Publications by authors named "Isabel Badell"

53 Publications

Measurable Residual Disease Assessed by Flow-Cytometry Is a Stable Prognostic Factor for Pediatric T-Cell Acute Lymphoblastic Leukemia in Consecutive SEHOP Protocols Whereas the Impact of Oncogenetics Depends on Treatment.

Front Pediatr 2020 5;8:614521. Epub 2021 Feb 5.

Haematology Laboratory, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.

Robust and applicable risk-stratifying genetic factors at diagnosis in pediatric T-cell acute lymphoblastic leukemia (T-ALL) are still lacking, and most protocols rely on measurable residual disease (MRD) assessment. In our study, we aimed to analyze the impact of , and mutations, the measurable residual disease (MRD) levels assessed by flow cytometry (FCM-MRD) and other reported risk factors in a Spanish cohort of pediatric T-ALL patients. We included 199 patients treated with SEHOP and PETHEMA consecutive protocols from 1998 to 2019. We observed a better outcome of patients included in the newest SEHOP-PETHEMA-2013 protocol compared to the previous SHOP-2005 cohort. FCM-MRD significantly predicted outcome in both protocols, but the impact at early and late time points differed between protocols. The impact of FCM-MRD at late time points was more evident in SEHOP-PETHEMA 2013, whereas in SHOP-2005 FCM-MRD was predictive of outcome at early time points. Genetics impact was different in SHOP-2005 and SEHOP-PETHEMA-2013 cohorts: mutations impacted on overall survival only in the SEHOP-PETHEMA-2013 cohort, whereas homozygous deletions of / had a significantly higher CIR in SHOP-2005 patients. We applied the clinical classification combining oncogenetics, WBC count and MRD levels at the end of induction as previously reported by the FRALLE group. Using this score, we identified different subgroups of patients with statistically different outcome in both Spanish cohorts. In SHOP-2005, the FRALLE classifier identified a subgroup of high-risk patients with poorer survival. In the newest protocol SEHOP-PETHEMA-2013, a very low-risk group of patients with excellent outcome and no relapses was detected, with borderline significance. Overall, FCM-MRD, WBC count and oncogenetics may refine the risk-stratification, helping to design tailored approaches for pediatric T-ALL patients.
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http://dx.doi.org/10.3389/fped.2020.614521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892614PMC
February 2021

Allogeneic hematopoietic stem cell transplantation in leukocyte adhesion deficiency type I and III.

Blood Adv 2021 Jan;5(1):262-273

Willem-Alexander Children's Hospital, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.

Type I and III leukocyte adhesion deficiencies (LADs) are primary immunodeficiency disorders resulting in early death due to infections and additional bleeding tendency in LAD-III. The curative treatment of LAD-I and LAD-III is allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this retrospective multicenter study, data were collected using the European Society for Blood and Marrow Transplantation registry; we analyzed data from 84 LAD patients from 33 centers, all receiving an allo-HSCT from 2007 to 2017. The 3-year overall survival estimate (95% confidence interval [CI]) was 83% (74-92) for the entire cohort: 84% (75-94) and 75% (50-100) for LAD-I and LAD-III, respectively. We observed cumulative incidences (95% CI) of graft failure (GF) at 3 years of 17% (9%-26%) and grade II to IV acute graft-versus-host disease (aGVHD) at 100 days of 24% (15%-34%). The estimate (95% CI) at 3 years for GF- and GVHD-II to IV-free survival as event-free survival (EFS) was 56% (46-69) for the entire cohort; 58% (46-72) and 56% (23-88) for LAD-I and LAD-III, respectively. Grade II to IV acute GVHD was a relevant risk factor for death (hazard ratio 3.6; 95% CI 1.4-9.1; P = .006). Patients' age at transplant ≥13 months, transplantation from a nonsibling donor, and any serological cytomegalovirus mismatch in donor-recipient pairs were significantly associated with severe acute GVHD and inferior EFS. The choice of busulfan- or treosulfan-based conditioning, type of GVHD prophylaxis, and serotherapy did not impact overall survival, EFS, or aGVHD. An intrinsic inflammatory component of LAD may contribute to inflammatory complications during allo-HSCT, thus providing the rationale for considering anti-inflammatory therapy pretreatment.
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http://dx.doi.org/10.1182/bloodadvances.2020002185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805328PMC
January 2021

Many signs, one mutation: Early onset of de novo GATA2 deficiency syndrome. A case report.

