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The main advantages of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) are the immediate availability of donors, the possibility of developing cell therapy approaches with different novel transplant platforms, and the procedure's cost savings.We retrospectively analyzed the pediatric haplo-HSCT activity of the Spanish hematopoietic stem-cell transplantation group (GETH) between 1999 and 2016, aiming to study clinical characteristics and outcomes by describing patient groups with non-malignant disease (NMD) or malignant disease (MD) and the impact of 2 different periods (1999-2009 and 2010-2016) on long-term outcomes.Twelve centers performed 232 haplo-HSCTs in 227 children, representing 10% of all pediatric allogeneic HSCT activity in Spain from 1999 to 2016, with a notable increase since 2013. Most haplo-HSCTs (86.7%) were performed in patients with MD; 95% received peripheral blood stem cells from donors, and 78.9% received ex vivo T-cell depleted grafts. Non-manipulated grafts using post-transplantation cyclophosphamide have been incorporated since 2012. We observed a higher percentage of graft failure in NMD versus MD (32% vs. 15.6%; p=0.029). Relapse and transplant-related mortality were the procedure's main limitations in MD and NMD, respectively. Five-year overall survival was 48.5% (SE 3.9), with no statistically significant difference when comparing the MD and NMD cohorts. Patients who received previously a HSCT the overall survival was significantly decreased. We observed no survival improvement over time.Although haplo-HSCT is an increasingly employed treatment option, our patients' results need improvement. We need to develop reference centers, especially for NMD whose rarity makes it difficult to gain experience.

Fanconi anemia (FA) is characterized by chromosome fragility, bone marrow failure (BMF) and predisposition to cancer. As reverse genetic mosaicism has been described as "natural gene therapy" in patients with FA, we sought to evaluate the clinical course of a cohort of FA mosaic patients followed at referral centers in Spain over a 30-year period. This cohort includes patients with a majority of T cells without chromosomal aberrations in the DEB-chromosomal breakage test. Relative to non-mosaic FA patients, we observed a higher proportion of adult patients in the cohort of mosaics, with a later age of hematologic onset and a milder evolution of (BMF). Consequently, the requirement for hematopoietic stem cell transplant (HSCT) was also lower. Additional studies allowed us to identify a sub-cohort of mosaic FA patients in whom the reversion was present in bone marrow (BM) progenitor cells leading to multilineage mosaicism. These multilineage mosaic patients are older, have a lower percentage of aberrant cells, have more stable hematology and none of them developed leukemia or myelodysplastic syndrome when compared to non-mosaics. In conclusion, our data indicate that reverse mosaicism is a good prognostic factor in FA and is associated with more favorable long-term clinical outcomes.

This phase 1 study investigated the recommended phase 2 dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple relapsed/refractory (R/R) CD22+ acute lymphoblastic leukemia (ALL). Patients (age ≥1 year or 2 (0.6, 0.4, 0.4 mg/m2) and DL2 was 1.8 mg/m2 (0.8, 0.5, 0.5 mg/m2). Secondary end points included safety, antileukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLTs) were enrolled. In course 1, the first cohort had 1 of 6 (DL1) and 2 of 5 (DL2) patients who experienced DLTs; subsequent review considered DL2 DLTs to be non–dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, in which 0 of 6 (DL1) and 1 of 6 (DL2) patients had a DLT. Twenty-three patients experienced grade 3 to 4 adverse events; hepatic sinusoidal obstruction syndrome was reported in 2 patients after subsequent chemotherapy. Overall response rate after course 1 was 80% (95% confidence interval [CI], 59% to 93%) (20 of 25 patients; DL1: 75% [95% CI, 43% to 95%], DL2: 85% [95% CI, 55% to 98%]). Of the responders, 84% (95% CI, 60% to 97%) achieved minimal residual disease (MRD)-negative complete response, and 12-month overall survival was 40% (95% CI, 25% to 66%). Nine patients received hematopoietic stem cell transplantation or chimeric antigen receptor T cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating antileukemic activity in heavily pretreated children with CD22+ R/R ALL. RP2D was established as 1.8 mg/m2 per course, as in adults. This trial was registered at https://www.clinicaltrialsregister.eu as EUDRA-CT 2016-000227-71. Key Points: • The recommended phase 2 dose of InO for pediatric patients with ALL was established at 1.8 mg/m2 per course. • Of the patients with multiple R/R ALL, 85% reached CR after 1 course of single-agent InO at the RP2D, 100% of whom had MRD negativity.

