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1.
Blood ; 140(14): 1635-1649, 2022 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-35344580

RESUMEN

Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT.


Asunto(s)
Bronquiectasia , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Adolescente , Adulto , Bronquiectasia/etiología , Niño , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Persona de Mediana Edad , Estudios Retrospectivos , Trasplante Homólogo , Adulto Joven
2.
Br J Cancer ; 129(3): 455-465, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37340093

RESUMEN

BACKGROUND: Recurrent genetic lesions provide basis for risk assessment in pediatric acute lymphoblastic leukemia (ALL). However, current prognostic classifiers rely on a limited number of predefined sets of alterations. METHODS: Disease-relevant copy number aberrations (CNAs) were screened genome-wide in 260 children with B-cell precursor ALL. Results were integrated with cytogenetic data to improve risk assessment. RESULTS: CNAs were detected in 93.8% (n = 244) of the patients. First, cytogenetic profiles were combined with IKZF1 status (IKZF1normal, IKZF1del and IKZF1plus) and three prognostic subgroups were distinguished with significantly different 5-year event-free survival (EFS) rates, IKAROS-low (n = 215): 86.3%, IKAROS-medium (n = 27): 57.4% and IKAROS-high (n = 18): 37.5%. Second, contribution of genetic aberrations to the clinical outcome was assessed and an aberration-specific score was assigned to each prognostically relevant alteration. By aggregating the scores of aberrations emerging in individual patients, personalized cumulative values were calculated and used for defining four prognostic subgroups with distinct clinical outcomes. Two favorable subgroups included 60% of patients (n = 157) with a 5-year EFS of 96.3% (excellent risk, n = 105) and 87.2% (good risk, n = 52), respectively; while 40% of patients (n = 103) showed high (n = 74) or ultra-poor (n = 29) risk profile (5-year EFS: 67.4% and 39.0%, respectively). CONCLUSIONS: PersonALL, our conceptually novel prognostic classifier considers all combinations of co-segregating genetic alterations, providing a highly personalized patient stratification.


Asunto(s)
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Medición de Riesgo , Factor de Transcripción Ikaros/genética , Eliminación de Gen
3.
J Clin Immunol ; 43(3): 557-567, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36383294

RESUMEN

PURPOSE: To assess the efficacy, pharmacokinetics, and safety of a new, highly purified 10% IVIg (BT595, Yimmugo®) administered in children with PID. METHODS: This was an open-label, prospective, uncontrolled, multicenter Phase III pivotal trial. Among the 67 subjects in the trial were 18 pediatric patients aged 2 to 17 years with diagnosis of PID included in this analysis. They received doses between 0.2 and 0.8 g/kg body weight for approximately 12 months at intervals of either 3 or 4 weeks. Dosage and dosing interval were based on each patient's pre-trial infusion schedule. The rates of acute serious bacterial infections (SBI), secondary efficacy, safety, and pharmacokinetic outcomes were evaluated. RESULTS: No SBI occurred in the pediatric population. Two hundred sixty infusions were administered to the 18 pediatric patients. The mean (SD) IgG trough level was 8.55 (1.67) g/L at baseline and 8.84 (2.17) g/L at the follow-up visit after the last BT595 infusion. At the single infusions respectively, the average mean IgG trough levels ranged between 8.52 and 10.58 g/L. More than 85% of all infusions administered were not associated with any infusional AE (start during or within 72 h post-infusion). None of the severe or serious AEs were related to the investigational medicinal product (IMP). No premedication was used. Thirteen children reached a maximum infusion rate between > 2.0 and 8 mL/kg/h; no AE with an onset during the infusion occurred at these infusion rates. CONCLUSION: BT595 is effective, convenient, well tolerated, and safe for the treatment of children with PID. TRIAL REGISTRATION: EudraCT: 2015-003652-52; NCT02810444, registered June 23, 2016.


