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1.
Artigo em Inglês | MEDLINE | ID: mdl-32029909

RESUMO

Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.

2.
Transplant Proc ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32035679

RESUMO

BACKGROUND: X-linked EDA-ID1 (ectodermal dysplasia, anhidrotic, with immunodeficiency 1, Online Mendelian Inheritance in Man [OMIM] 300291), or NEMO (nuclear factor kappa B essential modulator) deficiency syndrome, is caused by mutations in the IKBKG/NEMO gene. We report the case of a boy with EDA-ID1 who underwent allogeneic stem cell transplantation. METHODS: In early infancy, the patient developed an atypical, severe, initial manifestation resembling Omenn syndrome with infections, and he underwent allogeneic stem cell transplantation from an unrelated 9 of 10 HLA matched donor with a mismatch in the DQB1 allele after conditioning with treosulfan, fludarabine, thiotepa, and antithymocyte globulin (Grafalon). The post-transplant period was complicated by cytomegalovirus replication and mild, grade 2 graft vs host disease. Because of NEMO deficiency syndrome-associated enteropathy and continuous weight loss, parenteral nutrition was started and the patient was fed an elemental formula and a gluten-free diet. Over a period of 3 years, the patient had 7 incidents of blood stream infections caused by Staphylococci or gut-derived Gram-negative flora, with 1 incident of septic shock caused by Escherichia coli. The blood stream infection stopped after gastrointestinal tract decontamination was done once per month for 7-day courses alternately with rifaximin, vancomycin, and gentamicin sulfate. CONCLUSIONS: Patients with NEMO deficiency syndrome require very complex, multidisciplinary care, and immunodeficiency correction can only be observed as one of the critical points in patient care. Developmental problems, enteropathy with the need for intravenous hyperalimentation, and specific interventions for other clinical manifestations of multifaceted syndrome are needed for proper care.

3.
Lancet Haematol ; 7(1): e61-e72, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31818728

RESUMO

Sinusoidal obstructive syndrome, also known as hepatic veno-occlusive disease, is a potentially life-threatening complication that occurs in children undergoing haemopoietic stem-cell transplantation (HSCT). Differences in the incidence of genetic predisposition and clinical presentation of sinusoidal obstructive syndrome between children and adults have rendered the historical Baltimore and Seattle diagnostic criteria insufficient for children. In 2017, the European Society for Blood and Marrow Transplantation (EBMT) proposed the first paediatric diagnostic and severity grading guidelines for sinusoidal obstructive syndrome, intended for implementation across European centres. However, universally accepted paediatric criteria are needed to ensure prompt diagnosis, definitive treatment, and improved outcomes for children, adolescents, and young adults with sinusoidal obstructive syndrome, and to facilitate international clinical research collaboration. We convened an international panel of multidisciplinary experts including physicians with expertise in HSCT, paediatric intensive care, nephrology, hepatology, radiology, pathology, and transfusion medicine; HSCT advanced-practice providers and medical trainees; pharmacists; and translational and basic science researchers from the Pediatric Acute Lung Injury and Sepsis Investigators Network, the EBMT, the Pediatric Blood and Marrow Transplant Consortia, and several other institutions with extensive experience in sinusoidal obstructive syndrome. Panellists convened at The University of Texas, MD Anderson Cancer Center (Houston, TX, USA) in February, 2019, to evaluate the available evidence. In this expert position statement paper, we provide consensus recommendations for the international implementation of guidelines for the diagnosis, severity grading, and treatment of sinusoidal obstructive syndrome among children, adolescents, and young adults. We endorse universal adoption of paediatric diagnostic guidelines for sinusoidal obstruction syndrome as proposed by the EBMT, and provide implementation guidance for standardisation across centres; we have further proposed adjunctive use of age-appropriate organ-specific toxicity criteria for severity grading and provided prophylaxis and treatment considerations among children and adolescent and young adult patients. Key recommendations include: (1) liver biopsy, portal venous wedge pressure, and reversal of portal venous flow on Doppler ultrasonography should not be used for the routine diagnosis of sinusoidal obstructive syndrome in children, adolescents, and young adults; (2) platelet refractoriness can be defined as a corrected count increment of less than 5000-7500 following at least two sequential ABO-compatible fresh platelet transfusions; (3) hepatomegaly is best defined as an absolute increase of at least 1 cm in liver length at the midclavicular line; and if a baseline measurement is not available, hepatomegaly can be defined as greater than 2 SDs above normal for age; and (4) the presence and volume of ascites can be categorised as mild (minimal fluid by liver, spleen, or pelvis), moderate (<1 cm fluid), or severe (fluid in all three regions with >1 cm fluid in at least two regions).


