Original article
Hematopoietic stem cell transplantation in pediatric patients with β-thalassemia and sickle cell disease: An experience of the Spanish Working Group for Bone Marrow Transplantation in Children (GETMON)
Trasplante de progenitores hematopoyéticos en niños con β-talasemia y enfermedad drepanocítica: experiencia del grupo GETMON
Laura Alonsoa,
, Marta González-Vicentb, Cristina Belendezc, Isabel Badelld, Ana Sastree, Antonia Rodríguez-Villaf, Mar Bermúdez-Cortésg, Raquel Hladuna, Cristina Díaz de Herediaa
Corresponding author
a Unidad Pediátrica de Trasplante Hematopoyético, Hospital Universitario Vall d’Hebron, Barcelona, Spain
b Unidad Pediátrica de Trasplante Hematopoyético, Hospital Niño Jesús, Madrid, Spain
c Unidad Pediátrica de Trasplante Hematopoyético, Hospital Universitario Gregorio Marañón, Madrid, Spain
d Unidad Pediátrica de Trasplante Hematopoyético, Hospital de la Santa Creu i Sant Pau, Universidad Autónoma, Barcelona, Spain
e Unidad Pediátrica de Trasplante Hematopoyético, Hospital La Paz, Madrid, Spain
f Unidad Pediátrica de Trasplante Hematopoyético, Hospital Universitario Reina Sofía, Córdoba, Spain
g Unidad Pediátrica de Trasplante Hematopoyético, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
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Pediátrica de Trasplante Hematopoyético, Hospital Niño Jesús, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Unidad Pediátrica de Trasplante Hematopoyético, Hospital Universitario Gregorio Marañón, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Unidad Pediátrica de Trasplante Hematopoyético, Hospital de la Santa Creu i Sant Pau, Universidad Autónoma, Barcelona, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Unidad Pediátrica de Trasplante Hematopoyético, Hospital La Paz, Madrid, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Unidad Pediátrica de Trasplante Hematopoyético, Hospital Universitario Reina Sofía, Córdoba, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Unidad Pediátrica de Trasplante Hematopoyético, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Trasplante de progenitores hematopoyéticos en niños con β-talasemia y enfermedad drepanocítica: experiencia del grupo GETMON" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 849 "Ancho" => 2542 "Tamanyo" => 99475 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Results of event-free survival in patients with TM and SCD according to the period in which they underwent HSCT.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Sickle cell disease and thalassaemia are the most widely disseminated hereditary haemoglobinopathies in the world. The prevalence of these disorders is especially high in Southeast Asia, the Middle East, Africa, the Caribbean and the Mediterranean basin, although Spain is an exception. According to a study by Moreno Miralles published in 1999, the prevalence of β-thalassaemia in Spain was the lowest in the Mediterranean basin, although most studies available have been descriptive studies carried out in specific regions of Spain.<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">During the last two decades, migratory flows and the arrival of immigrants carrying haemoglobinopathy genes from sub-Saharan countries, Asia and the Western Pacific have radically changed the epidemiology of haemoglobinopathies in Spain. In 2013, Angastiniotis et al.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">3</span></a> explained that this increase in haemoglobinopathy genes in the population was a consequence of immigration.</p><p id="par0015" class="elsevierStylePara elsevierViewall">β-Thalassaemia mayor (TM) and sickle cell disease (SCD) pose serious health problems. Patients have a reduced life expectancy and require strict medical follow-up and chronic medical treatment. Patients with TM depend on chronic transfusions of red blood cells every 3–4 weeks, which causes iron overload and the need for chelation in order to prevent secondary tissue damage. SCD occurs with ischaemia and progressive tissue damage and associated high morbidity. The implementation of universal neonatal screening, penicillin prophylaxis, vaccination, transfusion therapy and hydroxyurea has improved survival: more than 95% of patients in developed countries reach adulthood. However, despite advances in supportive treatment, many patients still have high morbidity, with a consequential impact on quality of life, and mortality in adults reaches 2.5 per 100,000 people.<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">4–6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the curative treatment available in our setting for patients with severe haemoglobinopathies. The toxicity associated with the procedure has meant that this process is only reserved for symptomatic patients and those who have suitable donors. With the improvement of allo-HSCT results, this procedure has been extended to asymptomatic patients. After allo-HSCT, patients have been shown to stabilise and even improve their lung and neurological function in the long term, and in some children with sickle cell disease, there have even been signs of growth.