Asunto(s)
Infecciones Bacterianas , Síndromes de Inmunodeficiencia , Enfermedades de Inmunodeficiencia Primaria , Humanos , Niño , Estudios Prospectivos , Síndromes de Inmunodeficiencia/diagnóstico , Inmunoglobulina G/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Enfermedades de Inmunodeficiencia Primaria/tratamiento farmacológico
4.
Eur J Haematol ; 111(2): 254-262, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37194391

RESUMEN

BACKGROUND: FA patients are hypersensitive to preconditioning of bone marrow transplantation. OBJECTIVE: Assessment of the power of mitomycin C (MMC) test to assign FA patients. METHODS: We analysed 195 patients with hematological disorders using spontaneous and two types of chromosomal breakage tests (MMC and bleomycin). In case of presumed Ataxia telangiectasia (AT), patients' blood was irradiated in vitro to determine the radiosensitivity of the patients. RESULTS: Seven patients were diagnosed as having FA. The number of spontaneous chromosomal aberrations was significantly higher in FA patients than in aplastic anemia (AA) patients including chromatid breaks, exchanges, total aberrations, aberrant cells. MMC-induced ≥10 break/cell was 83.9 ± 11.4% in FA patients and 1.94 ± 0.41% in AA patients (p < .0001). The difference in bleomycin-induced breaks/cell was also significant: 2.01 ± 0.25 (FA) versus 1.30 ± 0.10 (AA) (p = .019). Seven patients showed increased radiation sensitivity. Both dicentric + ring, and total aberrations were significantly higher at 3 and 6 Gy compared to controls. CONCLUSIONS: MMC and Bleomycin tests together proved to be more informative than MMC test alone for the diagnostic classification of AA patients, while in vitro irradiation tests could help detect radiosensitive-as such, individuals with AT.


Asunto(s)
Anemia Aplásica , Anemia de Fanconi , Humanos , Anemia Aplásica/etiología , Anemia Aplásica/genética , Anemia de Fanconi/complicaciones , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Rotura Cromosómica , Diagnóstico Diferencial , Mitomicina , Bleomicina
5.
J Clin Immunol ; 42(1): 171-182, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34697698

RESUMEN

PURPOSE: WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a rare disease, caused by CXCR4 gene mutations, which incorporates features of combined immunodeficiency, congenital neutropenia, and a predisposition to human papillomavirus infection. Established conventional treatment for WHIM syndrome does not fully prevent infectious complications in these patients. Only single case reports of hematopoietic stem cell transplantation (HSCT) efficacy in WHIM have been published. METHODS: To summarize current information on HSCT efficacy in disease treatment, seven pediatric patients with WHIM syndrome who underwent allogeneic HSCT were identified in five centers worldwide. RESULTS: All patients presented early after birth with neutropenia. Two of seven patients exhibited severe disease complications: poorly controlled autoimmunity (arthritis and anemia) in one and progressive myelofibrosis with recurrent infections in the other. The remaining patients received HSCT to correct milder disease symptoms (recurrent respiratory infections, progressing thrombocytopenia) and/or to preclude severe disease course in older age. All seven patients engrafted but one developed graft rejection and died of infectious complications after third HSCT. Three other patients experienced severe viral infections after HSCT (including post-transplant lymphoproliferative disease in one) which completely resolved with therapy. At last follow-up (median 6.7 years), all six surviving patients were alive with full donor chimerism. One patient 1.4 years after HSCT had moderate thrombocytopenia and delayed immune recovery; the others had adequate immune recovery and were free of prior disease symptoms. CONCLUSION: HSCT in WHIM syndrome corrects neutropenia and immunodeficiency, and leads to resolution of autoimmunity and recurrent infections, including warts.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Neutropenia , Verrugas , Niño , Humanos , Neutropenia/complicaciones , Neutropenia/terapia , Enfermedades de Inmunodeficiencia Primaria , Receptores CXCR4/genética , Verrugas/diagnóstico , Verrugas/genética , Verrugas/terapia
6.
J Clin Immunol ; 42(3): 500-511, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34973143

RESUMEN

PURPOSE: The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI). METHODS: Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject's previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year ≥ 1 vs < 1]). IgG subclasses and specific pathogen antibody levels were also measured. RESULTS: Sixty-one subjects (19 children [≤ 12 years], 10 adolescents [> 12-16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008-0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83-1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate. CONCLUSIONS: IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI.