Josep Maria Ribera Santasusana,1 Alejandra de Andrés Saldaña,2 Nuria García-Muñoz,3 Joana Gostkorzewicz,2 Diana Martínez Llinàs,3 Cristina Díaz de Heredia4 1Clinical Hematology Department, Catalan Institute of Oncology - Hospital Germans Trias i Pujol, Barcelona, Spain; 2Health Economics and Outcomes Research, Novartis Farmacéutica S.A., Madrid, Spain; 3Oblikue Consulting, S.L., Barcelona, Spain; 4Paediatric Oncology and Hematology Department - Hematopoietic Stem Cell Transplantation, Hospital Universitari Vall d’Hebron, Barcelona, SpainCorrespondence: Diana Martínez LlinàsOblikue Consulting, S.L., C/Comte d’Urgell, 240, 2-D, Barcelona 08036, SpainTel +34 93 252 1377Fax +34 93 737 9984Email diana.martinez@oblikue.comPurpose: Tisagenlecleucel, a chimeric antigen receptor T-cell (CAR-T) therapy, is a promising alternative for the management of children and young adults with relapsed and refractory B-cell acute lymphoblastic leukemia (r/r ALL). The aim of this study was to determine whether treatment with tisagenlecleucel is a cost-effective intervention compared with salvage chemotherapy in paediatric and young adult patients with r/r ALL in Spain.Materials and Methods: A partitioned survival model of monthly cycles with three health states was used (event-free survival, progressive/relapsed disease and death). A lifetime time horizon and the Spanish National Health System perspective were adopted. During the first 5 years, permanence in the different health states was determined according to the results in the clinical studies. In successive years, mortality tables of the Spanish general population adjusted by standardized mortality rate for survivors of childhood cancer were used. Clinical, economic, and quality of life parameters were drawn from clinical trials and the literature. Only direct health costs (pharmacological costs and the costs derived from health resource use) were included. The robustness of the results was evaluated in a sensitivity analysis.Results: This cost-effectiveness analysis showed a greater benefit (10.10 and 8.97 life-years gained [LYGs] and quality-adjusted life-years [QALYs] gained, respectively) and a higher cost (€ 258,378.40) for tisagenlecleucel compared to salvage chemotherapy. The resulting incremental cost-effectiveness and cost-utility ratios were € 25,576.80 per LYG and € 28,818.52 per QALY gained, respectively. In the sensitivity analysis, all the results were below € 50,000/QALY.Conclusion: Tisagenlecleucel would represent a cost-effective intervention for the treatment of children and young adults with r/r ALL in Spain.Keywords: ALL, cost-effectiveness, tisagenlecleucel, acute lymphoblastic leukaemia, Spain, CAR-T

Congenital sideroblastic anaemias (CSA) are a rare group of disorders characterized by the presence of pathologic iron deposits within the mitochondria of erythroid precursors (ring sideroblasts) in the bone marrow due to heterogenous germline mutations leading to defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Patients present with anaemia and relative reticulocytopenia, and systemic iron overload secondary to chronic ineffective erythropoiesis, leading to end-organ damage. The disease is heterogenous underlying the genetic variability and the variable response to treatment. Although a number of CSA patients have received a bone marrow transplant, the outcomes and toxicities are not known. This status makes it very difficult to understand the role of BMT in the management of CSA. A search in the EBMT database identified 28 patients receiving a HSCT for CSA between 1998 to 2018 by 24 participating centres. The median year of transplantation was 2014 (IQR 2004-2016). The distribution was equal between males (n=14) and females (n=14). The median age at transplantation was 7 years of age (3-10 years). Fifteen patients had a sibling HSCT (88%), one a family matched donor HSCT (6%) and one an unrelated matched (6%), the type of transplant being unknown in others (n=11). The source of stem cells was bone marrow in 20 cases (74%), peripheral blood in 4 cases (15%), cord blood in 2 (7%) and combined bone marrow and cord in one (4%). Five cases had a Bu/Cy based conditioning regimen, 4 had Bu/fludarabine based regimen and three fludarabine/treosulfan based conditioning with the rest having a variety of approaches. Eighty-six percent of cases had serotherapy with ATG or alemtuzumab. The median follow-up was 31.6 months (95% CI, 12.2-74.1%). The overall survival at 12 and 24 months was 88% (76-100) and 82% (66-99), respectively (figure 1). The median neutrophil engraftment was 18 (15-21) days and platelet engraftment >20 x 109/L was 29 (20-51) days, with a graft failure incidence of 7% (0-17) at 12 months. Two patients suffered from VOD. There were four deaths, three of which were related to transplant complications. The event free survival (survival without graft failure, relapse and second transplant) at 12 and 24 months was 85% (72-99) (figure 2). Six patients developed acute GvHD grade II and one case grade III; giving a grade II/III incidence of 28% (10-46). There was one case of limited and one of chronic GvHD, giving an incidence of 11% (0-26%) at 12 months and 24 months. In conclusion, whilst HSCT for CSA is a rare occurrence, these data demonstrate that HSCT for this condition is feasible and the outcomes are in keeping with those obtained for transplantation for transfusion dependent anaemias during the same time-period. Disclosures Handgretinger: Amgen: Honoraria. Moraleda:Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Takeda: Consultancy, Other: Travel Expenses. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Peffault De Latour:Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Resumen Antecedentes y objetivos El incremento descrito en la prevalencia de hemoglobinopatias, de β-talasemia mayor (TM) y de enfermedad drepanocitica (ED) que ha ocurrido en las ultimas dos decadas en nuestro pais ha generado nuevas necesidades en cuanto a recursos medicos tanto para la prevencion como para el tratamiento de estos pacientes. El trasplante alogenico de progenitores hematopoyeticos (alo-TPH) es el tratamiento curativo disponible en nuestro medio para pacientes con hemoglobinopatias graves. El objetivo principal de este estudio fue conocer los resultados del alo-TPH en pacientes pediatricos con TM o ED realizados en unidades de trasplante hematopoyetico pediatrico incluidas dentro del Grupo Espanol de Trasplante de Medula Osea en Ninos (GETMON). Material y metodos Revision retrospectiva de los pacientes sometidos a TPH en unidades de TPH del GETMON hasta el ano 2015. Resultados Se analizaron un total de 65 pacientes (43 pacientes afectados de TM y 22 de ED) que recibieron el alo-TPH en 6 unidades GETMON entre noviembre de 1989 y diciembre de 2014. La supervivencia libre de eventos 3 anos postrasplante fue del 81% y la supervivencia global del 92% en pacientes con TM. La supervivencia libre de eventos 3 anos postrasplante fue del 79% y la supervivencia global del 85% en pacientes con ED. Conclusiones Los resultados de esta serie son comparables a los resultados de otras series internacionales y ofrecen un punto de partida para continuar intentando mejorar la evolucion de estos pacientes.

