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1.
Blood ; 132(17): 1737-1749, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30154114

RESUMO

The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG, or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4+ and CD4+CD45RA+ cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4+ cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune/imunologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/mortalidade , Imunodeficiência Combinada Severa/terapia , Genótipo , Humanos , Contagem de Linfócitos , Estudos Retrospectivos
2.
J Allergy Clin Immunol ; 139(4): 1282-1292, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27697500

RESUMO

BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. OBJECTIVES: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. METHODS: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. RESULTS: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. CONCLUSION: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.


Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Síndrome de Imunodeficiência com Hiper-IgM/mortalidade , Síndrome de Imunodeficiência com Hiper-IgM/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Tempo , Adulto Jovem
3.
N Engl J Med ; 371(5): 434-46, 2014 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-25075835

RESUMO

BACKGROUND: The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth. METHODS: We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009). RESULTS: Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell-depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pretransplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival. CONCLUSIONS: Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.).


Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa/terapia , Complexo CD3/sangue , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Imunoglobulina A/sangue , Incidência , Lactente , Contagem de Linfócitos , Masculino , Retratamento , Estudos Retrospectivos , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/mortalidade , Irmãos , Taxa de Sobrevida , Linfócitos T/imunologia , Condicionamento Pré-Transplante , Resultado do Tratamento
4.
PLoS Genet ; 9(8): e1003695, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24009516

RESUMO

Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1.


Assuntos
DNA Helicases/genética , Disceratose Congênita/genética , Disceratose Congênita/patologia , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Síndromes de Imunodeficiência/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Microcefalia/genética , Microcefalia/patologia , Adulto , Disceratose Congênita/etiologia , Feminino , Retardo do Crescimento Fetal/etiologia , Genes Recessivos , Mutação em Linhagem Germinativa , Homozigoto , Humanos , Síndromes de Imunodeficiência/genética , Deficiência Intelectual/etiologia , Judeus , Microcefalia/etiologia , Dados de Sequência Molecular , Mutação , Fenótipo , Telomerase/genética , Telômero/genética
5.
J Allergy Clin Immunol ; 133(2): 335-47, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24139498

RESUMO

The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives.


Assuntos
Síndromes de Imunodeficiência , Transplante de Células-Tronco Hematopoéticas , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/terapia , Recém-Nascido , Triagem Neonatal , Projetos Piloto , Sociedades Científicas
6.
Biol Blood Marrow Transplant ; 20(6): 787-93, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24548875

RESUMO

Cord blood transplantation (CBT) is a known risk factor for human herpesvirus-6 (HHV-6) infection. We analyzed the nature of HHV-6 infections in 125 double-unit CBT recipients (median age, 42 years) transplanted for hematologic malignancies with calcineurin inhibitor/mycophenolate mofetil prophylaxis and no antithymocyte globulin. One hundred seventeen patients (94%) reactivated HHV-6 by quantitative plasma PCR (median peak, 7600 copies/mL; range, 100 to 160,000) at a median of 20 days (range, 10 to 59) after transplantation. HHV-6 encephalitis occurred in 2 patients (1.6%), of whom 1 died and 1 recovered with therapy. No association was found between high-level HHV-6 viremia (≥10,000 or ≥25,000 copies/mL) and age, diagnosis, conditioning intensity, or dominant unit characteristics or between high-level viremia and transplant outcomes (engraftment, cytomegalovirus reactivation, day 100 grades II to IV acute graft-versus-host disease, day 100 transplant-related mortality, or 1-year disease-free survival). HHV-6 therapy delayed the onset of cytomegalovirus reactivation. Interestingly, HHV-6 resolution was observed in untreated patients, and resolution of viremia correlated with absolute lymphocyte count recovery. We observed a low incidence of encephalitis and no association with CBT outcomes. Our data suggest therapy in uncomplicated viremia may not be warranted. However, further investigation of the risk-to-benefit of HHV-6 viremia treatment and standardization of PCR testing is required.


