RESUMO
BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase. METHODS: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6. RESULTS: A total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was -53.5 percentage points (P<0.001), with a reduction in the lumasiran group of 65.4% and an effect seen as early as month 1. The between-group differences for all hierarchically tested secondary end points were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was -39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group (P<0.001). Mild, transient injection-site reactions were reported in 38% of lumasiran-treated patients. CONCLUSIONS: Lumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal levels after 6 months of treatment. (Funded by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number, NCT03681184.).
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Hiperoxalúria Primária/tratamento farmacológico , Oxalatos/urina , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi , Adolescente , Adulto , Criança , Creatinina/urina , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular , Humanos , Hiperoxalúria Primária/sangue , Hiperoxalúria Primária/complicações , Hiperoxalúria Primária/urina , Cálculos Renais/prevenção & controle , Masculino , Pessoa de Meia-Idade , Oxalatos/sangue , Oxalatos/metabolismo , RNA Interferente Pequeno/efeitos adversos , Adulto JovemRESUMO
Haematopoietic stem and progenitor cells (HSPCs) require a specific microenvironment, the haematopoietic niche, which regulates HSPC behaviour1,2. The location of this niche varies across species, but the evolutionary pressures that drive HSPCs to different microenvironments remain unknown. The niche is located in the bone marrow in adult mammals, whereas it is found in other locations in non-mammalian vertebrates, for example, in the kidney marrow in teleost fish. Here we show that a melanocyte umbrella above the kidney marrow protects HSPCs against ultraviolet light in zebrafish. Because mutants that lack melanocytes have normal steady-state haematopoiesis under standard laboratory conditions, we hypothesized that melanocytes above the stem cell niche protect HSPCs against ultraviolet-light-induced DNA damage. Indeed, after ultraviolet-light irradiation, unpigmented larvae show higher levels of DNA damage in HSPCs, as indicated by staining of cyclobutane pyrimidine dimers and have reduced numbers of HSPCs, as shown by cmyb (also known as myb) expression. The umbrella of melanocytes associated with the haematopoietic niche is highly evolutionarily conserved in aquatic animals, including the sea lamprey, a basal vertebrate. During the transition from an aquatic to a terrestrial environment, HSPCs relocated into the bone marrow, which is protected from ultraviolet light by the cortical bone around the marrow. Our studies reveal that melanocytes above the haematopoietic niche protect HSPCs from ultraviolet-light-induced DNA damage in aquatic vertebrates and suggest that during the transition to terrestrial life, ultraviolet light was an evolutionary pressure affecting the location of the haematopoietic niche.
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Evolução Biológica , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos da radiação , Melanócitos/citologia , Melanócitos/efeitos da radiação , Nicho de Células-Tronco/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Animais , Organismos Aquáticos/classificação , Citoproteção/efeitos da radiação , Dano ao DNA/efeitos da radiação , Rim , Mutação , Petromyzon/classificação , Filogenia , Dímeros de Pirimidina/efeitos da radiação , Nicho de Células-Tronco/fisiologia , Peixe-Zebra/classificação , Peixe-Zebra/genéticaRESUMO
RATIONALE & OBJECTIVE: Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease. STUDY DESIGN: Phase 3, open-label, single-arm trial. SETTING & PARTICIPANTS: Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate ≤45 mL/min/1.73 m2 (if age ≥12 months) or increased serum creatinine level (if age <12 months), and POx ≥20 µmol/L at screening, including patients with or without systemic oxalosis. INTERVENTION: Lumasiran administered subcutaneously; 3 monthly doses followed by monthly or quarterly weight-based dosing. OUTCOME: Primary end point: percent change in POx from baseline to month 6 (cohort A; not receiving hemodialysis at enrollment) and percent change in predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at enrollment). Pharmacodynamic secondary end points: percent change in POx area under the curve between dialysis sessions (cohort B only); absolute change in POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and 24-hour urinary oxalate adjusted for body surface area. RESULTS: All patients (N = 21; 43% female; 76% White) completed the 6-month primary analysis period. Median age at consent was 8 (range, 0-59) years. For the primary end point, least-squares mean reductions in POx were 33.3% (95% CI, -15.2% to 81.8%) in cohort A (n = 6) and 42.4% (95% CI, 34.2%-50.7%) in cohort B (n = 15). Improvements were also observed in all pharmacodynamic secondary end points. Most adverse events were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related adverse events were injection-site reactions, all of which were mild and transient. LIMITATIONS: Single-arm study without placebo control. CONCLUSIONS: Lumasiran resulted in substantial reductions in POx with acceptable safety in patients with PH1 who have advanced kidney disease, supporting its efficacy and safety in this patient population. FUNDING: Alnylam Pharmaceuticals. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT04152200 and at EudraCT with study number 2019-001346-17. PLAIN-LANGUAGE SUMMARY: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive hepatic oxalate production that frequently causes kidney failure. Lumasiran is an RNA interference therapeutic that is administered subcutaneously for the treatment of PH1. Lumasiran has been shown to reduce oxalate levels in the urine and plasma of patients with PH1 who have relatively preserved kidney function. In the ILLUMINATE-C study, the efficacy and safety of lumasiran were evaluated in patients with PH1 and advanced kidney disease, including a cohort of patients undergoing hemodialysis. During the 6-month primary analysis period, lumasiran resulted in substantial reductions in plasma oxalate with acceptable safety in patients with PH1 complicated by advanced kidney disease.
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Hiperoxalúria Primária , Hiperoxalúria , Nefropatias , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Hiperoxalúria Primária/complicações , Nefropatias/complicações , OxalatosRESUMO
BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that causes progressive kidney damage and systemic oxalosis due to hepatic overproduction of oxalate. Lumasiran demonstrated efficacy and safety in the 6-month primary analysis period of the phase 3, multinational, open-label, single-arm ILLUMINATE-B study of infants and children < 6 years old with PH1 (ClinicalTrials.gov: NCT03905694 (4/1/2019); EudraCT: 2018-004,014-17 (10/12/2018)). Outcomes in the ILLUMINATE-B extension period (EP) for patients who completed ≥ 12 months on study are reported here. METHODS: Of the 18 patients enrolled in the 6-month primary analysis period, all entered the EP and completed ≥ 6 additional months of lumasiran treatment (median (range) duration of total exposure, 17.8 (12.7-20.5) months). RESULTS: Lumasiran treatment was previously reported to reduce spot urinary oxalate:creatinine ratio by 72% at month 6, which was maintained at 72% at month 12; mean month 12 reductions in prespecified weight subgroups were 89%, 68%, and 71% for patients weighing < 10 kg, 10 to < 20 kg, and ≥ 20 kg, respectively. The mean reduction from baseline in plasma oxalate level was reported to be 32% at month 6, and this improved to 47% at month 12. Additional improvements were also seen in nephrocalcinosis grade, and kidney stone event rates remained low. The most common lumasiran-related adverse events were mild, transient injection-site reactions (3 patients (17%)). CONCLUSIONS: Lumasiran treatment provided sustained reductions in urinary and plasma oxalate through month 12 across all weight subgroups, with an acceptable safety profile, in infants and young children with PH1. A higher resolution version of the Graphical abstract is available as Supplementary information.
Assuntos
Hiperoxalúria Primária , Cálculos Renais , Criança , Pré-Escolar , Humanos , Lactente , Hiperoxalúria Primária/complicações , Hiperoxalúria Primária/tratamento farmacológico , Cálculos Renais/etiologia , Oxalatos/efeitos adversosRESUMO
More than 1 million apheresis platelet collections are performed annually in the United States. After 2 healthy plateletpheresis donors were incidentally found to have low CD4+ T-lymphocyte counts, we investigated whether plateletpheresis causes lymphopenia. We conducted a cross-sectional single-center study of platelet donors undergoing plateletpheresis with the Trima Accel, which removes leukocytes continuously with its leukoreduction system chamber. We recruited 3 groups of platelet donors based on the total number of plateletpheresis sessions in the prior 365 days: 1 or 2, 3 to 19, or 20 to 24. CD4+ T-lymphocyte counts were <200 cells per microliter in 0/20, 2/20, and 6/20 donors, respectively (P = .019), and CD8+ T-lymphocyte counts were low in 0/20, 4/20, and 11/20 donors, respectively (P < .001). The leukoreduction system chamber's lymphocyte-extraction efficiency was â¼15% to 20% for all groups. Immunophenotyping showed decreases in naive CD4+ T-lymphocyte and T helper 17 (Th17) cell percentages, increases in CD4+ and CD8+ effector memory, Th1, and regulatory T cell percentages, and stable naive CD8+ and Th2 percentages across groups. T-cell receptor repertoire analyses showed similar clonal diversity in all groups. Donor screening questionnaires supported the good health of the donors, who tested negative at each donation for multiple pathogens, including HIV. Frequent plateletpheresis utilizing a leukoreduction system chamber is associated with CD4+ and CD8+ T-cell lymphopenia in healthy platelet donors. The mechanism may be repeated extraction of these cells during plateletpheresis. The cytopenias do not appear to be harmful.