Background and objectives A recently occurring increase of the prevalence of haemoglobinopathies, β-thalassaemia major (TM) and sickle cell disease (SCD) over the last two decades in our country has generated new needs in terms of medical resources for both prevention and treatment of these patients. Allogeneic haematopoietic stem cell transplant (allo-HSCT) is a curative treatment available for patients who have severe haemoglobinopathies. The main objective of this study was to evaluate the results of allo-HSCT in paediatric patients with TM or SCD performed in paediatric haematopoietic transplant units within the Spanish Group of Bone Marrow Transplantation in Children (GETMON). Material and methods Retrospective review of patients undergoing HSCT in the GETMON units until 2015. Results A total of 65 patients were analysed (43 patients were affected with TM and 22 with SCD), who received allo-HSCT in 6 GETMON units between November 1989 and December 2014. Event-free survival three years post-transplant was 81% and overall survival 92% in patients with TM. Event-free survival three years post-transplant was 79% and overall survival 85% in patients with SCD. Conclusions The results of this series are comparable to the results of other international series and offer a platform from which to continue trying to improve the evolution of these patients.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in early cerebral adrenoleukodystrophy can stabilize neurologic function and improve survival but has associated risks including transplant-related mortality (TRM), graft failure, and graft-versus-host disease (GVHD). An observational study of 59 patients with median age at allo-HSCT of 8 years addressed impact of donor source, donor match, conditioning regimen, and cerebral disease stage on first allo-HSCT outcomes. Efficacy analyses included 53 patients stratified by disease category: advanced disease (AD; n = 16) with Loes score >9 or neurological function score (NFS) >1 and 2 early disease (ED) cohorts (ED1 [Loes ≤4 and NFS ≤1; n = 24] and ED2 [Loes >4-9 and NFS ≤1; n = 13]). Survival free of major functional disabilities and without second allo-HSCT at 4 years was significantly higher in the ED (66%) vs AD (41%) cohort (P = .015) and comparable between ED1 and ED2 cohorts (P = .991). The stabilization of neurologic function posttransplant was greater in the ED vs AD cohort, with a median change from baseline at 24 months after allo-HSCT in NFS and Loes score, respectively, of 0 and 0.5 in ED1 (n = 13), 0.5 and 0 in ED2 (n = 6), and 2.5 and 3.0 (n = 4) in AD cohort. TRM was lower in the ED (7%) compared with the AD (22%) cohort; however, the difference was not significant (P = .094). Transplant-related safety outcomes were also affected by transplant-related characteristics: graft failure incidence was significantly higher with unrelated umbilical cord grafts vs matched related donors (P = .039), and acute GVHD and graft failure incidences varied by conditioning regimen. This study was registered at www://clinicaltrials.gov as #NCT02204904.

© 2021 the Author(s)., Inherited bone marrow failure syndromes (IBMFSs) are a group of congenital rare diseases characterized by bone marrow failure, congenital anomalies, high genetic heterogeneity, and predisposition to cancer. Appropriate treatment and cancer surveillance ideally depend on the identification of the mutated gene. A next-generation sequencing (NGS) panel of genes could be 1 initial genetic screening test to be carried out in a comprehensive study of IBMFSs, allowing molecular detection in affected patients. We designed 2 NGS panels of IBMFS genes: version 1 included 129 genes and version 2 involved 145 genes. The cohort included a total of 204 patients with suspected IBMFSs without molecular diagnosis. Capture-based targeted sequencing covered > 99% of the target regions of 145 genes, with more than 20 independent reads. No differences were seen between the 2 versions of the panel. The NGS tool allowed a total of 91 patients to be diagnosed, with an overall molecular diagnostic rate of 44%. Among the 167 patients with classified IBMFSs, 81 patients (48%) were diagnosed. Unclassified IBMFSs involved a total of 37 patients, of whom 9 patients (24%) were diagnosed. The preexisting diagnosis of 6 clinically classified patients (6%) was amended, implying a change of therapy for some of them. Our NGS IBMFS gene panel assay is a useful tool in the molecular diagnosis of IBMFSs and a reasonable option as the first tier genetic test in these disorders.

