RESUMEN
Early-phase trials of venetoclax in children and teenagers/young adults with leukaemia have yielded promising results, but there remains a paucity of real-world data. To address this, we report a cohort of 41 children treated with venetoclax for a range of haematological malignancies, demonstrating complete remission in 43.6%, with most achieving minimal residual disease (MRD) negativity. Venetoclax was particularly effective as a bridge to transplant, with bridging successful in 75% of patients. Patients with MRD <1% at initiation of venetoclax were more likely to achieve MRD negativity (81.8% vs. 34.5%, p = 0.007) and had improved overall survival (54.5% vs. 17.9%, p = 0.004).
RESUMEN
The cytokine storm of secondary haemophagocytic lymphohistiocytosis (sHLH)/macrophage activation syndrome (MAS) can cause life-threatening multiorgan failure. Interleukin-1 (IL-1) receptor blockade with anakinra can be effective in the management of sHLH/MAS. Subcutaneous (SC) dosing regimens are widely described; however, intravenous (IV) dosing is advantageous where time-critical intervention is vital and where SC oedema and/or hypoperfusion limits absorption. We review three critically ill children (aged 9, 11 and 17) with sHLH and rapidly progressive multiorgan dysfunction, successfully treated with continuous IV anakinra infusion. This case series significantly enhances the incipient knowledge regarding the safety and efficacy of IV anakinra for life-threatening sHLH.
Asunto(s)
Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Linfohistiocitosis Hemofagocítica , Síndrome de Activación Macrofágica , Administración Intravenosa , Niño , Enfermedad Crítica , Síndrome de Liberación de Citoquinas , Humanos , Proteína Antagonista del Receptor de Interleucina 1/administración & dosificación , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Síndrome de Activación Macrofágica/tratamiento farmacológico , Insuficiencia Multiorgánica/tratamiento farmacológico , Insuficiencia Multiorgánica/etiologíaRESUMEN
Patients with an ABL-class fusion have a high risk of relapse on standard chemotherapy but are sensitive to tyrosine kinase inhibitors (TKI). In UKALL2011, we screened patients with post-induction MRD ≥1% and positive patients (12%) received adjuvant TKI. As the intervention started during UKALL2011, not all eligible patients were screened prospectively. Retrospective screening of eligible patients allowed the outcome of equivalent ABL-class patients who did and did not receive a TKI in first remission to be compared. ABL-class patients who received a TKI in first remission had a reduced risk of relapse/refractory disease: 0% vs. 63% at four years (P = 0·009).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Neoplasia Residual , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogénicas c-abl/genéticaAsunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adolescente , Niño , Femenino , Humanos , Inmunoterapia , Irlanda/epidemiología , Masculino , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/epidemiología , Análisis de Supervivencia , Reino Unido/epidemiología , Adulto JovenRESUMEN
Accurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next-generation-sequencing (NGS) has been used to investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical-grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically-reliable diagnostic test and minimize false-negative results we developed an open-source tool (CoverMi) to accurately determine base-coverage and the 'discoverability' of known mutations for every sample. We validated our 33-gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS-based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family.
Asunto(s)
Anemia/diagnóstico , Anemia/genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Biología Computacional/métodos , Manejo de la Enfermedad , Estudios de Asociación Genética , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Mutación , Polimorfismo de Nucleótido Simple , Enfermedades Raras , Reproducibilidad de los Resultados , Flujo de TrabajoRESUMEN
Acute myeloid leukemia (AML) is the most common acute leukemia in adults and the second most common frequent leukemia of childhood. Patients may present with lymphopenia or pancytopenia at diagnosis. We investigated the mechanisms by which AML causes pancytopenia and suppresses patients' immune response. This study identified for the first time that AML blasts alter the immune microenvironment through enhanced arginine metabolism. Arginase II is expressed and released from AML blasts and is present at high concentrations in the plasma of patients with AML, resulting in suppression of T-cell proliferation. We extended these results by demonstrating an arginase-dependent ability of AML blasts to polarize surrounding monocytes into a suppressive M2-like phenotype in vitro and in engrafted nonobese diabetic-severe combined immunodeficiency mice. In addition, AML blasts can suppress the proliferation and differentiation of murine granulocyte-monocyte progenitors and human CD34(+) progenitors. Finally, the study showed that the immunosuppressive activity of AML blasts can be modulated through small-molecule inhibitors of arginase and inducible nitric oxide synthase, suggesting a novel therapeutic target in AML. The results strongly support the hypothesis that AML creates an immunosuppressive microenvironment that contributes to the pancytopenia observed at diagnosis.
