Spanish registry of hemoglobinopathies and rare anemias (REHem-AR): demographics, complications, and management of patients with ß-thalassemia.

INTRODUCTION: The increase in the number of patients with hemoglobinopathies in Europe in recent decades highlights the need for more detailed epidemiological information in Spain. To fulfil this need, the Spanish Society of Pediatric Hematology and Oncology (SEHOP) sponsored the creation of a national registry of hemoglobinopathies known as REHem-AR (Spanish Registry of Hemoglobinopathies and Rare Anemias). Data from the transfusion-dependent (TDT) and non-transfusion-dependent (NTDT) ß-thalassemia cohorts are described and analyzed. METHODS: We performed an observational, multicenter, and ambispective study, which included patients of any age with TDT and NTDT, registered up to December 31, 2021. RESULTS: Among the 1741 patients included, 168 cases of thalassemia were identified (103 TDT and 65 NTDT-patients). Survival at 18 years was 93% for TDT and 100% for NTDT. Regarding management, 80 patients with TDT (77.7%) and 23 patients with NTDT (35.4%) started chelation treatment during follow-up, with deferasirox being the most widely used. A total of 76 patients within the TDT cohort presented at least 1 complication (73.8%), the most frequent being hemosiderosis and osteopenia-osteoporosis. Comparison of both cohorts revealed significant differences in the diagnosis of hepatic hemosiderosis (p = 0.00024), although these were not observed in the case of cardiac iron overload (p = 0.27). DISCUSSION: Our registry enabled us to describe the management of ß thalassemia in Spain and to analyze the morbidity and mortality of the cohorts of patients with TDT and NTDT. Complications related to iron overload in TDT and NTDT account for most of the morbidity and mortality of the disease, which is associated with a considerable social, psychological, and economic impact, although cardiac, osteopathy and endocrinological complications requiring more attention. The convenience and simplicity of online registries make it possible to homogenize variables and periodically update data, thus providing valuable information on these diseases.

Haploidentical versus Cord Blood Transplantation in Pediatric AML. A Retrospective Outcome Analysis on Behalf of the Pediatric Subcommittee of GETH (Grupo Español de Trasplante Hematopoyético).

Haploidentical stem cell transplantation (Haplo-SCT) and cord blood transplantation (CBT) are both effective alternative treatments in patients suffering from acute myeloid leukemia (AML) and lacking a matched HLA donor. In the last years, many centers have abandoned CBT procedures mostly due to concern about poorer immune recovery compared with Haplo-SCT. We conducted a retrospective multicenter study comparing the outcomes using both alternative approaches in AML. A total of 122 transplants (86 Haplo-SCTs and 36 CBTs) from 12 Spanish centers were collected from 2007 to 2021. Median age at hematopoietic stem cell transplantation (HSCT) was 7 years (0.4-20). Thirty-nine patients (31.9%) showed positive minimal residual disease (MRD) at HSCT and a previous HSCT was performed in 37 patients (30.3%). The median infused cellularity was 14.4 × 106/kg CD34+ cells (6.0-22.07) for Haplo-SCT and 4.74 × 105/kg CD34+ cells (0.8-9.4) for CBT. Median time to neutrophil engraftment was 14 days (7-44) for Haplo-SCT and 17 days (8-29) for CBT (P = .03). The median time to platelet engraftment was 14 days (6-70) for Haplo-SCT and 43 days (10-151) for CBT (P < .001). Graft rejection was observed in 13 Haplo-SCTs (15%) and in 6 CBTs (16%). The cumulative incidence of acute graft versus host disease (GvHD) grades II-IV was 54% and 51% for Haplo-SCT and CBT, respectively (P = .50). The cumulative incidence of severe acute GvHD (grades III-IV) was 22% for Haplo-SCT and 25% for CBT (P = .90). There was a tendency to a higher risk of chronic GvHD in the Haplo-SCT group being the cumulative incidence of 30% for Haplo-SCT and 12% for CBT (P = .09). The cumulative incidence of relapse was 28% and 20% for Haplo-SCT and CBT, respectively (P = .60). We did not observe statistically significant differences in outcome measures between Haplo-SCT and CBT procedures: 5-year overall survival (OS) was 64% versus 57% (P = .50), 5-year disease-free survival (DFS) 58% versus 57% (P = .80), GvHD-free and relapse-free survival (GFRFS) 41% versus 54% (P = .30), and cumulative incidence of transplant-related mortality (TRM) 14% versus 15% (P = .80), respectively. In the multivariate analysis, MRD positivity and a disease status >CR1 at the time of HSCT were significantly associated with poorer outcomes (P < .05). In conclusion, our study supports that both haploidentical and cord blood transplantation show comparable outcomes in pediatric AML patients. We obtained comparable survival rates, although CBT showed a trend to lower rates of chronic GvHD and higher GFRFS, demonstrating that it should still be considered a valuable option, particularly for pediatric patients.

