RESUMO
We investigated the molecular and cellular basis of severe combined immunodeficiency (SCID) in six patients with otofaciocervical syndrome type 2 who failed to attain T cell reconstitution after allogeneic hematopoietic stem cell transplantation, despite successful engraftment in three of them. We identified rare biallelic PAX1 rare variants in all patients. We demonstrated that these mutant PAX1 proteins have an altered conformation and flexibility of the paired box domain and reduced transcriptional activity. We generated patient-derived induced pluripotent stem cells and differentiated them into thymic epithelial progenitor cells and found that they have an altered transcriptional profile, including for genes involved in the development of the thymus and other tissues derived from pharyngeal pouches. These results identify biallelic, loss-of-function PAX1 mutations as the cause of a syndromic form of SCID due to altered thymus development.
Assuntos
Fatores de Transcrição Box Pareados/imunologia , Timo/imunologia , Síndrome Brânquio-Otorrenal/genética , Síndrome Brânquio-Otorrenal/imunologia , Síndrome Brânquio-Otorrenal/patologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Humanos , Lactente , Masculino , Fatores de Transcrição Box Pareados/genética , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Timo/patologiaRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. In the HLH-94 study, with an estimated 5-year probability of survival (pSu) of 54% (95% confidence interval, 48%-60%), systemic therapy included etoposide, dexamethasone, and, from week 9, cyclosporine A (CSA). Hematopoietic stem cell transplantation (HSCT) was indicated in patients with familial/genetic, relapsing, or severe/persistent disease. In HLH-2004, CSA was instead administered upfront, aiming to reduce pre-HSCT mortality and morbidity. From 2004 to 2011, 369 children aged <18 years fulfilled HLH-2004 inclusion criteria (5 of 8 diagnostic criteria, affected siblings, and/or molecular diagnosis in FHL-causative genes). At median follow-up of 5.2 years, 230 of 369 patients (62%) were alive (5-year pSu, 61%; 56%-67%). Five-year pSu in children with (n = 168) and without (n = 201) family history/genetically verified FHL was 59% (52%-67%) and 64% (57%-71%), respectively (familial occurrence [n = 47], 58% [45%-75%]). Comparing with historical data (HLH-94), using HLH-94 inclusion criteria, pre-HSCT mortality was nonsignificantly reduced from 27% to 19% (P = .064 adjusted for age and sex). Time from start of therapy to HSCT was shorter compared with HLH-94 (P =020 adjusted for age and sex) and reported neurological alterations at HSCT were 22% in HLH-94 and 17% in HLH-2004 (using HLH-94 inclusion criteria). Five-year pSu post-HSCT overall was 66% (verified FHL, 70% [63%-78%]). Additional analyses provided specific suggestions on potential pre-HSCT treatment improvements. HLH-2004 confirms that a majority of patients may be rescued by the etoposide/dexamethasone combination but intensification with CSA upfront, adding corticosteroids to intrathecal therapy, and reduced time to HSCT did not improve outcome significantly.
Assuntos
Dexametasona/uso terapêutico , Etoposídeo/uso terapêutico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclosporina/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Lactente , Estudos Longitudinais , Masculino , Resultado do TratamentoRESUMO
PURPOSE: Health-related quality of life (HRQOL) has not been examined in patients with predominant antibody deficiency both pre- and post-immunoglobulin G (IgG) treatment initiation. HRQOL and health resource utilization (HRU) were assessed in newly diagnosed patients with primary immunodeficiency disease (PIDD) pre- and 12 months post-IgG treatment initiation. METHODS: Adults (age ≥18 years) completed the 36-item Short Form Health Survey, version 2; pediatric patients (PP)/caregivers completed the Pediatric Quality of Life Inventory (PedsQL). Scores were compared with normative data from the US general population (GP) and patients with other chronic conditions (OCC). RESULTS: Seventeen adult patients (APs), 8 PPs, and 8 caregivers completed baseline assessments. APs had significantly lower baseline mean physical component summary scores versus GP (37.4 vs 50.5, p < 0.01) adults with chronic back pain (44.1, p < 0.05) or cancer (44.4, p < 0.05) and lower mental component summary scores versus GP (41.6 vs 49.2, p < 0.05). PPs had lower PedsQL total (63.1 vs 82.7), physical summary (64.5 vs 84.5), and psychosocial summary (62.5 vs 81.7) scores versus GP. Post-IgG treatment, 14 APs, 6 PPs, and 8 caregivers completed assessments. Hospital admissions (0.2 versus 1.8, p < 0.01), serious infections (3.3 versus 10.9, p < 0.01) and antibiotic prescriptions (3.0 versus 7.1; p < 0.01) decreased significantly overall. While APs reported significant improvement in role-physical (p = 0.01), general health (p < 0.01), and social functioning (p = 0.02) and caregivers in vitality (p < 0.01), PPs did not. CONCLUSIONS: Pre-IgG treatment, patients with PIDD experienced diminished HRQOL versus GP and patients with OCC; post-treatment, HRU decreased and certain HRQOL aspects improved for APs and caregivers.