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva , Adolescente , Bilirrubina/análise , Biomarcadores/análise , Criança , Colagogos e Coleréticos/uso terapêutico , Feminino , Fibrinolíticos/uso terapêutico , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/terapia , Humanos , Masculino , Polidesoxirribonucleotídeos/uso terapêutico , Fatores de Risco , Índice de Gravidade de Doença , Ultrassonografia Doppler , Ácido Ursodesoxicólico , Adulto Jovem
4.
Indian J Hematol Blood Transfus ; 35(4): 699-706, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31741622

RESUMO

The aim of this study was to determine the impact of ABCB1 polymorphism, BMI, age and drug co-administration on safety and efficiency of posaconazole (PCZ) oral suspension treatment in children with hematological diseases. Seventy children were included in the study. ABCB1 polymorphism in fifty-eight children was determined using a PCR-RFLP method. A protocol with data on the health condition, treatment and adverse events (AE), as well as a survey on treatment tolerance for the legal guardians was evaluated. Liver function tests were observed for the first 20 days, and AE during the complete medication period. For statistical analysis a χ2 test with Yates's correction, a Pearson's or Spearman's correlation test was performed (p < 0.05). Genetic testing showed 24% CC, 46% CT and 30% of TT variants. PCZ prophylaxis failed in twenty cases, where change in prophylactic treatment was needed. Fifty-two children suffered from at least one mild to moderate adverse event. Sixty-five legal guardians completed the survey, most of them reported the treatment to be well tolerated. ABCB1 polymorphism had no impact on AE occurrence and posaconazole prophylaxis efficiency. Age influenced the number of gastrointestinal (p = 0.02), visual (p = 0.05), neurological (p = 0.01), dermatological (p = 0.002) and flu-like (p = 0.02) complications. AST (p = 0.03) and LDH (p = 0.008) activity presented age dependency. The concomitant use of proton pump inhibitors (PPI) had impact on liver health parameters elevation (p = 0.009) and circulatory system complications (p = 0.008). High incidence of mild to moderate AE, and other factors influencing PCZ pharmacokinetics (PPI co-administration, obesity), suggest a need for careful pediatric onco-hematology patient evaluation.

5.
Pediatr Transplant ; 23(8): e13592, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31587440

RESUMO

BACKGROUND: The objective of the study was to analyze the profile of infections in children with BMF following alloHCT. METHODS: Data of 169 consecutive children with inherited and acquired BMF treated with alloHCT between 2012 and 2017 in Polish pediatric transplant departments were analyzed in registry-based retrospective study, with respect to the type of infection, and clinical outcome. RESULTS: At least 1 infection was diagnosed in 107/169 patients (60.4%). In total, 182 infections were diagnosed. The most common were VI (96; 52.7%), followed by BI (71; 39.0%), and FI (15; 8.2%), P < .001. The most common etiological factors of VI were as follows: CMV (38.5%), EBV (22.9%), and BK virus (24%); while of BI were as follows: Staphylococcus spp. (17; 23.9%), Enterococcus faecium (10; 14.1%), and Klebsiella pneumoniae (9; 12.7%). No difference was found between the occurrence of infections with respect to donor type, graft source, and conditioning type. GvHD had no impact on the incidence of VI, BI, and FI. Fifteen FI were diagnosed in 12 patients, of which 14 FI were diagnosed in children transplanted for FA. Of total 107 children, 9 died (8.4%), of which 4 (3.7%) due to infections: bacterial sepsis (2) and invasive FI (2). CONCLUSION: Infections in children with BMF following alloHCT remain an important cause of morbidity. Children with FA had high incidence of FI. In our analysis, aGvHD had no impact on the occurrence on infections, although the study was not strong enough to prove such a difference.

