Supportive Care During Pediatric Hematopoietic Stem Cell Transplantation: Prevention of Infections. A Report From Workshops on Supportive Care of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Terapia profiláctica antibiótica; Niños; VacunaciónTeràpia profilàctica antibiòtica; Nens; VacunacióAntibiotic prophylactic therapy; Children; VaccinationSpecific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis

Hematopoietic cell transplantation in severe combined immunodeficiency: The SCETIDE 2006-2014 European cohort

Genetic subgroups; Immune reconstitution; Pretransplantation infectionsSubgrupos genéticos; Reconstitución inmune; Infecciones previas al trasplanteSubgrups genètics; Reconstitució immune; Infeccions prèvies al trasplantamentBackground Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. Objective We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. Methods HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. Results Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P 0.5 × 10e3/μL at +1 year were identified as independent predictors of favorable clinical and immunologic outcome. Conclusion Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration

Current Prophylaxis and Treatment Approaches for Acute Graft-Versus-Host Disease in Haematopoietic Stem Cell Transplantation for Children With Acute Lymphoblastic Leukaemia

Acute lymphoblastic leukaemia; ChildrenLeucemia linfoblástica aguda; NiñosLeucèmia limfoblàstica aguda; NensAcute graft-versus-host disease (aGvHD) continues to be a leading cause of morbidity and mortality following allogeneic haematopoietic stem cell transplantation (HSCT). However, higher event-free survival (EFS) was observed in patients with acute lymphoblastic leukaemia (ALL) and grade II aGvHD vs. patients with no or grade I GvHD in the randomised, controlled, open-label, international, multicentre Phase III For Omitting Radiation Under Majority age (FORUM) trial. This finding suggests that moderate-severity aGvHD is associated with a graft-versus-leukaemia effect which protects against leukaemia recurrence. In order to optimise the benefits of HSCT for leukaemia patients, reduction of non-relapse mortality—which is predominantly caused by severe GvHD—is of utmost importance. Herein, we review contemporary prophylaxis and treatment options for aGvHD in children with ALL and the key challenges of aGvHD management, focusing on maintaining the graft-versus-leukaemia effect without increasing the severity of GvHD.This study received funding from the St. Anna Children's Cancer Research Institute, Vienna, Austria

Upregulation of NKG2D ligands impairs hematopoietic stem cell function in Fanconi anemia

Cellular immune response; Immunology; Stem cellsRespuesta inmune celular; Inmunología; Células madreResposta immune cel·lular; Immunologia; Cèl·lules mareFanconi anemia (FA) is the most prevalent inherited bone marrow failure (BMF) syndrome. Nevertheless, the pathophysiological mechanisms of BMF in FA have not been fully elucidated. Since FA cells are defective in DNA repair, we hypothesized that FA hematopoietic stem and progenitor cells (HSPCs) might express DNA damage–associated stress molecules such as natural killer group 2 member D ligands (NKG2D-Ls). These ligands could then interact with the activating NKG2D receptor expressed in cytotoxic NK or CD8+ T cells, which may result in progressive HSPC depletion. Our results indeed demonstrated upregulated levels of NKG2D-Ls in cultured FA fibroblasts and T cells, and these levels were further exacerbated by mitomycin C or formaldehyde. Notably, a high proportion of BM CD34+ HSPCs from patients with FA also expressed increased levels of NKG2D-Ls, which correlated inversely with the percentage of CD34+ cells in BM. Remarkably, the reduced clonogenic potential characteristic of FA HSPCs was improved by blocking NKG2D–NKG2D-L interactions. Moreover, the in vivo blockage of these interactions in a BMF FA mouse model ameliorated the anemia in these animals. Our study demonstrates the involvement of NKG2D–NKG2D-L interactions in FA HSPC functionality, suggesting an unexpected role of the immune system in the progressive BMF that is characteristic of FA.This work was supported by the “Ministerio de Ciencia e Innovación y Competitividad y Fondo Europeo de Desarrollo Regional (FEDER)” (SAF2015-68073-R, SAF2015-64152-R, and RTI2018-097125-B-I00); Next Generation EU; Plan de Recuperación Transformación y Resilencia (Instituto de Salud Carlos III; TERAV) (RD12/0019/0023); Programs of the European Commission (HEALTHF5-2012-305421 and EUROFANCOLEN); the “Ministerio de Sanidad, Servicios Sociales e Igualdad” (EC11/060 and EC11/550 “Comunidad de Madrid” (AvanCell, B2017/BMD-3692); and the ICREA-Academia program