<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">7–10</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The increase in the prevalence of haemoglobinopathies over the last two decades in our country has generated new needs in terms of medical resources both for the prevention and for the treatment of these patients. Among the medical resources developed to respond to new needs in our country are the establishment of a progressive form of neonatal screening for sickle cell disease that aims to reduce early morbidity associated with it, the registration of patients with SCD and TM (Rep-Hem) and clinical-therapeutic recommendation guidelines for patients with SCD and TM from the Spanish Society of Paediatric Haematology and Oncology (SEHOP).<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Objectives</span><p id="par0030" class="elsevierStylePara elsevierViewall">The main objective of this study was to understand the results of allo-HSCT performed in paediatric patients with TM or SCD, in paediatric haematopoietic transplant units included in the Spanish Group of Bone Marrow Transplantation in Children (GETMON) registry.</p><p id="par0035" class="elsevierStylePara elsevierViewall">A secondary objective was to compare the results in patients who received transplants before 2010 compared to those patients who received transplants after 2010. This cut-off point was selected because it was the date on which the paediatric clinical disease guide for paediatric sickle cell disease was published by the Spanish Society of Paediatric Haematology and Oncology (SEHOP).</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patients and methods</span><p id="par0040" class="elsevierStylePara elsevierViewall">This was a descriptive, retrospective study into paediatric patients undergoing allo-HSCT in paediatric GETMON HSCT units.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The Paediatric Allogeneic Haematopoietic Stem Cells Transplantation units that treat patients with TM or SCD were identified through the GETMON registry database. All these units are authorised to perform HSCT in children.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Data were requested regarding pre-transplant status, procedures and results.</p><p id="par0055" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Pre-transplant patients’ characteristic</span>: age at HSCT, indication of the transplant, number of transfusions and iron overload data – ferritin and evaluation by liver biopsy or magnetic resonance imaging (MRI) in patients with TM.</p><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Transplant procedure data</span>: donor type; HLA identity, source of haematopoietic progenitors, conditioning, T depletion in vivo, prophylaxis of graft versus host disease (GVHD) prophylaxis of hepatic veno-occlusive disease (HVOD), cellularity graft.</p><p id="par0065" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Results</span>: leucocyte graft, primary or secondary implant failure, acute and chronic GVHD, presence of neurological and hepatic complications, overall survival and event-free survival were evaluated.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Overall survival was defined as the time from transplantation to death from any cause. Event-free survival was calculated from the date of transplantation until the first event, including deaths and implant failures.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Neutrophil recovery was defined as the first of three consecutive days that showed a neutrophil count of at least 0.5<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>/l. Primary implant failure was defined as autologous recovery or absence of neutrophil recovery >0.5<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>/l, and secondary implant failure as loss of donor haematopoiesis with a relapse of haemoglobinopathy after a functioning implant donor being achieved.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Acute GVHD and chronic GVHD were diagnosed and graduated according to published criteria.<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">12–14</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The likelihood of overall survival and that of survival free of haemoglobinopathy were calculated using Kaplan Meier analysis compared to the log-rank test. In the case of non-events, the observations were censored at the time of the last follow-up.</p><p id="par0090" class="elsevierStylePara elsevierViewall">The multivariate analysis was not performed due to the low number of events reported.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><p id="par0095" class="elsevierStylePara elsevierViewall">A total of 65 patients were analysed (43 patients affected by TM and 22 by SCD) who received allo-HSCT in six GETMON units between November 1989 and December 2014. All patients with SCD were affected by Haemoglobin SS disease (Hb SS), except one patient who was double heterozygous HbS/β0.