Clin Case Rep 2020 Dec 30;8(12):3193-3197. Epub 2020 Sep 30.

Department of Hematology Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona IIB Sant Pau and Institut Josep Carreras Barcelona Spain.

We report a case with a broad spectrum of symptoms, related to GATA2 deficiency syndrome, which emerged as early as at 6 months of age. They ranged from lymphedema, deafness to myelodysplastic syndrome (MDS).
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http://dx.doi.org/10.1002/ccr3.3304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752306PMC
December 2020

Long-term outcome after allogeneic hematopoietic stem cell transplantation for Shwachman-Diamond syndrome: a retrospective analysis and a review of the literature by the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (SAAWP-EBMT).

Bone Marrow Transplant 2020 09 19;55(9):1796-1809. Epub 2020 Mar 19.

G. Gaslini Research Institute (IRRCS), Genova, Italy.

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.
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http://dx.doi.org/10.1038/s41409-020-0863-zDOI Listing
September 2020

Effects of a home-exercise programme in childhood survivors of acute lymphoblastic leukaemia on physical fitness and physical functioning: results of a randomised clinical trial.

Support Care Cancer 2020 Jul 10;28(7):3171-3178. Epub 2019 Nov 10.

Navarrabiomed-Universidad Pública de Navarra (UPNA)-Complejo Hospitalario de Navarra (CHN), Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008, Pamplona, Navarra, Spain.

Purpose: The aim of this study was to evaluate the effects of a home-exercise programme on physical fitness indicators and physical functioning after completion of chemotherapy in children and adolescents diagnosed with acute lymphoblastic leukaemia (ALL).

Methods: Twenty-four survivors of ALL were assigned to usual care (control group, n = 12, 11.0 ± 3.7 years) or to a home-exercise programme (intervention group, n = 12, 11.8 ± 4.3 years). Peak oxygen uptake (VOpeak ml/kg/min), minute ventilation (VE L/min), output of carbon dioxide (VCO L/min), respiratory exchange ratio (RER), peak heart rate (beats/min), maximal load (W), VO at anaerobic threshold (VO at AT, ml/kg/min), pulse oxygen (PO ml/beat), heart rate at anaerobic threshold (beats/min), handgrip test (pounds), flexibility (cm), Timed Up & Go test TUG (s), and Timed Up and Down Stairs test (TUDS s) were measured at baseline and over 16 weeks of intervention.

Results: Adjusted mixed linear models revealed a significant group-time interaction + 6.7 (95% CI = 0.6-12.8 ml/kg/min; η partial = 0.046, P = 0.035) for VOpeak. Similarly, changes in mean values were observed after the home-exercise programme compared with baseline for VE (L/min) - 8.8 (3.0) (P = 0.035), VCO - 0.2 (0.08), (P = 0.041), maximal load (W) - 35.5 (12.8) (P = 0.024), TUDS (s) 0.8 (2.6) (P = 0.010), and TUG (s) 0.6 (0.1) (P = 0.001); however, the group-time interaction was not significant.

Conclusion: The home-exercise programme resulted in changes in measures of VOpeak, VE, VCO, and functional capacity during daily life activities (TUDS and TUG test). This is an interesting and important study that surely adds to the current body of knowledge/literature on the safety of exercise interventions, especially in children with haematological cancer.
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http://dx.doi.org/10.1007/s00520-019-05131-2DOI Listing
July 2020

Haploidentical transplantation in high-risk pediatric leukemia: A retrospective comparative analysis on behalf of the Spanish working Group for bone marrow transplantation in children (GETMON) and the Spanish Grupo for hematopoietic transplantation (GETH).

Am J Hematol 2020 01 5;95(1):28-37. Epub 2019 Nov 5.

Pediatric Hemato-Oncology, Hospital Niño Jesus, Madrid, Spain.

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.
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http://dx.doi.org/10.1002/ajh.25661DOI Listing
January 2020

Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies.