Haploidentical vs. HLA-matched donor hematopoietic stem-cell transplantation for pediatric patients with acute lymphoblastic leukemia in second remission: A collaborative retrospective study of the Spanish Group for Bone Marrow Transplantation in Children (GETMON/GETH) and the Spanish Childhood Relapsed ALL Board (ReALLNet)

Acute lymphoblastic leukemia; Children; Stem cell transplantationLeucemia linfoblástica aguda; Niños; Trasplante de células madreLeucèmia limfoblàstica aguda; Nens; Trasplantament de cèl·lules mareIntroduction: Studies addressing the role of haploidentical as alternative to HLA-matched donors for stem cell transplantation (SCT) often include patients with diverse hematological malignancies in different remission statuses. Methods: We compared outcomes of children with acute lymphoblastic leukemia (ALL) undergoing SCT in second complete remission (CR2) from haploidentical (n = 25) versus HLA-matched donor (n = 51). Results: Patients were equally distributed across both groups according to age, immunophenotype, time to and site of relapse, relapse risk-group allocation, and minimal residual disease (MRD) before SCT. Incidence of graft failure, acute graft versus host disease (GVHD), and other early complications did not differ between both groups. We found no differences in overall survival (58.7% versus 59.5%; p = .8), leukemia free survival (LFS) (48% versus 36.4%; p = .5), event free survival (40% versus 34.4%; p = .69), cumulative incidence (CI) of subsequent relapse (28% versus 40.9%; p = .69), treatment related mortality (24% versus 23.6%; p = .83), CI of cGVHD (4.5% versus 18.7%; p = .2), and chronic GVHD-free and leukemia-free survival (44% versus 26.3%; p = .3) after haploidentical donor SCT. Chronic GVHD (HR = 0.09; p=.02) had protective impact, and MRD ≥ 0.01% before SCT (HR = 2.59; p=.01) had unfavorable impact on LFS. Discussion: These results support the role of haploidentical donor SCT in children with ALL in CR2

Improved collection of hematopoietic stem cells and progenitors from Fanconi anemia patients for gene therapy purposes

Anèmia de Fanconi; Mozobil; Teràpia gènicaAnemia de Fanconi; Mozobil; Terapia génicaFanconi anemia; Mozobil; Gene therapyDifficulties 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.This work was supported by grants from the European Commission’s Seventh Framework Program (HEALTH-F5-2012-305421 to the EUROFANCOLEN Consortium, J.A.B., J. Sevilla, C.D.-d.-H., J. Soulier, and J. Surralles), Ministerio de Sanidad, Servicios Sociales e Igualdad (EC11/060 and EC11/550 to C.D.-d.-H., J. Sevilla, J.A.B., and J. Surralles), Ministerio de Economía, Comercio y Competitividad and Fondo Europeo de Desarrollo Regional (SAF2015-68073-R, RTI2018-097125-B-I00 to P.R. and RTI2018-098419-B-I00 to J. Surralles), Fondo de Investigaciones Sanitarias at the Instituto de Salud Carlos III (RD12/0019/0023 to J.C.S.), and Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid (AvanCell Project; B2017/BMD3692). CIBERER is an initiative of the Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional. J. Surralles is supported by ICREA Academia and FARF

Use of Eculizumab in Pediatric Patients With Transplant Associated Thrombotic Microangiopathy

Complement inhibitor; Eculizumab; Hematopoietic stem cell transplant (HSCT)Inhibidor del complemento; Eculizumab; Trasplante de células madre hematopoyéticas (TCMH)Inhibidor del complement; Eculizumab; Trasplantament de cèl·lules mare hematopoètiques (HSCT)Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic stem cell transplantation (HSCT) associated with high morbidity and mortality. High-risk TA-TMA (hrTA-TMA) is characterized by multifactorial endothelial damage caused by environmental stressors, dysregulation of the complement system, and genetic predisposition. Complement inhibitors have significantly decreased mortality and are the current treatment of choice. In this article, we describe our experience with the use of eculizumab in pediatric patients diagnosed with hrT-TMA after HSCT. Method: Retrospective study of pediatric patients with hrTA-TMA treated with eculizumab between January 2016 and December 2020. Results: Four pediatric patients aged 1, 12, 14, and 17 years at the time of HSCT were diagnosed with hrTA-TMA and treated with eculizumab during the study. At diagnosis, they all had renal impairment with proteinuria, and hypertension under treatment with at least two antihypertensive drugs. The patient who presented multisystemic involvement died instead of treatment. The three patients with exclusive renal involvement achieved TA-TMA resolution after treatment with eculizumab for 65, 52, and 40.6 weeks and were able to stop treatment. The two patients with follow-up data one year after eculizumab withdrawal sustained a favorable response. Eculizumab was well tolerated, and with adequate vaccination and antibiotic prophylaxis, did not increase the risk of infection. Conclusions: Eculizumab appears to be both safe and effective for the treatment of hrTA-TMA in patients with renal impairment. Early diagnosis and initiation of treatment may improve response. Eculizumab withdrawal can be contemplated in patients who achieve laboratory and clinical resolution of TA-TMA

