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Haematologica ; 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33440924


Pediatric-onset Evans syndrome (pES) is defined by both immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) before the age of 18 years. There have been no comprehensive long-term studies of this rare disease, which can be associated to various immunopathological manifestations (IMs). We report outcomes of the 151 patients with pES and more than 5 years of follow-up from the nationwide French prospective OBS'CEREVANCE cohort. Median age at final follow-up was 18.5 (6.8-50.0) years and the median follow-up period was 11.3 (5.1-38.0) years. At 10 years, ITP and AIHA were in sustained complete remission in 54.5% and 78.4% of patients, respectively. The frequency and number of clinical and biological IMs increased with age: at 20 years old, 74% had at least one clinical cIM. A wide range of cIMs occurred, mainly lymphoproliferation, dermatological, gastrointestinal/hepatic and pneumological IMs. The number of cIMs was associated with a subsequent increase in the number of second-line treatments received (other than steroids and immunoglobulins; hazard ratio, 1.4; 95% confidence interval, 1.15-1.60; p = 0.0002, Cox proportional hazards method). Survival at 15 years after diagnosis was 84%. Death occurred at a median age of 18 (1.7-31.5) years, and the most frequent cause was infection. The number of second-line treatments and severe/recurrent infections were independently associated with mortality. In conclusion, longterm outcomes of pES showed remission of cytopenias but frequent IMs linked to high secondline treatment burden. Mortality was associated to drugs and/or underlying immunodeficiencies, and adolescents-young adults are a high-risk subgroup.

PLoS One ; 13(4): e0193862, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29608607


Unrelated umbilical cord blood transplantation (UCBT) is an alternative to provide transplants in children with acute leukemia or myelodysplastic syndrome who lack a related donor. Intravenous Busulfan (Bu) combined with therapeutic drug monitoring-guided dosing has been increasingly used, with more predictable bioavailability and better outcomes comparing to oral Bu. There is still an important variation in Bu pharmacokinetic between patients that is associated with an increased risk of toxicity and graft failure. The objective of the study was to analyze the impact of first-dose pharmacokinetic adapted myeloablative conditioning regimen of intravenous Bu on the different outcomes after transplantation. Data of 36 children who underwent allogeneic HSCT with Bu plus a second alkylating agent at Sainte Justine Hospital in Montreal, Canada, between December 2000 and April 2012 were analyzed. For children with high risk myeloid malignancies receiving an UCBT, first dose Bu pharmacokinetic seems to be a significant prognostic factor, influencing neutrophil (100% vs 67.9%) and platelet recovery (95.5% vs 70.5%), non-relapse mortality (0% vs 18.6%), EFS (64% vs 28.6%) and OS (81.3% vs 37.5%) for a first-dose steady-state concentration (Css) <600ng/mL vs >600ng/mL, respectively. These data reinforce the importance of Busulfan therapeutic drug monitoring-guided dosing in pediatric HSCT patients, particularly in the context of UCBT.

Bussulfano/uso terapêutico , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Leucemia Mieloide Aguda/cirurgia , Agonistas Mieloablativos/uso terapêutico , Síndromes Mielodisplásicas/cirurgia , Condicionamento Pré-Transplante/métodos , Adolescente , Bussulfano/farmacocinética , Criança , Pré-Escolar , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Lactente , Masculino , Agonistas Mieloablativos/farmacocinética , Prognóstico , Resultado do Tratamento , Adulto Jovem
Leuk Lymphoma ; 58(6): 1433-1445, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27736268


Iron is an essential nutrient, acting as a catalyst for metabolic reactions that are fundamental to cell survival and proliferation. Iron complexed to transferrin is delivered to the metabolism after endocytosis via the CD71 surface receptor. We found that transformed cells from a murine PTEN-deficient T-cell lymphoma model and from T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LL) cell lines overexpress CD71. As a consequence, the cells developed an addiction toward iron whose chelation by deferoxamine (DFO) dramatically affected their survival to induce apoptosis. Interestingly, DFO displayed synergistic activity with three ALL-specific drugs: dexamethasone, doxorubicin, and L-asparaginase. DFO appeared to act through a reactive oxygen species-dependent DNA damage response and potentiated the action of an inhibitor of the PARP pathway of DNA repair. Our results demonstrate that targeting iron metabolism could be an interesting adjuvant therapy for acute lymphoblastic leukemia.