Assuntos
Soro Antilinfocitário/administração & dosagem , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Encefalite Viral/etiologia , Herpesvirus Humano 6/isolamento & purificação , Infecções por Roseolovirus/etiologia , Viremia/virologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Encefalite Viral/virologia , Feminino , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Infecções por Roseolovirus/virologia , Adulto Jovem
7.
Blood ; 119(11): 2644-56, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22138512

RESUMO

We evaluated HLA-compatible donor leukocyte infusions (DLIs) and HLA-compatible or HLA-disparate EBV-specific T cells (EBV-CTLs) in 49 hematopoietic cell transplantation recipients with biopsy-proven EBV-lymphoproliferative disease (EBV-LPD). DLIs and EBV-CTLs each induced durable complete or partial remissions in 73% and 68% of treated patients including 74% and 72% of patients surviving ≥ 8 days after infusion, respectively. Reversible acute GVHD occurred in recipients of DLIs (17%) but not EBV-CTLs. The probability of complete response was significantly lower among patients with multiorgan involvement. In responders, DLIs and EBV-CTLs regularly induced exponential increases in EBV-specific CTL precursor (EBV-CTLp) frequencies within 7-14 days, with subsequent clearance of EBV viremia and resolution of disease. In nonresponders, EBV-CTLps did not increase and EBV viremia persisted. Treatment failures were correlated with impaired T-cell recognition of tumor targets. Either donor-derived EBV-CTLs that had been sensitized with autologous BLCLs transformed by EBV strain B95.8 could not lyse spontaneous donor-derived EBV-transformed BLCLs expanded from the patient's blood or biopsied tumor or they failed to lyse their targets because they were selectively restricted by HLA alleles not shared by the EBV-LPD. Therefore, either unselected DLIs or EBV-specific CTLs can eradicate both untreated and Rituxan-resistant lymphomatous EBV-LPD, with failures ascribable to impaired T-cell recognition of tumor-associated viral antigens or their presenting HLA alleles.


Assuntos
Infecções por Vírus Epstein-Barr/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunoterapia Adotiva , Linfoma/terapia , Transtornos Linfoproliferativos/terapia , Linfócitos T Citotóxicos/transplante , Linfócitos T/imunologia , Adolescente , Adulto , Criança , DNA Viral/genética , Infecções por Vírus Epstein-Barr/etiologia , Feminino , Herpesvirus Humano 4/patogenicidade , Humanos , Linfoma/etiologia , Transtornos Linfoproliferativos/etiologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Linfócitos T Citotóxicos/imunologia , Transplante Homólogo , Adulto Jovem
8.
Biol Blood Marrow Transplant ; 19(3): 387-92, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23092814

RESUMO

Adenovirus (ADV) is an important cause of viral mortality in hematopoietic stem cell transplantation (HSCT). Recipients of T cell-depleted (TCD) HSCT are at increased risk for viral infections. We compared the rates and outcomes of ADV viremia and disease between TCD and conventional (CONV) HSCT at our institution. This was an observational study of 624 adult and pediatric recipients of myeloablative HSCT at Memorial Sloan-Kettering Cancer Center between January 1, 2006, and March 11, 2011. Viral cultures and ADV PCR were ordered as clinically indicated. ADV viremia by quantitative PCR assay was defined as 1 or more positive values ≥1,000 copies/mL or 2 or more consecutive positive values. Competing-risk regression analyses were used to identify predictors for ADV viremia. ADV viremia at 1 year after HSCT occurred in 8% of TCD HSCT recipients and in 4.0% of CONV HSCT recipients (P = .041). Among the TCD recipients, ADV viremia was seen in 15% of children, compared with 5% of adults (P = .008). Young age (hazard ratio [HR], 3.0; P < .001) and acute graft-versus-host disease (GVHD) (HR, 3.2; P = .001) were identified as risk factors for ADV viremia. ADV viremia was predictive of mortality (HR, 6.0; P < .001). ADV disease developed in 3.5% of TCD HSCT recipients and in 0.4% of CONV HSCT recipients (P = .022), with an attributable mortality of 27%. Among TCD HSCY recipients, grade II to IV GVHD was a risk factor for ADV disease (HR, 13; P < .001), but age was not. More than 90% of the cases of ADV disease involved a viral load of ≥10,000 copies/mL. Rates of ADV disease were 10-fold greater in TCD HSCT recipients compared with CONV HSCT recipients, predominantly in patients who developed acute GVHD. The benefit of preemptive therapy for an ADV viral load ≥10,000 copies/mL for preventing ADV disease in TCD HSCT recipients should be evaluated in prospective clinical trials.