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Regarding the period during which allo-HSCT was performed, 32 of the 43 patients affected with TM had undergone HSCT before 2010 and 11 after 2010. Regarding patients with SCD, 13 of the 22 patients underwent HSCT after 2010 (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Transplantation of haematopoietic progenitors in patients with thalassaemia major</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Patients’ characteristics pre-transplantation</span><p id="par0105" class="elsevierStylePara elsevierViewall">The indication for transplantation was transfusion dependence in all patients. Patients’ mean age at transplant was 6.3 (0.6–16).</p><p id="par0110" class="elsevierStylePara elsevierViewall">Thirty-one patients had received more than 20 transfusions of packed red blood cells before transplantation; 30 of these patients received iron chelation treatment. The median ferritin prior to HSCT was 2160<span class="elsevierStyleHsp" style=""></span>ng/ml (70–9000). Hepatic iron overload was assessed by liver biopsy in 18 patients and by magnetic resonance imaging in 26 patients. The liver biopsy allowed us to classify patients into risk categories according to Pesaro. Five patients were included in category 1, six in group 2 and seven in risk group 3. Patients who were evaluated by MRI were classified as mild overload in 11 cases, moderate in six and severe in seven.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Transplant procedure data</span><p id="par0115" class="elsevierStylePara elsevierViewall">Progenitoral donors were an identical HLA sibling in 29 patients, a family member with an HLA difference in five patients and an identical unrelated HLA donor in nine patients.</p><p id="par0120" class="elsevierStylePara elsevierViewall">The source of haematopoietic progenitors was bone marrow in the majority of patients (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>35). Three patients received peripheral blood, one received umbilical cord blood and four received combined treatment with bone marrow and umbilical cord.</p><p id="par0125" class="elsevierStylePara elsevierViewall">The conditioning regimens used and the prophylaxis of the GVHD varied according to the risk group assigned, by evaluating the iron overload, and the transplant centre's criteria. Conditioning consisted of 33 patients in the combination of busulfan<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>cyclophosphamide at myeloablative dose and in some patients a third component was added (radiotherapy, thiotepa or melphalan). Ten patients received a combination of busulfan or treosulfan together with fludarabine and ±thiotepa.</p><p id="par0130" class="elsevierStylePara elsevierViewall">The conditioning included T-cell depletion with ATG in 13 patients (seven undergoing HSCT from identical HLA sibling, an alternate relative, five unrelated donors) and alemtuzumab in a patient who received an identical HLA sibling transplant.</p><p id="par0135" class="elsevierStylePara elsevierViewall">GVHD prophylaxis consisted of cyclosporine and methotrexate in 57% of patients (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>24). The remaining patients received monotherapy with a calcineurin inhibitor (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>9), cyclosporine and mycophenolate (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>7) or triple combination with cyclosporine, mycophenolate and methotrexate (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2).</p><p id="par0140" class="elsevierStylePara elsevierViewall">Thirty-nine of 43 patients received prophylaxis of hepatic veno-occlusive disease: heparin in 23 patients, defibrotide in 12, ursochol in three, and one patient received combined prophylaxis with ursochol and defibrotide.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Characteristics of the infused product</span><p id="par0145" class="elsevierStylePara elsevierViewall">The median CD34 infused was 7.09<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>106/kg (2.41–23).</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Implant</span><p id="par0150" class="elsevierStylePara elsevierViewall">The median neutrophil implant was day<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>20 (10–34).</p><p id="par0155" class="elsevierStylePara elsevierViewall">Thirty-four patients presented complete donor chimerism and four stable mixed chimerism and are free of thalassaemia without requiring transfusional support.</p><p id="par0160" class="elsevierStylePara elsevierViewall">A primary implant failure and four secondary implant failures were reported. The evolution of patients with secondary implant failure was the following: one patient is alive and living with their underlying disease, one patient successfully received a second transplant with the same donor, one patient died of sepsis and one patient was lost to follow-up.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Toxicity</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Graft-versus-host disease</span><p id="par0165" class="elsevierStylePara elsevierViewall">≥grade 2 acute GVHD was diagnosed in 10 patients and chronic GVHD in nine patients: two extensive chronic GVHD and seven limited.