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Doadores de Sangue/estatística & dados numéricos , Plaquetas/citologia , Linfopenia/etiologia , Plaquetoferese/efeitos adversos , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Prognóstico , Adulto JovemRESUMO
BACKGROUND: Recently, plateletpheresis donations using a widely used leukoreduction system (LRS) chamber have been associated with T-cell lymphopenia. However, clinical health consequences of plateletpheresis-associated lymphopenia are still unknown. STUDY DESIGN AND METHODS: A nationwide cohort study using the SCANDAT3-S database was conducted with all platelet- and plasmapheresis donors in Sweden between 1996 and 2017. A Cox proportional hazards model, using donations as time-dependent exposures, was used to assess the risk of infections associated with plateletpheresis donations using an LRS chamber. RESULTS: A total of 74 408 apheresis donors were included. Among donors with the same donation frequency, plateletpheresis donors using an LRS chamber were at an increased risk of immunosuppression-related infections and common bacterial infections in a dose-dependent manner. While very frequent donors and infections were rare in absolute terms resulting in wide confidence intervals (CIs), the increased risk was significant starting at one-third or less of the allowed donation frequency in a 10-year exposure window, with hazard ratios reaching 10 or more. No plateletpheresis donors that used an LRS chamber experienced a Pneumocystis jirovecii, aspergillus, disseminated mycobacterial, or cryptococcal infection. In a subcohort (n = 42), donations with LRS were associated with low CD4+ T-cell counts (Pearson's R = -0.41; 95% CI, - 0.63 to -0.12). CONCLUSION: Frequent plateletpheresis donation using an LRS chamber was associated with CD4+ T-cell lymphopenia and an increased risk of infections. These findings suggest a need to monitor T-lymphocyte counts in frequent platelet donors and to conduct future investigations of long-term donor health and for regulators to consider steps to mitigate lymphodepletion in donors.
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Doadores de Sangue , Infecções/epidemiologia , Procedimentos de Redução de Leucócitos/instrumentação , Linfopenia/etiologia , Plaquetoferese/efeitos adversos , Adulto , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/etiologia , Doadores de Sangue/estatística & dados numéricos , Bases de Dados Factuais , Suscetibilidade a Doenças , Feminino , Seguimentos , Humanos , Hospedeiro Imunocomprometido , Infecções/etiologia , Contagem de Linfócitos , Linfopenia/epidemiologia , Masculino , Pessoa de Meia-Idade , Micoses/epidemiologia , Micoses/etiologia , Plaquetoferese/instrumentação , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Risco , Suécia/epidemiologia , Adulto JovemRESUMO
BACKGROUND: We recently discovered that 30% of current frequent apheresis platelet donors in a study at our donor center had CD4+ counts below 200 cells/µL. How long CD4+ lymphopenia persists after ceasing plateletpheresis is unknown. Whether there are infectious or other complications in former frequent donors that could relate to CD4+ lymphopenia is also unknown. STUDY DESIGN AND METHODS: We mailed a letter to former frequent apheresis platelet donors who had not donated platelets for at least 12 months. Frequent donation was defined as 20 to 24 plateletpheresis sessions in at least one 365-day period starting in 2011. Donors who expressed interest in the study were contacted to schedule a study visit. Participants in the study provided a blood sample and completed a health questionnaire that included questions about opportunistic infections and malignancies. RESULTS: Of 50 potential study candidates who were mailed a letter, 15 participated in the study. There were 2 participants with CD4+ counts below 200 cells/µL, one of whom had prior counts that documented a small improvement with cessation of plateletpheresis. Three participants had counts between 200 and 300 cells/µL. No study participant had a history of an opportunistic infection or a malignancy associated with immune dysregulation. CONCLUSION: We detected CD4+ lymphopenia in former frequent apheresis platelet donors who had ceased platelet donation for more than 1 year. There was no evidence that the CD4+ lymphopenia predisposes to opportunistic infections or to malignancies associated with immune dysregulation.