J Med Genet 2020 04 5;57(4):258-268. Epub 2019 Oct 5.

Department of Genetics, Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona (UAB), Barcelona, Spain.

Purpose: Patients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients' characterisation, we developed a simplified but effective methodology based on whole exome sequencing (WES) and functional studies.

Methods: 68 patients with FA were analysed by commercial WES services. Copy number variations were evaluated by sequencing data analysis with RStudio. To test missense variants, wt FANCA cDNA was cloned and variants were introduced by site-directed mutagenesis. Vectors were then tested for their ability to complement DNA repair defects of a FANCA-KO human cell line generated by TALEN technologies.

Results: We identified 93.3% of mutated alleles including large deletions. We determined the pathogenicity of three FANCA missense variants and demonstrated that two variants reported in mutations databases as 'affecting functions' are SNPs. Deep analysis of sequencing data revealed patients' true mutations, highlighting the importance of functional analysis. In one patient, no pathogenic variant could be identified in any of the 22 known FA genes, and in seven patients, only one deleterious variant could be identified (three patients each with FANCA and FANCD2 and one patient with FANCE mutations) CONCLUSION: WES and proper bioinformatics analysis are sufficient to effectively characterise patients with FA regardless of the rarity of their complementation group, type of mutations, mosaic condition and DNA source.
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http://dx.doi.org/10.1136/jmedgenet-2019-106249DOI Listing
April 2020

Coinheritance of hereditary ellyptocytosis, pyruvate kinase, and glucose-6-phosphate dehidrogenase mutations. A rare anemia diagnostic paradigm.

Int J Lab Hematol 2020 04 20;42(2):e55-e58. Epub 2019 Sep 20.

Red Cell Pathology and Hematopoietic Disorders Unit (Rare Anaemias Expert Centre), Institute for Leukaemia Research Josep Carreras (IJC), Badalona (Barcelona), Spain.

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http://dx.doi.org/10.1111/ijlh.13110DOI Listing
April 2020

Author Correction: Donor lymphocyte infusions for B-cell malignancies relapse after T-cell replete allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2019 Jul;54(7):1176

Hematology Department, Hospital Universitari Vall d´Hebron, Departament de Medicina, Universitat Autonoma de Barcelona, Barcelona, Spain.

In the original version of this article, author 'Lucia López-Corral' was incorrectly listed as 'Lucia López'. This has now been corrected in both the PDF and HTML versions of the article to 'Lucia López-Corral'.
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http://dx.doi.org/10.1038/s41409-019-0471-yDOI Listing
July 2019

[Subsequent malignancies after long-term follow-up of pediatric hematopoietic stem cell transplantation].

An Pediatr (Barc) 2019 Mar 5;90(3):157-164. Epub 2018 Sep 5.

Pediatric Hematology, Oncology and HSCT Unit, Santa Creu i Sant Pau University Hospital, Barcelona, España.

Introduction: Survival after hematopoietic stem cell transplantation has improved dramatically in recent years. Unfortunately, there is an increased risk of subsequent malignant neoplasms (SMN) in this population and this represents a significant cause of late mortality.

Patients And Methods: In this study, we analyzed the incidence of SMN and the associated risk factors in patients referred at a pediatric age for hematopoietic stem cell transplantation (allogeneic or autologous) in our center.

Results: We observed 19 cases of SMN in a cohort of 371 patients, with a cumulative incidence of 6, 12, and 36% at 15, 20, and 30 years of follow-up, respectively. The solid tumors were the most prevalent malignancies. The risk was significantly higher than expected in the general population for each tumor type and in the different age ranges (p<.0001). Radiotherapy and chronic GvHD were the main risk factors for the development of SMN in our series.

Conclusions: We observed a high incidence of SMN among hematopoietic stem cell transplantation survivors highlighting the need for life-long surveillance.
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http://dx.doi.org/10.1016/j.anpedi.2018.05.023DOI Listing
March 2019

Haematopoietic stem cell transplantation for mucopolysaccharidosis type VII: A case report.

Pediatr Transplant 2018 11 9;22(7):e13278. Epub 2018 Aug 9.

