lymphoblastic leukemia after allogeneic stem cell transplantation in a multicenter study based on standardized transplantation protocols. Within a median observation time of 4.5 years, relapses have occurred in 41/162 patients at a median of 0.6 years after transplantation (range, 0.13-5.7 years). Prospective screening at defined consecutive time points revealed that reappearance of recipient-derived cells within the CD34(+) and CD8(+) cell subsets display the most significant association with the occurrence of relapses with hazard ratios of 5.2 (P=0.003) and 2.8 (P=0.008), respectively. The appearance of recipient cells after a period of pure donor chimerism in the CD34(+) and CD8(+) leukocyte subsets revealed dynamics indicative of a significantly elevated risk of relapse or imminent disease recurrence. Assessment of chimerism within these lineages can therefore provide complementary information for further diagnostic and, potentially, therapeutic purposes aiming at the prevention of overt relapse. This study was registered at clinical.gov with the number NC01423747.

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.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.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.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.Gentium SpA, European Group for Blood and Marrow Transplantation.

Between August 1996 and December 2004, 369 patients with a median age of 41 years (range: 1-68 years) received stem cell transplantation (SCT) from unrelated donors after an antithymocyte-globulin (ATG)-containing conditioning regimen. In 268 patients, complete molecular typing (4-digit) of HLA-A, -B, -C, -DRB1, and -DQB1 was available: 110 patients were completely matched for 10 alleles, 91 patients had 1 allele-mismatch (9/10), and 67 patients were mismatched for 2-4 alleles (6-8/10). The incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 33% in the 10/10, 41% in the 9/10, and 40% in the 6-8/10 group, respectively (P = .1). The cumulative incidence of treatment-related mortality (TRM) and relapse among the groups were similar (27%, 31%, and 32%, P = .2; and 28%, 27%, and 26%, P = .9. After a median follow-up of 35 months (range: 3-120 months), the estimated 5-year disease-free survival (DFS) was 42% and did not differ among the 10/10, the 9/10, and the 6-8/10-mismatched groups (45% versus 42% versus 39%) (P = .5). In multivariate analysis, only age (hazard ratio [HR] 1.013) (P = .004) and bad-risk disease (HR 1.975) (P < .001) were independent risk factors for DFS. In conclusion, pretransplant ATG allows allogeneic SCT from unrelated donors with HLA disparities.

SummaryWe have prospectively evaluated the biologic response to desmopressin (DDAVP) in 28 children with type 2 von Willebrand disease (VWD) in correlation with the phenotype and the molecular defect of VWF. The diagnosis of VWD type 2 was mainly based on VWF functional parameters and/or an aberrant VWF multimer pattern. Seventeen different mutations were identified (6 of them novel). No response with respect to the functional parameters VWF:RCo and/or VWF:CB was seen in patients with severe abnormality of the VWF multimer pattern. One patient with VWD type 2A phenotype IIC Miami did not respond with respect to VWF:CB, but showed a good response of VWF:Ag and FVIII:C as expected. Interestingly he showed a persistently high level of VWF:Ag and FVIII:C up to 4 hours after DDAVP infusion. Patients with minor alterations of multimer structure and particular mutations responded well to DDAVP, whereas patients with normal multimer structure but a defect in platelet dependent functional parameters did not respond with VWF:RCo. Conclusion: Children with VWD type 2 show a variable response to desmopressin depending on the mutation that correlates with the functional defect and the presence or absence as well as the half-life of large VWF multimers. Our data emphasize the usefulness of DDAVP testing even in patients with VWD type 2, possibly with the exception of VWD type 2B.