Assuntos
Síndromes de Imunodeficiência/epidemiologia , Aceitação pelo Paciente de Cuidados de Saúde , Qualidade de Vida , Adulto , Criança , Pré-Escolar , Feminino , Recursos em Saúde , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
The biology of engraftment syndrome is poorly understood, and the degree of overlap with acute graft-versus-host disease (GVHD) is unclear. To understand engraftment syndrome better, plasma cytokine profiles were evaluated in 56 pediatric allogeneic bone marrow transplant recipients before transplant, on the day of stem cell infusion, and weekly until day +100. Patients were divided into 4 groups: those with isolated engraftment syndrome (n = 8), acute GVHD (n = 12), both engraftment syndrome and acute GVHD (n = 4), and neither engraftment syndrome nor acute GVHD (n = 32). Engraftment syndrome was observed a median of 13.5 days (range, 10 to 28) after transplant, whereas acute GVHD was diagnosed a median of 55 days (range, 19 to 95) after transplant. Four patients developed both engraftment syndrome at a median of 10.5 days (range, 10 to 11) and acute GVHD at a median of 35 days (range, 23 to 56) after stem cell infusion. Median plasma levels of IL-1ß, IL-6, IL-12, IL-4, and IL-13 were significantly elevated in patients with isolated engraftment syndrome when compared with isolated acute GVHD. A rise of proinflammatory cytokines (IL-1ß, IL-6, and IL-12) was followed by surge in anti-inflammatory cytokines (IL-4 and IL-13) in patients with isolated engraftment syndrome. The observation of elevated IL-1ß suggests that engraftment syndrome could be an inflammasome mediated phenomenon.
Assuntos
Citocinas/biossíntese , Doença Enxerto-Hospedeiro/imunologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Condicionamento Pré-Transplante , Doença Aguda , Adolescente , Alemtuzumab , Anticorpos Monoclonais Humanizados/uso terapêutico , Soro Antilinfocitário/uso terapêutico , Criança , Pré-Escolar , Ciclosporina/uso terapêutico , Citocinas/imunologia , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Humanos , Lactente , Inflamassomos/imunologia , Masculino , Agonistas Mieloablativos/uso terapêutico , Estudos Prospectivos , Análise de Sobrevida , Transplante Homólogo , Adulto JovemRESUMO
Reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) with alemtuzumab, fludarabine, and melphalan is an effective approach for patients with nonmalignant disorders. Mixed chimerism and graft-versus-host-disease (GVHD) remain limitations on success. We hypothesized that higher levels of alemtuzumab at day 0 would result in a low risk of acute GVHD, a higher risk of mixed chimerism, and delayed early lymphocyte recovery and that alemtuzumab level thresholds for increased risks of these outcomes would be definable. We collected data from 105 patients to examine the influence of peritransplant alemtuzumab levels on acute GVHD, mixed chimerism, and lymphocyte recovery. The cumulative incidences of initial grades I-IV, II-IV, and III-IV acute GVHD in patients with alemtuzumab levels ≤0.15 vs ≥0.16 µg/mL were 68% vs 18% (P < .0001), 47% vs 13% (P = .0002), and 32% vs 8%, respectively (P = .005). The cumulative incidence of mixed chimerism in patients with an alemtuzumab level ≤0.15 µg/mL was 21%, vs 42% with levels of 0.16 to 4.35 µg/mL, and 100% with levels >4.35 µg/mL (P = .003). Patients with alemtuzumab levels ≤0.15 or 0.16 to 0.56 µg/mL had higher lymphocyte counts at day +30 and higher T-cell counts at day +100 compared with patients with levels ≥0.57 µg/mL (all P < .05). We conclude that peritransplant alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following RIC HCT with alemtuzumab, fludarabine, and melphalan. Precision dosing trials are warranted. We recommend a day 0 therapeutic range of 0.2 to 0.4 µg/mL.