Asunto(s)
Síndromes de Inmunodeficiencia , Adolescente , Adulto , Niño , Humanos , Inmunoglobulina G/uso terapéutico , Inmunoglobulinas Intravenosas , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Infusiones Subcutáneas
7.
J Clin Immunol ; 42(8): 1748-1765, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35947323

RESUMEN

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.


Asunto(s)
Agammaglobulinemia , Síndromes de Inmunodeficiencia , Linfopenia , Neutropenia , Verrugas , Humanos , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/epidemiología , Síndromes de Inmunodeficiencia/genética , Verrugas/diagnóstico , Verrugas/epidemiología , Verrugas/genética , Agammaglobulinemia/genética , Receptores CXCR4/genética , Neutropenia/genética , Linfopenia/complicaciones , Progresión de la Enfermedad
8.
Genet Med ; 24(8): 1781-1788, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35503103

RESUMEN

PURPOSE: This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib). METHODS: This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe. RESULTS: Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals. CONCLUSION: Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib.


Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo I , Neutropenia , Adolescente , Adulto , Compuestos de Bencidrilo , Niño , Preescolar , Glucósidos , Enfermedad del Almacenamiento de Glucógeno Tipo I/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo I/patología , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Lactante , Recién Nacido , Neutropenia/tratamiento farmacológico , Estudios Retrospectivos , Encuestas y Cuestionarios , Adulto Joven
9.
Vox Sang ; 117(10): 1153-1162, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35944615

RESUMEN

BACKGROUND AND OBJECTIVES: To evaluate the efficacy, safety and pharmacokinetics of a new, highly purified 10% IVIg (BT595, Yimmugo®) administered in children and adults with Primary immunodeficiency diseases (PID). MATERIALS AND METHODS: Prospective, uncontrolled, multicentre Phase III trial. Patients aged 2 to <76 years with PID were switched from their pre-trial IVIg replacement therapy to BT595. In all, 67 patients (49 adults, 18 children) received doses between 0.2 and 0.8 g/kg body weight for approximately 12 months at intervals of 3 or 4 weeks. Dosing and dosing intervals were based on each patient's pre-trial infusion schedule. The primary end point was the rate of acute serious bacterial infections (SBIs); secondary efficacy, safety and pharmacokinetic outcomes were also evaluated. RESULTS: The primary efficacy end point was met, and the unadjusted SBI rate was 0.01 per subject-year (adjusted SBI rate 0.015 per subject-year, with an upper limit of the one-sided 99% confidence interval of 0.151). A single adult patient experienced one event classified as an SBI. All secondary end points, including those related to infections, supported the efficacy. Infusion rates were increased up to 8 ml/kg/h. Overall, 8% of infusions were associated with ≥1 infusional adverse event (AE) (start during or within 72 h post-infusion), comprising mainly headache (2.4%), fatigue (0.9%) and nausea (0.5%). There were no infusional AEs at infusion rates of >4.0 ml/kg/h, and only one patient required a single premedication. The observed patterns, severity and frequency of treatment-emergent adverse events are consistent with the established safety profile for IVIgs and did not show clinically relevant differences between all age groups. CONCLUSION: BT595 is effective, safe and well tolerated for treating patients with PID.