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Veno-occlusive disease and neurological toxicity</span><p id="par0170" class="elsevierStylePara elsevierViewall">Five patients with TM developed veno-occlusive liver disease. In all cases the issue was resolved with usual medical treatment. Seven patients developed reversible posterior encephalopathy syndrome.</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Survival</span><p id="par0175" class="elsevierStylePara elsevierViewall">There was an 81% post-transplant event-free survival rate of at least three years for patients with TM, and an overall survival rate of 92% (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0180" class="elsevierStylePara elsevierViewall">Three patients with TM died of sepsis: one patient with secondary implant failure and two patients with chronic GVHD.</p><p id="par0185" class="elsevierStylePara elsevierViewall">The possible influence of variables such as donor type, source of progenitors or T-cell depletion in vivo were analysed, and no association was found between these variables and overall survival or event-free survival.</p><p id="par0190" class="elsevierStylePara elsevierViewall">The impact of the transplant period on the results was analysed, and although no statistically significant differences were found, a trend towards better overall survival and event-free survival was observed in patients with SCD who underwent allo-HSCT after 2010 (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Transplantation of haematopoietic progenitors in patients with sickle cell disease</span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Patients’ characteristics pre-transplantation</span><p id="par0195" class="elsevierStylePara elsevierViewall">Patients’ mean age at transplant was 6.3 (0.6–16).</p><p id="par0200" class="elsevierStylePara elsevierViewall">The indication for transplant in all patients was the presence of significant complications secondary to SCD: acute thoracic syndrome in 12, nephropathy in three, and central nervous system involvement in nine patients.</p><p id="par0205" class="elsevierStylePara elsevierViewall">Eight patients had received more than 20 transfusions of packed red blood cells before transplantation; six of these patients received iron chelation treatment. The median ferritin prior to HSCT was 600<span class="elsevierStyleHsp" style=""></span>ng/ml (55–1450).</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Transplant procedure data</span><p id="par0210" class="elsevierStylePara elsevierViewall">The progenitor donor was an identical HLA sibling in 21 of the 22 patients; the remaining patient did not have an identical HLA sibling and had suffered significant neurological complications and received an unrelated umbilical cord blood transplant with an HLA 4/6 match.</p><p id="par0215" class="elsevierStylePara elsevierViewall">The source of haematopoietic progenitors was bone marrow in 19 patients. Two patients received umbilical cord blood and one received combined treatment with bone marrow and umbilical cord.</p><p id="par0220" class="elsevierStylePara elsevierViewall">Twenty patients received busulfan and cyclophosphamide as conditioning; the other two patients received other fludarabine-based preparations. The conditioning included T-cell depletion with ATG in eight patients and alemtuzumab in 12.</p><p id="par0225" class="elsevierStylePara elsevierViewall">The prophylaxis of GVHD consisted of cyclosporine and methotrexate in 19 patients (86%); the rest received monotherapy with a calcineurin inhibitor or cyclosporine and mycophenolate.</p><p id="par0230" class="elsevierStylePara elsevierViewall">The prophylaxis of veno-occlusive disease consisted of ursochol in 16 patients, heparin in five and defibrotide in one.</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Characteristics of the infused product</span><p id="par0235" class="elsevierStylePara elsevierViewall">The infused product cellularity was 4.51<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span>/kg (0.53–8.97).</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Implant</span><p id="par0240" class="elsevierStylePara elsevierViewall">The median neutrophil implant was day<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>20 (16–28).</p><p id="par0245" class="elsevierStylePara elsevierViewall">Twenty-one patients have complete donor chimerism and one patient has a stable mixed chimeric.</p><p id="par0250" class="elsevierStylePara elsevierViewall">One secondary implant failure was reported. This patient is alive and living with their underlying disease.</p><p id="par0255" class="elsevierStylePara elsevierViewall">All patients with complete chimerism and stable mixed chimerism are free of transfusions.</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Toxicity</span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Graft-versus-host disease</span><p id="par0260" class="elsevierStylePara elsevierViewall">≥grade 2 acute GVHD was diagnosed in seven patients and chronic GVHD in three patients: two extensive chronic GVHD and one limited.