Asunto(s)
Arginasa/fisiología , Tolerancia Inmunológica , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Microambiente Tumoral/inmunología , Animales , Arginasa/metabolismo , Proliferación Celular , Células Cultivadas , Humanos , Tolerancia Inmunológica/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Linfocitos T/inmunología , Linfocitos T/patología , Linfocitos T/fisiología , Trasplante Heterólogo , Escape del Tumor/fisiología , Microambiente Tumoral/fisiologíaAsunto(s)
Síndrome de Bernard-Soulier , Mutación Missense , Complejo GPIb-IX de Glicoproteína Plaquetaria/genética , Púrpura Trombocitopénica Idiopática , Corticoesteroides/administración & dosificación , Sustitución de Aminoácidos , Benzoatos/administración & dosificación , Síndrome de Bernard-Soulier/diagnóstico , Síndrome de Bernard-Soulier/genética , Síndrome de Bernard-Soulier/patología , Síndrome de Bernard-Soulier/terapia , Niño , Diagnóstico Diferencial , Humanos , Hidrazinas/administración & dosificación , Inmunoglobulinas Intravenosas/administración & dosificación , Masculino , Transfusión de Plaquetas , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/patología , Púrpura Trombocitopénica Idiopática/terapia , Pirazoles/administración & dosificación , Receptores Fc/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Trombopoyetina/administración & dosificaciónAsunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Hidroxiurea/uso terapéutico , Adolescente , Adulto , Anemia de Células Falciformes/diagnóstico , Anemia de Células Falciformes/patología , Niño , Preescolar , Femenino , Hematología , Humanos , Hidroxiurea/efectos adversos , Lactante , Masculino , Sociedades Médicas , Reino UnidoRESUMEN
OBJECTIVE: To describe a series of paediatric orbital lymphoma patients in a single tertiary referral centre. METHODS: A retrospective case-note search in the Oxford Eye Hospital of all patients under the age of 18 years with orbital lymphoma between 2010 and 2020. Demographic and clinical data were obtained, and a literature review was conducted. RESULTS: Five patients were identified with orbital lymphoma, mean age 48.2 ± 36 months (1-109 months), three were males. Clinical presentation included: ptosis, proptosis, lethargy, visual loss, and strabismus. Two patients had bilateral orbital disease and one patient was diagnosed within the first month of life. The tissue diagnosis revealed four cases of Burkitt's lymphoma and one case of T- lymphoblastic lymphoma. Central nervous system (CNS) sampling was also positive in the four cases of Burkitt's lymphoma. All patients were treated systemically for the lymphoma with chemotherapy. Complete remission was achieved in all cases post chemotherapy. Follow-up of 36.4 ± 18.9 months (10-61 months). CONCLUSION: This is the largest published case series of paediatric orbital lymphoma. We described a patient diagnosed within the first month of life and we believe this to have developed intra-uterine. In this series, patients were younger, had more bilateral disease and had better outcome than previously described. This rare condition should be considered in any child with an orbital mass, at any age. When managed appropriately, good outcomes can be achieved.