Asunto(s)
Síndromes de Inmunodeficiencia , Enfermedades de Inmunodeficiencia Primaria , Adulto , Niño , Humanos , Inmunoglobulinas Intravenosas/efectos adversos , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Infusiones Intravenosas , Estudios Prospectivos
10.
Am J Hematol ; 96(5): 571-579, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33606297

RESUMEN

Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for bone marrow failure or hematopoietic malignant diseases for Fanconi anemia (FA) patients. Although results have improved over the last decades, reaching more than 90% survival when a human leukocyte antigen (HLA)-identical donor is available, alternative HCT donors are still less reported. We compared HCT outcomes using HLA-mismatched unrelated donors (MMUD; n = 123) or haplo-identical donors (HDs), either using only in vivo T cell depletion (n = 33) or T cells depleted in vivo with some type of graft manipulation ex vivo (n = 59) performed for FA between 2000 and 2018. Overall survival (OS) by 24 months was 62% (53-71%) for MMUD, versus 80% (66-95%) for HDs with only in vivo T cell depletion and 60% (47-73%) for HDs with in vivo and ex vivo T cell depletion (p = .22). Event-free survival (EFS) was better for HD-transplanted FA patients with only in vivo T cell depletion 86% (73-99%) than for those transplanted from a MMUD 58% (48-68%) or those with graft manipulation 56% (42-69%) (p = .046). Grade II-IV acute graft-versus-host disease (GVHD) was 41% (MMUD) versus 40% (HDs with no graft manipulation) versus 17% (HDs with T cell depleted graft), (p = .005). No differences were found for the other transplant related outcomes. These data suggest that HDs might be considered as an alternative option for FA patients with better EFS using unmanipulated grafts.


Asunto(s)
Trasplante de Médula Ósea , Anemia de Fanconi/terapia , Antígenos HLA/inmunología , Histocompatibilidad , Trasplante de Células Madre de Sangre Periférica , Adolescente , Aloinjertos , Trasplante de Médula Ósea/estadística & datos numéricos , Niño , Anemia de Fanconi/genética , Anemia de Fanconi/mortalidad , Femenino , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Antígenos HLA/genética , Haplotipos , Histocompatibilidad/genética , Histocompatibilidad/inmunología , Prueba de Histocompatibilidad , Humanos , Estimación de Kaplan-Meier , Donadores Vivos , Depleción Linfocítica , Masculino , Trasplante de Células Madre de Sangre Periférica/estadística & datos numéricos , Disfunción Primaria del Injerto/epidemiología , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Hermanos , Subgrupos de Linfocitos T/inmunología , Resultado del Tratamiento
11.
Vox Sang ; 115(1): 18-26, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31667887

RESUMEN

BACKGROUND AND OBJECTIVES: Administration of virus-specific T cells (VSTs) is a viable antiviral treatment strategy after allogeneic HSCT, even if conventional therapies fail. Third-party donors are often chosen for the generation of the VST product. The eligibility of the donor has to be tested in a rigorous donor screening procedure, since the isolation technology only targets pre-existing VSTs. MATERIALS AND METHODS: In a period of 3 years, we performed 32 VST treatments for 28 patients. Targeting four different viruses, 284 healthy individuals underwent 417 donor screening procedures. VSTs were counted by flow cytometry detecting interferon-gamma (IFN-γ) producing T cells. Generation of the VSTs was performed from leukapheresis products in a fully automated and closed system using magnetic cell separation. RESULTS: The mean circulating VST frequencies ranged from 0·006% to 0·328%. The average yield of viable VSTs in the product was 1·83·106 cells, while the average VST dose calculated for the patient's body weight was 4·63·104 /kg. The mean purity - percentage of VSTs within the T cells - of all T-cell products was 62·9%. Correlation was identified between the frequency of the VSTs in the peripheral blood of the donor and the VST numbers of the end product; the strongest correlation was seen for CMV. CONCLUSION: This paper focuses on the T-cell donors, highlighting some key points on the donor selection process. Based on the findings in connection with the CMV therapies, peripheral VST seems to be the best predictor of the VST content of the final product administered to the patient.