Quelantes de Ferro/farmacologia , Ferro/metabolismo , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , PTEN Fosfo-Hidrolase/deficiência , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Apoptose/efeitos dos fármacos , Asparaginase/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Quimioterapia Adjuvante , Dano ao DNA , Desferroxamina/farmacologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Expressão Gênica , Humanos , Quelantes de Ferro/uso terapêutico , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/mortalidade , Camundongos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Espécies Reativas de Oxigênio/metabolismo , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo
Transfusion ; 55(3): 571-5, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25355613


BACKGROUND: Intravenous immunoglobulin (IVIG) is frequently given in autoimmune disorders. Side effects are usually mild but severe complications such as thrombosis may occur. After one patient with IVIG-associated thrombotic complication at Sainte-Justine Hospital, the incidence of serious adverse events (SAEs) reported to the Quebec Hemovigilance System (QHS) was reviewed. STUDY DESIGN AND METHODS: This study was a retrospective review of QHS database of IVIG-related thrombotic complications since 2003, including a case report of a pediatric patient. RESULTS: QHS is one of the rare national hemovigilance systems that have included IVIG reports for almost a decade. Over an extended period of 11 years (2003-2013), there have been eight cases of IVIG-related thrombosis, seven in adults and one in the pediatric population (respective rate of 0.06 case and 0.17 case per 100,000 g of IVIG given). The single pediatric case occurred in a 16-year-old female receiving IVIG for severe immune thrombocytopenia. CONCLUSION: Thrombosis after IVIG is a rare though SAE occurring mostly in adults. This underlines the importance of properly reporting IVIG SAEs to improve hemovigilance data and study such rare events.

Imunoglobulinas Intravenosas/efeitos adversos , Trombose do Seio Sagital/etiologia , Adolescente , Idoso , Doenças Autoimunes/terapia , Segurança do Sangue , Anticoncepcionais Orais Hormonais/efeitos adversos , Anticoncepcionais Orais Hormonais/uso terapêutico , Feminino , Cefaleia/etiologia , Humanos , Incidência , Meningite Asséptica/etiologia , Menorragia/tratamento farmacológico , Menorragia/etiologia , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Púrpura Trombocitopênica Idiopática/terapia , Quebeque/epidemiologia , Recidiva , Estudos Retrospectivos , Trombose do Seio Sagital/epidemiologia , Seio Sagital Superior , Trombofilia/epidemiologia , Trombofilia/etiologia , Transtornos da Visão/etiologia
J Pediatr Hematol Oncol ; 37(2): 109-16, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24936742


We evaluated the impact of central nervous system irradiation (CNSI) on long-term health status and quality of life (QoL) of childhood lymphoblastic leukemia survivors included in the French L.E.A. (Childhood and Adolescent Leukemia) multicentric cohort. QoL was self-reported in adults and assessed by parents in children and adolescents, using adapted questionnaires. From 2004 to 2009, 630 nongrafted patients were assessed after 11.8±6.3 years from diagnosis. Patients receiving CNSI (18.6%) or chemotherapy alone (81.4%) were compared. The risk of having long-term physical effects was increased with CNSI (odds ratio=3.3; 95% confidence interval, 1.8-5.9), especially regarding growth failure, second tumor, cataract, and overweight. QoL did not differ significantly according to the treatment received, despite a tendency toward lower scores with CNSI in children and adolescents (summary score 63.6±13.3 vs. 71.7±12.4, P=0.14). Compared with French norms, adult survivors had an impaired QoL, especially in mental domains (mental composite score 45.2±9.8 vs. 47.9±2.1, P<0.001). In pediatric survivors, QoL was not impaired and even tended to be higher than population norms (summary score 71.7±12.4 vs. 70.0±4.2, P=0.054), mainly in social and relational domains. In conclusion, QoL seems to be impaired by the trauma of a life-threatening illness in childhood, as well as by the treatment received.

Neoplasias Encefálicas/psicologia , Irradiação Craniana/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/psicologia , Qualidade de Vida , Sobreviventes/psicologia , Doença Aguda , Adolescente , Adulto , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Feminino , Seguimentos , Nível de Saúde , Humanos , Lactente , Recém-Nascido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Prognóstico , Estudos Prospectivos , Inquéritos e Questionários , Taxa de Sobrevida , Tempo , Adulto Jovem