Pediatric Hematology, Oncology and HSCT Unit, Hospital Santa Creu i Sant Pau, Barcelona, Spain.

Mucopolysaccharidosis type VII (MPS VII) is an inherited disease characterized by the cellular accumulation of undegraded GAGs due to the deficiency of the lysosomal enzyme β-glucuronidase. We describe a case of a 2-year-old female affected by a moderate form of MPS VII and submitted twice to HSCT with the aim of stabilizing skeletal problems and preventing neurocognitive alterations. The child underwent a second transplantation due to the rejection of the graft after a reduced-intensity conditioning in the first transplant. A myeloablative regimen allowed to achieve a stable full donor engraftment and normal enzyme levels during the 6 years of follow-up. Clinically, we observed stabilization of skeletal deformities and normal neurocognitive development. This is one of the few reports of mucopolysaccharidosis type VII treated with allogeneic HSCT.
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http://dx.doi.org/10.1111/petr.13278DOI Listing
November 2018

Unexpected High Incidence of Human Herpesvirus-6 Encephalitis after Naive T Cell-Depleted Graft of Haploidentical Stem Cell Transplantation in Pediatric Patients.

Biol Blood Marrow Transplant 2018 11 19;24(11):2316-2323. Epub 2018 Jul 19.

Pediatric Hemato-Oncology, La Paz University Hospital, Madrid, Spain.

The CD45RA T cell depletion (TCD) method has been used to deplete naive T cells, preventing graft-versus-host disease (GVHD) but preserving memory cells, providing immediate functional T cells with anti-infection, antileukemia, and antirejection effects. We describe a series of 25 consecutive high-risk patients with leukemia who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with CD45RA TCD. Each patient received 2 cell products: 1 created by CD34 positive selection and the other through CD45RA depletion from the CD34 negative fraction by a CliniMACS device. CD45RA-depleted haplo-HSCT was well tolerated, with rapid engraftment and low risk of severe acute GVHD and chronic GVHD. Although this treatment achieved a good control of viral reactivations, such as cytomegalovirus and adenovirus, we observed an unexpectedly high rate of limbic encephalitis due to human herpesvirus-6 (HHV-6; 8 cases). Characteristically, the infection appeared early in almost all patients, just after the engraftment. Although no patient died from encephalitis, 1 patient showed neuropsychological sequelae, and another experienced secondary graft failure just after the HHV-6 reactivation.
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http://dx.doi.org/10.1016/j.bbmt.2018.07.016DOI Listing
November 2018

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).

Med Clin (Barc) 2019 02 9;152(4):135-140. Epub 2018 Jul 9.

Unidad Pediátrica de Trasplante Hematopoyético, Hospital Universitario Vall d'Hebron, Barcelona, España.

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 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.
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http://dx.doi.org/10.1016/j.medcli.2018.05.013DOI Listing
February 2019

From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia.

Genet Med 2019 01 14;21(1):189-194. Epub 2018 Jun 14.

Genetics Department and Biomedical Research Institute, Hospital de Sant Pau, Center for Biomedical Research on Rare Diseases (CIBERER), and Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.

Purpose: In about 10% of patients affected by Fanconi anemia (FA) the diagnosis is delayed until adulthood, and the presenting symptom in these "occult" FA cases is often a solid cancer and cancer treatment-related toxicity. Highly predictive clinical parameter(s) for diagnosing such an adult-onset cases are missing.

Methods: (1) Exome sequencing (ES), (2) Sanger sequencing of FANCA, (3) diepoxybutane (DEB)-induced chromosome breakage test.

Results: ES identified a pathogenic homozygous FANCA variant in a patient affected by Sertoli cell-only syndrome (SCOS) and in his azoospermic brother. Although they had no overt anemia, chromosomal breakage test revealed a reverse somatic mosaicism in the former and a typical FA picture in the latter. In 27 selected SCOS cases, 1 additional patient showing compound heterozygous pathogenic FANCA variants was identified with positive chromosomal breakage test.