Assuntos
Infecções por Adenoviridae/patologia , Transplante de Células-Tronco Hematopoéticas , Depleção Linfocítica , Linfócitos T/imunologia , Condicionamento Pré-Transplante , Viremia/patologia , Adenoviridae/crescimento & desenvolvimento , Infecções por Adenoviridae/imunologia , Infecções por Adenoviridae/mortalidade , Infecções por Adenoviridae/virologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/virologia , Doenças Hematológicas/imunologia , Doenças Hematológicas/mortalidade , Doenças Hematológicas/patologia , Doenças Hematológicas/terapia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/farmacologia , Agonistas Mieloablativos/uso terapêutico , Análise de Sobrevida , Linfócitos T/transplante , Transplante Homólogo , Carga Viral , Viremia/imunologia , Viremia/mortalidade , Viremia/virologia
9.
J Clin Immunol ; 33(7): 1156-64, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23818196

RESUMO

The Primary Immune Deficiency Treatment Consortium (PIDTC) consists of 33 centers in North America. We hypothesized that the analysis of uniform data on patients with severe combined immunodeficiency (SCID) enrolled in a prospective protocol will identify variables that contribute to optimal outcomes following treatment. We report baseline clinical, immunologic, and genetic features of the first 50 patients enrolled, and the initial therapies administered, reflecting current practice in the diagnosis and treatment of both typical (n = 37) and atypical forms (n = 13) of SCID. From August 2010 to May 2012, patients with suspected SCID underwent evaluation and therapy per local center practices. Diagnostic information was reviewed by the PIDTC eligibility review panel, and hematopoietic cell transplantation (HCT) details were obtained from the Center for International Blood and Marrow Transplant Research. Most patients (92 %) had mutations in a known SCID gene. Half of the patients were diagnosed by newborn screening or family history, were younger than those diagnosed by clinical signs (median 15 vs. 181 days; P = <0.0001), and went to HCT at a median of 67 days vs. 214 days of life (P = <0.0001). Most patients (92 %) were treated with HCT within 1-2 months of diagnosis. Three patients were treated with gene therapy and 1 with enzyme replacement. The PIDTC plans to enroll over 250 such patients and analyze short and long-term outcomes for factors beneficial or deleterious to survival, clinical outcome, and T- and B-cell reconstitution, and which biomarkers are predictive of these outcomes.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/terapia , Biomarcadores/metabolismo , Criança , Pré-Escolar , Feminino , Seguimentos , Testes Genéticos , Genótipo , Humanos , Imunofenotipagem , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Imunodeficiência Combinada Severa/mortalidade , Análise de Sobrevida , Resultado do Tratamento
10.
Blood ; 118(6): 1675-84, 2011 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-21659547

RESUMO

In this retrospective collaborative study, we have analyzed long-term outcome and donor cell engraftment in 194 patients with Wiskott-Aldrich syndrome (WAS) who have been treated by hematopoietic cell transplantation (HCT) in the period 1980- 2009. Overall survival was 84.0% and was even higher (89.1% 5-year survival) for those who received HCT since the year 2000, reflecting recent improvement of outcome after transplantation from mismatched family donors and for patients who received HCT from an unrelated donor at older than 5 years. Patients who went to transplantation in better clinical conditions had a lower rate of post-HCT complications. Retrospective analysis of lineage-specific donor cell engraftment showed that stable full donor chimerism was attained by 72.3% of the patients who survived for at least 1 year after HCT. Mixed chimerism was associated with an increased risk of incomplete reconstitution of lymphocyte count and post-HCT autoimmunity, and myeloid donor cell chimerism < 50% was associated with persistent thrombocytopenia. These observations indicate continuous improvement of outcome after HCT for WAS and may have important implications for the development of novel protocols aiming to obtain full correction of the disease and reduce post-HCT complications.