</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Veno-occlusive disease and neurological toxicity</span><p id="par0265" class="elsevierStylePara elsevierViewall">No patient developed hepatic veno-occlusive disease.</p><p id="par0270" class="elsevierStylePara elsevierViewall">Seven patients developed neurological toxicity in the form of PRES or Moyamoya.</p></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Survival</span><p id="par0275" class="elsevierStylePara elsevierViewall">There was a 79% post-transplant event-free survival rate of at least three years in patients with TM, and overall survival rate of 85% (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><p id="par0280" class="elsevierStylePara elsevierViewall">Three of the 22 patients transplanted with SCD died. The causes of death were septic shock in two patients and acute GVHD with probable invasive fungal infection in the other. The infections were caused by gram-negative germs related to the transplant process, neutropenia and mucosal damage and not to functional asplenia.</p><p id="par0285" class="elsevierStylePara elsevierViewall">The possible influence of variables such as donor type, source of progenitors or the graft T-cell depletion in vivo were analysed, and no association was found between these variables and overall survival or event-free survival.</p><p id="par0290" class="elsevierStylePara elsevierViewall">The impact of the transplant period on the results was analysed, and although no statistically significant differences were found, a trend towards better overall survival and event-free survival was observed in patients with SCD who underwent allo-HSCT after 2010 (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p></span></span></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Discussion</span><p id="par0295" class="elsevierStylePara elsevierViewall">Haematopoietic stem cell transplantation is the only treatment available for SCD patients, but its use is limited by the availability of identical HLA donors and a lack of awareness of the potential benefit of this treatment. Gene therapy in patients with TM has recently become a reality<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">15–17</span></a>; however, haematopoietic stem cell transplantation remains the only widely available treatment in the developed world.</p><p id="par0300" class="elsevierStylePara elsevierViewall">Obtaining a donor chimerism after HSCT allows a synthesis of normal haemoglobin chains and cures the symptoms of disease in patients with SCD and TM. In patients with SCD, disease-free survival greater than 90% has been reported when the transplant is performed in young patients with little associated morbidity, the donor is an identical HLA sibling and the source is bone marrow. Transplantation in patients with multiple morbidities or the use of alternative donors is associated with increased morbidity and mortality.</p><p id="par0305" class="elsevierStylePara elsevierViewall">This retrospective study summarises the results of haematopoietic stem cell transplantation in patients with SCD and MT performed in GETMON hospitals, and offers information on how this therapeutic option has evolved in recent years. Thus, 13 of the 22 transplants in patients with SCD have been performed since 2010, year in which the SEHOP clinical practice guide was published. We cannot ignore one of the study's limitations and the issue that emerges from it: the study is retrospective and covers a broad period of time.</p><p id="par0310" class="elsevierStylePara elsevierViewall">Over the last decade, the results of allo-HSCT have improved significantly thanks to a better stratification of patients and better support treatment. In our series, although without reaching statistical significance due to the number of patients, a trend towards better results was observed in terms of overall survival and thalassaemia-free survival in patients with SCD and TM. The reasons that could be associated with this trend were not analysed in this paper.</p><p id="par0315" class="elsevierStylePara elsevierViewall">In 2014, Angelucci et al.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">18</span></a> published a series of recommendations regarding HSCT in patients with TM and SCD. These recommendations addressed, among other issues, the selection of a donor. For patients with TM, guidelines recommend offering HSCT as soon as possible to patients with identical HLA siblings, in order to avoid iron overload and tissue damage. In these cases, the use of bone marrow or umbilical cord blood is equally acceptable. For patients who do not have an identical HLA sibling, the use of an identical HLA unrelated donor is considered an acceptable alternative. For patients with SCD, the recommendation is to use an identical HLA sibling and to reserve the use of an unrelated donor for specific cases, e.g. when patients are very symptomatic and, if possible, in the context of clinical studies, since the use of donors who are unrelated to patients with SCD has been associated with a high graft failure rate as well as acute and extensive chronic GVHD.