Assuntos
Anticorpos Monoclonais Humanizados/sangue , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Melfalan/sangue , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Adolescente , Adulto , Alemtuzumab , Anticorpos Monoclonais Humanizados/uso terapêutico , Criança , Pré-Escolar , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Linfócitos/efeitos dos fármacos , Melfalan/uso terapêutico , Estudos Prospectivos , Quimeras de Transplante , Condicionamento Pré-Transplante/efeitos adversos , Vidarabina/sangue , Vidarabina/uso terapêutico , Adulto JovemAssuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia/terapia , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Doenças do Sistema Imunitário/congênito , Transplante de Células-Tronco , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Diarreia/genética , Diarreia/imunologia , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/terapia , Mutação , Transplante de Células-Tronco/métodos , Resultado do TratamentoRESUMO
Invasive fungal infections are a significant cause of morbidity and mortality in recipients of hematopoietic stem cell transplantation (HSCT), warranting antifungal prophylaxis as a standard of care in these patients. Voriconazole is commonly used in this setting because of its broad-spectrum activity and available dosage forms. There is wide well-known inter- and intrapatient variability in voriconazole concentrations, in part because concentrations are affected by common CYP2C19 polymorphisms. In 2 successive studies we have optimized voriconazole dosing to achieve target voriconazole serum concentrations using a genotype-specific dosing algorithm for antifungal prophylaxis in the post-HSCT period. In our pilot study all patients undergoing HSCT who received voriconazole antifungal prophylaxis were prospectively followed. Voriconazole concentrations were monitored weekly and doses adjusted until concentrations reached between 1 and 5.5 µg/L. The most common CYP2C19 polymorphisms were determined and correlated with voriconazole dose and time required to reach the target concentration range. In the subsequent study patients receiving voriconazole prophylaxis were dosed based on their CYP2C19 genotype and followed prospectively. In the pilot study 25 patients received voriconazole as antifungal prophylaxis for a median of 49 days (range, 15 to 196 days). The median time to reach the target concentration was 34 days for extensive metabolizers and 11 days for poor metabolizers. Three patients were genotyped as intermediate metabolizers; they reached the target concentration in a median of 56 days. Similarly, 2 patients who were genotyped as ultrarapid metabolizers reached the target range in 18 and 25 days. The time and dose required to reach the adequate concentration showed a trend toward correlation with individual CYP2C19 genotype, although voriconazole concentrations showed large interpatient variability in wild-type patients (extensive metabolizers). In our follow-up study, 20 patients received voriconazole prophylaxis prospectively dosed based on their CYP2C19 genotype. The median times to reach the target concentration using genotype-guided dosing were 9, 6.5, and 4 days for ultrarapid, extensive, and intermediate metabolizers, respectively. Overall, the median time to reach the target concentration with genotype-guided dosing was 6.5 days compared with a median time of 29 days when all patients were started on the same dose regardless of CYP2C19 genotype (P < .001). Our data show that traditional voriconazole dosing does not lead to timely achievement of target levels for fungal prophylaxis. However, a genotype-directed dosing algorithm allows patients to reach the voriconazole target range significantly sooner, providing better prophylaxis against fungal infections in the immediate post-transplant period.