Assuntos
Linhagem da Célula , Transplante de Células-Tronco Hematopoéticas/métodos , Quimeras de Transplante/sangue , Síndrome de Wiskott-Aldrich/cirurgia , Autoimunidade/imunologia , Doadores de Sangue , Criança , Pré-Escolar , Seguimentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Mutação , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/imunologia , Estudos Retrospectivos , Análise de Sobrevida , Trombocitopenia/sangue , Trombocitopenia/etiologia , Fatores de Tempo , Síndrome de Wiskott-Aldrich/sangue , Síndrome de Wiskott-Aldrich/genética
11.
Pediatr Blood Cancer ; 60(12): 2018-24, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24038967

RESUMO

BACKGROUND: Autologous or allogeneic hematopoietic stem cell transplant (SCT) is often considered in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) but there are limited data on the use of SCT for the treatment of NHL in the pediatric setting. PROCEDURE: To evaluate the role of SCT for children with NHL, we reviewed 36 consecutive pediatric patients with NHL who underwent an allogeneic (n = 21) or autologous (n = 15) SCT at our institution between 1982 and 2004. Pathologic classification included: lymphoblastic lymphoma (n = 12), Burkitt lymphoma (BL) (n = 5), diffuse large B-cell lymphoma (n = 4), anaplastic large cell lymphoma (ALCL) (n = 13), peripheral T cell lymphoma (n = 1), and undifferentiated NHL (n = 1). Donor source for allogeneic-SCT recipients was an HLA-matched related donor (n = 15), a matched unrelated donor (n = 4), or a mismatched donor (related n = 1; unrelated n = 1). Twenty-eight patients (78%) had chemotherapy responsive disease at the time of transplant (either CR or PR). RESULTS: Overall survival (OS) and disease-free survival (DFS) were 55% and 53% with a median follow-up of 9.75 years. Outcomes were similar in patients receiving autologous and allogeneic-SCT (DFS 53% in both groups). Patients with ALCL had a DFS of 76.9%. In contrast, of five patients transplanted for BL, none survived. DFS among patients with chemotherapy sensitive disease was 61%, compared with 25% among patients with relapsed/refractory disease (P = 0.019). CONCLUSIONS: Allogeneic and autologous SCT offer the prospect of durable, disease-free survival for a significant proportion of pediatric patients with relapsed or refractory NHL. Survival is superior among patients with chemotherapy sensitive disease.


Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Linfoma não Hodgkin/terapia , Adolescente , Autoenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Linfoma não Hodgkin/mortalidade , Masculino , Transplante Homólogo , Adulto Jovem
12.
Biol Blood Marrow Transplant ; 18(1): 145-9, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21820392

RESUMO

Given the high morbidity and mortality associated with meningococcal disease, in 2007 the Advisory Committee of Immunization Practices recommended immunization of all children ages 11-18 with a protein-conjugated meningococcal vaccine. There are limited data on the immunogenicity of this vaccine after allogeneic hematopoietic stem cell transplantation (allo-HCT). Since 2007, we have immunized 48 patients with the MCV4 vaccine. Two vaccinated patients who lacked follow-up titers were excluded from this analysis. Stem cells were derived from an HLA-identical sibling (n = 17) or an alternative donor (n = 29). The median time to vaccination was 2.34 years after allo-HCT. Only 7 patients responded to all 4 serogroups, and 16 patients responded to none of the serogroups. The response to serogroups A, C, Y, and W-135 was 52%, 30%, 46%, and 33%, respectively. The ability to respond to 2 or more serogroups was not affected by age, diagnosis, time to vaccination, or history of graft-versus-host disease. Receipt of a T cell-depleted graft was associated with a poorer response (P = .044). Eight of 16 patients who received a second MCV4 vaccination responded to all 4 serogroups. This retrospective study suggests that response to a single MCV4 vaccination is poor after allo-HCT. Administration of a 2-dose series, as currently recommended for patients with asplenia, complement deficiency, and HIV infection, should be evaluated in this patient population.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Infecções Meningocócicas/prevenção & controle , Vacinas Meningocócicas/imunologia , Adolescente , Anticorpos Antibacterianos/biossíntese , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Criança , Feminino , Humanos , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Infecções Meningocócicas/imunologia , Vacinas Meningocócicas/administração & dosagem , Estudos Retrospectivos , Adulto Jovem
13.
Biol Blood Marrow Transplant ; 18(1): 6-15, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22100979