Ruxolitinib, a selective Janus Kinase (JAK) 1/2 inhibitor, is a promising treatment for the steroid-refractory graft-vs-host disease (GvHD) after hematopoietic stem cell transplantation (HSCT). Most studies have been performed in the adult population showing efficacy against GvHD. In this retrospective study, we evaluated the outcomes of 19 children who received ruxolitinib for refractory acute or chronic GvHD (cGvHD) after HSCT from two Pediatric Hemato-Oncology Departments in Spain between March 2017 and December 2018. Patients received a median number of 4 (IQR 2) previous lines of treatment before starting ruxolitinib. The overall response rate in acute GvHD (aGvHD) and cGvHD was 87% and 91%, respectively. Complete response (CR) was observed in 37% of aGvHD and 8.3% of cGvHD. Remarkably, 43% and 40% of patients with steroid-refractory gastrointestinal aGvHD and lung cGvHD achieved CR. During ruxolitinib treatment, there were 36%, 31%, and 10% infections caused by viruses, bacteria, and fungi, respectively. Overall, four patients interrupted ruxolitinib due to infectious complications, hematological, and liver toxicity. The 2-year overall survival was 71.9% (CI 95% 58.6-85.2). Our experience supports the use of ruxolitinib as an effective treatment for steroid-refractory acute and cGvHD in children with a moderate toxicity profile.

Difficulties in the collection of hematopoietic stem and progenitor cells (HSPCs) from Fanconi anemia (FA) patients have limited the gene therapy in this disease. We have investigated (ClinicalTrials.gov, NCT02931071) the safety and efficacy of filgrastim and plerixafor for mobilization of HSPCs and collection by leukapheresis in FA patients. Nine of eleven enrolled patients mobilized beyond the threshold level of 5 CD34+ cells/μL required to initiate apheresis. A median of 21.8 CD34+ cells/μL was reached at the peak of mobilization. Significantly, the oldest patients (15 and 16 years old) were the only ones who did not reach that threshold. A median of 4.27 million CD34+ cells/kg was collected in 2 or 3 aphereses. These numbers were markedly decreased to 1.1 million CD34+ cells/kg after immunoselection, probably because of weak expression of the CD34 antigen. However, these numbers were sufficient to facilitate the engraftment of corrected HSPCs in non-conditioned patients. No procedure-associated serious adverse events were observed. Mobilization of CD34+ cells correlated with younger age, higher leukocyte counts and hemoglobin values, lower mean corpuscular volume, and higher proportion of CD34+ cells in bone marrow (BM). All these values offer crucial information for the enrollment of FA patients for gene therapy protocols., Graphical abstract, Mobilization and collection of HSPCs from FA patients with sufficient HSPC reserve is a safe and efficient procedure, incorporating filgrastim and plerixafor as mobilization agents. Adequate HSPC mobilization correlates with younger age, higher leukocyte counts and hemoglobin values, lower mean corpuscular volume, and higher BM CD34+ cell numbers.

[Objective]: Describe the GETH haploidentical stem cell transplantation (haplo‐HSCT) activity in non‐malignant disease (NMDs)., [Methods]: We retrospectively analyzed data from children with NMDs who underwent haplo‐HSCT., [Results]: From January 2001 to December 2016, 26 pediatric patients underwent 31 haplo‐HSCT through ex vivo T cell‐depleted (TCD) graft platforms or post‐transplantation cyclophosphamide (PT‐Cy) at 7 Spanish centers. Five cases employed unmanipulated PT‐Cy haplo‐HSCT, 16 employed highly purified CD34+ cells, and 10 employed ex vivo TCD grafts manipulated either with CD3+CD19+ depletion, TCRαβ+CD19+ selection or naive CD45RA+ T‐cell depletion. Peripheral blood stem cells were the sole source for patients following TCD haplo‐HSCT, and bone marrow was the source for one PT‐Cy haplo‐HSCT. The most common indications for transplantation were primary immunodeficiency disorders (PIDs), severe aplastic anemia, osteopetrosis, and thalassemia. The 1‐year cumulative incidence of graft failure was 27.4%. The 1‐year III‐IV acute graft‐versus‐host disease (GvHD) and 1‐year chronic GvHD rates were 34.6% and 16.7%, respectively. The 2‐year overall survival was 44.9% for PIDs, and the 2‐year graft‐versus‐host disease‐free and relapse‐free survival rate was 37.6% for the other NMDs. The transplantation‐related mortality at day 100 was 30.8%., [Conclusion]: Although these results are discouraging, improvements will come if procedures are centralized in centers of expertise., This work was supported in part by the National Health Service of Spain, Carlos III Health Institute (ISCIII), FONDOS FEDER grant (FIS) PI18/01301, the CRIS Cancer Foundation (http://criscancer.org), and the Association Pablo Ugarte (http://www.asociacionpablougarte.es/).