Multidisciplinary, evidence-based consensus guidelines for human papillomavirus (HPV) vaccination in high-risk populations, Spain, 2016

High-risk populations; Human papillomavirus infection; VaccinesPoblacions d'alt risc; Virus del papil·loma humà; VacunesPoblaciones de alto riesgo; Virus del papiloma humano; VacunasINTRODUCTION: Although human papillomavirus (HPV) routine vaccination programmes have been implemented around the world and recommendations have been expanded to include other high-risk individuals, current recommendations often differ between countries in Europe, as well as worldwide. AIM: To find and summarise the best available evidence of HPV vaccination in high-risk patients aiding clinicians and public health workers in the day-to-day vaccine decisions relating to HPV in Spain. METHODS: We conducted a systematic review of the immunogenicity, safety and efficacy/effectiveness of HPV vaccination in high-risk populations between January 2006 and June 2016. HPV vaccination recommendations were established with levels of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: A strong recommendation about HPV vaccination was made in the following groups: HIV infected patients aged 9-26 years; men who have sex with men aged 9-26 years; women with precancerous cervical lesions; patients with congenital bone marrow failure syndrome; women who have received a solid organ transplant or hematopoietic stem cell transplantation aged 9-26 years; and patients diagnosed with recurrent respiratory papillomatosis. CONCLUSIONS: Data concerning non-routine HPV vaccination in populations with a high risk of HPV infection and associated lesions were scarce. We have developed a document to evaluate and establish evidence-based guidelines on HPV vaccination in high-risk populations in Spain, based on best available scientific evidence

Multidisciplinary, evidence-based consensus guidelines for human papillomavirus (HPV) vaccination in highrisk populations, Spain, 2016

Introduction: Although human papillomavirus (HPV) routine vaccination programmes have been implemented around the world and recommendations have been expanded to include other high-risk individuals, current recommendations often differ between countries in Europe, as well as worldwide. Aim: To find and summarise the best available evidence of HPV vaccination in high-risk patients aiding clinicians and public health workers in the day-to-day vaccine decisions relating to HPV in Spain. Methods: We conducted a systematic review of the immunogenicity, safety and efficacy/effectiveness of HPV vaccination in high-risk populations between January 2006 and June 2016. HPV vaccination recommendations were established with levels of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Results: A strong recommendation about HPV vaccination was made in the following groups: HIV infected patients aged 9-26 years; men who have sex with men aged 9-26 years; women with precancerous cervical lesions; patients with congenital bone marrow failure syndrome; women who have received a solid organ transplant or hematopoietic stem cell transplantation aged 9-26 years; and patients diagnosed with recurrent respiratory papillomatosis. Conclusions: Data concerning non-routine HPV vaccination in populations with a high risk of HPV infection and associated lesions were scarce. We have developed a document to evaluate and establish evidence- based guidelines on HPV vaccination in highrisk populations in Spain, based on best available scientific evidence

Voriconazole Use in Children : Therapeutic Drug Monitoring and Control of Inflammation as Key Points for Optimal Treatment

Voriconazole plasma concentrations (PC) are highly variable, particularly in children. Dose recommendations in 2-12-year-old patients changed in 2012. Little data on therapeutic drug monitoring (TDM) after these new recommendations are available. We aimed to evaluate voriconazole monitoring in children with invasive fungal infection (IFI) after implementation of new dosages and its relationship with safety and effectiveness. A prospective, observational study, including children aged 2-12 years, was conducted. TDM was performed weekly and doses were changed according to an in-house protocol. Effectiveness, adverse events, and factors influencing PC were analysed. A total of 229 PC from 28 IFI episodes were obtained. New dosing led to a higher rate of adequate PC compared to previous studies; still, 35.8% were outside the therapeutic range. In patients aged < 8 years, doses to achieve therapeutic levels were higher than recommended. Severe hypoalbuminemia and markedly elevated C-reactive protein were related to inadequate PC. Therapeutic PC were associated with drug effectiveness and safety. Higher doses in younger patients and a dose adjustment protocol based on TDM should be considered. Voriconazole PC variability has decreased with current updated recommendations, but it remains high and is influenced by inflammatory status. Additional efforts to control inflammation in children with IFI should be encouraged