Conclusion: We report an extraordinarily high frequency of FA in a specific subgroup of azoospermic patients (7.1%). The screening for FANCA pathogenic variants in such patients has the potential to identify undiagnosed FA before the appearance of other severe clinical manifestations of the disease. The definition of this high-risk group for "occult" FA, based on specific testis phenotype with mild/borderline hematological alterations, is of unforeseen clinical relevance.
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http://dx.doi.org/10.1038/s41436-018-0037-1DOI Listing
January 2019

Autoimmune hemolytic anemia (AIHA) following allogeneic hematopoietic stem cell transplantation (HSCT): A retrospective analysis and a proposal of treatment on behalf of the Grupo Español De Trasplante de Medula Osea en Niños (GETMON) and the Grupo Español de Trasplante Hematopoyetico (GETH).

Transfus Med Rev 2018 Mar 3. Epub 2018 Mar 3.

Hematology Department, Hospital La Fe, Valencia, Spain.

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.
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http://dx.doi.org/10.1016/j.tmrv.2018.02.005DOI Listing
March 2018

Analysis of relapse after transplantation in acute leukemia: A comparative on second allogeneic hematopoietic cell transplantation and donor lymphocyte infusions.

Exp Hematol 2018 06 8;62:24-32. Epub 2018 Mar 8.

Hematology Department, Hospital Universitario Vall d'Hebron (VHIO), Universitat Autonoma de Barcelona, Barcelona, Spain.

Relapse of acute leukemia (AL) after allogeneic hematopoietic cell transplantation (Allo-HCT) entails a dismal prognosis. In this scenario, donor lymphocyte infusions (DLIs) and second Allo-HCT are two major approaches. We compared outcomes of AL patients treated for relapse with DLI or second Allo-HCT after receiving debulking therapy. In total, 46 patients were included in the study; 30 (65%) had acute myeloid leukemia and 16 (35%) had acute lymphoblastic leukemia. The median age was 38 years (range 4-66). Twenty-seven patients received a second Allo-HCT and 19 patients received DLI. The median follow-up of the cohort was 273 days (range 9-7013). Overall survival (OS), disease-free survival (DFS), nonrelapse mortality, and cumulative incidence (CI) of relapse were calculated from DLI or second Allo-HCT date. In univariate analysis, second Allo-HCT was associated with higher OS (p = 0.021) and a trend to higher DFS (p = 0.097) and CI of relapse (p = 0.094) on univariate analysis. However, multivariate analysis showed comparable outcomes between DLI and second Allo-HCT, with the time interval to relapse before DLI or second Allo-HCT the only statistically significant factor with an impact on OS and DFS. Within the DLI cohort, T-cell-depleted Allo-HCT was associated with higher OS (p = 0.003) and DFS (p < 0.001) and lower CI of relapse (p = 0.002) than T-cell-replete Allo-HCT. Overall, in this cohort of AL patients, second Allo-HCT and DLI associated similar outcomes. As in other relapse studies, the length of remission (time to relapse) was identified as a factor with statistical impact on survival. Further studies are warranted.
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http://dx.doi.org/10.1016/j.exphem.2018.03.002DOI Listing
June 2018

[Reduced-intensity conditioning haematopoietic stem cell transplantation in genetic diseases: Experience of the Spanish Working Group for Bone Marrow Transplantation in Children].

An Pediatr (Barc) 2018 Apr 8;88(4):196-203. Epub 2017 Jul 8.

Unidad Pediátrica de Trasplante Hematopoyético, Hospital Santa Creu i Sant Pau, Universidad Autónoma, Barcelona, España.

Introduction: Haematopoietic stem cell transplantation (HSCT) involves implanting cellular elements capable of generating a new and healthy haematopoietic system. Reduced intensity conditioning (RIC) consists of an immunosuppressive treatment to facilitate a progressive implant with lower morbidity. This type of conditioning can also lead to myelosuppression, which is potentially reversible over time. Reduced intensity conditioning enables HSCT to be performed on patients with genetic diseases for whom added comorbidity is undesirable due to the high doses of chemotherapy that accompanies conventional myeloablative regimens.

Patients And Methods: An analysis was performed on the outcomes of 68 paediatric patients with genetic diseases who underwent HSCT with RIC between 2005 and 2013 in the of Paediatric Haematopoietic Stem Cell Transplantation Units that are part of the Spanish Working Group for Bone Marrow Transplantation in Children. A multicentre study was conducted including 68 patients, of whom 43 had Primary Immunodeficiency, 21 with congenital haematological diseases, and 4 with metabolic diseases.