Cryopreservation was recommended to ensure continuity of unrelated donor (UD) hematopoietic stem cell transplantation (HSCT) during COVID-19 pandemic. However, its impact on clinical outcomes and feasibility was not well known. We compared 32 patients who underwent UD HSCT using cryopreserved peripheral blood stem cells (PBSC) during the COVID-19 pandemic with 32 patients who underwent UD HSCT using fresh PBSC in the previous period. Median neutrophil engraftment was 17.5 and 17.0 days with cryopreserved and fresh grafts, respectively. Non-significant delays were found in platelet recovery days (25.5 versus 19.0; P = 0.192) and full donor chimerism days (35.0 and 31.5; P = 0.872) using cryopreserved PBSC. The rate of acute graft-versus-host disease at 100 days was 41% (95% CI [21-55%]) in cryopreserved group versus 31% (95% CI [13-46%]) in fresh group (P = 0.380). One-hundred days progression-relapse free survival and overall survival did not differ significantly. During COVID-19 pandemic, six frozen UD donations were not transfused and logistical and clinical issues regarding cryopreservation procedure, packaging, and transporting appeared. In summary, UD HSCT with cryopreserved PBSC was safe during this challenging time. More efforts are needed to ensure that all frozen grafts are transplanted and cryopreservation requirements are harmonized.

BACKGROUND: Defibrotide is approved in European Union for the treatment of severe sinusoidal obstruction syndrome (SOS) after HSCT. However, it has also been used for SOS prophylaxis, moderate SOS and in other complications such as transplant-associated thrombotic microangiopathy (TAM). The objective of this study was to evaluate current uses, effectiveness and safety of defibrotide in patients with HSCT. METHODS: This multicenter, retrospective study included patients treated with defibrotide for any indication at 28 HSCT centers of the Grupo Español de Trasplante Hematopoyetico (GETH) including the pediatric subgroup Grupo Español de Trasplante de Medula en Niños (GETMON). RESULTS: Three hundred and eighty eight patients treated with defibrotide between January 2011 and December 2018 were included. 253 patients were children, and 135 patients were adults. In total, 332 transplants were allogeneic, and the remainder were autologous. Main indications for defibrotide use were severe/very severe SOS in 173 patients, SOS prophylaxis in 135 patients, moderate SOS in 41 patients, TAM in six patients and suspected SOS in 33 patients. Overall survival (OS) at day +100 in the SOS prophylaxis group was 89% (95% CI, 87%-91%). In the group of patients with moderate and severe/very severe SOS, the OS at day +100 was 80% (95% CI, 74%-86%) and 62% (95% CI, 59%-65%), respectively (P = .0015). With a longer follow-up, median of 2 years (4 months-7 years), OS was 63% (95% CI, 59%-67%) in the SOS prophylaxis patients. OS for patients with moderate and severe/very severe SOS groups was 53% (95% CI, 47%-61%) and 26% (95% CI, 22%-30%), respectively (P = .006). 191 patients died, and SOS was the main cause of death in 23 patients (12%). CONCLUSIONS: Defibrotide has an acceptable safety profile with an improved response in severe/very severe SOS compared with historical controls, mainly in pediatric patients. Use of defibrotide for prophylaxis may improve prognosis of patients at high risk of complications due to endothelial damage such as those who receive a second transplant. SOS has an important impact on the HSCT long-term survival, as can be concluded from our study.

Kaposi sarcoma (KS) is an angioproliferative disease associated with human herpesvirus 8 (HHV-8). We report the case of a 10-year-old male from a high HHV-8 prevalence area, diagnosed with severe aplastic anemia who underwent an upfront hematopoietic stem cell transplantation (HSCT). Five months after transplant, the patient was diagnosed with KS with skin, mucosae, lymph nodes and lung involvement. After withdrawal of immunosuppression the patient achieved complete remission without requiring further treatments. KS may occur after HSCT in patients from high HHV-8 prevalence areas. Considering that, we propose that screening of HHV-8 by antibody testing could be considered in HSCT donors/recipients from these areas.