Lentivirus-mediated gene therapy corrects ribosomal biogenesis and shows promise for Diamond Blackfan anemia.

This study lays the groundwork for future lentivirus-mediated gene therapy in patients with Diamond Blackfan anemia (DBA) caused by mutations in ribosomal protein S19 (RPS19), showing evidence of a new safe and effective therapy. The data show that, unlike patients with Fanconi anemia (FA), the hematopoietic stem cell (HSC) reservoir of patients with DBA was not significantly reduced, suggesting that collection of these cells should not constitute a remarkable restriction for DBA gene therapy. Subsequently, 2 clinically applicable lentiviral vectors were developed. In the former lentiviral vector, PGK.CoRPS19 LV, a codon-optimized version of RPS19 was driven by the phosphoglycerate kinase promoter (PGK) already used in different gene therapy trials, including FA gene therapy. In the latter one, EF1α.CoRPS19 LV, RPS19 expression was driven by the elongation factor alpha short promoter, EF1α(s). Preclinical experiments showed that transduction of DBA patient CD34+ cells with the PGK.CoRPS19 LV restored erythroid differentiation, and demonstrated the long-term repopulating properties of corrected DBA CD34+ cells, providing evidence of improved erythroid maturation. Concomitantly, long-term restoration of ribosomal biogenesis was verified using a potentially novel method applicable to patients' blood cells, based on ribosomal RNA methylation analyses. Finally, in vivo safety studies and proviral insertion site analyses showed that lentivirus-mediated gene therapy was nontoxic.

Diagnosis, treatment, and surveillance of Diamond-Blackfan anaemia syndrome: international consensus statement.

Diamond-Blackfan anaemia (DBA), first described over 80 years ago, is a congenital disorder of erythropoiesis with a predilection for birth defects and cancer. Despite scientific advances, this chronic, debilitating, and life-limiting disorder continues to cause a substantial physical, psychological, and financial toll on patients and their families. The highly complex medical needs of affected patients require specialised expertise and multidisciplinary care. However, gaps remain in effectively bridging scientific discoveries to clinical practice and disseminating the latest knowledge and best practices to providers. Following the publication of the first international consensus in 2008, advances in our understanding of the genetics, natural history, and clinical management of DBA have strongly supported the need for new consensus recommendations. In 2014 in Freiburg, Germany, a panel of 53 experts including clinicians, diagnosticians, and researchers from 27 countries convened. With support from patient advocates, the panel met repeatedly over subsequent years, engaging in ongoing discussions. These meetings led to the development of new consensus recommendations in 2024, replacing the previous guidelines. To account for the diverse phenotypes including presentation without anaemia, the panel agreed to adopt the term DBA syndrome. We propose new simplified diagnostic criteria, describe the genetics of DBA syndrome and its phenocopies, and introduce major changes in therapeutic standards. These changes include lowering the prednisone maintenance dose to maximum 0·3 mg/kg per day, raising the pre-transfusion haemoglobin to 9-10 g/dL independent of age, recommending early aggressive chelation, broadening indications for haematopoietic stem-cell transplantation, and recommending systematic clinical surveillance including early colorectal cancer screening. In summary, the current practice guidelines standardise the diagnostics, treatment, and long-term surveillance of patients with DBA syndrome of all ages worldwide.