6.
Transplant Proc ; 51(9): 3150-3154, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31611124

RESUMO

BACKGROUND: X-linked immunodysregulation syndrome with polyendocrinopathy and enteropathy (IPEX) is caused by FOXP3 gene mutations that block the generation of regulatory T lymphocytes. We report an 18-month-old boy with classic IPEX who underwent 2 hematopoietic stem cell transplantations (HSCTs). METHODS: The first HSCT from an unrelated 8/10 HLA-matched umbilical cord blood donor (UCB) was performed after a conditioning regimen consisting of treosulfan, fludarabine, thiotepa, and thymoglobulin. Due to complete rejection of the UCB transplant, a second transplantation from a 6/10 HLA-matched mother was performed after alpha-beta T-cell depletion. The second conditioning regimen consisted of busulfan, fludarabine, a single dose of cyclophosphamide 1 g/m2, and Grafalon (Neovii Pharmaceuticals, Rapperswil, Switzerland). The T-cell depletion product contained 15.06 x 106 CD34+ cells per kilogram body weight (BW) and 4.19 x 105 alpha-beta T lymphocytes per kilogram BW. Due to acute graft rejection, the boy was treated with thymoglobulin, and full donor chimerism in both T lymphocytes and mononuclear cells was achieved. The immunosuppressive therapy was stopped 1 year after transplantation. To date, the patient remains free from graft-vs-host disease (GVHD) and immunosuppression. CONCLUSIONS: HSCT after busulfan-based reduced-toxicity conditioning in patients with IPEX syndrome is feasible and well tolerated and can result in full donor engraftment. Monitoring of chimerism and aggressive therapy in cases of graft rejection are warranted due to the high reactivity of residual autologous T lymphocytes. T-cell depletion reduces the risk of GVHD and the need for steroid therapy, which is especially challenging in patients with diabetes.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Síndromes de Imunodeficiência/cirurgia , Depleção Linfocítica/métodos , Condicionamento Pré-Transplante/métodos , Soro Antilinfocitário/uso terapêutico , Bussulfano/administração & dosagem , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Fatores Imunológicos/uso terapêutico , Lactente , Masculino , Suíça
7.
Transplant Proc ; 51(9): 3155-3158, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31611125

RESUMO

We present a case report of a boy diagnosed with both chronic granulomatous disease (CGD) and familial celiac disease (CD) who underwent cord blood transplantation from a partially matched sibling donor. The presentation of CD resembled Crohn-like enteropathy, which is a canonical manifestation of CGD. Nearly 1 year post-hematopoietic stem cell transplantation (HSCT), a gluten-containing diet was reintroduced, and no reappearance of clinical, serologic, or histologic markers of CD was observed. The relatively high incidence of rare genetic diseases in pediatric patients suggests the need for additional caution in the interpretation of symptoms mimicking already known hallmarks of more common conditions. In addition, the presented data confirm the previous rare observations that allogeneic HSCT leads to durable induction of gluten tolerance in patients with CD, which can warrant its use in patients with refractory subtypes of CD.


Assuntos
Doença Celíaca/complicações , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/cirurgia , Doença Celíaca/genética , Criança , Pré-Escolar , Doença Granulomatosa Crônica/genética , Humanos , Lactente , Masculino , Irmãos , Transplante Homólogo
8.
Adv Clin Exp Med ; 28(9): 1223-1228, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31430069