Asunto(s)
Linfoma de Burkitt , Linfoma , Neoplasias Orbitales , Masculino , Niño , Humanos , Lactante , Preescolar , Adolescente , Femenino , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/patología , Estudios Retrospectivos , Linfoma/diagnóstico , Linfoma/patología , Neoplasias Orbitales/diagnóstico , Neoplasias Orbitales/patologíaAsunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Trombosis de los Senos Intracraneales/epidemiología , Trombosis de los Senos Intracraneales/etiología , Adolescente , Niño , Preescolar , Humanos , Lactante , Evaluación del Resultado de la Atención al Paciente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Estudios Retrospectivos , Factores de Riesgo , Trombosis de los Senos Intracraneales/diagnóstico , Trombosis de los Senos Intracraneales/terapia , Reino Unido/epidemiología , Adulto JovenRESUMEN
We retrospectively analysed the outcome of consecutive children with idiopathic severe aplastic anaemia in the United Kingdom who received immunosuppressive therapy (IST) or matched unrelated donor (MUD) haematopoietic stem cell transplantation (HSCT). The 6-month cumulative response rate following rabbit antithymocyte globulin (ATG)/ciclosporin (IST) was 32·5% (95% CI 19·3-46·6) (n = 43). The 5-year estimated failure-free survival (FFS) following IST was 13·3% (95% confidence interval [CI] 4·0-27·8). In contrast, in 44 successive children who received a 10-antigen (HLA-A, -B, -C, -DRB1, -DQB1) MUD HSCT there was an excellent estimated 5-year FFS of 95·01% (95% CI 81·38-98·74). Forty of these children had failed IST previously. HSCT conditioning was a fludarabine, cyclophosphamide and alemtuzumab (FCC) regimen and did not include radiotherapy. There were no cases of graft failure. Median donor chimerism was 100% (range 88-100%). A conditioning regimen, such as FCC that avoids total body irradiation is ideally suited in children. Our data suggest that MUD HSCT following IST failure offers an excellent outcome and furthermore, if a suitable MUD can be found quickly, MUD HSCT may be a reasonable alternative to IST.
Asunto(s)
Anemia Aplásica/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Donante no Emparentado , Adolescente , Suero Antilinfocítico/uso terapéutico , Niño , Preescolar , Ciclosporina/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped/etiología , Humanos , Inmunosupresores/uso terapéutico , Lactante , Estimación de Kaplan-Meier , Masculino , Infecciones Oportunistas/etiología , Recurrencia , Estudios Retrospectivos , Quimera por Trasplante , Acondicionamiento Pretrasplante/métodos , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
BACKGROUND: Anthracycline cardiomyopathy is of concern in children treated for acute myeloid leukaemia (AML), but there are few data on the incidence and natural history of cardiotoxicity after AML treatment in the United Kingdom, where regimens have included high anthracycline exposure. PROCEDURE: Prevalence and predictors of cardiotoxicity were retrospectively reviewed in 124 children treated on the MRC AML 10 and AML 12 trials in a single, large centre from November 1987 to September 2004. Subclinical cardiotoxicity was defined as a shortening fraction of less than 28% and clinical cardiomyopathy as evidence of heart failure, and both were classified as late cardiotoxicity 1 year after completing first line therapy. RESULTS: Cumulative survival was 61% at 10 years. The prevalence of early and late cardiotoxicity was 13.7% (95%-CI: 8.2-22.0%) and 17.4% (95%-CI: 10.9-26.8%), respectively. Early cardiotoxicity was a strong predictor (OR = 9.18; 95%-CI: 2.10-40.11; P < 0.005) and children who received salvage therapy following relapse showed a trend towards increased late cardiotoxicity (OR = 3.53; 95%-CI: 0.86-14.48; P < 0.08). Subclinical cardiotoxicity resolved spontaneously in all but one case, but clinical cardiomyopathy always required continuing therapy. Two children died of cardiomyopathy and six remained on medical therapy. CONCLUSIONS: Anthracycline cardiotoxicity remains a major concern for survivors of childhood AML and correlates with early cardiotoxicity and treatment intensity. Long-term follow-up is required to fully determine the outcome for children with subclinical cardiotoxicity.
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Antraciclinas/efectos adversos , Antineoplásicos/efectos adversos , Cardiomiopatías/inducido químicamente , Corazón/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Cardiomiopatías/diagnóstico , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Lactante , Leucemia Mieloide Aguda/mortalidad , Masculino , Tasa de SupervivenciaRESUMEN
We report the incidence and outcome of venous thrombosis (VT) in the UK acute lymphoblastic leukaemia (ALL) 2003 trial. VT occurred in 59/1824 (3.2%) patients recruited over 5 years with 90% occurring during a period of Asparagine depletion. Pegylated Escherichia Coli Asparaginase (Peg-ASP) 1000 units/m(2) was used throughout. Thirty-four children received further Peg-ASP, most with concurrent heparin prophylaxis. There were no episodes of bleeding or recurrent thrombosis. Optimal Asparagine depletion is central to success of modern regimes for treatment of ALL. This report confirms a significant risk of thrombosis with such therapy, but demonstrates that re-exposure to Asparaginase is feasible and safe.