RESUMO

Defective immune reconstitution is a major barrier to successful hematopoietic cell transplantation (HCT), and has important implications in the pediatric population. There are many factors that affect immune recovery, including stem cell source and graft-versus-host disease (GVHD). Complete assessment of immune recovery, including T and B lymphocyte evaluation, innate immunity, and response to neoantigens, may provide insight as to infection risk and optimal time for immunizations. The increasing use of cord blood grafts requires additional study regarding early reconstitution and impact upon survival. Immunization schedules may require modification based upon stem cell source and immune reconstitution, and this is of particular importance as many children have been incompletely immunized, or not at all, before school entry. Additional studies are needed in children post-HCT to evaluate the impact of differing stem cell sources upon immune reconstitution, infectious risks, and immunization responses.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Síndromes de Imunodeficiência/etiologia , Sangue Fetal , Humanos , Síndromes de Imunodeficiência/imunologia
14.
Biol Blood Marrow Transplant ; 18(3): 473-80, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22079789

RESUMO

The development of treatment-related myelodysplastic syndrome (tMDS) or treatment-related acute myelogenous leukemia (tAML) is a complication that can occur after chemotherapy or radiation therapy. Eighteen patients with a previous malignancy treated at our institution and three patients with a nonmalignant primary tumor received an allogeneic hematopoietic stem cell transplant (HSCT) on the pediatric bone marrow (BM) transplantation service for the treatment of tMDS/tAML over a 15-year period. Five patients proceeded to HSCT without induction chemotherapy. Fourteen patients received high-dose cytarabine according to the Capizzi II regimen as first-line induction therapy with 13 of them achieving complete remission (CR) or refractory anemia (RA) with persistent cytogenetic abnormalities after this treatment. Two patients received an anthracycline-based induction therapy. Conditioning regimens were selected according to previous therapies: 11 patients received busulfan-melphalan-fludarabine (BU-MEL-FLU), which consisted of busulfan (0.8 mg/kg/dose every 6 hours ×10 doses), melphalan (70 mg/m(2)/dose × two doses), and fludarabine (25 mg/m(2)/dose × five doses) for cytoreduction; three patients received a total body irradiation (TBI)-containing regimen; seven patients received myeloablative regimens containing busulfan and/or melphalan and/or thiotepa with doses modified for organ toxicity. Sixteen patients received T cell-depleted (TCD) grafts; four patients received unmodified grafts; one patient received a double-unit cord blood transplantation (DUCBT). Donors included HLA-matched (n = 9), or mismatched (n = 3) related donors, or HLA-matched (n = 4), or mismatched (n = 4) unrelated donors, or DUCBT (n = 1). Disease status at the time of HSCT was: morphologic and cytogenetic CR (n = 12); RA with positive cytogenetics (n = 6); and refractory disease (n = 3). With a median follow-up of 5.9 years (2.2-15.7 years), the 5-year overall survival (OS) and disease-free survival (DFS) rates for the entire group were 61.1% with 12 patients alive without evidence of either primary disease or tMDS/tAML. The OS and DFS rate for the 11 patients who received the BU-MEL-FLU cytoreduction with TCD grafts was 54.5%. DFS was 65.7% for patients in RA or CR at HSCT compared with 0% for patients with >5% residual marrow blasts (P = .015). Nine patients died; the cause of death was relapse of MDS/AML (n = 4) or primary disease (n = 2), graft-versus-host disease (GVHD; n = 2), and infection (n = 1). Four patients developed grade II to IV acute GVHD. One patient developed localized chronic GVHD. Our results suggest that the strategy of induction with high-dose cytarabine therapy followed by allogeneic stem cell transplantation improves the overall outcome for patients with tMDS/tAML. In addition, the use of a TCD transplantation with BU-MEL-FLU as cytoreduction may decrease the toxicity of transplantation in heavily pretreated patients without an increase in relapse rate.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/cirurgia , Síndromes Mielodisplásicas/cirurgia , Segunda Neoplasia Primária/cirurgia , Adolescente , Adulto , Criança , Intervalo Livre de Doença , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Síndromes Mielodisplásicas/etiologia , Transplante Homólogo , Adulto Jovem
15.
Blood ; 116(24): 5111-8, 2010 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-20826719