RESUMO

BACKGROUND: Unmanipulated haploidentical stem cell transplantation (haploSCT) with post-transplant cyclophosphamide is an option for patients with advanced hematologic malignancies. It offers a platform both for non-major histocompatibility complex-restricted alloimmunity due to killer-like immunoglobulin receptor (KIR)-mediated mechanisms of natural killer lymphocyte regulation and for classical T-cell mediated antileukemic effects. OBJECTIVES: The devastating long-term sequelae after total body irradiation (TBI) in children are encouraging omission of irradiation techniques in pediatric stem cell transplantations (SCT). MATERIAL AND METHODS: Five children, 4 with acute leukemia and 1 with hemophagocytic lymphohistiocytosis, aged from 1 to 10 years, underwent haploSCT with post-transplantation cyclophosphamide. In all children, the conditioning regimen consisted of chemotherapy without TBI. The graft material was bone marrow (BM) in 4 cases and peripheral blood stem cells in 1 case. Three out of 5 leukemic patients showed better KIR haplotype associated with augmented alloreactivity. RESULTS: Engraftment with complete donor chimerism was achieved in 4 patients, and 1 recipient died before leukocyte recovery. Three patients developed skin acute graft-versus-host-disease (aGvHD), 1 gut aGvHD and 1 liver aGvHD. In 2 recipients, chronic graft-versus-host-disease (cGvHD) was observed (1 limited and 1 extensive). The 4 engrafted patients were alive and in complete remission 3, 9, 32, and 36 months after transplantation. A T-cell count of 200 cells/uL was reached 90 days after haploSCT in all patients. CONCLUSIONS: HaploSCT with TBI-free protocols can be a viable option for heavily pretreated patients with advanced malignancies.


Assuntos
Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Criança , Pré-Escolar , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Lactente , Condicionamento Pré-Transplante , Irradiação Corporal Total
9.
Adv Clin Exp Med ; 28(9): 1185-1192, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31430073

RESUMO

BACKGROUND: Acute graft-versus-host disease (aGvHD) is a potentially fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Identifying its risk factors would enable the proper prophylaxis and management, which may significantly improve the general outcome of children treated with HSCT. OBJECTIVES: The aim of this single-center, retrospective cohort study was to assess the potential risk factors for grades II-IV of aGvHD in children after the 1st allo-HSCT from an unrelated donor (UD), performed as a result of an underlying malignant disease. MATERIAL AND METHODS: From among patients who received HSCT in our center in the years 2004-2015, 237 were included in the study cohort. All the patients received standard aGvHD prophylaxis consisting of cyclosporine (CsA) and a short course of methotrexate (MTX). Various clinical and epidemiological features, the transplant proceedings, graft composition, conditioning regimens, as well as the duration and coherence of aGvHD prophylaxis were analyzed as potential risk factors for aGvHD. RESULTS: The incidence of II-IV aGvHD in the study cohort was 58.6%. The median time of the diagnosis of aGvHD was 18 days post-HSCT. In the multivariate analysis, risk factors significantly associated with grades II-IV of aGvHD were: myeloablative conditioning regimen containing total body irradiation (TBI-MAC) (RR (relative risk): 1.69; p = 0.03), premature termination of CsA administration due to its toxicity (RR: 1.99; p = 0.0003) and HSCT performed before the year 2009 (RR: 1.97; p = 0.0001). Donor and recipient age, donor-recipient sex mismatch, stem cell source, risk of disease, and amount of infused CD34+ cells seem to be insignificant as risk factors for aGvHD. The overall survival (OS) of patients with aGvHD was noticeably worse that in those who were aGvHD-free: 60.8% vs 74.1% (p = 0.08). CONCLUSIONS: The conditioning regimen and the proper aGvHD prophylaxis, including continuous CsA administration, have a major impact on aGvHD occurrence. According to our results, the termination of CsA therapy should be carefully considered, and avoided if possible.


Assuntos
Ciclosporina/administração & dosagem , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Criança , Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Retrospectivos , Doadores não Relacionados
10.
Ann Hematol ; 98(9): 2197-2211, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31321454