Minor eyelid abnormalities are commonly encountered in mucopolysaccharidosis, but only rarely leading to a clinically relevant situation. The authors report a clinical case of severe bilateral cicatricial entropion of the upper eyelids, leading to recurrent conjunctival infections, corneal erosion, persistent epiphora, and a major decline in life quality in a 7-year-old boy with mucopolysaccharidosis type I who underwent hematopoietic stem cell transplantation at 1.6 years old. A bilateral anterior lamellar repositioning including eyelid split and cryoepilation was performed to correct bilateral upper eyelid entropium and trichiasis. Three months after the surgical intervention, the patient showed a persistent regular eyelid position with only mild recurrent right-sided lateral upper eyelid entropion. A significant reduction in conjunctival infections and epiphora with complete discontinuation of topical therapy was achieved. Although mucopolysaccaridosis is associated with eyelid abnormalities, the authors conclude that the described case is most likely due to chronic graft versus host disease.

Purpose Although hematopoietic stem-cell transplantation is widely performed in children with high-risk acute lymphoblastic leukemia (ALL), the influence of donor types is poorly understood. Thus, transplantation outcomes were compared in the prospective multinational Berlin-Frankfurt-Muenster (BFM) study group trial: ALL-SCT-BFM 2003 (Allogeneic Stem Cell Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia). Patients and Methods After conditioning with total-body irradiation and etoposide, 411 children with high-risk ALL received highly standardized stem-cell transplantations during the first or later remissions. Depending on donor availability, grafts originated from HLA-genoidentical siblings or from HLA-matched unrelated donors who were identified and matched by high-resolution allelic typing and were compatible in at least 9 of 10 HLA loci. Results Four-year event-free survival (± standard deviation [SD]) did not differ between patients with transplantations from unrelated or sibling donors (0.67 ± 0.03 v 0.71 ± 0.05; P = .405), with cumulative incidences of nonrelapse mortality (± SD) of 0.10 ± 0.02 and 0.03 ± 0.02 (P = .017) and relapse rates (± SD) of 0.22 ± 0.02 and 0.24 ± 0.04 (P = .732), respectively. Among recipients of transplantations from unrelated donors, no significant differences in event-free survival, overall survival, or nonrelapse mortality were observed between 9/10 and 10/10 matched grafts or between peripheral blood stem cells and bone marrow. The absence of chronic graft-versus-host disease had no effect on event-free survival. Engraftment was faster after bone marrow transplantation from siblings and was associated with fewer severe infections and pulmonary complications. Conclusion Outcome among high-risk pediatric patients with ALL after hematopoietic stem-cell transplantation was not affected by donor type. Standardized myeloablative conditioning produced a low incidence of treatment-related mortality and effective control of leukemia.

We investigated the efficacy of an antithymocyte globulin/cyclophosphamide preparative regimen prior to allogeneic stem cell transplantation from HLA-identical siblings in patients with severe aplastic anemia. Since 1990, 21 patients, 6 males and 15 females, with a median age of 25 years (range: 7-43) have been enrolled in the protocol consisting of 200 mg/kg cyclophosphamide and 90-120 mg/kg antithymocyte globulin (ATG, rabbit, Fresenius, Bad Homburg, Germany). For further graft-versus-host disease (GVHD) prophylaxis all patients received cyclosporin A and a short course of methotrexate (MTX). Only one patient had a primary graft failure (5%). All other patients engrafted with a leukocyte count1.0 x 10(9)/l and a platelet count20 x 10(9)/l after a median of 19 (range: 11-28) and 26 days (range: 13-67), respectively. No late graft failure or relapse was observed. Two patients experienced mild acute GVHD grade I (10%), and one patient developed grade II GVHD (5%). No severe grade III/IV GVHD was observed; 17% of the patients developed limited chronic GVHD. The treatment-related mortality was 14% and mainly due to fungal infection. After a median follow-up of 70 months (range: 2-139), the estimated overall and event-free survival at 10 years for all patients is 86% (95% confidence interval: 70-100%). We conclude that ATG plus cyclophosphamide is an effective conditioning regimen in patients with aplastic anemia undergoing stem cell transplantation with a low treatment-related mortality, resulting in an excellent outcome.