Assuntos
Algoritmos , Citocromo P-450 CYP2C19/genética , Genótipo , Transplante de Células-Tronco Hematopoéticas , Micoses , Polimorfismo Genético , Voriconazol , Adolescente , Aloenxertos , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Micoses/genética , Micoses/prevenção & controle , Medicina de Precisão , Voriconazol/administração & dosagem , Voriconazol/farmacocinéticaAssuntos
Citometria de Fluxo/métodos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Mutação/genética , Perforina/metabolismo , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Ensaios de Triagem em Larga Escala , Humanos , Lactente , Recém-Nascido , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/metabolismo , Masculino , Pessoa de Meia-Idade , Perforina/genética , Prognóstico , Curva ROCRESUMO
Hemophagocytic Lymphohistiocytosis (HLH), an inherited life-threatening inflammatory disorder, has gained growing recognition not only in children but also increasingly in adults over the past 2 decades. HLH involves inborn defects in lymphocytes, which normally mediate control of infectious and inflammatory conditions within the immune system and in other tissues. In the context of inherited defects in cytotoxic cells and other immune cells, the disorder is classified as familial or primary HLH. Secondary HLH occurs in the settings of infections or underlying rheumatologic disorders. Secondary HLH also accompanies some lymphoid malignancies.
Assuntos
Linfo-Histiocitose Hemofagocítica/etiologia , Terapia Combinada , Predisposição Genética para Doença , Variação Genética , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/mortalidade , Linfo-Histiocitose Hemofagocítica/terapia , Transdução de Sinais , Resultado do TratamentoRESUMO
Mutations in the LRBA gene (encoding the lipopolysaccharide-responsive and beige-like anchor protein) cause a syndrome of autoimmunity, lymphoproliferation, and humoral immune deficiency. The biological role of LRBA in immunologic disease is unknown. We found that patients with LRBA deficiency manifested a dramatic and sustained improvement in response to abatacept, a CTLA4 (cytotoxic T lymphocyte antigen-4)-immunoglobulin fusion drug. Clinical responses and homology of LRBA to proteins controlling intracellular trafficking led us to hypothesize that it regulates CTLA4, a potent inhibitory immune receptor. We found that LRBA colocalized with CTLA4 in endosomal vesicles and that LRBA deficiency or knockdown increased CTLA4 turnover, which resulted in reduced levels of CTLA4 protein in FoxP3(+) regulatory and activated conventional T cells. In LRBA-deficient cells, inhibition of lysosome degradation with chloroquine prevented CTLA4 loss. These findings elucidate a mechanism for CTLA4 trafficking and control of immune responses and suggest therapies for diseases involving the CTLA4 pathway.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doenças Autoimunes/tratamento farmacológico , Antígeno CTLA-4/deficiência , Imunodeficiência de Variável Comum/tratamento farmacológico , Imunoconjugados/uso terapêutico , Abatacepte , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Doenças Autoimunes/metabolismo , Antígeno CTLA-4/genética , Criança , Cloroquina/farmacologia , Imunodeficiência de Variável Comum/metabolismo , Endossomos/metabolismo , Feminino , Fatores de Transcrição Forkhead/análise , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/metabolismo , Ativação Linfocitária , Lisossomos/metabolismo , Masculino , Proteólise , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Adulto JovemRESUMO
Acute graft-versus-host disease (aGVHD) is mediated by allogeneic T cell responses. We hypothesized that increases of peripheral blood-activated CD8+ effector memory T (TEM) cells would be observed after hematopoietic stem cell transplantation (HSCT) before onset of aGVHD symptoms. Blood was collected twice weekly after HSCT for 7 weeks in 49 consecutive pediatric and adult HSCT recipients. Samples were incubated with fluorochrome-conjugated antibodies against CD45, CD3, CD8, CD38, CD45RA, and CCR7 and analyzed using flow cytometry. TEM cells were defined as CD3+ CD8+ CCR7- CD45RA(-) lymphocytes. CD38 expression was used as a marker of T cell activation. Patients were followed for 100 days for development of aGVHD. Twenty-three patients developed grade 1 to 4 aGVHD at a median of 37 days (range, 15 to 79 days) after HCST. Absolute CD38 bright CD8+ TEM of > 35 cells/µL predicted aGVHD at a median of 8 days (range, 1 to 34) before aGVHD onset with a sensitivity of 82.6% and specificity of 91.6%. The cumulative incidence of aGVHD was 90% in patients with absolute CD38 bright CD8+ TEM >35 cells/µL and 15% in patients without (P < .0001). Quantification of CD38 bright CD8+ TEM cells may predict aGVHD in children and young adult HSCT recipients.