Trasplante de médula ósea en pacientes con anemia falciforme. Experiencia en un centro / Bone marrow transplant in patients with sickle cell anaemia. Experience in one centre

INTRODUCCIÓN: La enfermedad de células falciformes (ECF), pese a la mejora en el manejo médico, persiste asociada a morbilidad y a menor supervivencia. El alotrasplante de progenitores hematopoyéticos (alo-TPH) es actualmente la única opción curativa. Describir la evolución clínico-analítica de los pacientes trasplantados en nuestro centro. MATERIAL Y MÉTODO: Estudio unicéntrico descriptivo, incluye a pacientes con ECF en los que se realiza alo-TPH de médula ósea de hermano HLA-idéntico desde enero del 2010 hasta diciembre del 2014. Se recogen datos epidemiológicos, clínicos y analíticos con tiempo de seguimiento hasta diciembre del 2015. Los datos se presentan como frecuencias, porcentajes y medianas (rango). RESULTADOS: Se recluta a 11 pacientes (8 varones), mediana de edad: 7 años (2-13), todos ellos con comorbilidad previa al TPH. Se consigue injerto estable en 10/11 pacientes, quimerismo completo en 9/11 y quimerismo mixto estable tras un año del TPH en 1/11. Un paciente presenta fallo secundario de injerto con reaparición de clínica el día +180. Complicaciones post-TPH: complicaciones neurológicas 4/11 pacientes (hemorragia subaracnoidea, crisis), HTA 7/11, fallo renal agudo 3/11, reactivación CMV 9/11, EICHa cutáneo 6/11, uno de ellos desarrolla EICH intestinal grado IV causando su fallecimiento (día +51). Ningún paciente desarrolla EICH crónico. Supervivencia global y libre de eventos a los 3,1 años de seguimiento: 90,9 y 81,9%, respectivamente. CONCLUSIONES: El alo-TPH, única opción curativa, no está exento de morbimortalidad, encontramos un riesgo de muerte similar a otras series (1/11), siendo su primera causa el EICH agudo. Otros problemas son fallo de injerto (1/11) y complicaciones neurológicas (4/11), aunque las secuelas permanentes son leves

INTRODUCTION: Sickle cell disease (SCD), despite the improvement in the medical management, is still associated with severe morbidity and decreased survival. Allogenic hematopoietic stem cell transplantation (Allo-HSCT) currently provides the only curative therapy. A report is presented on our experience in children with SCD, who underwent Allo-HSCT in a single centre. Material and method. A single centre descriptive study was conducted on patients with SCD who underwent a bone marrow transplant from an HLA-identical sibling donor between January 2010 and December 2014. Epidemiological, clinical and analytical parameters were collected with a follow-up to December 2015. Data are presented as frequencies, percentages, and medians (range). RESULTS: Allo-HCST was performed in 11 patients (8 males) with a median age of 7 years (2-13), all of them with comorbidity prior to the HCST. A stable graft was achieved in 10 out of 11 patients, 9 of them with complete donor chimerism, and one patient with stable mixed chimerism after 1 year of allo-HSCT. One patient has secondary graft failure with re-appearance of symptoms associated with SCD on day 180. Complications of Allo-HSCT are: arterial hypertension 7/11, acute renal failure 3/11, CMV reactivation 9/11, neurological complications 4/11 (subarachnoid haemorrhage, seizure), and acute graft versus host disease (aGVHD) of the skin 6/11, one of whom developed grade IV intestinal aGVHD, causing his death (day 51). None of the patients developed chronic GVHD. The overall survival and event-free survival was 90.9% and 81.9%, respectively, with a median follow-up of 3.1 (1-5.7) years. CONCLUSIONS: Allo-HSCT, the only curative therapy, remains associated with morbidity. There was a transplant related mortality in our study, consistent with multicentre studies (1/11), and with aGVHD being the main cause. Other problems still include graft failure (1/11), and neurological complications (4/11), although the permanent sequelae are mild