We investigated the feasibility and efficacy of a fludarabine-based dose-reduced conditioning regimen followed by stem cell transplantation from related (n = 5) or unrelated HLA-matched donors (n = 7) in 12 patients with high risk MDS, who were not eligible for a standard myeloablative conditioning regimen. The conditioning regimen consisted of fludarabine 30 mg/m(2) daily for 6 days, busulfan 4 mg/kg daily for 2 days and anti-thymocyte globulin (ATG, rabbit) 10 mg/kg daily for 4 days in 11 patients, while one patient received fludarabine, ATG, cyclophosphamide and thiotepa. Graft-versus-host disease prophylaxis consisted of cyclosporine and a short course of methotrexate. The median age of the patients was 53 years (range 37-59). The median percentage of blasts in bone marrow aspirate at transplantation was 15% (range

We evaluated the cytomegalovirus (CMV) serostatus as a risk factor for survival and treatment-related mortality (TRM) in 125 patients allografted from an unrelated donor between 1994 and 1999. All patients received pretransplant in vivo T-cell depletion using rabbit anti-thymocyte globulin (ATG). Only one patient had primary graft failure and severe grade III/IV graft-versus-host disease occurred in 14% of the patients. The overall survival (OS) at 3 years was 70% for CMV-negative patients (n = 76) and 29% in the seropositive cohort (n = 49) (P > 0.001). In multivariate analyses, CMV seropositivity remained an independent negative prognostic factor for OS (RR: 2.1; CI: 1.2-3.8; P = 0.014), apart from age > 20 years (RR: 2.74; CI: 1.2-3.8; P = 0.004) and late leucocyte engraftment (RR: 2.4; CI: 1.2-4.9; P = 0.015). The TRM for all patients was 27%. Despite monitoring for CMV antigenaemia and preemptive therapy with ganciclovir when reactivation occurred, seropositive patients had a three times higher risk of fatal treatment-related complications than seronegative patients. In multivariate analyses, CMV seropositivity remained the strongest independent negative factor for TRM (RR: 5.3; CI: 1.9-14.6; P = 0.002), followed by age > 20 years (RR: 4.8; CI: 1.3-18.1; P = 0.02) and delayed leucocyte engraftment (RR: 3.6; CI: 1.2-11; P = 0.02). The TRM was identical in seropositive patients with (n = 27) or without (n = 22) CMV reactivation (44% versus 50%). We conclude that CMV seropositivity, despite preemptive ganciclovir therapy and even without reactivation, is a major negative prognostic factor for survival as well as for TRM in unrelated stem cell transplantation using pretransplant in vivo T-cell depletion with ATG.

Voriconazole is a second-generation triazole antifungal approved for the treatment of invasive fungal infections, particularly with Aspergillus, Candida, Fusarium, and Scedosporium spp. Frequently reported adverse effects of voriconazole include visual disturbance (21 %), elevated liver enzymes (15.6 %) and rashes (7 %), which are largely attributable to drug-induced photosensitivity. We report a case of serious phototoxicity in a 8 year old boy who underwent chemotherapy for AML. He received voriconazole for the treatment and subsequent re-infection prophylaxis after pulmonary aspergillosis. One year after the start of therapy he developed blistering eruptions on his face after minimal sunlight exposure. Recent reports about the development of squamous cell carcinoma and melanoma, respectively, in children during and after oral therapy with voriconazole seem to warrant systematic follow-up investigations of all voriconazole-treated patients.

A rare case of primary intestinal T-cell lymphoma (ITL) of an 8-year-old boy is reported. Medium- to large-sized tumor cells were βF1+, CD3+, CD8+. TIA-1+, but CD4−, CD5−, CD30−, CD56−, CD20−, CD79a−, TdT−, consistent with an intraepithelial lymphocyte (IEL) origin. They showed monoclonal rearrangement of the T-cell receptor γ-chain and no evidence of EBV infection. No clinical, histologic, laboratory, or genetic evidence of celiac disease was detected. In adults, ITL is often associated with enteropathy and has a very poor outcome. Our patient remains in first remission 30 months after finishing the acute lymphoblastic leukemia protocol COALL-07-03 high risk standard. Pediatr Blood Cancer 2010;54:610–612. © 2009 Wiley-Liss, Inc.