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfopenia/metabolismo , Linfopenia/terapia , Plaquetoferese/métodos , Adulto , Idoso , Doadores de Sangue , Plaquetas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de PlaquetasRESUMO
BACKGROUND: In a recent study, we determined that 30% of frequent plateletpheresis donors collected using the Trima Accel Automated Blood Collection System (Terumo BCT) had a CD4+ T-cell count below 200 cells/µL. Whether CD4+ T-cell lymphopenia is associated with donation using other plateletpheresis instruments is unknown. STUDY DESIGN AND METHODS: We obtained blood samples from 30 current frequent Fenwal Amicus plateletpheresis donors. All participants had made 20 to 24 plateletpheresis donations in the most recent 365-day period, and all had previously donated over 50 times on the Fenwal Amicus instrument. Blood samples were analyzed to determine blood counts, including CD4+ and CD8+ counts. RESULTS: Of 30 study participants, none had a CD4+ count below 200 cells/µL. There was one participant with a CD4+ count between 200 and 300 cells/µL. This individual was over the age of 55 and had a history of more than 300 lifetime plateletpheresis sessions. One participant had a CD8+ count below the lower limit of normal (125 cells/µL) and a normal CD4+ count. CONCLUSION: We did not detect severe CD4+ lymphopenia in frequent platelet donors undergoing plateletpheresis with the Fenwal Amicus. Since the Fenwal Amicus does not incorporate a leukoreduction system chamber, this finding supports the hypothesis that such chambers-found in the Trima Accel instrument-contribute to CD4+ lymphopenia in frequent platelet donors.
Assuntos
Doadores de Sangue/estatística & dados numéricos , Linfócitos T CD4-Positivos/patologia , Linfopenia/epidemiologia , Plaquetoferese/instrumentação , Plaquetoferese/estatística & dados numéricos , Idoso , Estudos de Coortes , Desenho de Equipamento , Feminino , Humanos , Incidência , Linfopenia/etiologia , Linfopenia/patologia , Masculino , Pessoa de Meia-Idade , Plaquetoferese/métodos , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Idiopathic scoliosis is a form of spinal deformity that affects 2-3% of children and results in curvature of the spine without structural defects of the vertebral units. The pathogenesis of idiopathic scoliosis remains poorly understood, in part due to the lack of a relevant animal model. RESULTS: We performed a forward mutagenesis screen in zebrafish to identify new models for idiopathic scoliosis. We isolated a recessive zebrafish mutant, called skolios, which develops isolated spinal curvature that arises independent of vertebral malformations. Using meiotic mapping and whole genome sequencing, we identified a nonsense mutation in kinesin family member 6 (kif6(gw326) ) unique to skolios mutants. Three additional kif6 frameshift alleles (gw327, gw328, gw329) were generated with transcription activator-like effector nucleases (TALENs). Zebrafish homozygous or compound heterozygous for kif6 frameshift mutations developed a scoliosis phenotype indistinguishable from skolios mutants, confirming that skolios is caused by the loss of kif6. Although kif6 may play a role in cilia, no evidence for cilia dysfunction was seen in kif6(gw326) mutants. CONCLUSIONS: Overall, these findings demonstrate a novel role for kif6 in spinal development and identify a new candidate gene for human idiopathic scoliosis.
