Solid organ transplantation after hematopoietic stem cell transplantation in childhood: A multicentric retrospective survey.

We report data obtained from a retrospective multicenter pediatric survey on behalf of the European Society for Blood and Marrow Transplantation (EBMT). Information on solid organ transplantation (SOT) performed in pediatric recipients of either autologous or allogeneic hematopoietic stem cell transplantation (HSCT) between 1984 and 2016 was collected in 20 pediatric EBMT Centers (25.6%). Overall, we evaluated data on 44 SOTs following HSCT including 20 liver (LTx), 12 lung (LuTx), 6 heart (HTx), and 6 kidney (KTx) transplantations. The indication for SOT was organ failure related to intractable graft-vs-host disease in 16 children (36.3%), acute or chronic HSCT-related toxicity in 18 (40.9%), and organ dysfunction related to the underlying disease in 10 (22.8%). The median follow-up was 10.9 years (95% confidence interval: 1.7-29.5). The overall survival rate at 1 and 5 years after SOT was 85.7% and 80.4%, respectively: it was 74% and 63.2% after LTx, 83.2% after HTx, and 100% equally after LuTx and KTx. This multicenter survey confirms that SOT represents a promising option in children with severe organ failure occurring after HSCT. Additional studies are needed to further establish the effectiveness of SOT after HSCT and to better understand the mechanism underlying this encouraging success.

Chronic hypogammaglobulinemia after allogeneic stem cell transplantation and their treatment with subcutaneous immunoglobulin in pediatric patients.

INTRODUCTION: Hypogammaglobulinemia in the first months after allogeneic hematopoietic stem cell transplantation (HSCT) is common in paediatric patients. During this phase, replacement therapy with human immunoglobulin must be administered parenterally to prevent infections. In some cases, this hypogammaglobulinemia persists over time, which forces further treatment when the patient is usually no longer a carrier of a central line, making them ideal candidates for subcutaneous replacement therapy. There is little published literature describing the use of this method in paediatric patients undergoing HSCT, widely described in replacement treatment in children with primary immunodeficiencies with very good results. PATIENTS AND METHODS: An observational, descriptive, longitudinal and retrospective study is carried out. During the years 2008-2019, we evaluated all paediatric patients undergoing HSCT in our center with persistent chronic hypogammaglobulinemia (for over a year). The treatment phase with intravenous immunoglobulin (Privigen®) and the first four years of treatment with subcutaneous immunoglobulin (Hizentra®) are evaluated using a questionnaire. RESULTS: During the years 2008-2019, 175 patients underwent HSCT, 143 (82%) of whom exceeded three months after transplantation. Three (2%) of them had persistent hypogammaglobulinemia. All three share factors described in the literature involved in immune reconstitution. After analysing the questionnaire, it is observed that switching from intravenous to subcutaneous gammaglobulin has involved a great improvement in their quality of life. CONCLUSIONS: The origin of chronic hypogammaglobulinemia in our patients shows different factors and cannot be attributed to a single cause. Due to the limited number of patients no conclusions can be drawn at the population level. We have been able to observe that replacement treatment with Hizentra 20% has been as effective as the intravenous administration without evidence of an increase in bacterial infections. Furthermore, it has also led to an improvement in quality of life and increased comfort, as the patients themselves have stated.

Experience of the Spanish Group for Hematopoietic Transplantation (GETMON-GETH) in allogenic Hematopoietic stem cell Transplantation in Philadelphia acute lymphoblastic leukemia.