RESUMO

Incidence and outcome of microbiologically documented bacterial/viral infections and invasive fungal disease (IFD) in children and adults after hematopoietic cell transplantation (HCT) were compared in 650 children and 3200 adults in multicenter cross-sectional nationwide study. Infections were diagnosed in 60.8% children and 35.0% adults, including respectively 69.1% and 63.5% allo-HCT, and 33.1% and 20.8% auto-HCT patients. The incidence of bacterial infections was higher in children (36.0% vs 27.6%; p < 0.0001). Infections with Gram-negative bacteria were more frequent than Gram-positives in adults (64.6% vs 44.8%; p < 0.0001). Outcome of bacterial infections was better in children (95.5% vs 91.4%; p = 0.0011). The IFD incidence (25.3% vs 6.3%; p < 0.0001) and outcome (88.0% vs 74.9%; p < 0.0001) were higher in children. The incidence of viral infections was higher in children after allo-HCT (56.3% vs 29.3%; p < 0.0001), and auto-HCT (6.6% vs 0.8%; p < 0.0001). Outcome of viral infections was better in children (98.6% vs 92.3%; p = 0.0096). Infection-related mortality was 7.8% in children and 18.4% in adults (p < 0.0001). No child after auto-HCT died of infection. Adult age, mismatched transplants, acute leukemia, chronic GVHD, CMV reactivation, infection with Gram-negatives, and duration of infection > 21 days were risk factors for death from infection. In conclusion, pediatric patients have 2.9-fold higher incidence and 2.5-fold better outcome of infections than adults after HCT.


Assuntos
Infecções Bacterianas/epidemiologia , Infecções por Citomegalovirus/epidemiologia , Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas , Infecções Fúngicas Invasivas/epidemiologia , Doença Aguda , Adolescente , Adulto , Fatores Etários , Idoso , Infecções Bacterianas/etiologia , Criança , Pré-Escolar , Doença Crônica , Estudos Transversais , Infecções por Citomegalovirus/etiologia , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Incidência , Lactente , Recém-Nascido , Infecções Fúngicas Invasivas/etiologia , Leucemia , Masculino , Pessoa de Meia-Idade , Fatores de Risco
11.
Biol Blood Marrow Transplant ; 25(11): 2197-2210, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31319153

RESUMO

Eligibility criteria for hematopoietic stem cell transplantation (HSCT) in acute lymphoblastic leukemia (ALL) vary according to disease characteristics, response to treatment, and type of available donor. As the risk profile of the patient worsens, a wider degree of HLA mismatching is considered acceptable. A total of 138 children and adolescents who underwent HSCT from HLA-identical sibling donors (MSDs) and 210 who underwent HSCT from matched donors (MDs) (median age, 9 years; 68% male) in 10 countries were enrolled in the International-BFM ALL SCT 2007 prospective study to assess the impact of donor type in HSCT for pediatric ALL. The 4-year event-free survival (65 ± 5% vs 61 ± 4%; P = .287), overall survival (72 ± 4% versus 68 ± 4%; P = .235), cumulative incidence of relapse (24 ± 4% versus 25 ± 3%; P = .658) and nonrelapse mortality (10 ± 3% versus 14 ± 3%; P = .212) were not significantly different between MSD and MD graft recipients. The risk of extensive chronic (cGVHD) was lower in MD graft recipients than in MSD graft recipients (hazard ratio [HR], .38; P = .002), and the risks of severe acute GVHD (aGVHD) and cGVHD were higher in peripheral blood stem cell graft recipients than in bone marrow graft recipients (HR, 2.06; P = .026). Compared with the absence of aGVHD, grade I-II aGVHD was associated with a lower risk of graft failure (HR, .63; P = .042) and grade III-IV aGVHD was associated with a higher risk of graft failure (HR, 1.85; P = .020) and nonleukemic death (HR, 8.76; P < .0001), despite a lower risk of relapse (HR, .32; P = .021). Compared with the absence of cGVHD, extensive cGVHD was associated with a higher risk of nonleukemic death (HR, 8.12; P < .0001). Because the outcomes of transplantation from a matched donor were not inferior to those of transplantation from an HLA-identical sibling, eligibility criteria for transplantation might be reviewed in pediatric ALL and possibly in other malignancies as well. Bone marrow should be the preferred stem cell source, and the addition of MTX should be considered in MSD graft recipients.