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Antineoplásicos/efectos adversos , Asparaginasa/efectos adversos , Trombosis de la Vena/inducido químicamente , Adolescente , Anticoagulantes/uso terapéutico , Antineoplásicos/uso terapéutico , Asparaginasa/uso terapéutico , Niño , Preescolar , Estudios de Factibilidad , Femenino , Heparina de Bajo-Peso-Molecular/uso terapéutico , Humanos , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Estudios Prospectivos , Trombosis de la Vena/prevención & controlRESUMEN
BACKGROUND: Hepatic veno-occlusive disease (VOD) is a common (10-50%) and serious complication of haematological stem cell transplantation (HSCT), with up to 90% mortality rates. We carried out a study to assess whether the use of prophylactic defibrotide in paediatric patients undergoing HSCT results in a lower frequency or severity of hepatic VOD. PROCEDURE: Forty-seven successive patients who underwent transplantation between April 2004 and December 2005 were given defibrotide prophylaxis and were compared with 56 historical controls transplanted between November 2001 and April 2004. No serious side effects were reported. High risk patients in the control group received ursodeoxycholic acid and tinzaparin as VOD prophylaxis. The groups were matched for sex, age, type of transplant and risk. RESULTS: In the defibrotide group, four patients developed clinical VOD (Seattle criteria) although two had liver biopsies which showed graft versus host disease (GvHD). Defibrotide dose was increased and symptoms resolved within 14 days. Of the control group four patients had VOD. Two of these patients had reversed hepatic vein flow and died 30 days post-transplant, partly due to VOD. VOD was associated with busulfan conditioning (P = 0.001) and not with age, sex, type of transplant, GvHD, abnormal liver function prior to transplant or type of antifungal prophylaxis. CONCLUSIONS: VOD incidence and severity was reduced in the defibrotide group which suggests that defibrotide might be effective in preventing and treating VOD. Sufficiently powered randomised trials are now required to definitively test the role of defibrotide in this setting.
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Fibrinolíticos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Veno-Oclusiva Hepática/prevención & control , Polidesoxirribonucleótidos/uso terapéutico , Adolescente , Busulfano/uso terapéutico , Niño , Preescolar , Femenino , Enfermedad Injerto contra Huésped , Enfermedad Veno-Oclusiva Hepática/etiología , Humanos , Lactante , Masculino , Agonistas Mieloablativos/uso terapéutico , Trasplante Autólogo/efectos adversos , Trasplante Homólogo/efectos adversosRESUMEN
Background Sickle cell disease (SCD) is one of the most common causes of stroke in children worldwide. Based on the results of the Stroke Prevention Trial in Sickle Cell Anemia (STOP), annual transcranial Doppler ultrasound (TCD) screening for affected children is standard practice. However, the need for TCD surveillance programs could override the accuracy of the screening, affecting the correct stratification of stroke risk and subsequent clinical management of the target population. Aims To shed light on this issue, a systematic review of the literature on TCD screening for children and adolescents with SCD was carried out (CRD42016050549), according to a list of clinically relevant questions, with a particular focus on screening practices in European countries. Quality of the evidence was rated using the grading of recommendations assessment, development and evaluation. Summary of review Thirty-three studies published in English or French were included (5 randomized controlled trials, 8 experimental non-randomized, and 20 observational studies). The quality of the retrieved evidence ranged between low and high, but was rated as moderate or high most of the times. TCD is effective as a screening tool for the primary prevention of stroke in SCD children. There is no high-quality evidence on the effectiveness of alternative screening methods, such as imaging-TCD with or without angle correction or magnetic resonance angiography. No evidence was found on effectiveness of the screening on children on hydroxyurea and with genotypes other than HbSS and HbS/ß0. No European data were found on screening rates or adherence of screening practices to the STOP protocol. Conclusions High-quality studies on alternative screening methods that are currently used in real-world practice, and on screening applicability to specific subgroups of patients are urgently needed. Considering the low awareness of the disease in European countries and the lack of data on screening practices and adherence, clinicians need up-to-date guidelines for more uniform and evidence-based surveillance of children with SCD.