Results: Fifty (73.5%) of the 68 patients were still alive. The Overall Survival (OS) at nine years was 0.74. Twenty-three (33.8%) had some event during the course of the HSCT, with an event-free survival rate of 0.66. The OS in patients with haematological diseases was 0.81, being 0.7 in primary immunodeficiencies, and 0.4 in metabolic diseases. No significant difference was observed between the 3 groups of diseases. As regards the source of haematopoietic progenitors, there was an OS rate of 0.74 in patients transplanted with peripheral blood, 0.70 with bone marrow, and 0.70 and with cord blood, with no statistically significant differences.

Conclusions: Favourable results have been obtained in HSCT with reduced intensity conditioning in genetic diseases. It should be noted that the risks and benefits of the RIC in patients with metabolic diseases need to be assessed on an individual basis.
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http://dx.doi.org/10.1016/j.anpedi.2017.02.015DOI Listing
April 2018

Early and Long-Term Impaired T Lymphocyte Immune Reconstitution after Cord Blood Transplantation with Antithymocyte Globulin.

Biol Blood Marrow Transplant 2017 Mar 22;23(3):491-497. Epub 2016 Nov 22.

Banc de Sang i Teixits, Barcelona, Spain.

Immune reconstitution is crucial to the success of allogeneic hematopoietic stem cell transplantation. Umbilical cord blood transplantation (UCBT) has been associated with delayed immune reconstitution. We characterized the kinetics and investigated the risk variables affecting recovery of the main lymphocyte subsets in 225 consecutive pediatric and adult patients (males, n = 126; median age, 15; range, .3 to 60; interquartile range, 4 to 35) who underwent myeloablative single UCBT between 2005 and 2015 for malignant and nonmalignant disorders. Low CD4 and CD8 T cell counts were observed up to 12 months after UCBT. In contrast, B and natural killer cells recovered rapidly early after transplantation. In a multivariate regression model, factors favoring CD4 T cell recovery ≥ 200 cells/µL were lower dose antithymocyte globulin (ATG) (hazard ratio [HR], 3.93; 95% confidence interval [CI], 2.3 to 5.83; P = .001), negative recipient cytomegalovirus (CMV) serostatus (HR, 3.76; 95% CI, 1.9 to 5.74; P = .001), and younger age (HR, 2.61; 95% CI, 1.01 to 3.47; P = .03). Factors favoring CD8 T cell recovery ≥ 200 cells/µL were lower dose ATG (HR, 3.03; 95% CI, 1.4 to 5.1; P = .03) and negative recipient CMV serostatus (HR, 1.9; 95% CI, 1.63 to 2.15; P = .01). Our results demonstrate the significant negative impact of ATG on lymphocyte recovery. A reduction of the dose or omission of ATG could improve immune reconstitution and perhaps reduce opportunistic infections after UCBT.
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http://dx.doi.org/10.1016/j.bbmt.2016.11.014DOI Listing
March 2017

Cord Blood Units with High CD3(+) Cell Counts Predict Early Lymphocyte Recovery After In Vivo T Cell-Depleted Single Cord Blood Transplantation.

Biol Blood Marrow Transplant 2016 06 30;22(6):1073-1079. Epub 2016 Mar 30.

Banc de Sang i Teixits, Barcelona, Spain.