Assuntos
ADP-Ribosil Ciclase 1/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunodeficiência de Variável Comum/terapia , Doença Enxerto-Hospedeiro/diagnóstico , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Glicoproteínas de Membrana/imunologia , Condicionamento Pré-Transplante , ADP-Ribosil Ciclase 1/genética , Doença Aguda , Adolescente , Adulto , Biomarcadores/análise , Linfócitos T CD8-Positivos/patologia , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/patologia , Feminino , Expressão Gênica , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Teste de Histocompatibilidade , Humanos , Memória Imunológica , Imunofenotipagem , Imunossupressores/uso terapêutico , Lactente , Ativação Linfocitária , Masculino , Glicoproteínas de Membrana/genética , Agonistas Mieloablativos/uso terapêutico , Transplante HomólogoRESUMO
Alemtuzumab, fludarabine, and melphalan reduced-intensity conditioning (RIC) regimens are increasingly used for the hematopoietic cell transplantation (HCT) of pediatric and young adult patients with nonmalignant diseases. Early experience suggests that these regimens are associated with good survival but a high incidence of mixed chimerism, which we have previously shown to be influenced by the alemtuzumab schedule. We hypothesized that the underlying diagnosis and donor graft source would also affect the development of mixed chimerism and that the majority of patients would survive RIC HCT without graft loss. To examine this, we conducted a retrospective study of 206 patients with metabolic diseases, non-Fanconi anemia marrow failure disorders, and primary immune deficiencies who underwent 210 consecutive RIC HCT procedures at Cincinnati Children's Hospital. Ninety-seven percent of the patients engrafted. Mixed donor and recipient chimerism developed in 46% of patients. Patients with marrow failure had a low risk of mixed chimerism (hazard ratio [HR], .208; 95% confidence interval [CI], .061 to .709; P = .012). The risk of mixed chimerism was high in patients who received a cord blood graft (HR, 3.122; 95% CI, 1.236 to 7.888; P = .016). As expected, patients who received a proximal or higher dose per kilogram of alemtuzumab schedule also experienced higher rates of mixed chimerism (all HR > 2, all P < .05). At the time of last follow-up (median, 654 days; range, 13 to 3337), over 75% of patients had greater than 90% whole blood donor chimerism. A second transplantation was performed in 5% of patients. Three-year survival without retransplantation was 84% (95% CI, 71% to 98%) for patients who underwent transplantation with an HLA-matched sibling donor. Survival without retransplantation was negatively affected by lack of a matched related donor, increasing age, and development of grades III and IV acute graft-versus-host disease. We conclude that alemtuzumab, fludarabine, and melphalan RIC HCT offers good results for many patients and that the risk of developing mixed chimerism is influenced by underlying diagnosis, graft source, and alemtuzumab dosing.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melfalan/uso terapêutico , Vidarabina/análogos & derivados , Adolescente , Adulto , Alemtuzumab , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Criança , Pré-Escolar , Quimerismo , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Melfalan/administração & dosagem , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/uso terapêutico , Adulto JovemRESUMO
Patients with Langerhans cell histiocytosis (LCH) refractory to conventional chemotherapy have a poor outcome. There are currently two promising treatment strategies for high-risk patients: the first involves the combination of 2-chlorodeoxyadenosine and cytarabine; the other approach is allogeneic haematopoietic stem cell transplantation (HSCT). Here we evaluated 87 patients with high-risk LCH who were transplanted between 1990 and 2013. Prior to the year 2000, most patients underwent HSCT following myeloablative conditioning (MAC): only 5 of 20 patients (25%) survived with a high rate (55%) of transplant-related mortality (TRM). After the year 2000 an increasing number of patients underwent HSCT with reduced intensity conditioning (RIC): 49/67 (73%) patients survived, however, the improved survival was not overtly achieved by the introduction of RIC regimens with similar 3-year probability of survival after MAC (77%) and RIC transplantation (71%). There was no significant difference in TRM by conditioning regimen intensity but relapse rates were higher after RIC compared to MAC regimens (28% vs. 8%, P = 0·02), although most patients relapsing after RIC transplantation could be salvaged with further chemotherapy. HSCT may be a curative approach in 3 out of 4 patients with high risk LCH refractory to chemotherapy: the optimal choice of HSCT conditioning remains uncertain.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Histiocitose de Células de Langerhans/terapia , Condicionamento Pré-Transplante , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Histiocitose de Células de Langerhans/mortalidade , Histiocitose de Células de Langerhans/patologia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
X-linked thrombocytopenia (XLT) is a mild form of the Wiskott-Aldrich syndrome (WAS) caused by mutations in the WAS gene. A recent retrospective study of the clinical outcome and molecular basis of a large cohort of XLT patients demonstrated that although overall survival is excellent, event free survival is severely affected with conservative treatment. To answer the question whether hematopoietic stem cell transplantation (HSCT) offers a viable alternative therapeutic option in XLT, we retrospectively investigated the outcome of HSCT in a cohort of 24 XLT patients who received HSCT between 1990 and 2011 at 14 transplant centers in the United States, Italy, Germany, Canada, and Japan. The engraftment rate was 100% and the overall survival rate was 83.3%. Of the four non-survivors, 2 underwent splenectomy prior to HSCT and died of sepsis, and two of aspergillus infections associated with severe GVHD. In all but one patient, pretransplant complications were resolved by HSCT. Our data indicate that HSCT following myeloablative conditioning is curative and associated with acceptable risks as a treatment option for XLT.
Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Transplante de Células-Tronco Hematopoéticas , Mutação , Trombocitopenia/genética , Trombocitopenia/terapia , Proteína da Síndrome de Wiskott-Aldrich/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Intervalo Livre de Doença , Doenças Genéticas Ligadas ao Cromossomo X/mortalidade , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Estudos Retrospectivos , Trombocitopenia/mortalidade , Síndrome de Wiskott-Aldrich/genética , Adulto JovemRESUMO
Mixed donor chimerism is increasingly common in the pediatric hematopoietic stem cell transplantation (HSCT) setting because of the increased use of reduced-intensity preparative regimens for nonmalignant diseases. Donor lymphocyte infusion (DLI) is potentially useful in the treatment of mixed donor chimerism, but little are data available on the use of DLI in this setting. We conducted a retrospective review of 27 pediatric patients who received DLI for mixed donor chimerism between January 2006 and December 2010 after receiving a preparative regimen of alemtuzumab, fludarabine, and melphalan. Twenty-one patients (78%) were alive at a median of 35 months post-transplant. Seven patients (26%) sustained full donor chimerism after DLI only at a median of 35 months post-HSCT. Nine patients (33%) continued with mixed donor chimerism (median, 38% [range, 18% to 70%]) at a median of 37 months after DLI only. Five patients underwent unconditioned stem cell boosts or second conditioned transplants after no improvement in donor chimerism was seen following DLI. Donor source appeared to contribute to outcomes after DLI; patients with mismatched unrelated donors had earlier first decline in chimerism and timing of first DLI, a higher response rate to DLI, and an increased rate of graft-versus-host disease (GVHD). There was no response to DLI in patients with matched sibling donors. Ten patients, all with improvement in chimerism after DLI, developed acute GVHD after DLI, with 3 having grade III GVHD. Three patients developed chronic GVHD after DLI. These data illustrate the potential efficacy of DLI in the treatment of mixed donor chimerism after a reduced-intensity preparative regimen.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Transfusão de Linfócitos , Linfo-Histiocitose Hemofagocítica/terapia , Transtornos Linfoproliferativos/terapia , Mucopolissacaridoses/terapia , Imunodeficiência Combinada Severa/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Alemtuzumab , Anticorpos Monoclonais Humanizados/uso terapêutico , Criança , Pré-Escolar , Quimerismo , Feminino , Humanos , Lactente , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/patologia , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia , Masculino , Melfalan/uso terapêutico , Mucopolissacaridoses/imunologia , Mucopolissacaridoses/patologia , Agonistas Mieloablativos/uso terapêutico , Estudos Retrospectivos , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Irmãos , Transplante Homólogo , Resultado do Tratamento , Doadores não Relacionados , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoRESUMO
BACKGROUND: In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus-based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1. METHODS: We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc). RESULTS: All patients received bone marrow-derived CD34+ cells transduced with the SIN-γc vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2, MECOM, and other lymphoid proto-oncogenes in our patients. CONCLUSIONS: This modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01410019, NCT01175239, and NCT01129544.).