RESUMO

Invasive fungal infection (IFI) is a serious threat after allogeneic hematopoietic cell transplant (HCT). This multicenter, randomized, double-blind trial compared fluconazole (N = 295) versus voriconazole (N = 305) for the prevention of IFI in the context of a structured fungal screening program. Patients undergoing myeloablative allogeneic HCT were randomized before HCT to receive study drugs for 100 days, or for 180 days in higher-risk patients. Serum galactomannan was assayed twice weekly for 60 days, then at least weekly until day 100. Positive galactomannan or suggestive signs triggered mandatory evaluation for IFI. The primary endpoint was freedom from IFI or death (fungal-free survival; FFS) at 180 days. Despite trends to fewer IFIs (7.3% vs 11.2%; P = .12), Aspergillus infections (9 vs 17; P = .09), and less frequent empiric antifungal therapy (24.1% vs 30.2%, P = .11) with voriconazole, FFS rates (75% vs 78%; P = .49) at 180 days were similar with fluconazole and voriconazole, respectively. Relapse-free and overall survival and the incidence of severe adverse events were also similar. This study demonstrates that in the context of intensive monitoring and structured empiric antifungal therapy, 6-month FFS and overall survival did not differ in allogeneic HCT recipients given prophylactic fluconazole or voriconazole. This trial was registered at www.clinicaltrials.gov as NCT00075803.


Assuntos
Fluconazol/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Micoses/prevenção & controle , Adolescente , Adulto , Idoso , Antifúngicos , Aspergilose/tratamento farmacológico , Aspergilose/prevenção & controle , Criança , Pré-Escolar , Intervalo Livre de Doença , Método Duplo-Cego , Monitoramento de Medicamentos , Fluconazol/efeitos adversos , Galactose/análogos & derivados , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Mananas/sangue , Pessoa de Meia-Idade , Micoses/tratamento farmacológico , Agonistas Mieloablativos/uso terapêutico , Taxa de Sobrevida , Transplante Homólogo , Adulto Jovem
16.
Haematologica ; 97(3): 344-52, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22133780

RESUMO

BACKGROUND: Thrombosis is the major risk factor for death in patients with paroxysmal nocturnal hemoglobinuria. Previous case reports indicate that venous thrombosis in patients with paroxysmal nocturnal hemoglobinuria is amenable to thrombolysis. DESIGN AND METHODS: We reviewed the outcome of thrombolytic therapy for patients with paroxysmal nocturnal hemoglobinuria who had thromboses refractory to anticoagulation at our institutions. RESULTS: In this study of 41 patients who had at least one thrombotic event, we confirmed a very high incidence of recurrence despite anticoagulation. Nine patients with thrombosis were regarded as eligible for administration of intravenous tissue plasminogen activator, which was effective in reversing thrombi in all of 15 occasions in which it was given. Serious hemorrhagic complications developed in three cases. At last follow-up visit, of the nine patients treated, three had died, and six were in very good to excellent condition in terms of clinical outcome and radiological findings. The only patient in whom thrombolysis may have contributed to a fatal outcome also had complications of "heparin induced thrombocytopenia with thrombosis", which we diagnosed in three additional patients. In our review of the literature, nine out of 15 patients treated with thrombolysis have had a good outcome. CONCLUSIONS: Although it is associated with a significant but manageable risk of bleeding, systemic thrombolysis is a highly effective treatment for reversing venous thromboses in patients with paroxysmal nocturnal hemoglobinuria.