Although high absolute lymphocyte count (ALC) early after transplantation is a simple surrogate for immune reconstitution, few studies to date have established the predictive factors for ALC after umbilical cord blood transplantation (UCBT). We retrospectively studied the factors associated with early lymphocyte recovery and the impact of the ALC on day +42 (ALC42) of ≥300 × 10(6)/L on outcomes in 210 consecutive pediatric and adult patients (112 males; median age, 15 years; range, 0.3 to 60 years; interquartile range, 4 to 36 years) who underwent myeloablative in vivo T cell-depleted single UCBT between 2005 and 2014 for malignant and nonmalignant disorders. In a logistic multivariate regression model, factors favoring a higher ALC42 were higher infused CD3(+) cell dose (odds ratio [OR], 2.7; 95% CI, 1.4 to 5.2; P = .004), lower antithymocyte globulin dose (OR, 2.3; 95% CI, 1.2 to 4.5; P = .01), and better HLA match (OR, 2.1; 95% CI, 1.1 to 4.1; P = .03). In multivariate analysis, lower ALC42 was associated with higher nonrelapse mortality (hazard ratio [HR], 1.76; 95% CI, 1.34 to 2.32; P = .001), whereas a higher ALC42 was associated with better disease-free survival (HR, 2.03; 95% CI, 1.15 to 3.6; P < .001) and overall survival (HR, 2.03; 95% CI, 1.17 to 3.6; P < .001). Our study suggests that the selection of better HLA-matched cord blood units containing higher CD3(+) cell counts and the use of conditioning regimens with lower ATG doses could improve immune reconstitution after UCBT.
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http://dx.doi.org/10.1016/j.bbmt.2016.03.009DOI Listing
June 2016

A novel gain-of-function STAT1 mutation resulting in basal phosphorylation of STAT1 and increased distal IFN-γ-mediated responses in chronic mucocutaneous candidiasis.

Mol Immunol 2015 Dec;68(2 Pt C):597-605

Department of Immunology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain. Electronic address:

Gain-of-function STAT1 mutations have recently been associated with autosomal dominant chronic mucocutaneous candidiasis (CMC). The purpose of this study was to characterize the three members of a non-consanguineous family, the father and his two sons, who presented with recurrent oral thrush and ocular candidiasis since early childhood. The three patients had reduced levels of IL-17-producing T cells. This reduction affected specifically IL-17(+)IFN-γ(-) T cells, because the levels of IL-17(+)IFN-γ(+) T cells were similar to controls. We found that PBMC (peripheral blood mononuclear cells) from the patients did not respond to Candida albicans ex vivo. Moreover, after polyclonal activation, patients' PBMC produced lower levels of IL-17 and IL-6 and higher levels of IL-4 than healthy controls. Genetic analyses showed that the three patients were heterozygous for a new mutation in STAT1 (c.894A>C, p.K298N) that affects a highly conserved residue of the coiled-coil domain of STAT1. STAT1 phosphorylation levels were significantly higher in patients' cells than in healthy controls, both in basal conditions and after IFN-γ stimulation, suggesting a permanent activation of STAT1. Cells from the patients also presented increased IFN-γ-mediated responses measured as MIG and IP-10 production. In conclusion, we report a novel gain-of-function mutation in the coiled-coil domain of STAT1, which increases STAT1 phosphorylation and impairs IL-17-mediated immunity. The mutation is responsible for CMC in this family with autosomal dominant inheritance of the disease.
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http://dx.doi.org/10.1016/j.molimm.2015.09.014DOI Listing
December 2015

Few and nonsevere adverse infusion events using an automated method for diluting and washing before unrelated single cord blood transplantation.

Biol Blood Marrow Transplant 2015 Apr 27;21(4):682-7. Epub 2014 Dec 27.

Cell Therapy Laboratory, Banc de Sang i Teixits, Barcelona, Spain.

Graft dilution and DMSO washing before cord blood (CB) administration using an automated system may offer low incidence of adverse infusion events (AIE), ensuring reproducible cell yields. Hence, we analyzed the incidences and significance of immediate AIE, cellular yield, and engraftment after single CB infusion. One hundred and fifty-seven patients (median age, 20 years; range, 1 to 60) received a single CB unit for treatment of hematologic and nonhematologic malignancies with myeloablative conditioning after graft dilution and washing. The median total nucleated cell (TNC) doses was 3.4 × 10(7)/kg (range, 2 to 26) and the median post-thaw recovery was 84% (range, 45 to 178). The cumulative incidence of neutrophil engraftment at 50 days was 84% (95% confidence interval [CI], 83 to 93). A total of 118 immediate AIE were observed in fifty-two (33%) patients. All reported AIE were transient, graded from 1 to 2 by Common Terminology Adverse Events version 4. The most frequent toxicity was cardiovascular but without any life-threatening reaction. Infused TNC, recipient's weight, and rate of infusion per kilogram were risk factors associated with cardiovascular AIE in multivariate analysis (odds ratio [OR], 1.2 (95% CI, 1.1 to 1.4); P < .001; OR, .94 (95% CI, .9 to .97); P < .001; and OR, 1.5 (95% CI, 1.2 to 1.8); P < .001; respectively). In summary, use of an automated method for graft washing before CB administration showed low incidence of AIE without compromising cell yields and engraftment. Infused TNC dose, recipient's weight, and rate of infusion per kilogram were risk factors associated with infusion reactions.
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http://dx.doi.org/10.1016/j.bbmt.2014.12.015DOI Listing
April 2015