12.
Eur J Cancer ; 115: 17-23, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31082688

RESUMO

BACKGROUND: Chronic myeloid leukaemia (CML) is very rare in children. The aim of the study is to report the experience within the I-CML-Ped study in children and adolescents presenting at diagnosis with advanced phase disease and to describe their characteristics and outcomes. METHODS: Of 479 children and adolescents enrolled in the international registry for childhood chronic myeloid leukaemia (I-CML-Ped Study; www.clinicaltrials.govNCT01281735), 36 children (7.5%) presented at initial diagnosis with CML in advanced phase according to the European LeukemiaNet criteria. RESULTS: Nineteen (4%) patients were diagnosed in accelerated phase (CML-AP), and among the 17 patients (3.5%) diagnosed in blastic phase (CML-BP), 70% presented with lymphoid immunophenotype. Initial treatment of CML-AP/CML-BP consisted of tyrosine kinase inhibitors (TKIs) with or without chemotherapy, leading to complete haematologic response in 33 of 36 (92%) patients. Seventeen patients proceeded to haematopoietic stem cell transplantation. At the last follow-up, 18 of 19 patients with de novo CML-AP are alive in at least major molecular response (MMR) (n = 16), in progression (n = 1) or in molecular relapse (n = 1) and 13 of 17 patients with de novo CML-BP are alive in at least MMR. Five-year overall survival rates are 94% (95% confidence interval [CI]: 66%-99%) and 74% (95% CI: 44%-89%) for patients diagnosed in CML-AP and CML-BP, respectively. CONCLUSION: Children with advanced phase at diagnosis of CML seem to have a better survival rate than that reported for advanced phases evolving under TKI treatment.

13.
Biol Blood Marrow Transplant ; 25(9): 1792-1797, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31085306

RESUMO

The prognosis of resistant or relapsing children with neuroblastoma remains very poor, and the search for new therapies is ongoing. In this analysis, we assessed the toxicity of a treosulfan, melphalan, and thiotepa (TMT) regimen in 17 children with recurrent or refractory neuroblastoma who underwent stem cell transplantation (SCT). For allogeneic SCT, fludarabine and antithymocyte globulin were added. The stem cell source was autologous in 8 patients, haploidentical in 8 patients, and a matched unrelated donor in 1 patient. The reported nonhematologic toxicities included grade 3 mucositis, grade 1 to 3 hypertransaminasemia, and in 3 patients, veno-occlusive disease. No neurologic, cardiac, or dermatologic toxicities were observed. The probability of overall survival (OS) in patients with primary resistance was superior to that in patients with relapsed disease (100% versus 22.6%; P = .046). Post-transplantation dinutuximab beta immunotherapy was associated with superior 5-year OS (66.7% versus 11.4%; P = .0007). The use of an allogeneic donor, previous autologous SCT with busulfan and melphalan, and pretreatment with high-dose metaiodobenzylguanidine therapy demonstrated no effect on outcomes. In 4 patients, TMT megatherapy alone was enough to achieve complete remission. The TMT conditioning regimen was well tolerated in heavily pretreated patients with neuroblastoma. The manageable toxicity and addition of new anticancer drugs with optional post-SCT immunotherapy or chemotherapy support further trials with the TMT regimen in patients with neuroblastoma.

14.
Neoplasia ; 21(3): 294-310, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30763910

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy originating from T-cell precursors. The genetic landscape of T-ALL has been largely characterized by next-generation sequencing. Yet, the transcriptome of miRNAs (miRNome) of T-ALL has been less extensively studied. Using small RNA sequencing, we characterized the miRNome of 34 pediatric T-ALL samples, including the expression of isomiRs and the identification of candidate novel miRNAs (not previously annotated in miRBase). For the first time, we show that immunophenotypic subtypes of T-ALL present different miRNA expression profiles. To extend miRNome characteristics in T-ALL (to 82 T-ALL cases), we combined our small RNA-seq results with data available in Gene Expression Omnibus. We report on miRNAs most abundantly expressed in pediatric T-ALL and miRNAs differentially expressed in T-ALL versus normal mature T-lymphocytes and thymocytes, representing candidate oncogenic and tumor suppressor miRNAs. Using eight target prediction algorithms and pathway enrichment analysis, we identified differentially expressed miRNAs and their predicted targets implicated in processes (defined in Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) of potential importance in pathogenesis of T-ALL, including interleukin-6-mediated signaling, mTOR signaling, and regulation of apoptosis. We finally focused on hsa-mir-106a-363 cluster and functionally validated direct interactions of hsa-miR-20b-5p and hsa-miR-363-3p with 3' untranslated regions of their predicted targets (PTEN, SOS1, LATS2), overrepresented in regulation of apoptosis. hsa-mir-106a-363 is a paralogue of prototypic oncogenic hsa-mir-17-92 cluster with yet unestablished role in the pathogenesis of T-ALL. Our study provides a firm basis and data resource for functional analyses on the role of miRNA-mRNA interactions in T-ALL.