Actualización del registro español de hemoglobinopatías de niños y adultos / Update of the Spanish registry of haemoglobinopathies in children and adults

ANTECEDENTES Y OBJETIVO: Los pacientes con talasemia mayor (TM) y enfermedad de células falciformes (ECF) en España se han empezado a contabilizar desde la creación del registro español de hemoglobinopatías (REHem). El objetivo del trabajo es actualizar los datos publicados previamente, tras el aumento de casos por la inclusión de adultos y la introducción del cribado neonatal en casi todo el país. MATERIAL Y MÉTODOS: Estudio observacional, descriptivo, multicéntrico y ambispectivo, que incluye pacientes con hemoglobinopatías registrados en REHem, iniciado en enero de 2014 y de seguimiento anual. Los datos presentados corresponden hasta el 31 de diciembre de 2017. RESULTADOS: Se recogieron 959 pacientes. Se registraron 75 casos de talasemia (62 TM), 826 de ECF y 58 de otro tipo de hemoglobinopatías. El motivo de diagnóstico principal en la TM fue la clínica de anemia (70,6%), con una media de edad al diagnóstico de 0,7 años; en la ECF fue el cribado neonatal (33,1%), con una media de edad al diagnóstico de 2,7 años; 26 pacientes con TM (41,9%) y 30 con ECF (3,6%) fueron sometidos a trasplante. Hubo 2 fallecimientos (3,2%) con TM y 19 (2,3%) con ECF. La supervivencia global fue del 96,7% en la TM y del 97,5% en la ECF a los 15 años. CONCLUSIONES: Desde la publicación previa y tras la difusión del cribado neonatal, el método diagnóstico más frecuente, en la mayoría de comunidades autónomas, y la inclusión de pacientes adultos al registro, el REHem se ha visto incrementado en más de 240 casos, llegando hasta un total de 959 registros

BACKGROUND AND OBJECTIVE: Patients with thalassaemia major (TM) and sickle cell disease (SCD) in Spain have been counted since the creation of the Spanish registry of haemoglobinopathies (REHem). The objective of this paper is to update the published data after the increase in cases due to the inclusion of adults and introduction of new-born screening in almost the whole country. MATERIAL AND METHODS: An observational, descriptive, multicentre and ambispective study that included patients with haemoglobinopathies registered in the REHem, started in January 2014 and followed up annually. The data presented correspond until December 31, 2017. RESULTS: Nine hundred and fifty-nine patients were collected. There were 75 cases of thalassaemia (62 TM), 826 of ECF and 58 of other types of haemoglobinopathies. The main diagnostic reason in the TM cohort was anaemia symptoms (70.6%), with a mean age at diagnosis of .7 years; in the SCD cohort it was neonatal screening (33.1%), with a mean age at diagnosis of 2.7 years; 26 patients with TM (41.9%) and 30 with SCD (3.6%) underwent a transplant. There were 2 deaths (3.2%) with TM and 19 (2.3%) with SCD. Overall survival was 96.7% in the TM and 97.5% in the SCD cases at 15 years. CONCLUSIONS: Since the previous publication and after the diffusion of new-born screening, the most frequent diagnostic method, to the majority of autonomous regions, and the inclusion of adult patients to the registry, the REHem has increased by more than 240 cases, reaching a total of 959 records

Trasplante de progenitores hematopoyéticos en niños con ß-talasemia y enfermedad drepanocítica: experiencia del grupo GETMON / Hematopoietic stem cell transplantation in pediatric patients with thalassemia and sickle cell disease: An experience of the Spanish Working Group for Bone Marrow Transplantation in Children (GETMON)