</p><p id="par0320" class="elsevierStylePara elsevierViewall">An obstacle to the transplantation of haemoglobinopathy patients is the fact that only a limited number of patients have an identical HLA family donor. In addition, the possibility of finding an unrelated donor depends greatly on the ethnicity of the patient. The use of umbilical cord blood units or haploidentical donors has the potential advantage of allowing more patients the possibility of benefiting from a transplant. However, these types of transplants have been associated with an increased risk of implant failure, GVHD, and poor immune reconstitution and their use have been limited. In the last decade, improvements in the HLA typing and in the selection of umbilical cord units, in the prophylaxis and treatment of GVHD, the study of anti-HLA antibodies and support and anti-infective treatments have piqued the interest of various authors who have published successful experiences in both TM and SCD patients. However, they are still considered experimental procedures because of the associated risk.<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">19–23</span></a></p><p id="par0325" class="elsevierStylePara elsevierViewall">The selection of donors carried out by this study conforms to the criteria recommended by Angelucci et al.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">18</span></a>. The progenitor donor chosen in our series varied according to patients with SCD and TM. All patients with SCD except one received a transplant from an identical HLA sibling; the patient who received an unrelated umbilical cord blood unit had many complications associated with SCD. 21% of patients with TM received an unrelated donor transplant.</p><p id="par0330" class="elsevierStylePara elsevierViewall">The toxicity of myeloablative conditioning in the short and medium term is significant; some authors have used conditioning of reduced intensity to achieve a stable implant with less toxicity for these patients.<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">24–26</span></a> The first attempts had a high rate of implant failure, but recent modifications in the conditioning and in the GVHD prophylaxis have improved the results, in some cases it was even comparable to myeloablative conditioning. We did not see a conditioning intensity effect on the results. However, the conditioning was very varied and the number of patients was too small to have observed this effect.</p><p id="par0335" class="elsevierStylePara elsevierViewall">Regarding toxicity, the cause of death in patients was infections, in some cases related to GVHD, or implant failure. Hepatic veno-occlusive disease, when it occurred, was treatable. A significant percentage of patients presented neurological toxicity. The rates of acute and chronic severe GVHD were acceptable, possibly related to the poor use of peripheral blood as a source of progenitors.</p><p id="par0340" class="elsevierStylePara elsevierViewall">In total, in this series, 56 of 65 patients achieved complete chimerism or stable mixed chimerism; they are currently cured, free of transfusion and do not have symptoms associated with haemoglobinopathy. It was not an objective of this study to evaluate the long-term toxicity of patients undergoing HSCT.</p><p id="par0345" class="elsevierStylePara elsevierViewall">TM and SCD are increasingly frequent indications of HSCT in Spain due to the increase in its prevalence as a result of immigration. The results emerging from this study are comparable to the results of other international studies and offer a basis on which to try to improve the evolution of these patients.</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Conflict of interest</span><p id="par0350" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1148382" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1077687" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1148383" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1077686" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Objectives" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Patients and methods" ] 7 => array:3 [ "identificador" => "sec0020" "titulo" => "Results" "secciones" => array:2 [ 0 => array:3 [ "identificador" => "sec0025" "titulo" => "Transplantation of haematopoietic progenitors in patients with thalassaemia major" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Patients’ characteristics pre-transplantation" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Transplant procedure data" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Characteristics of the infused product" ] 3 => array:2 [ "identificador" => "sec0045" "titulo" => "Implant" ] 4 => array:3 [ "identificador" => "sec0050" "titulo" => "Toxicity" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Graft-versus-host disease" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Veno-occlusive disease and neurological toxicity" ] ] ] 5 => array:2 [ "identificador" => "sec0065" "titulo" => "Survival" ] ] ] 1 => array:3 [ "identificador" => "sec0070" "titulo" => "Transplantation of haematopoietic progenitors in patients with sickle cell disease" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0075" "titulo" => "Patients’ characteristics pre-transplantation" ] 1 => array:2 [ "identificador" => "sec0080" "titulo" => "Transplant procedure data" ] 2 => array:2 [ "identificador" => "sec0085" "titulo" => "Characteristics of the infused product" ] 3 => array:2 [ "identificador" => "sec0090" "titulo" => "Implant" ] 4 => array:3 [ "identificador" => "sec0095" "titulo" => "Toxicity" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0100" "titulo" => "Graft-versus-host disease" ] 1 => array:2 [ "identificador" => "sec0105" "titulo" => "Veno-occlusive disease and neurological toxicity" ] ] ] 5 => array:2 [ "identificador" => "sec0110" "titulo" => "Survival" ] ] ] ] ] 8 => array:2 [ "identificador" => "sec0115" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0120" "titulo" => "Conflict of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-01-16" "fechaAceptado" => "2018-05-10" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1077687" "palabras" => array:4 [ 0 => "Thalassaemia" 1 => "Sickle cell disease" 2 => "Bone marrow transplant" 3 => "Haematopoietic stem cell transplantation" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1077686" "palabras" => array:4 [ 0 => "Talasemia" 1 => "Drepanocitosis" 2 => "Trasplante de médula ósea" 3 => "Trasplante de progenitores" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">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).</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Retrospective review of patients undergoing HSCT in the GETMON units until 2015.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">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.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">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.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes y objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El incremento descrito en la prevalencia de hemoglobinopatías, de β-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).</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Revisión retrospectiva de los pacientes sometidos a TPH en unidades de TPH del GETMON hasta el año 2015.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">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 años postrasplante fue del 81% y la supervivencia global del 92% en pacientes con TM. La supervivencia libre de eventos 3 años postrasplante fue del 79% y la supervivencia global del 85% en pacientes con ED.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">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.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Alonso L, González-Vicent M, Belendez C, Badell I, Sastre A, Rodríguez-Villa A, et al. Trasplante de progenitores hematopoyéticos en niños con β-talasemia y enfermedad drepanocítica: experiencia del grupo GETMON. Med Clin (Barc). 2019;152:135–140.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 772 "Ancho" => 2565 "Tamanyo" => 105736 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Overall survival and event-free survival in patients with TM and SCD.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 849 "Ancho" => 2542 "Tamanyo" => 99475 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Results of event-free survival in patients with TM and SCD according to the period in which they underwent HSCT.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">β-Thalassaemia major \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sickle cell disease \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Number of patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">43 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Date of first HSCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22/11/1991 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">01/12/1995 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Transplants before 2010 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Transplants in 2010 or later \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age at transplantation, average (min.–max.) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.31 (0.65–16.42) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8.58 (2.09–15) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HSCT indication \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Transfusion dependence \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Serious or recurring symptoms \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1959479.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Patients with haemoglobinopathies who received a haematopoietic stem cell transplant.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:26 [ 0 => array:3 [ "identificador" => "bib0135" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The molecular changes in thalassemias in Spain. 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