Asunto(s)
Donantes de Sangre , Trasplante de Células/métodos , Inmunoterapia Adoptiva/métodos , Leucaféresis , Linfocitos T , Virosis/terapia , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
12.
J Allergy Clin Immunol ; 143(6): 2238-2253, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30660643

RESUMEN

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.


Asunto(s)
Ligando de CD40/deficiencia , Trasplante de Células Madre Hematopoyéticas , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/terapia , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Resultado del Tratamiento , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/mortalidad
13.
Biol Blood Marrow Transplant ; 24(5): 989-996, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29339271

RESUMEN

Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is a multifactorial complication, and its prediction is largely unresolved. Our aim was to analyze changes of complement profile after HSCT to identify potential markers of TA-TMA development. Thirty-three consecutive pediatric patients (9.6 ± 4.4 years old) who underwent allogeneic HSCT due to malignant (n = 17) or nonmalignant (n = 16) indications were included in this study. Graft-versus-host disease (GVHD) was diagnosed using Glucksberg criteria, viral reactivation was monitored, 5 different TA-TMA diagnostic criteria were applied, and all important clinical and laboratory parameters of TA-TMA activity were registered. Complement pathway activities, components and terminal pathway activation marker (sC5b-9) levels were systematically measured before transplantation and on days 28, 56, and 100 after HSCT. During the first 100 days after HSCT, 1 of 33 patients died (day 50, multiple organ failure), whereas 10 subjects met the criteria for TA-TMA, typically on day 61 (range, 16 to 98 days). TA-TMA was preceded by acute GVHD in 3 of 10 patients, by viral reactivation in 2 of 10, or by both in 4 of 10 cases. Baseline sC5b-9 levels did not differ in patients without (200 [interquartile range, 144 to 266] ng/mL), or with (208 [interquartile range, 166 to 271] ng/mL) subsequent TA-TMA; however, on day 28 significant differences were observed (201 [interquartile range, 185 to 290] ng/mL versus 411 [interquartile range, 337 to 471] ng/mL; P = .004). Importantly, all 10 patients with TMA showed increase in sC5b-9 level from baseline level to day 28, whereas in patients without TMA the same tendency was observed for only 9 of 23 patients (P = .031). No additional complement parameters were closely associated with the development of TA-TMA. Development of TA-TMA occurred in 30% of our patients, typically after GVHD and/or viral reactivation. However, early raise of sC5b-9 activation marker was predictive for later development of TA-TMA, and should therefore be considered as an alarming sign necessitating a careful monitoring of all TA-TMA activity markers. Further studies enrolling a higher number of patients are necessary to determine if terminal pathway activation is an independent predictor of TA-TMA.


Asunto(s)
Complejo de Ataque a Membrana del Sistema Complemento/análisis , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Microangiopatías Trombóticas/etiología , Adolescente , Biomarcadores/análisis , Niño , Preescolar , Enfermedad Injerto contra Huésped , Humanos , Valor Predictivo de las Pruebas , Microangiopatías Trombóticas/diagnóstico , Factores de Tiempo , Activación Viral
14.
Pediatr Transplant ; 22(8): e13302, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30345623

