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1.
Clin Pharmacol Ther ; 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31701524

RESUMO

Treosulfan is given off-label in pediatric allogeneic hematopoietic stem cell transplant. This study investigated treosulfan's pharmacokinetics (PKs), efficacy, and safety in a prospective trial. Pediatric patients (n = 87) receiving treosulfan-fludarabine conditioning were followed for at least 1 year posttransplant. PKs were described with a two-compartment model. During follow-up, 11 of 87 patients died and 12 of 87 patients had low engraftment (≤ 20% myeloid chimerism). For each increase in treosulfan area under the curve from zero to infinity (AUC(0-∞) ) of 1,000 mg hour/L the hazard ratio (95% confidence interval) for mortality increase was 1.46 (1.23-1.74), and the hazard ratio for low engraftment was 0.61 (0.36-1.04). A cumulative AUC(0-∞) of 4,800 mg hour/L maximized the probability of success (> 20% engraftment and no mortality) at 82%. Probability of success with AUC(0-∞) between 80% and 125% of this target were 78% and 79%. Measuring PK at the first dose and individualizing the third dose may be required in nonmalignant disease.

2.
Br J Haematol ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31566733

RESUMO

Viral respiratory infections (VRIs) contribute to the morbidity and transplant-related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and strategies to prevent and treat VRIs are warranted. We monitored VRIs before and after transplant in children undergoing allogeneic HSCT with nasopharyngeal aspirates (NPA) and assessed the impact on clinical outcome. Between 2007 and 2017, 585 children underwent 620 allogeneic HSCT procedures. Out of 75 patients with a positive NPA screen (12%), transplant was delayed in 25 cases (33%), while 53 children started conditioning with a VRI. Patients undergoing HSCT with a positive NPA screen had a significantly lower overall survival (54% vs. 79%) and increased TRM (26% vs. 7%) compared to patients with a negative NPA. Patients with a positive NPA who delayed transplant and cleared the virus before conditioning had improved overall survival (90%) and lower TRM (5%). Pre-HSCT positive NPA was the only significant risk factor for progression to a lower respiratory tract infection and was a major risk factor for TRM. Transplant delay, whenever feasible, in case of a positive NPA screen for VRIs can positively impact on survival of children undergoing HSCT.

3.
Nat Med ; 25(9): 1408-1414, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31477906

RESUMO

Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL)1-5, but toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, limits broader application. Moreover, 40-60% of patients relapse owing to poor CAR T cell persistence or emergence of CD19- clones. Some factors, including the choice of single-chain spacer6 and extracellular7 and costimulatory domains8, have a profound effect on CAR T cell function and persistence. However, little is known about the impact of CAR binding affinity. There is evidence of a ceiling above which increased immunoreceptor affinity may adversely affect T cell responses9-11. We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies1-4. CAT CAR T cells showed increased proliferation and cytotoxicity in vitro and had enhanced proliferative and in vivo antitumor activity compared with FMC63 CAR T cells. In a clinical study (CARPALL, NCT02443831 ), 12/14 patients with relapsed/refractory pediatric B cell acute lymphoblastic leukemia treated with CAT CAR T cells achieved molecular remission. Persistence was demonstrated in 11 of 14 patients at last follow-up, with enhanced CAR T cell expansion compared with published data. Toxicity was low, with no severe CRS. One-year overall and event-free survival were 63% and 46%, respectively.


Assuntos
Antígenos CD19/administração & dosagem , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/imunologia , Adolescente , Antígenos CD19/genética , Antígenos CD19/imunologia , Criança , Pré-Escolar , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/uso terapêutico , Recidiva , Linfócitos T/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
5.
J Allergy Clin Immunol ; 144(1): 280-293, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30731121