Assuntos
Fibrinolíticos/uso terapêutico , Hemoglobinúria Paroxística/tratamento farmacológico , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/uso terapêutico , Adolescente , Adulto , Idoso , Anticoagulantes/uso terapêutico , Evolução Fatal , Feminino , Fibrinolíticos/administração & dosagem , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Gravidez , Recidiva , Fatores de Risco , Ativador de Plasminogênio Tecidual/administração & dosagem , Resultado do Tratamento , Trombose Venosa/diagnóstico , Trombose Venosa/tratamento farmacológico , Trombose Venosa/etiologia , Adulto Jovem
17.
Pediatr Blood Cancer ; 59(3): 525-9, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22147651

RESUMO

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease in children. The most significant clinical features of PNH include: bone marrow failure, intravascular hemolysis, and thrombosis. To further characterize the clinical presentation and outcome to treatment we performed a retrospective analysis of pediatric patients with PNH. PROCEDURE: We reviewed the medical records of 12 consecutive pediatric patients with PNH diagnosed at our institution from 1992 to 2010. RESULTS: Presenting clinical symptoms included: bone marrow failure (N = 10); gross hemoglobinuria with isolated red cell anemia (N = 1); and jaundice, hepatitis, and isolated thrombocytopenia (N = 1). Immunosuppressive therapy was the initial treatment for 8 patients. Five patients had myelodysplastic features without developing excessive blasts or leukemic transformation. Thrombosis occurred in 6 patients. Five patients underwent hematopoietic stem cell transplant (HSCT) of whom 3 patients are alive and disease-free. Three patients received anti-complement therapy with eculizumab. Two patients died following complications related to thrombosis and 2 patients are transfusion independent with stable disease. CONCLUSION: This report highlights a high rate of bone marrow failure along with a low rate of hemoglobinuria at presentation, a high rate of thrombosis, and for some patients the spontaneous resolution of myelodysplastic features. Delay in diagnosis is common and we recommend appropriate PNH testing in all patients with AA, MDS, unexplained Coombs-negative hemolysis, or thrombosis. While HSCT remains the only curative option the high prevalence of hemolysis and thrombosis should warrant the consideration of early treatment with anti-complement therapy.


Assuntos
Hemoglobinúria Paroxística/diagnóstico , Adolescente , Anemia/etiologia , Medula Óssea/patologia , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas , Hemoglobinúria Paroxística/patologia , Hemoglobinúria Paroxística/terapia , Hemólise , Humanos , Imunossupressores/uso terapêutico , Masculino , Estudos Retrospectivos , Trombose/etiologia
18.
Biol Blood Marrow Transplant ; 17(11): 1708-13, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21664979

RESUMO

There are limited studies assessing the live attenuated varicella vaccine following allogeneic hematopoietic cell transplantation (alloHCT). Because of the morbidity of varicella acquired after childhood, we immunized and retrospectively analyzed the safety and immunogenicity of this vaccine in 46 varicella zoster virus (VZV) seronegative patients <20 years old at HCT who achieved a CD4 cell count ≥200/µL, were off immunosuppression, and responded to ≥1 post-HCT vaccines. Two vaccinated patients lacking follow-up titers were excluded from analysis. Stem cells were derived from an HLA-matched sibling (n = 18) or an alternative (HLA mismatched related or unrelated) donor (n = 26). Median time to vaccination was 4 years. Sixty-four percent of patients seroconverted following 1 immunization. There was no significant difference in response between recipients of a matched related or alternative donor graft (P = .2) or between those given a T cell-depleted or T-replete alternative donor graft (P = .27). Three of 44 patients developed a self-limited varicella-like rash within 2.5 weeks of immunization. With a median follow-up of 29.1 (range: 6.9-167.1) months, there were no subsequent cases of varicella-like rashes. No patient developed shingles. This study suggests that this vaccine is safe and immunogenic when given according to preset clinical and immunologic milestones, warranting larger prospective studies in patients ≥24 months following HCT as outlined in current post-HCT vaccine guidelines.