Antecedentes y objetivos: El incremento descrito en la prevalencia de hemoglobinopatías, de ß-talasemia mayor (TM) y de enfermedad drepanocítica (ED) que ha ocurrido en las últimas dos décadas en nuestro país ha generado nuevas necesidades en cuanto a recursos médicos tanto para la prevención como para el tratamiento de estos pacientes. El trasplante alogénico de progenitores hematopoyéticos (alo-TPH) es el tratamiento curativo disponible en nuestro medio para pacientes con hemoglobinopatías graves. El objetivo principal de este estudio fue conocer los resultados del alo-TPH en pacientes pediátricos con TM o ED realizados en unidades de trasplante hematopoyético pediátrico incluidas dentro del Grupo Español de Trasplante de Médula Ósea en Niños (GETMON). Material y métodos: Revisión retrospectiva de los pacientes sometidos a TPH en unidades de TPH del GETMON hasta el año 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 3años postrasplante fue del 81% y la supervivencia global del 92% en pacientes con TM. La supervivencia libre de eventos 3años 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 evolución de estos pacientes

Background and objectives: A recently occurring increase of the prevalence of haemoglobinopathies, ß-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 hematopoietic 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

Lesión crónica cerebral en la anemia falciforme y su relación con la calidad de vida / Chronic brain damage in sickle cell disease and its relation with quality of life

Antecedentes y objetivo: La anemia falciforme provoca una lesión orgánica progresiva. El objetivo de este trabajo es describir el rendimiento escolar de pacientes con anemia falciforme y los parámetros clínicos y de calidad de vida que pueden influir. La hipótesis es que si las alteraciones escolares se presentan sin otros datos objetivos, factores añadidos deben concurrir aparte de la propia enfermedad. Pacientes y métodos: Estudio transversal realizado en noviembre de 2015 considerando variables analíticas, complicaciones e imágenes neurorradiológicas de niños con anemia falciforme, y encuesta familiar sobre rendimiento escolar y calidad de vida. Resultados: Se incluyeron 60 pacientes. La mediana de edad fue de 6,8 años, y el 78% se diagnosticaron al nacimiento. El rendimiento escolar estaba alterado en el 51% y se relacionó con hipoxemia nocturna. El accidente cerebrovascular se presentó en el 6,7%. La ecografía doppler transcraneal fue patológica en el 4% y la resonancia magnética en el 16%. La calidad de vida arrojó resultados patológicos en todas las esferas y aumentó la proporción con valores bajos a mayor edad. El accidente cerebrovascular afectó la esfera física-social, y la neumopatía, la física-emocional. Conclusiones: El fracaso escolar como expresión de lesión crónica cerebral en la anemia falciforme afecta a la mitad de los pacientes y se relaciona con hipoxemia nocturna, aunque otros factores de confusión socioculturales pueden influir. La calidad de vida está alterada en la mayoría de los niños, independientemente del retraso escolar. La ausencia de una lesión orgánica objetiva en la neuroimagen o de parámetros de gravedad clínica no implican que la calidad de vida o la escolarización sean normales (AU)

Background and objective: Sickle cell anaemia causes progressive organ damage. The objective is to describe school performance of patients with sickle cell anaemia and their clinical parameters and quality of life that may have an influence. The hypothesis is that if school alterations occur without other objective data, additional factors must be present besides the disease itself. Patients and methods: Transversal study performed in November 2015 considering analytical variables, complications and neuroradiological images of children with sickle cell anaemia, and family survey on school performance and quality of life. Results: Median age was 6.8 years and 78% were diagnosed at birth. Sixty patients were included. School performance was altered in 51% of cases and was related to nocturnal hypoxemia. Acute stroke incidence was 6.7%. Transcranial ultrasound was abnormal in 4% of cases and magnetic resonance imaging in 16% of cases. Quality of life showed pathological findings in all areas and the low values increased proportionally in older ages. The stroke affected the physical and social sphere, and lung disease affected the physical and emotional spheres. Conclusions: Poor school performance affects half of the patients and it is related to nocturnal hypoxemia, although other socio-cultural factors may have an influence. Quality of life is affected in most of these cases independently of academic results. The absence of alterations in neuroimaging or the apparent lack of severe clinical parameters do not mean that quality of life and schooling are normal (AU)