RESUMO

BACKGROUND: Mismatched stem cell transplantation is associated with a high risk of graft loss, graft-versus-host disease (GvHD), and transplant-related mortality. Alternative graft manipulation strategies have been used over the last 11 years to reduce these risks. OBJECTIVE: We investigated the outcome of using different graft manipulation strategies among children with primary immunodeficiencies. METHODS: Between 2006 and 2017, 147 patients with primary immunodeficiencies received 155 mismatched grafts: 30 T-cell receptor (TCR) αß/CD19-depleted grafts, 43 cord blood (CB) grafts (72% with no serotherapy), 17 CD34+ selection with T-cell add-back grafts, and 65 unmanipulated grafts. RESULTS: The estimated 8-year survival of the entire cohort was 79%, transplant-related mortality was 21.7%, and the graft failure rate was 6.7%. Posttransplantation viral reactivation, grade II to IV acute graft-versus-host disease (aGvHD), and chronic graft-versus-host disease (cGvHD) complicated 49.6%, 35%, and 15% of transplantations, respectively. Use of TCRαß/CD19 depletion was associated with a significantly lower incidence of grade II to IV aGvHD (11.5%) and cGvHD (0%), although with a greater incidence of viral reactivation (70%) in comparison with other grafts. T-cell immune reconstitution was robust among CB transplants, although with a high incidence (56.7%) of grade II to IV aGvHD. Stable full donor engraftment was significantly greater at 80% among TCRαß+/CD19+-depleted and CB transplants versus 40% to 60% among the other groups. CONCLUSIONS: Rapidly accessible CB and haploidentical grafts are suitable alternatives for patients with no HLA-matched donor. Cord transplantation without serotherapy and TCRαß+/CD19+-depleted grafts produced comparable survival rates of around 80%, although with a high rate of aGvHD with the former and a high risk of viral reactivation with the latter that need to be addressed.

6.
Br J Haematol ; 184(3): 397-404, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30460979

RESUMO

Allogeneic haematopoietic stem cell transplantation is still the only available curative option for Familial Haemophagocytic Lymphohistiocytosis (FHLH). Most studies report outcomes after bone marrow or peripheral blood stem cell transplantation. We analysed the outcomes of 118 children with FHLH undergoing single-unit umbilical cord blood transplantation performed from 1996 to 2014. Myeloablative conditioning regimen was given to 90% of the patients, and was mostly busulfan-based (n = 81, 76%), including anti-thymocyte globulin or alemtuzumab (n = 102, 86%). The cumulative incidence of Day 60 neutrophil engraftment was 85%; and that of non-relapse mortality and acute graft-versus-host disease (GvHD) was 21% and 33% at 100 days, respectively. The 6-year cumulative incidence of chronic GvHD was 17% and the 6-year probability of overall survival was 55%. In multivariate analysis, children receiving a graft with a total nucleated cell dose greater than 9·9 × 107 /kg had a better overall survival (hazard ratio [HR]: 0·49, 95% CI: 0·27-0·88, P = 0·02). Degree of human leucocyte antigen (HLA) matching was associated with improved disease-free survival (5/6 vs. 6/6 HR: 2·11, 95% confidence interval [CI]: 1·01-4·4, P = 0·05 and ≤4/6 vs. 6/6, HR: 2·82, CI: 1·27-6·23, P = 0·01). Umbilical cord blood transplantation with a high cell dose and good HLA match is a suitable alternative option to haematopoietic stem cell transplantation in children with FHLH who lack a HLA-matched donor.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Linfo-Histiocitose Hemofagocítica , Condicionamento Pré-Transplante , Doadores não Relacionados , Adolescente , Aloenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Linfo-Histiocitose Hemofagocítica/mortalidade , Linfo-Histiocitose Hemofagocítica/terapia , Masculino , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
7.
Eur J Haematol ; 102(3): 210-217, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30418684

RESUMO

OBJECTIVE: Adenovirus (AdV) infections are potentially life-threatening for allogeneic hematopoietic stem cell transplant (allo-HCT) recipients. The AdVance study aimed to evaluate the incidence, management, and outcomes of AdV infections in European allo-HCT recipients. METHODS: As part of the study, physician surveys were conducted to determine current AdV screening and treatment practices at their center. RESULTS: All of the 28 respondents who treat pediatric patients reported routine AdV screening practices, with 93% screening all allo-HCT recipients and others screening those with transplant-related risk factors. Nearly all centers take a pre-emptive approach to AdV treatment in both high- (89%) and low-risk patients (75%). Among the 14 respondents who treat adult patients, 5 (36%) reported routine screening practices and few (21%) screen all allo-HCT recipients unless risk factors are present. In adults, pre-emptive AdV treatment is uncommon and quantitative AdV thresholds are rare. Typical treatment for all patients with symptomatic AdV infection is off-label intravenous cidofovir. CONCLUSIONS: Our findings confirm that screening for AdV is more common in pediatric patients. Antiviral treatment is employed in both pediatric and adult patients, although adults are generally treated when AdV disease is diagnosed. The approach to AdV screening and treatment is risk-based and consistent with clinical guidelines.