Assuntos
Vacina contra Varicela/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Herpesvirus Humano 3/imunologia , Linfócitos T/imunologia , Transplante Homólogo/métodos , Adolescente , Adulto , Vacina contra Varicela/administração & dosagem , Vacina contra Varicela/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Imunização , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia , Adulto Jovem
19.
Biol Blood Marrow Transplant ; 17(10): 1460-71, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21310254

RESUMO

Factors contributing to infection risk after cord blood transplantation (CBT) include the use of anti-thymocyte globulin (ATG), prolonged neutropenia, and failure to transfer immunity. In the present study, we investigated the potential of double-unit CBT without ATG to reduce the risk of infection and evaluated the nature of serious infections in the first year after CBT using this approach. Seventy-two predominantly adult patients underwent CBT for hematologic malignancies; of these, 52 patients received myeloablative conditioning, and 20 received nonmyeloablative conditioning. The peak incidences of bacterial infections (32%), fungal infections (14%), and bacterial/fungal pneumonias (10%) occurred in the first 30 days posttransplantation. Three such infections contributed to early mortality. The peak incidence of viral infections was 31-60 days posttransplantation, affecting 30% of patients. Cytomegalovirus (CMV) was the most common viral infection. CMV infections occurring before day 120 (n = 23) had no relationship with graft-versus-host disease (GVHD), whereas CMV infections occurring after day 120 (n = 5), along with all cases of Epstein-Barr virus viremia (n = 5) and adenoviral enteritis (n = 2), occurred exclusively in the context of GVHD therapy or corticosteroid use for another indication. Viral infections had the highest lethality: 2 were a direct cause of death, and 3 contributed to death. Patients exhibited steady immune recovery, achieving a median CD3(+)4(+) T cell count >200 cells/µL by day 120 post-CBT, and no infection-related deaths occurred after day 120. Our results suggest that double-unit CBT without ATG is associated with prompt T cell recovery, and, unlike in CBT incorporating ATG, infection is rarely a primary cause of death. However, CBT without ATG is associated with a significant risk of GVHD, and serious infections remain a challenge, especially in the setting of GVHD. New strategies are needed to further reduce infectious complications after CBT; these will require earlier neutrophil recovery and more effective prevention of GVHD, ideally without the profound T cell depletion associated with ATG therapy.


Assuntos
Soro Antilinfocitário/administração & dosagem , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Infecções por Citomegalovirus/mortalidade , Infecções por Vírus Epstein-Barr/mortalidade , Fatores Imunológicos/administração & dosagem , Condicionamento Pré-Transplante , Adulto , Idoso , Criança , Pré-Escolar , Citomegalovirus , Infecções por Citomegalovirus/prevenção & controle , Infecções por Vírus Epstein-Barr/prevenção & controle , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Herpesvirus Humano 4 , Humanos , Lactente , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
20.
Biol Blood Marrow Transplant ; 17(9): 1335-42, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21232623

RESUMO

We report a prospective phase II clinical trial in 35 adult patients (median age 40.5 years) with hematologic malignancies who received T cell-depleted, hematopoietic stem cell transplants from HLA-compatible, unrelated donors. The cytoreductive regimen consisted of hyperfractionated total-body irradiation, thiotepa, and fludarabine. The preferred graft source was granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSC). PBSC were CD34(+) selected, followed by sheep erythrocyte rosetting to deplete residual T cells. Anti-thymocyte globulin provided graft rejection prophylaxis. No additional graft-versus-host disease (GVHD) prophylaxis was planned. Estimated disease-free survival at 4 years is 56.8% for the entire group and 75% in patients with standard-risk disease. The cumulative incidence of relapse is 6%. Acute GVHD grade II-III developed in 9% and chronic GVHD in 29% of patients. Fatal infections occurred in 5 of 35 (14%) patients. There was 1 late graft failure. This study demonstrates durable engraftment with a low overall incidence of GVHD. Its curative potential is reflected in the remarkably low relapse rate at 4 years.


Assuntos
Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Depleção Linfocítica/métodos , Adolescente , Adulto , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro , Neoplasias Hematológicas/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T , Doadores de Tecidos , Resultado do Tratamento , Adulto Jovem
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