Assuntos
Regulação Leucêmica da Expressão Gênica , MicroRNAs/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Interferência de RNA , RNA Mensageiro/genética , Transcriptoma , Apoptose/genética , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Genes Reporter , Imunofenotipagem , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico
15.
Adv Clin Exp Med ; 28(8): 1111-1118, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30740947

RESUMO

Acute kidney injury (AKI), one of the major complications in children undergoing hematopoietic stem cell transplantation (HSCT), is an independent predictor of the patient's survival and a prognostic factor of progression to chronic kidney disease (CKD). Despite the multifaceted role of AKI, its early diagnosis in the course of HSCT remains a challenge. These difficulties may result from the inefficiency of traditional methods used to assess kidney function, like serum creatinine or estimated glomerular filtration rate. Moreover, the list of potential AKI markers tested in HSCT conditions is limited and does not involve indexes evaluated in the pediatric population. This review summarizes current knowledge on the pathophysiology of AKI developing in the course of HSCT; presents well-known markers of AKI that are potentially applicable in children who have undergone HSCT; discusses the role of new markers in diagnosing AKI and predicting the renal outcome in children undergoing HSCT; and analyzes the prospects for the use of new tools for assessing kidney injury in everyday clinical practice.


Assuntos
Lesão Renal Aguda , Biomarcadores , Transplante de Células-Tronco Hematopoéticas , Insuficiência Renal Crônica , Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/etiologia , Biomarcadores/análise , Criança , Creatinina , Taxa de Filtração Glomerular , Humanos , Insuficiência Renal Crônica/diagnóstico
16.
J Allergy Clin Immunol ; 143(6): 2238-2253, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30660643

RESUMO

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.

17.
Biol Blood Marrow Transplant ; 24(11): 2245-2249, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30454873

RESUMO

Ataxia-telangiectasia (A-T) syndrome is an autosomal recessive chromosomal breakage syndrome caused by mutation of the ataxia-telangiectasia mutated gene manifested by progressive neurodegeneration, telangiectasias of sclera and skin, immune deficiency with sinopulmonary infections, and increased incidence of lymphoid malignancies and solid tumors. Three children with A-T underwent allogeneic stem cell transplantation (SCT) using protocols for Fanconi anemia. All 3 patients were engrafted with a mixed donor-recipient chimerism, but the full donor engraftment was observed in the T lymphocyte compartment. Immunologic recovery resulted in T cell production and lack of symptomatic infections. Regular intravenous immunoglobulin supplementation was needed until IgG production recovered, which depended on pretransplant serotherapy. During the observation period patients did not require hospital admission, and none of the transplanted patients developed sinopulmonary infections. Neurologic functions in reported patients were impaired and slowly deteriorated after transplantation, but no immediate toxicities were observed. The following hallmark features of A-T were present after SCT: neurologic symptoms, growth failure, telangiectasia formation, or increased serum alpha fetoprotein. SCT can help control immune deficiency constituting 1 of the features of A-T, and elimination of autologous hematopoiesis reduces the risk of lymphoid malignancies. Resolving crucial problems with qualification for SCT depends on balancing the risk and benefits of transplant therapy.


Assuntos
Ataxia Telangiectasia/terapia , Anemia de Fanconi/complicações , Transplante de Células-Tronco Hematopoéticas/métodos , Linfócitos T/imunologia , Condicionamento Pré-Transplante/métodos , Ataxia Telangiectasia/patologia , Quimerismo , Feminino , Humanos , Masculino
18.
Pediatr Blood Cancer ; 65(12): e27431, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30160364

RESUMO

Since the patent for imatinib has expired, the role of generic imatinib (GI) in the management of Philadelphia chromosome-positive (Ph+) leukemia in pediatric patients has had ongoing discussion. Some studies in adults demonstrated that equivalent doses of GI and branded imatinib (BI) result in comparable plasma concentrations and clinical efficacy. However, other studies found that GI users are more likely to stop imatinib, with intolerance and decreased persistence as the main causes. Economic factors also heavily influence GI selection. This article aims to review the present knowledge to support further discussion on the role of GI in the management of pediatric Ph+ leukemia.