Assuntos
Infecções por Adenoviridae/diagnóstico , Infecções por Adenoviridae/etiologia , Infecções por Adenoviridae/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Padrões de Prática Médica , Antivirais/uso terapêutico , Testes Diagnósticos de Rotina , Gerenciamento Clínico , Europa (Continente) , Pesquisas sobre Serviços de Saúde , Humanos , Pediatras , Transplante Homólogo , Resultado do Tratamento
8.
Blood ; 132(19): 2088-2096, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30104219

RESUMO

Asymptomatic carriers (ACs) of pathogenic biallelic mutations in causative genes for primary hemophagocytic lymphohistiocytosis (HLH) are at high risk of developing life-threatening HLH, which requires allogeneic hematopoietic stem cell transplantation (HSCT) to be cured. There are no guidelines on the management of these asymptomatic patients. We analyzed the outcomes of pairs of index cases (ICs) and subsequently diagnosed asymptomatic family members carrying the same genetic defect. We collected data from 22 HSCT centers worldwide. Sixty-four children were evaluable. ICs presented with HLH at a median age of 16 months. Seven of 32 ICs died during first-line therapy, and 2 are alive after chemotherapy only. In all, 23/32 underwent HSCT, and 16 of them are alive. At a median follow-up of 36 months from diagnosis, 18/32 ICs are alive. Median age of ACs at diagnosis was 5 months. Ten of 32 ACs activated HLH while being observed, and all underwent HSCT: 6/10 are alive and in complete remission (CR). 22/32 ACs remained asymptomatic, and 6/22 have received no treatment and are in CR at a median follow-up of 39 months. Sixteen of 22 underwent preemptive HSCT: 15/16 are alive and in CR. Eight-year probability of overall survival (pOS) in ACs who did not have activated HLH was significantly higher than that in ICs (95% vs 45%; P = .02), and pOS in ACs receiving HSCT before disease activation was significantly higher than in ACs receiving HSCT after HLH activation (93% vs 64%; P = .03). Preemptive HSCT in ACs proved to be safe and should be considered.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfo-Histiocitose Hemofagocítica/terapia , Criança , Pré-Escolar , Gerenciamento Clínico , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Linfo-Histiocitose Hemofagocítica/genética , Masculino , Mutação , Análise de Sobrevida , Resultado do Tratamento
10.
J Infect Dis ; 218(8): 1261-1271, 2018 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-29917114

RESUMO

Background: Adenoviruses are significant pathogens for the immunocompromised, arising from primary infection or reinfection. Serotyping is insufficient to support nosocomial transmission investigations. We investigate whether whole-genome sequencing (WGS) provides clinically relevant information on transmission among patients in a pediatric tertiary hospital. Methods: We developed a target-enriched adenovirus WGS technique for clinical samples and retrospectively sequenced 107 adenovirus-positive residual diagnostic samples, including viremias (>5 × 104 copies/mL), from 37 patients collected January 2011-March 2016. Whole-genome sequencing was used to determine genotype and for phylogenetic analysis. Results: Adenovirus sequences were recovered from 105 of 107 samples. Full genome sequences were recovered from all 20 nonspecies C samples and from 36 of 85 species C viruses, with partial genome sequences recovered from the rest. Whole-genome phylogenetic analysis suggested linkage of 3 genotype A31 cases and uncovered an unsuspected epidemiological link to an A31 infection first detected on the same ward 4 years earlier. In 9 samples from 1 patient who died, we identified a mixed genotype adenovirus infection. Conclusions: Adenovirus WGS from clinical samples is possible and useful for genotyping and molecular epidemiology. Whole-genome sequencing identified likely nosocomial transmission with greater resolution than conventional genotyping and distinguished between adenovirus disease due to single or multiple genotypes.