Combined cord blood and bone marrow transplantation from the same human leucocyte antigen-identical sibling donor for children with malignant and non-malignant diseases.

Br J Haematol 2015 Apr 18;169(1):103-10. Epub 2014 Dec 18.

Hospital Saint Louis, AP-HP, and IUH University Paris VII, Eurocord, Paris, France; Centro de Oncologia, Hospital Sirio-Libanes, Sao Paulo, Brazil.

Umbilical cord blood (UCB) from an human leucocyte antigen (HLA)-identical sibling can be used for transplantation of patients with malignant and non-malignant diseases. However, the low cellular content of most UCB units represents a limitation to this approach. An option to increase cell dose is to harvest bone marrow (BM) cells from the same donor and infuse them along with the UCB. We studied 156 children who received such a combined graft between 1992 and 2011. Median age was 7 years and 78% of patients (n = 122) were transplanted for non-malignant diseases, mainly haemoglobinopathies. Acute leukaemia (n = 26) was the most frequent malignant diagnosis. Most patients (91%) received myeloablative conditioning. Median donor age was 1·7 years, median infused nucleated cell dose was 24·4 × 10(7) /kg and median follow-up was 41 months. Sixty-days neutrophil recovery occurred in 96% of patients at a median of 17 d. The probabilities of grade-II-IV acute and chronic graft-versus-host disease (GVHD) were 19% and 10%, respectively. Four-year overall survival was 90% (68% malignant; 97% non-malignant diseases) with 3% probability of death. In conclusion, combined UCB and BM transplantation from an HLA-identical sibling donor is an effective treatment for children with malignant and non-malignant disorders with high overall survival and low incidence of GVHD.
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http://dx.doi.org/10.1111/bjh.13267DOI Listing
April 2015

Genome-wide DNA methylation profiling predicts relapse in childhood B-cell acute lymphoblastic leukaemia.

Br J Haematol 2013 Feb 30;160(3):406-9. Epub 2012 Oct 30.

Cancer Epigenetics and Biology Programme, Bellvitge Biomedical Research Institute, L Hospitalet de Llobregat, Barcelona, Catalonia, Spain.

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http://dx.doi.org/10.1111/bjh.12113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568176PMC
February 2013

Study of three families with Hb Agrinio [α29(B10)Leu→Pro, CTG>CCG (α2)] in the Spanish population: three homozygous cases.

Hemoglobin 2012 24;36(6):526-32. Epub 2012 Oct 24.

Servicio de Hematología, Hospital Clínico San Carlos de Madrid, Madrid, Spain.

Most α-thalassemia (α-thal) mechanisms are deletions of one or both α-globin genes and less than 5.0-10.0% are point mutations. Hb Agrinio [α29(B10)Leu→Pro, CTG>CCG (α2)] is a hyperunstable α chain structural variant in which the thalassemic phenotype is determined by a post translational precipitation of the structurally anomalous chain in erythroid precursors. This study involved 14 cases with Hb Agrinio from three families. Selective sequencing of the α2 gene showed a CTG(Leu)>CCG(Pro) mutation at codon 29. The mutation was found in a heterozygous state in 11 cases and in a homozygous state in three cases. These are the first cases with Hb Agrinio described in Spain. In all cases where a leucine is exchanged for a proline, an unstable hemoglobin (Hb) will occur both in the α and the β chain. Some of these are as unstable as Hb Agrinio and their presence is difficult to detect except by DNA sequencing.
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http://dx.doi.org/10.3109/03630269.2012.733988DOI Listing
April 2013