Congenital hypoplasminogenemia (HPG) is characterized by markedly impaired extracellular fibrinolysis leading to the formation of ligneous (woody) pseudomembranes on mucosal surfaces, including the eye, mouth, bronchopulmonary tree, and genitourinary tract. HPG is caused by homozygous or compound-heterozygous mutations in the plasminogen gene (PLG; 6q26). We present a report of the first therapeutic use of replacement therapy with plasminogen purified from human plasma. A male of Turkish descent was diagnosed at 4 weeks of age with congenital hypoplasminogenemia following presentation with typical ligneous conjunctivitis. The serum plasminogen activity level was < 2% (Reference range 75-140%), and the diagnosis was confirmed by genetic testing showing a novel homozygous splice-site mutation in PLG (c.1587+1 G>A). At 2 months of age he suffered a severe respiratory syncytial virus (RSV) infection requiring ventilatory support for 5 days and a 1 month hospitalization. From this time he had recurrent respiratory problems. From 4 months of age he was treated with fresh frozen plasma (FFP) 20 mL/kg/week. At 18 months of age he was found to have exophytic lesions within both the right and left main bronchi. He had one incident of acute severe dyspnea with cyanosis which responded to non- invasive oxygen insufflation. Subsequently he had repeated bronchoscopies with laser removal of bronchial lesions with FFP cover. At 20 months of age during preparation for bronchoscopy he had an episode of acute cyanosis and cardiac arrest with asystole and was resuscitated after 30 minutes. CXR showed atelectasis of the left lung and of the right lower lobe. He was admitted to the ICU and required both ventilatory and circulatory support. Profuse viscous lung secretions were aspirated. One week later he was given a dose of plasminogen of 4 mg/kg, with a second dose of 6 mg/kg and subsequent doses of 6.5 mg/kg every 48 hours. The pharmacokinetics are shown in the Figure. Note that baseline level before the first dose is 21% due to FFP therapy. Progressive dissolution of the membranes and exophytic lesions with some blood spotting, was noted, and was associated with decreased oxygen requirements. Improvement in the ligneous eye lesions was also observed. After 4 days he was extubated., but required reintubation after 36 hours due to exhaustion; he was finally extubated 1 week after receiving the first dose of plasminogen. Plasminogen replacement has continued with a regimen of 6.5 mg/kg every second day. There has been progressive dissolution of the membranes with greatly reduced lesions seen after 6 weeks of treatment. CXR before administration of plasminogen showed atelectasis of the left lung and of the right lower lobe (left panel). Six weeks after initiation of regulalar plasminogen substitution ventilation in both lungs had improved significantly (right panel) In this patient substitution with plasminogen was effective and showed no significant side effects. Patients with severe plasminogen deficiency might benefit from prophylactic or early treatment to prevent severe complications such as occurred in this patient. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Moran: ProMetic Life Sciences, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Schneppenheim:Baxalta, now part of Shire: Membership on an entity's Board of Directors or advisory committees.

Voriconazole is a second-generation triazole antifungal approved for the treatment of invasive fungal infections, particularly with Aspergillus, Candida, Fusarium, and Scedosporium spp. Frequently reported adverse effects of voriconazole include visual disturbance (21 %), elevated liver enzymes (15.6 %) and rashes (7 %), which are largely attributable to drug-induced photosensitivity. We report a case of serious phototoxicity in a 8 year old boy who underwent chemotherapy for AML. He received voriconazole for the treatment and subsequent re-infection prophylaxis after pulmonary aspergillosis. One year after the start of therapy he developed blistering eruptions on his face after minimal sunlight exposure. Recent reports about the development of squamous cell carcinoma and melanoma, respectively, in children during and after oral therapy with voriconazole seem to warrant systematic follow-up investigations of all voriconazole-treated patients.