Assuntos
Adenoviridae/genética , Infecções por Adenovirus Humanos/virologia , Infecção Hospitalar/virologia , Genótipo , Hospedeiro Imunocomprometido , Sequenciamento Completo do Genoma , Adenoviridae/classificação , Infecções por Adenovirus Humanos/transmissão , Adolescente , Criança , Pré-Escolar , Infecção Hospitalar/transmissão , Genômica , Humanos , Lactente , Epidemiologia Molecular , Filogenia
11.
Cytotherapy ; 20(6): 830-838, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29753677

RESUMO

BACKGROUND: Adenovirus (ADV) reactivation can cause significant morbidity and mortality in children after allogeneic stem cell transplantation. Antiviral drugs can control viremia, but viral clearance requires recovery of cell-mediated immunity. METHOD: This study was an open-label phase 1/2 study to investigate the feasibility of generating donor-derived ADV-specific T cells (Cytovir ADV, Cell Medica) and to assess the safety of pre-emptive administration of ADV-specific T cells in high-risk pediatric patients after allogeneic hematopoietic stem cell transplantation (HSCT) to treat adenoviremia. Primary safety endpoints included graft-versus-host disease (GvHD), and secondary endpoints determined antiviral responses and use of antiviral drugs. RESULTS: Between January 2013 and May 2016, 92 donors were enrolled for the production of ADV T cells at three centers in the United Kingdom (UK), and 83 products were generated from 72 mobilized peripheral blood harvests and 20 steady-state whole blood donations. Eight children received Cytovir ADV T cells after standard therapy and all resolved ADV viremia between 15 and 127 days later. ADV-specific T cells were detectable using enzyme-linked immunospot assay (ELISpot) in the peripheral blood of all patients analyzed. Serious adverse events included Grade II GvHD, Astrovirus encephalitis and pancreatitis. CONCLUSION: The study demonstrates the safety and feasibility of pre-emptively manufacturing peptide pulsed ADV-specific cells for high-risk pediatric patients after transplantation and provides early evidence of clinical efficacy.


Assuntos
Infecções por Adenoviridae/prevenção & controle , Adenoviridae/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva/métodos , Linfócitos T/transplante , Infecções por Adenoviridae/complicações , Infecções por Adenoviridae/imunologia , Adolescente , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/virologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/virologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunidade Celular , Lactente , Masculino , Fatores de Risco , Linfócitos T/imunologia , Imunologia de Transplantes , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Ativação Viral/imunologia
12.
Blood Adv ; 2(7): 777-786, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29618462

RESUMO

Patients with juvenile idiopathic arthritis (JIA) can experience a severe disease course, with progressive destructive polyarthritis refractory to conventional therapy with disease-modifying antirheumatic drugs including biologics, as well as life-threatening complications including macrophage activation syndrome (MAS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative immunomodulatory strategy for patients with such refractory disease. We treated 16 patients in 5 transplant centers between 2007 and 2016: 11 children with systemic JIA and 5 with rheumatoid factor-negative polyarticular JIA; all were either refractory to standard therapy, had developed secondary hemophagocytic lymphohistiocytosis/MAS poorly responsive to treatment, or had failed autologous HSCT. All children received reduced toxicity fludarabine-based conditioning regimens and serotherapy with alemtuzumab. Fourteen of 16 patients are alive with a median follow-up of 29 months (range, 2.8-96 months). All patients had hematological recovery. Three patients had grade II-IV acute graft-versus-host disease. The incidence of viral infections after HSCT was high, likely due to the use of alemtuzumab in already heavily immunosuppressed patients. All patients had significant improvement of arthritis, resolution of MAS, and improved quality of life early following allo-HSCT; most importantly, 11 children achieved complete drug-free remission at the last follow-up. Allo-HSCT using alemtuzumab and reduced toxicity conditioning is a promising therapeutic option for patients with JIA refractory to conventional therapy and/or complicated by MAS. Long-term follow-up is required to ascertain whether disease control following HSCT continues indefinitely.