Assuntos
Antineoplásicos/uso terapêutico , Medicamentos Genéricos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Criança , Feminino , Humanos , Masculino , Inibidores de Proteínas Quinases/uso terapêutico
19.
Transfus Apher Sci ; 57(3): 316-322, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29880247

RESUMO

The purpose of the survey was to evaluate the development and current use of hematopoietic stem cell transplantation (HSCT) in Poland between 1989-2016. The data for analysis (indication, number of performed HSCT, HSCT type, donor type, and stem cell source, year) have been collected annually using a standardized form. In Poland, between 1989-2016, the number of pediatric transplant beds grew from one to 40 and number and rate of transplants increased annually from 1/year (0.8/10 million) to 186/year (248/10 million). During the analyzed time period 2506 HSCTs were performed, including 1718 (68.6%) allogeneic transplants (allo-HSCT) with142 in 2016 and 788 (31.4%) autologous transplants (auto-HSCT) with 44 in 2016. Among 1718 allo-HSCT, 74% were performed for malignancy (ALL 47.2%, AML 26.2%, MDS 10.8%, CML 8.1%, NHL/HD 6.1%, others 2.5%), and 26% for non-malignant disorders (SAA 41%, congenital immunodeficiencies 35.4%, hereditary bone marrow failure 16%, metabolic disorders 7%). Among 788 auto-HSCTs, 30.8% were done for hematological malignancy (NHL 41.2%, AML 23.9%, HD 17.7%, ALL 15.6%, other 1.5%), while the remaining 69.2% for solid tumors (neuroblastoma 59.8%, Ewing's sarcoma 20.4%, other 19.8%). In Poland, between 1989-2016, the infrastructure indispensable to perform HSCT in every child with indication for this therapeutic procedure was created, and HSCT became an important part of pediatric treatment, especially in pediatric oncology, hematology, and in primary immunodeficiencies.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Adolescente , Criança , Feminino , Humanos , Masculino , Polônia
20.
Hum Immunol ; 79(6): 403-412, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29605688

RESUMO

Serious risks in unrelated hematopoietic stem cell transplantation (HSCT) including graft versus host disease (GvHD) and mortality are associated with HLA disparity between donor and recipient. The increased risks might be dependent on disparity in not-routinely-tested multiple polymorphisms in genetically dense MHC region, being organized in combinations of two extended MHC haplotypes (Ehp). We assessed the clinical role of donor-recipient Ehp disparity levels in N = 889 patients by the population-based detection of HLA allele phase mismatch. We found increased GvHD incidences and mortality rates with increasing Ehp mismatch level even with the same HLA mismatch level. In multivariate analysis HLA mismatch levels were excluded from models and Ehp disparity level remained independent prognostic factor for high grade acute GvHD (p = 0.000037, HR = 10.68, 95%CI 5.50-32.5) and extended chronic GvHD (p < 0.000001, HR = 15.51, CI95% 5.36-44.8). In group with single HLA mismatch, patients with double Ehp disparity had worse 5-year overall survival (45% vs. 56%, p = 0.00065, HR = 4.05, CI95% 1.69-9.71) and non-relapse mortality (40% vs. 31%, p = 0.00037, HR = 5.63, CI95% 2.04-15.5) than patients with single Ehp disparity. We conclude that Ehp-linked factors contribute to the high morbidity and mortality in recipients given HLA-mismatched unrelated transplant and Ehp matching should be considered in clinical HSCT.


Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Haplótipos/genética , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Histocompatibilidade , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Antígenos HLA/imunologia , Neoplasias Hematológicas/mortalidade , Humanos , Lactente , Isoantígenos/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
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