A rare case of primary intestinal T-cell lymphoma (ITL) of an 8-year-old boy is reported. Medium- to large-sized tumor cells were betaF1+, CD3+, CD8+. TIA-1+, but CD4-, CD5-, CD30-, CD56-, CD20-, CD79a-, TdT-, consistent with an intraepithelial lymphocyte (IEL) origin. They showed monoclonal rearrangement of the T-cell receptor gamma-chain and no evidence of EBV infection. No clinical, histologic, laboratory, or genetic evidence of celiac disease was detected. In adults, ITL is often associated with enteropathy and has a very poor outcome. Our patient remains in first remission 30 months after finishing the acute lymphoblastic leukemia protocol COALL-07-03 high risk standard.

Abstract 530 In 2003 the Berlin-Frankfurt-M ünster (BFM)-Study group initiated a prospective international multicenter trial (ALL-SCT-BFM 2003) for allogeneic hematopoetic stem cell transplantation (HSCT) in children with ALL. Main goals were 1. to answer the question, whether HSCT from a matched sibling donor (MSD) was equivalent to HSCT from a 9/10 or 10/10 HLA matched donor (MD) and 2. to standardize and harmonize the HSCT procedure. Another intention was to determine the efficacy of HSCT from HLA-mismatched donors (MMD) compared to HSCT from MD/MSD as well as the incidence of acute and chronic graft-versus-host disease (GvHD) and the antileukemic efficacy of the procedure. Between September 2003 and September 2009, 387 patients (188 in CR1, 199 ≥ CR2) were transplanted in 27 participating HSCT centers in Austria, Germany and Switzerland. Mean age of the patients at HSCT was 10 years (range 0.5 to 18). Indications for HSCT were poor response to induction treatment, either detected by morphology on day 33 or by minimal residual disease load measured after 12 weeks of treatment, cytogenetic aberrations [t(9;22), t(4;11)], early bone marrow relapse, or any subsequent ALL relapse. 97 patients received a MSD-HSCT, 251 patients a MD-HSCT, and 39 patients a MMD-HSCT. Median follow-up was 2.4 years. The compliance with HLA-typing procedures according to the trial guidelines (high resolution typing of HLA A, B, C, DRB1 and DQB1) improved over time to 100% since 2007. Unmanipulated bone marrow was used in 81% of MSD-HSCT and in 65% of MD-HSCT as determined by the protocol. The conditioning regimens consisted of TBI+VP16 for MSD, TBI+VP16+ATG for MD, and TBI+Flu+VP16+ATG for MMD; TBI was substituted by BU+Cy in children younger than 2 years). GvHD prophylaxis (CSA for MSD, and CSA plus MTX on day 1, 3 and 6 for MD) were given in the vast majority of patients according to the trial guidelines. Protocol deviations were mostly due to clinical reasons. Results: Acute GvHD (Grade III and IV) occurred in 10% of all patients, the 2-year cumulative incidence of extensive chronic GvHD was 15% after MSD and 12 % after MD HSCT. The 4-year probability of event-free survival (pEFS) after MSD-HSCT was equivalent to MD-HSCT (70% vs. 68%; p=0.37). The cumulative incidence of treatment related mortality (TRM) after 1 year was 5% for MSD and 8% for MD HSCT (n.s.). The 2-years cumulative incidence of relapse was 18% after MSD-HSCT and 20% after MD-HSCT (n.s.) For patients with very high risk of relapse the results for MD/MSD HSCT (n=187) and MMD HSCT (n=39) differed significantly (2-year pEFS 68% vs. 28%; p The results from this ALL-SCT-BFM 2003 trial, which is the largest prospective, international and multicenter HSCT trial ever performed in childhood ALL, demonstrate the feasibility of a harmonized HSCT approach across multiple international centers. We demonstrate that allogeneic HSCT from well HLA-matched unrelated donors or geno-identical sibling donors is an effective treatment option with acceptable toxicity in children with high risk ALL. Precise HLA typing and matching and ATG resulted in a low incidence of extensive chronic GvHD which is an important achievement for the quality of life in children and adolescents. These data will form a solid basis for subsequent ALL-HSCT trials, focussing on controlled modifications and interventions in patients at highest risk for relapse after HSCT. Disclosures: No relevant conflicts of interest to declare.