RESUMEN

Primary CNS PTLD is an extremely rare complication after allogeneic HSCT. At our centre, an 11-year-old patient developed nausea, vomiting, and diplopy on day +82 following HSCT. On brain MRI, multiple white matter lesions were seen. Histology showed a diffuse large B-cell lymphoma with high load of EBV in tissue. Despite stopping immunosuppression, treatment with EBV-specific cytotoxic T cells, systemic rituximab, HD-MTX, and intrathecal chemotherapy, progression was observed. With a combination of HD-MTX and cytarabine, only a partial response could be achieved. Having all conventional modalities not only failed but resulted in significant toxicity, a salvage monotherapy with biweekly nivolumab has been instituted. The starting dose was 1.1 mg/kg, later escalated to 2.2 mg/kg. After 8 months of nivolumab therapy, PET-CT showed complete metabolic remission. Subsequently, the patient has been switched to a maintenance dosage of 1.1 mg/kg. No cytopenias, graft failure, GvHD, or any other alloimmune complications were seen during nivolumab therapy. In conclusion, nivolumab may be considered as an effective and safe option for CNS PTLD therapy when all other modalities have failed.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Trastornos Linfoproliferativos/terapia , Nivolumab/uso terapéutico , Trasplante de Células Madre , Antineoplásicos/uso terapéutico , Niño , Citarabina/uso terapéutico , Infecciones por Virus de Epstein-Barr/complicaciones , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Terapia de Inmunosupresión , Inyecciones Espinales , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Linfoma de Células B/inmunología , Imagen por Resonancia Magnética , Tomografía Computarizada por Tomografía de Emisión de Positrones , Periodo Posoperatorio , Inducción de Remisión , Rituximab/uso terapéutico , Trasplante Homólogo , Resultado del Tratamiento
15.
Orv Hetil ; 159(42): 1710-1719, 2018 10.
Artículo en Húngaro | MEDLINE | ID: mdl-30334483

RESUMEN

INTRODUCTION: Acquired bone marrow failures are rare but fatal diseases in childhood. Since 2013, Hungary has been participating as a full member in the work of the European Working Group on uniform diagnostics and therapy in patients with acquired bone marrow failure syndromes. Hypocellular refractory cytopenia of childhood has been emphasized as a frequent entity, transplanted by reduced intensity conditioning with excellent outcomes. AIM: To analyse and compare the results of treatment before and after our joining. METHOD: A total of 55 patients have been treated in the 8 centres of the Hungarian Pediatric Oncology Network during 5 years between 2013 and 2017 (severe aplastic anemia: 9, myelodysplastic syndrome: 41, juvenile myelomonocytic leukemia: 5 patients). Allogeneic hematopoietic stem cell transplantation was performed in severe aplastic anemia in 7 cases, while antithymocyte globulin was administered in one case and one patient died before diagnosis. In patients with myelodysplastic syndromes, watch and wait strategy was applied in 4, while transplantation in 37 cases. Reduced intensity conditioning was used in 54 percent of these cases. Transplantation was the treatment of choice in all 5 patients with juvenile myelomonocytic leukemia. RESULTS: In the whole patient cohort, the time from diagnosis to treatment was median 92 (3-393) days, while in severe aplastic anemia median 28 (3-327) days only. Grade II-IV acute graft versus host disease occurred in 22.6%, grade III-IV in 6.8% and chronic in 11.2%. All the patients treated with severe aplastic anemia are alive and in complete remission (100%). The overall estimated survival rate is 85.1% in myelodysplastic syndrome, while 75% in juvenile myelomonocytic leukemia. The median follow-up was 30.4 (1.1-62.5) months. There was a remarkable increase in overall survival comparing the data before (1992-2012) and after (2013) joining the international group, 70% vs. 100% (p = 0.133) in severe aplastic anemia and 31.3% vs. 85.1% (p = 0.000026) in myelodysplastic syndrome. CONCLUSION: Due to a change in the paradigm of the conditioning regimen in hypocellular refractory cytopenia of childhood, the overall survival rate has significantly increased. Orv Hetil. 2018; 159(42): 1710-1719.