INTRODUCTION: Outcomes in patients diagnosed of acute lymphoblastic leukemia with Philadelphia chromosome (Ph-ALL) remains unfavourable compared to other subtypes of acute lymphoblastic leukemia despite improvements in drug treatments as well as advances in hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: The role of allogeneic HSCT in Ph-ALL patients has been analysed through a multicentric study where data belonging to 70 patients diagnosed of this entity in different centers that received HSCT between years 1998 and 2014, were reported by the Grupo Español de Trasplante Hematopoyético (GETH). RESULTS: The performance of HSCT from year 2004, in first complete remission (CR) status with thymoglobulin (ATG) based conditioning had a favorable impact on overall survival (OS). HSTC performance from year 2004, in first CR with ATG-based conditioning in addition to acute graft versus host disease (aGvHD) development, increased event free survival (EFS). Treatment with imatinib as well as undetectable minimal residual disease (MRD) prior to HSCT, combined with aGvHD, reduced risk of relapse (RR). Patient age less than 10 years when HSCT, first CR and ATG-based conditioning were associated to a lower transplant related mortality (TRM). CONCLUSIONS: Patients that could achieve first CR that also received ATG-based conditioning had a better OS and EFS, so HSCT should be considered for this group of patients.

[Experience of the Spanish Group for Hematopoietic Transplantation (GETMON-GETH) in allogenic hematopoietic stem cell transplantation in Philadelphia acute lymphoblastic leukemia]. / Experiencia del Grupo Español de Trasplante Hematopoyético (GETMON-GETH) en el trasplante alogénico de progenitores hematopoyéticos en leucemia aguda linfoblástica Philadelphia.

INTRODUCTION: Outcomes in patients diagnosed of acute lymphoblastic leukemia with Philadelphia chromosome (Ph-ALL) remains unfavourable compared to other subtypes of acute lymphoblastic leukemia despite improvements in drug treatments as well as advances in hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: The role of allogeneic HSCT in Ph-ALL patients has been analysed through a multicentric study where data belonging to 70 patients diagnosed of this entity in different center that received HSCT between years 1998 and 2014, were reported by the Grupo Español de Trasplante Hematopoyético (GETH). RESULTS: The performance of HSCT from year 2004, in first complete remission (CR) status with thymoglobulin (ATG) based conditioning had a favorable impact on overall survival (OS). HSTC performance from year 2004, in first CR with ATG-based conditioning in addition to acute graft versus host disease (aGvHD) development, increased event free survival (EFS). Treatment with imatinib as well as undetectable minimal residual disease (MRD) prior to HSCT, combined with aGvHD, reduced risk of relapse (RR). Patient age less than 10 years when HSCT, first CR and ATG-based conditioning were associated to a lower transplant related mortality (TRM). CONCLUSIONS: Patients that could achieve first CR that also received ATG-based conditioning had a better OS and EFS, so HSCT should be considered for this group of patients.

Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies.

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available.

Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies.

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available.

Genetic analyses of aplastic anemia and idiopathic pulmonary fibrosis patients with short telomeres, possible implication of DNA-repair genes.

BACKGROUND: Telomeres are nucleoprotein structures present at the terminal region of the chromosomes. Mutations in genes coding for proteins involved in telomere maintenance are causative of a number of disorders known as telomeropathies. The genetic origin of these diseases is heterogeneous and has not been determined for a significant proportion of patients. METHODS: This article describes the genetic characterization of a cohort of patients. Telomere length was determined by Southern blot and quantitative PCR. Nucleotide variants were analyzed either by high-resolution melting analysis and Sanger sequencing of selected exons or by massive sequencing of a panel of genes. RESULTS: Forty-seven patients with telomere length below the 10% of normal population, affected with three telomeropathies: dyskeratosis congenita (4), aplastic anemia (22) or pulmonary fibrosis (21) were analyzed. Eighteen of these patients presented known pathogenic or novel possibly pathogenic variants in the telomere-related genes TERT, TERC, RTEL1, CTC1 and ACD. In addition, the analyses of a panel of 188 genes related to haematological disorders indicated that a relevant proportion of the patients (up to 35%) presented rare variants in genes related to DNA repair or in genes coding for proteins involved in the resolution of complex DNA structures, that participate in telomere replication. Mutations in some of these genes are causative of several syndromes previously associated to telomere shortening. CONCLUSION: Novel variants in telomere, DNA repair and replication genes are described that might indicate the contribution of variants in these genes to the development of telomeropathies. Patients carrying variants in telomere-related genes presented worse evolution after diagnosis than the rest of patients analyzed.