Assuntos
Artrite Juvenil/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Terapia de Salvação/métodos , Adolescente , Alemtuzumab/uso terapêutico , Artrite Juvenil/complicações , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Imunossupressão/métodos , Lactente , Linfo-Histiocitose Hemofagocítica/etiologia , Masculino , Transplante Homólogo , Resultado do Tratamento
15.
Biol Blood Marrow Transplant ; 24(3): 529-536, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29155317

RESUMO

We previously published results for 70 children who received conditioning with treosulfan and cyclophosphamide (n = 30) or fludarabine (n = 40) before undergoing hematopoietic stem cell transplantation (HSCT) for primary immunodeficiency (PID). Toxicity was lower and T cell chimerism was better in the patients receiving fludarabine, but cohort numbers were relatively small and follow-up was short. Here we report outcomes of 160 children who received homogeneous conditioning with treosulfan, fludarabine, and, in most cases, alemtuzumab (n = 124). The median age at transplantation was 1.36 years (range, .09 to 18.25 years). Donors included 73 matched unrelated, 54 1 to 3 antigen-mismatched unrelated, 12 matched sibling, 17 other matched family, and 4 haploidentical donors. Stem cell source was peripheral blood stem cells (PBSCs) in 70, bone marrow in 49, and cord blood in 41. Median duration of follow-up was 4.3 years (range, .8 to 9.4 years). Overall survival was 83%. No patients had veno-occlusive disease. Seventy-four patients (46%) had acute GVHD, but only 14 (9%) greater than grade II. Four patients underwent successful retransplantation for graft loss or poor immune reconstitution. Another patient experienced graft rejection and died. There was no association between T cell chimerism >95% and stem cell source, but a significant association was seen between myeloid chimerism >95% and use of PBSCs without an increased risk of significant GVHD compared with other sources. All 11 patients with severe combined immunodeficiency diagnosed at birth were alive at up to 8.7 years of follow-up. Long-term studies are needed to determine late gonadotoxic effects, and pharmacokinetic studies are needed to identify whether specific targeting is advantageous. The combination of treosulfan, fludarabine, and alemtuzumab is associated with excellent results in HSCT for PID.


Assuntos
Bussulfano/análogos & derivados , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Adolescente , Adulto , Alemtuzumab/administração & dosagem , Aloenxertos , Bussulfano/administração & dosagem , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Síndromes de Imunodeficiência/mortalidade , Síndromes de Imunodeficiência/terapia , Lactente , Masculino , Fatores de Risco , Taxa de Sobrevida , Reino Unido , Vidarabina/administração & dosagem
16.
J Allergy Clin Immunol ; 141(4): 1417-1426.e1, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28780238

RESUMO

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is used as a therapeutic approach for primary immunodeficiencies (PIDs). The best outcomes have been achieved with HLA-matched donors, but when a matched donor is not available, a haploidentical or mismatched unrelated donor (mMUD) can be useful. Various strategies are used to mitigate the risk of graft-versus-host disease (GvHD) and rejection associated with such transplants. OBJECTIVE: We sought to evaluate the outcomes of haploidentical or mMUD HSCT after depleting GvHD-causing T-cell receptor (TCR) αß CD3+ cells from the graft. METHODS: CD3+TCRαß+/CD19+ depleted grafts were given in conditioned (except 3) children with PIDs. Treosulfan (busulfan in 1 patient), fludarabine, thiotepa, and anti-thymocyte globulin or alemtuzumab conditioning were used in 77% of cases, and all but 4 received GvHD prophylaxis. RESULTS: Twenty-five patients with 12 types of PIDs received 26 HSCTs. Three underwent transplantation for refractory GvHD that developed after the first cord transplantation. At a median follow-up of 20.8 months (range, 5 month-3.3 years), 21 of 25 patients survived and were cured of underlying immunodeficiency. Overall and event-free survival at 3 years were 83.9% and 80.4%, respectively. Cumulative incidence of grade II to IV acute GvHD was 22% ± 8.7%. No case of visceral or chronic GvHD was seen. Cumulative incidences of graft failure, cytomegalovirus, and/or adenoviral infections and transplant-related mortality at 1 year were 4.2% ± 4.1%, 58.8% ± 9.8%, and 16.1% ± 7.4%, respectively. Patients undergoing transplantation with systemic viral infections had poor survival in comparison with those with absent or resolved infections (33.3% vs 100%). CONCLUSION: CD3+TCRαß+ and CD19+ cell-depleted haploidentical or mMUD HSCT is a practical and viable alternative for children with a range of PIDs.