Assuntos
Gammaretrovirus/genética , Terapia Genética , Vetores Genéticos , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia , Animais , Antígenos CD34 , DNA Complementar/uso terapêutico , Expressão Gênica , Inativação Gênica , Terapia Genética/efeitos adversos , Humanos , Lactente , Subunidade gama Comum de Receptores de Interleucina/genética , Masculino , Camundongos , Mutação , Linfócitos T/imunologia , Transdução Genética , Transgenes/fisiologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologiaRESUMO
Therapy of refractory autoimmunity remains challenging. In this study, we evaluated the therapeutic effect of bortezomib, a proteasome inhibitor, by targeting plasma cells in 7 patients (median age, 9.9 years). Four doses of bortezomib were administered at a dose of 1.3 mg/m(2) intravenously (n = 6) or subcutaneously (n = 1) every 72 hours. Bortezomib was administered at a median of 120 days from laboratory confirmation of autoantibodies. All patients had failed 2 or more standard therapies. Rituximab was administered on the first day if B cells were present, and all patients received plasmapheresis 2 hours before bortezomib administration. Six patients experienced resolution of cytopenias. Two of 6 patients experienced recurrence of cytopenias after initial response. Adverse effects include nausea (n = 1), thrombocytopenia (n = 2), Clostridium difficile colitis (n = 1)), febrile neutropenia (n = 1), and cellulitis at the subcutaneous injection site (n = 1). Our experience suggests that bortezomib may be beneficial in the treatment of refractory autoimmunity in children.
Assuntos
Anemia Hemolítica Autoimune/tratamento farmacológico , Autoimunidade/efeitos dos fármacos , Ácidos Borônicos/uso terapêutico , Neutropenia/tratamento farmacológico , Inibidores de Proteassoma/uso terapêutico , Pirazinas/uso terapêutico , Trombocitopenia/tratamento farmacológico , Adolescente , Adulto , Anemia Hemolítica Autoimune/imunologia , Anemia Hemolítica Autoimune/patologia , Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Bortezomib , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Humanos , Lactente , Masculino , Neutropenia/imunologia , Neutropenia/patologia , Plasmócitos/efeitos dos fármacos , Plasmócitos/imunologia , Plasmócitos/patologia , Plasmaferese , Estudos Retrospectivos , Rituximab , Trombocitopenia/imunologia , Trombocitopenia/patologiaRESUMO
OBJECTIVE: Macrophage activation syndrome (MAS), a life-threatening complication of systemic juvenile idiopathic arthritis (JIA), resembles familial hemophagocytic lymphohistiocytosis (HLH), a constellation of autosomal-recessive immune disorders resulting from deficiency in cytolytic pathway proteins. We undertook this study to test our hypothesis that MAS predisposition in systemic JIA could be attributed to rare gene sequence variants affecting the cytotolytic pathway. METHODS: Whole-exome sequencing was used in 14 patients with systemic JIA and MAS and in their parents to identify protein-altering single-nucleotide polymorphisms/indels in known HLH-associated genes. To discover new candidate genes, the entire whole-exome sequencing data were filtered to identify protein-altering, rare recessive homozygous, compound heterozygous, and de novo variants with the potential to affect the cytolytic pathway. RESULTS: Heterozygous protein-altering rare variants in the known genes (LYST,MUNC13-4, and STXBP2) were found in 5 of 14 patients with systemic JIA and MAS (35.7%). This was in contrast to only 4 variants in 4 of 29 patients with systemic JIA without MAS (13.8%). Homozygosity and compound heterozygosity analysis applied to the entire whole-exome sequencing data in systemic JIA/MAS revealed 3 recessive pairs in 3 genes and compound heterozygotes in 73 genes. We also identified 20 heterozygous rare protein-altering variants that occurred in at least 2 patients. Many of the identified genes encoded proteins with a role in actin and microtubule reorganization and vesicle-mediated transport. "Cellular assembly and organization" was the top cellular function category based on Ingenuity Pathways Analysis (P < 3.10 × 10(-5) ). CONCLUSION: Whole-exome sequencing performed in patients with systemic JIA and MAS identified rare protein-altering variants in known HLH-associated genes as well as in new candidate genes.