Abstract 653 Background: Hepatic VOD is a life-threatening complication following SCT with a particularly high incidence in children. Development of VOD is one of the most common causes of early death after SCT. DF (Gentium SpA), a polydisperse oligonucleotide, demonstrates a protective effect on vascular endothelial cells in vitro. Small non-randomized trials to assess DF for the prophylaxis of VOD were promising without significant anticoagulant effects. Methods: Eligibility criteria included pts 2 mg/dL, hepatomegaly, ascites and/or unexplained weight gain > 5%). VOD was assessed by physical exam; hepatomegaly and ascites were confirmed by abdominal ultrasound. A blinded independent review committee of 3 expert hematologists confirmed the diagnosis of VOD. Although the study was not powered to assess mortality, a composite score was assessed as a secondary endpoint that incorporated VOD-associated toxicity (respiratory failure, renal failure, encephalopathy) and mortality. Incidence and severity of graft versus host disease (GvHD) was assessed. As the true incidence of VOD in this population was unknown, the trial incorporated a planned adaptive interim analysis to be reviewed by an independent DSMB. Results: Based on the recommendations of the DSMB, 360 pts were enrolled between January 2006 and January 2009 by 28 centers in the EU and Israel. An Intent-to-Treat (ITT) analysis was performed on all randomized pts who signed informed consent (DF: 180; control: 176). Median age was 4.8 years; 24% infants, 52% children (ages 2-11 years) and 23% adolescents. 41% were female, 59% male. 68% were allo-, 31% auto-SCT. There were no significant differences between the two arms in disease types or risk factors. Ninety-three percent (93%) of the patients completed the primary endpoint at day +30. In the ITT analysis, 12% (22/180) of the pts of the DF arm and 20% (35/176) of the control group developed VOD by D+30 (P=0.054); in the PP analysis, the VOD incidence was 12% (20/164) vs 21% (35/169) (P=0.037). VOD was experienced by 23% of the infants, 14% of the children and 13% of the adolescents. The composite score (assessing VOD morbidity and mortality) was significantly in favor of the DF arm (P=0.034). Significantly less acute GvHD by D+100 was reported in the DF pts (32% (57/180) vs 43% (75/176); P=0.023 by Wilcoxon test). Observation of VOD in either arm led to a higher mortality: mortality of pts with VOD equaled 24.6% (14/57) compared to 7% in pts without VOD (21/299). Renal failure was observed in 1% (2/180 pts) of DF pts vs 6% (10/176) of the control (P=0.017); respiratory failure was observed in 7% vs 9% (NS); and encephalopathy in 1% vs 2% (NS). SAEs were experienced by 58% of the DF pts vs 59% of the control, including infections (24% vs 27%) and respiratory disorders (12% vs 9%); 9 hemorrhagic events were seen in the DF arm compared to 21 in the control. Conclusions: This Phase II/III randomized study demonstrates the efficacy and safety of DF in preventing VOD in pediatric pts at high risk of VOD. Use of prophylactic DF results in a 40% reduction in the incidence of VOD. Consistent with the role of DF in endothelial protection, both renal failure and acute GvHD were significantly lower in the DF arm. Safety of DF was confirmed by lack of significant toxicity (including hemorrhage). DF can be recommended for the prevention of VOD in this high risk population. Disclosures: Corbacioglu: Gentium S.p.A.: Consultancy, Research Funding. Massaro:Gentium S.p.A.: Consultancy. D'Agostino:Gentium S.p.A.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hoyle:Gentium S.p.A.: Employment. Iacobelli:Gentium: Employment.