Asunto(s)
Anemia Aplásica/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedades de la Médula Ósea/terapia , Enfermedad Injerto contra Huésped/prevención & control , Hemoglobinuria Paroxística/terapia , Trastornos de Fallo de la Médula Ósea , Niño , Preescolar , Supervivencia sin Enfermedad , Humanos , Hungría , Tasa de Supervivencia , Factores de Tiempo , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo
16.
Magy Onkol ; 62(4): 230-236, 2018 Dec 12.
Artículo en Húngaro | MEDLINE | ID: mdl-30540865

RESUMEN

The survival of children treated with Ewing sarcoma at Semmelweis University were investigated. Pediatric patients with Ewing sarcoma treated at Semmelweis University from 2001 through 2013 were analyzed in terms of overall survival and clinical factors (age, primary localization and extent of the tumor, time interval from primary complaints to diagnosis). For statistical analysis Kaplan-Meier estimated survival and log rank test were applied. Mean age and follow-up time of the 78 patients were 11.16 and 6.29 years, respectively. In 57% of patients time interval from primary symptoms to diagnosis was less than half year. In 53.8% of the patients the disease was metastatic at primary diagnosis (pulmonary only: 29.5%, any other: 24.3%). 5- and 10-year overall survival of patients were 68.1% and 60.4%, respectively. Among the analyzed factors, the presence of metastasis impaired 5-year overall survival significantly (88.5% for localized disease, 63.5% for pulmonary only and 40.9% for any other metastasis). The survival rate of pediatric patients with Ewing sarcoma treated at Semmelweis University is similar to the result in Western European countries.


Asunto(s)
Neoplasias Óseas/mortalidad , Neoplasias Óseas/terapia , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/terapia , Adolescente , Factores de Edad , Neoplasias Óseas/patología , Niño , Preescolar , Estudios de Cohortes , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Hospitales Universitarios , Humanos , Hungría , Estimación de Kaplan-Meier , Masculino , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Sarcoma de Ewing/patología , Factores Sexuales , Análisis de Supervivencia
17.
J Clin Immunol ; 37(6): 539-547, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28711959

RESUMEN

This multicentre, open-label, prospective, single-arm study was designed to evaluate the efficacy, pharmacokinetics, and safety of IqYmune®, a highly purified 10% polyvalent immunoglobulin preparation for intravenous administration in patients with primary immunodeficiency. IqYmune® was administered to 62 patients (aged 2-61 years) with X-linked agammaglobulinemia or common variable immune deficiency at a dose from 0.22 to 0.97 g/kg every 3 to 4 weeks for 12 months with an infusion rate up to 8 mL/kg/h. A pharmacokinetic study was performed at steady state between the 8th and the 9th infusion. A single case of serious bacterial infection was observed, leading to an annualized rate of serious bacterial infections/patient (primary endpoint) of 0.017 (98% CI: 0.000, 0.115). Overall, 228 infections were reported, most frequently bronchitis, chronic sinusitis, nasopharyngitis and upper respiratory tract infection. The mean annualized rate of infections was 3.79/patient. A lower risk of infections was associated with an IgG trough level > 8 g/L (p = 0.01). The mean annualized durations of absence from work or school and of hospitalization due to infections were 1.01 and 0.89 days/patient, respectively. The mean serum IgG trough level before the 6th infusion was 7.73 g/L after a mean dose of IqYmune® of 0.57 g/kg. The pharmacokinetic profile of IqYmune® was consistent with that of other intravenous immunoglobulins. Overall, 15.5% of infusions were associated with an adverse event occurring within 72 h post infusion. Headache was the most common adverse event. In conclusion, IqYmune® was shown to be effective and well tolerated in patients with primary immunodeficiency.


Asunto(s)
Agammaglobulinemia/terapia , Inmunodeficiencia Variable Común/terapia , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunoterapia/métodos , Adolescente , Adulto , Agammaglobulinemia/inmunología , Niño , Preescolar , Ensayos Clínicos como Asunto , Inmunodeficiencia Variable Común/inmunología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Europa (Continente) , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Cefalea/diagnóstico , Cefalea/etiología , Humanos , Inmunoglobulinas Intravenosas/efectos adversos , Inmunoglobulinas Intravenosas/farmacocinética , Inmunoterapia/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto Joven
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