The Catalonian Newborn Screening Program (CNSP) began in 1969, in Barcelona. It was promoted by Dr. Juan Sabater Tobella and supported by Barcelona Provincial Council and Juan March Foundation. That is how the Institute of Clinical Biochemistry was born, whose aims were diagnosis, research and teaching, along with the spirit of contributing to the prevention of mental retardation. The CNSP began with the detection of phenylketonuria (PKU), and, in 1982, the Program was expanded with the inclusion of congenital hypothyroidism detection. Towards 1990, the Program covered almost 100% of all newborns (NB) in Catalonia. In 1999, the CNSP was expanded with the incorporation of cystic fibrosis. It took fourteen years, until 2013, to make the largest expansion so far, with the incorporation of 19 metabolic diseases to the screening panel. The detection of sickle cell disease began in 2015 and in 2017 the detection of severe combined immunodeficiency was included. Currently, the CNSP includes 24 diseases in its main panel. Since 1969, 2,787,807 NBs have been screened, of whom 1,724 have been diagnosed with any of these diseases, and 252 of other disorders by differential diagnosis with those included in the main panel. The global prevalence is 1: 1,617 NBs affected by any of the diseases included in the CNSP and 1: 1,140 NBs if incidental findings diagnosed through the CNSP are included.El Programa de Cribado Neonatal de Cataluña (PCNC) se inició en el año 1969, en Barcelona, impulsado por el Dr. Juan Sabater Tobella y apoyado por la Diputación de Barcelona y la Fundación Juan March. Así nació el Instituto de Bioquímica Clínica para acometer funciones asistenciales, de investigación y docencia, con el espíritu de contribuir a la prevención del retraso mental. El PCNC se inició con la detección de la fenilcetonuria (PKU) y en el año 1982 se amplió con la detección del hipotiroidismo congénito. Hacia el año 1990 la cobertura territorial llegó casi al 100% de todos los recién nacidos en Cataluña. En 1999 se amplió el PCNC con la incorporación de la fibrosis quística y tras catorce años, en 2013, se realizó la ampliación más numerosa hasta ahora, con la incorporación de la detección de 19 enfermedades metabólicas hereditarias. En el año 2015 comenzó la detección de la enfermedad de células falciformes y en el 2017 la detección de la inmunodeficiencia combinada grave. Actualmente, el PCNC incluye la detección de 24 enfermedades. Desde su inicio en el año 1969, se han cribado 2.787.807 recién nacidos, de los cuales 1.724 han sido diagnosticados de alguna de las 24 enfermedades que componen nuestro panel principal y 252 por diagnóstico diferencial de las primeras. En total la prevalencia global es de 1:1.617 RN afectos de alguna de las enfermedades incluidas en el PCNC y de 1:1.140 RN si se incluyen los hallazgos incidentales encontrados.

Objectives The prevalence of sickle cell disease (SCD) in Spain is markedly inferior compared with other European and Mediterranean countries. However, the diagnosis of new patients with SCD is expected to increase. In this multicenter retrospective study, we analyze the hematopoietic stem cell transplantation (HSCT) results obtained in Spain. Methods Forty-five patients who underwent a matched sibling donor (MSD) HSCT between 1999 and 2018 were included. Primary endpoint was event-free survival (EFS), and secondary endpoints included acute and chronic graft-versus-host disease (GvHD) and overall survival (OS). Results Bone marrow was the most frequent stem cell source (93.3%). Most patients received a conditioning regimen based on busulfan and cyclophosphamide (69%). Cumulative incidence of grade III-IV acute GvHD and chronic GvHD was 6.8% (95% CI: 2.3%-20.1%) and 5.4% (95% CI: 1.38%-19.9%), respectively. EFS and overall survival (OS) at 3 years post-HSCT were 89.4% (95% CI: 73.9%-95.9%) and 92.1% (95% CI: 77.2%-97.4%), respectively. All patients aged ≤ 5 presented 100% EFS and OS. Conclusions An early referral to HSCT centers should be proposed early in life, before severe complications occur. MSD HSCT should be considered a curative option for all patients aged ≤ 5 years and for older pediatric patients who present complications derived from the disease.

Pediatric allogeneic hematopoietic cell transplantation (HCT) practices differ from those of adults, particularly the heterogeneity of transplantable nonmalignant diseases and the lower incidence of graft-versus-host disease (GVHD). Several guidelines regarding the management of acute (a) GVHD in adult HCT have been published. We aimed to capture the real-life approaches for pediatric aGVHD prophylaxis/treatment, and data from 75/193 (response rate 39%) EBMT centers (26 countries) were included, representing half (48%) of the pediatric EBMT-HCT activity. Results with >= 75% approval from respondents (74/75) for GVHD prophylaxis after myeloablative HCT for malignancies partially contradict published guidelines: Single-agent cyclosporine A (CsA) was used for matched sibling donor HCT in 47%; blood CsA levels were reported lower; the relapse risk in malignant diseases influenced GVHD prophylaxis with early withdrawal of CsA; distinct longer duration of CsA was employed in nonmalignant diseases. Most centers used additional anti-thymocyte globulin for matched unrelated and mismatched donor HCT, but not for matched siblings. Regarding prophylaxis in nonmyeloablative conditioning (mainly for nonmalignant diseases), responses showed broad heterogeneity. High conformity was found for first-line treatment; however, results regarding steroid-refractory aGVHD indicate an earlier diagnosis in children. Our findings highlight the need for standardized pediatric approaches toward aGVHD prophylaxis/treatment differentiated for malignant and nonmalignant underlying diseases.