Abstract 3344 Poster Board III-232 Background: Hepatic VOD is a life-threatening complication following SCT with a high incidence in children. Development of VOD is one of the most common causes of early death after SCT. Busulfan (BU), an alkylating agent with a very narrow therapeutic index is a commonly used conditioning agent in pediatric stem cell transplantation (SCT) with a strong correlation between AUC and both efficacy and toxicity. Oral BU (poBU) has significant age-related and interpatient pharmacokinetic differences and was linked with an increased risk for VOD. IV busulfan (ivBU) yielded promising results in some studies to be associated with low toxicity profile, especially with a reduced incidence of VOD. Methods: Patients 2 mg/dL, hepatomegaly, ascites and/or unexplained weight gain > 5%). VOD was assessed by physical exam; hepatomegaly and ascites were confirmed by ultrasound. A blinded IRC of 3 expert hematologists confirmed the diagnosis of VOD. Although the study was not powered to assess mortality, a composite score was assessed as a secondary endpoint that incorporated VOD-associated toxicity (respiratory failure, renal failure, encephalopathy) and mortality. The additional analysis of the influence of BU on VOD was not planned and is therefore explorative. Results: 360 pts were enrolled between January 2006 and January 2009 by 28 centers in the EU and Israel. An Intent-to-Treat (ITT) analysis was performed on all pts who signed informed consent (n=356). 251 (71%) pts from the ITT population were conditioned with BU (64% ivBU; 36% poBU). 202 (55%) were treated with BU and Melphalan (MEL) (60% ivBU; 40% poBU). In 49 (14%) BU was used without MEL (80% ivBU; 20% poBU). In children The median age of patients with iv BU was 3.65 yrs and 5,13 yrs with poBU; 28% infants, 50% children (ages 2-11 yrs) and 22% adolescents (evenly distributed). 45% female, 55% male (evenly distributed). Allo-SCT was performed in 69% with ivBU and 46% with poBU (remaining with auto-SCT). The diagnoses were evenly distributed between poBU and ivBU. Except in AML 18% were conditioned with ivBU and 32% with poBU. Preexisting liver disease was present in 23% ivBU and 9% poBU pts, of which 46% (17/37) ivBU and 37% (3/8) poBU had elevated transaminases. Overall VOD was experienced by 23% of the infants, 14% of the children and 13% of the adolescents. The overall incidence of VOD in pts treated with BU was 18%. VOD was diagnosed in 24% ivBU vs 8% poBU pts. In pts treated with BU/MEL VOD was diagnosed in 16%. VOD in ivBU/MEL was 21% (26) vs 8% (6) in poBU/MEL. In BU without MEL VOD was diagnosed in 27% (13/49). 31% (12/39) in ivBU pts and 10% (1/10) in poBU pts. In infants treated with BU/MEL the incidence of VOD in the ivBU group was 23% (6/26) and 11% (2/18) in poBU. In BU without MEL in infants the incidences were 41% (9/22) ivBU versus none (0/4) in poBU. The diagnosis of VOD independent of severity was associated with a higher mortality and equaled 24.6% (14/57) compared to 7% in pts without VOD (21/299). Respiratory failure was observed in 10% (16/161) of ivBU vs 2% (2/90) of poBU pts (9% (11/122) vs 1% (1/80) iv vs po BU/MEL); renal failure in 5% (8/161) ivBu vs 1% (1/90) poBU (5% (6/122) vs none in iv vs po BU/MEL). The incidence of multi-organ-failure (MOF) by day +100 was 12% (19/161) in ivBU vs 3% (3/90) in poBU (p=0.022). Compared to all other pts the risk to develop VOD in infants treated with allo-SCT and ivBU is 2.4 times higher (p=0.003). Conclusions: Although the scope of this trial was not to assess the influence of BU on the incidence of VOD and there was an imbalanced distribution of liver diseases and a potential bias for other risk factors the incidence of VOD in ivBU was unexpectedly high especially in infants. Inasmuch this is due to a high interpatient variability of the AUC should be explored prospectively. Disclosures: Corbacioglu: Gentium S.p.A.: Consultancy, Research Funding.