Assuntos
Antígenos CD19/imunologia , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Alemtuzumab/imunologia , Soro Antilinfocitário/imunologia , Bussulfano/análogos & derivados , Bussulfano/imunologia , Complexo CD3/imunologia , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Estudos Retrospectivos , Tiotepa/imunologia , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Vidarabina/imunologia
17.
Blood ; 129(14): 2033-2037, 2017 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-28153824

RESUMO

Cidofovir is preemptively used for controlling adenoviremia and preventing disseminated viral disease in hematopoietic cell transplant (HCT) recipients but does not lead to resolution of viremia without T-cell immune-reconstitution. The lipid-conjugated prodrug of cidofovir, brincidofovir, has improved oral bioavailability and achieves higher intracellular concentrations of active drug. We present retrospective multicenter data comparing the kinetics of viremia and toxicities following preemptive treatment with and brincidofovir in children and adolescents diagnosed with HCT-related adenoviremia. Forty-one episodes (18 = brincidofovir; 23 = cidofovir) of antiviral therapy were observed in 27 patients. The 2 groups had comparable immune-reconstitution and viral burden. Major (≥2 log-reduction in 2 weeks; n = 13) and minor (≥1 to ≤2 log-reduction in 2 weeks; n = 2) virological responses were observed in 15 (83%) brincidofovir episodes compared to only 2 (9%) major virological responses with cidofovir (P < .0001). Brincidofovir mediated major responses in 9 of 11 cidofovir-unresponsive patients and resulted in complete responses (CR) despite significant lymphopenia (Brincidofovir vs cidofovir; CR = 13 (80%) vs 8 (35%); median lymphocyte count = 320/µl vs 910/µl; P < .05). One patient experienced abdominal cramps and diarrhea necessitating interruption of brincidofovir and none developed nephrotoxicity with brincidofovir. Thus, brincidofovir is well-tolerated and highly efficacious in controlling adenoviremia during the lymphopenic phase of HCT.


Assuntos
Infecções por Adenoviridae/tratamento farmacológico , Adenoviridae , Citosina/análogos & derivados , Transplante de Células-Tronco Hematopoéticas , Organofosfonatos/administração & dosagem , Viremia/tratamento farmacológico , Infecções por Adenoviridae/etiologia , Adolescente , Aloenxertos , Criança , Pré-Escolar , Citosina/administração & dosagem , Citosina/efeitos adversos , Feminino , Humanos , Masculino , Organofosfonatos/efeitos adversos , Viremia/etiologia
20.
J Allergy Clin Immunol ; 138(4): 1152-1160, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27241891

RESUMO

BACKGROUND: Reduced-intensity conditioning (RIC) regimens are increasingly being used in the transplantation of patients with primary immunodeficiency disorders (PIDs), but there are no large studies looking at long-term lineage-specific chimerism. OBJECTIVES: We sought to analyze long-term chimerism and event-free survival in children undergoing transplantation for PIDs using RIC with fludarabine and melphalan (Flu/Melph) and to study the effect of donor type and stem cell source. METHODS: One hundred forty-two children underwent transplantation with RIC by using Flu/Melph and for PIDs by using bone marrow (n = 93) or peripheral blood stem cells (PBSCs; n = 49). Donors were matched unrelated donors (n = 72), mismatched unrelated donors (n = 37), matched sibling donors (n = 14), matched family donors (n = 12), and mismatched family donors (n = 7). RESULTS: Overall survival at a median follow-up of 7.5 years was 78%, irrespective of stem cell source or donor type. When bone marrow was used as the stem cell source, 26% of patients ended up with very low levels of donor chimerism (<10% donor), especially in the myeloid lineage. Event-free survival in this group was significantly lower compared with that in the rest of the group (25% vs 70%, P < .001). With the use of PBSCs, more than 90% of patients achieved complete donor chimerism or high-level mixed chimerism (>50% donor chimerism) in all lineages. CONCLUSIONS: On the basis of our experience, we would suggest that PBSCs should be the stem cell source of choice in children with PIDs undergoing transplantation with Flu/Melph RIC from a matched donor source. This is most likely to ensure sustained high-level donor chimerism.


Assuntos
Quimerismo , Intervalo Livre de Doença , Síndromes de Imunodeficiência/terapia , Melfalan/uso terapêutico , Transplante de Células-Tronco/normas , Células-Tronco/citologia , Vidarabina/análogos & derivados , Linhagem da Célula , Quimioterapia Combinada , Seguimentos , Humanos , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/mortalidade , Lactente , Recém-Nascido , Vidarabina/uso terapêutico
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