Use of adoptive immunotherapy with virus-specific T cells (VST) in patients with inborn errors of immunity prior to hematopoietic stem cell transplantation (HSCT) has been reported in few patients. We report our experience, reviewing all the cases previously reported. We report four children with inborn errors of immunity who received VST infusion in a pre-HSCT setting in two reference centers in Spain and review all inborn errors of immunity cases previously reported. Taking into account our four cases, nine children have been reported to receive VST prior to HSCT to date: 3 severe combined immunodeficiency, 2 CTPS1 deficiency, 1 dyskeratosis congenital, 1 ORAI1 deficiency, 1 Rothmund-Thomson syndrome, and 1 combined immunodeficiency without confirmed genetic defect. In four patients, immunotherapy resulted in clinical improvement, allowing to proceed to HSCT. In these cases, the infusion was started closely to viral diagnosis [mean time 28 days (IQR; 17–52 days)], and the VST was followed shortly thereafter by HSCT [mean time 28 days (IQR; 10–99 days)]. Viremia was controlled after HSCT in two cases (performed 7 and 36 days after the infusion). Multiple infusions were required in many cases. Five out of nine patients died before receiving HSCT. These patients presented with a prolonged and uncontrolled infection before VST administration [mean time from viral diagnosis to VST infusion was 176 days (IQR; 54–1687)]. In patients with inborn errors of immunity, the efficacy of VST for treating disseminated viral infections in pre-transplant settings seems to have a limited efficacy. However, this therapy could be used in a pre-emptive setting before severe viral disease occurs or closely to HSCT.

Background Primary antifungal prophylaxis in paediatric allogeneic HSCT recipients is mainly based on azoles, which can have related toxicity and drug interactions. Low-dose liposomal amphotericin B (L-AmB) is an attractive intravenous alternative because of its low toxicity and lower risk of interactions. Objectives To evaluate the effectiveness and safety of L-AmB (1 mg/kg/day) for primary antifungal prophylaxis in pre-engraftment paediatric HSCT patients. Patients and methods Retrospective, observational study including all consecutive patients aged ≤18 years who underwent HSCT and received antifungal prophylaxis with intravenous L-AmB (1 mg/kg/day, from day −1 to 48 h before discharge) between January 2012 and December 2016. Results In total, 125 HSCT procedures in 118 patients were included, median age 7.2 years (IQR 4.2–11.5). Haematological malignancies were the main underlying condition (63.6%), and 109 (87.2%) were considered at high risk for invasive fungal infection (IFI). Ten patients (7.7%), all high risk, developed breakthrough IFI (three Candida spp., seven invasive mould infections) and tended to have higher overall mortality. The only statistically significant risk factor for IFI was cytomegalovirus co-infection. Adverse events, all grade I, occurred in 25 (20%), requiring L-AmB withdrawal in one case. Overall survival at 30 days was 99.2%. At study completion, one patient had died of IFI. Conclusions The incidence of breakthrough IFI was comparable to that of previous reports, with a very low rate of significant toxicity. Thus, prophylactic L-AmB may be a safe, effective option for antifungal prophylaxis in the pre-engraftment phase for children undergoing HSCT, even those at high risk.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative procedure in patients with Shwachman–Diamond syndrome (SDS) with bone marrow abnormalities. The results of 74 patients with SDS (6 acute myeloid leukemia, 7 myelodysplastic syndrome, and 61 bone marrow failure) treated with HSCT between 1988 and 2016 are reported. The donor source was: 24% sibling, 8% parent, and 68% unrelated donor. The stem cell source was: 70% bone marrow, 19% peripheral blood stem cells, and 11% cord blood. The conditioning regimen was myeloablative in 54% and reduced intensity in 46%. Neutrophil engraftment was achieved in 84% of patients after a median time of 17.5 days. Graft failure occurred in 15% of HSCTs. Grades I–IV acute and chronic GVHD were observed in 55% and 20% of patients, respectively. After a median follow-up of 7.3 years (95% CI 4.8–10.2), 28 patients died for progression/relapse (7) or toxicity (21). The 5-year overall survival and nonrelapse mortality were 63.3% (95% CI 50.8–73.4) and 19.8% (95% CI 10.8–30.8), respectively. In conclusion, this is the largest series so far reported and confirms that HSCT is a suitable option for patients with SDS. Further efforts are needed to lower transplant-related toxicity and reduce graft failure.

A total of 192 pediatric patients, median age 8.6 years, with high‐risk hematological malignancies, underwent haploidentical stem cell transplantation (haplo‐HSCT) using post‐transplantation cyclophosphamide (PT‐Cy), or ex vivo T cell‐depleted (TCD) graft platforms, from January 1999 to December 2016 in 10 centers in Spain. Some 41 patients received an unmanipulated graft followed by PT‐Cy for graft‐vs‐host disease (GvHD) prophylaxis. A total of 151 patients were transplanted with CD3‐depleted peripheral blood stem cells (PBSCs) by either CD34+ selection, CD3+CD19+ depletion, TCRαβ+CD19+ depletion or CD45RA+ depletion, added to CD34+ selection for GvHD prophylaxis. The PBSCs were the only source in patients following ex vivo TCD haplo‐HSCT; bone marrow was the source in 9 of 41 patients following PT‐CY haplo‐HSCT. Engraftment was achieved in 91.3% of cases. A donor younger than 30 years, and the development of chronic GvHD were positive factors influencing survival, whereas positive minimal residual disease (MRD) before transplant and lymphoid disease were negative factors. The probability of relapse increased with lymphoid malignancies, a donor killer‐cell immunoglobulin‐like receptor (KIR) haplotype A and positive MRD pretransplant. No difference was found in overall survival, disease‐free survival or relapse incidence between the two platforms. Relapse is still of concern in both platforms, and it should be the focus of future efforts. In conclusion, both platforms for haplo‐HSCT were effective and could be utilized depending on the comfort level of the center., Research funding: National Health Service of Spain, Instituto de Salud Carlos III (ISCIII), FONDOS FEDER grant (FIS). Grant Number: PI18/01301, the CRIS Cancer Foundation, the Association Pablo Ugarte.

Chimeric antigen receptor (CAR) T-cell therapy is one of the most promising emerging treatments for B-cell malignancies. Recently, two CAR T-cell products (axicabtagene ciloleucel and tisagenlecleucel) have been approved for patients with aggressive B-cell lymphoma and acute lymphoblastic leukemia; many other CAR-T constructs are in research for both hematological and non-hematological diseases. Most of the patients receiving CAR-T therapy will develop fever at some point after infusion, mainly due to cytokine release syndrome (CRS). The onset of CRS is often indistinguishable from an infection, which makes management of these patients challenging. In addition to the lymphodepleting chemotherapy and CAR T cells, the treatment of complications with corticosteroids and/or tocilizumab increases the risk of infection in these patients. Data regarding incidence, risk factors and prevention of infections in patients receiving CAR-T cell therapy are scarce. To assist in patient care, a multidisciplinary team from hospitals designated by the Spanish Ministry of Health to perform CAR-T therapy prepared these recommendations. We reviewed the literature on the incidence, risk factors, and management of infections in adult and pediatric patients receiving CAR-T cell treatment. Recommendations cover different areas: monitoring and treatment of hypogammaglobulinemia, prevention, prophylaxis, and management of bacterial, viral, and fungal infections as well as vaccination prior and after CAR-T cell therapy.

Dyskeratosis congenita (DC) is a genetic multisystem disorder with frequent involvement of the bone marrow. Haematopoietic stem cell transplantation (HSCT) is the only definitive cure to restore haematopoiesis, even though it cannot correct other organ dysfunctions. We collected data on the outcome of HSCT in the largest cohort of DC (n = 94) patients ever studied. Overall survival (OS) and event-free survival (EFS) at 3 years after HSCT were 66% and 62%, respectively. Multivariate analysis showed better outcomes in patients aged less than 20 years and in patients transplanted from a matched, rather than a mismatched, donor. OS and EFS curves tended to decline over time. Early lethal events were infections, whereas organ damage and secondary malignancies appeared afterwards, even a decade after HSCT. A non-myeloablative conditioning regimen appeared to be most advisable. Organ impairment present before HSCT seemed to favour the development of chronic graft-versus-host disease and T-B immune deficiency appeared to enhance pulmonary fibrosis. According to the present data, HSCT in DC is indicated in cases of progressive marrow failure, whereas in patients with pre-existing organ damage, this should be carefully evaluated. Further efforts to investigate treatment alternatives to HSCT should be encouraged.

Autoimmune hemolytic anemia (AIHA) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT) associated with poor outcome. However, an optimal therapeutic approach is lacking. Between 2000 and 2015, 4099 allogeneic HSCT were performed in eight pediatric centers of the Grupo Español De Trasplante de Medula Osea en Niños (GETMON) and six adult centers of the Grupo Español de Trasplante Hematopoyetico (GETH). Sixty cases of AIHA were registered with a cumulative incidence of 1.5% occurring at a median of 6 months after HSCT. Patients aged less than 15 years (P=.005), and patients using cord blood (P=.005) or an HLA mismatch donor (P=.005) were more likely to develop AIHA. Most patients were lymphopenic at the time of diagnosis of AIHA, including a low number of regulatory T lymphocytes (median 3/μL). Median lines of treatment received for AIHA was 3 (range, 1-7). Almost all patients received corticosteroids (88%) and more than half received immunoglobulins or rituximab (63% and 67%, respectively). Complete resolution of AIHA was achieved in 33 of 60 cases (55%). Cumulative incidence of AIHA-related mortality was 17±6%. We found a correlation of AIHA outcome with age (better outcome in younger than 15 years, RR=1.87, P=.01) and rituximab response (higher rate of complete remission in patients responding to rituximab, RR=1.72, P=.025). We analyzed the factors involved in the response to rituximab and found a better response when there was ABO donor/receptor disparity (P=.014) and in those patients with B lymphocytes count above the median (38/μL) (P=.05).Thirty-six of 60 patients survived yielding a disease free survival of 52±8% at 40 months. In Cox analysis, age (children vs adults, HR: 8.19, CI 95%: 2.39-28.12, P=.001) and AIHA outcome (complete remission vs partial remission/non-response, HR: 4.18, CI 95%: 1.55-11.22, P=.005) were associated with a better survival. Our data suggest that patients who developed AIHA after HSCT are severely lymphopenic and have a high risk of mortality. Outcome is better in children and in patients treated with rituximab. We also propose an algorithm for treatment of AIHA after HSCT.