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Cinesinas/metabolismo , Escoliose/embriologia , Coluna Vertebral/embriologia , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Animais , Códon sem Sentido , Modelos Animais de Doenças , Mutação da Fase de Leitura , Humanos , Cinesinas/genética , Fenótipo , Escoliose/genética , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genéticaAssuntos
Anemia Aplástica/genética , Doenças da Medula Óssea/genética , Hemoglobinúria Paroxística/genética , Complicações Hematológicas na Gravidez/genética , Resultado da Gravidez , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/etiologia , Adulto , Anemia Aplástica/complicações , Anemia Aplástica/diagnóstico , Anemia Aplástica/terapia , Doenças da Medula Óssea/complicações , Doenças da Medula Óssea/diagnóstico , Doenças da Medula Óssea/terapia , Transtornos da Insuficiência da Medula Óssea , Reações Falso-Negativas , Feminino , Morte Fetal/etiologia , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/diagnóstico , Hemoglobinúria Paroxística/terapia , Humanos , Recém-Nascido , Infertilidade Feminina/etiologia , Transtornos da Lactação/etiologia , Gravidez , Complicações Hematológicas na Gravidez/diagnóstico , Complicações Hematológicas na Gravidez/terapia , RNA/genética , Sistema de Registros , Telomerase/genética , Estados Unidos/epidemiologiaRESUMO
Introduction: Patients with primary hyperoxaluria type 1 (PH1), a genetic disorder associated with hepatic oxalate overproduction, frequently experience recurrent kidney stones and worsening kidney function. Lumasiran is indicated for the treatment of PH1 to lower urinary and plasma oxalate (POx). Methods: ILLUMINATE-A (NCT03681184) is a phase III trial in patients aged ≥6 years with PH1 and estimated glomerular filtration rate (eGFR) ≥30 ml/min per 1.73 m2. A 6-month double-blind placebo-controlled period is followed by an extension period (≤54 months; all patients receive lumasiran). We report interim data through month 36. Results: Of 39 patients enrolled, 24 of 26 (lumasiran/lumasiran group) and 13 of 13 (placebo/lumasiran group) entered and continue in the extension period. At month 36, in the lumasiran/lumasiran group (36 months of lumasiran treatment) and placebo/lumasiran group (30 months of lumasiran treatment), mean 24-hour urinary oxalate (UOx) reductions from baseline were 63% and 58%, respectively; 76% and 92% of patients reached a 24-hour UOx excretion ≤1.5× the upper limit of normal (ULN). eGFR remained stable. Kidney stone event rates decreased from 2.31 (95% confidence interval: 1.88-2.84) per person-year (PY) during the 12 months before consent to 0.60 (0.46-0.77) per PY during lumasiran treatment. Medullary nephrocalcinosis generally remained stable or improved; approximately one-third of patients (both groups) improved to complete resolution. The most common lumasiran-related adverse events (AEs) were mild, transient injection-site reactions. Conclusion: In patients with PH1, longer-term lumasiran treatment led to sustained reduction in UOx excretion, with an acceptable safety profile and encouraging clinical outcomes.See for Video Abstract.
RESUMO
Background: Measurement of plasma oxalate (POx) is challenging, but critical, for management of patients with primary hyperoxaluria type 1. A novel LC-MS/MS assay was developed, validated and used to quantify POx in patients with primary hyperoxaluria type 1. Methods: Samples (100 µl of plasma in K2EDTA) were spiked with internal standard (13C2-labeled oxalic acid), acidified and cleaned by protein precipitation before analysis using anion HPLC-ESI-MS/MS. The assay was validated with a quantitation range of 0.500-50.0 µg/ml (5.55-555 µmol/l). All parameters successfully met acceptance criteria, including 15% (20% at lower limit of quantification) for accuracy and precision. Conclusion: This assay has advantages over previously published POx quantitation methods, was validated in accordance with regulatory guidelines and accurately determined POx levels in humans.
A novel assay to measure plasma oxalate was developed and validated successfully in accordance with regulatory guidelines. The required sample volume was only 100 µl of plasma, which is especially favorable in the pediatric population, and there is no need to acidify blood at the collection site before processing. The assay accurately determines plasma oxalate levels, which were used as a measure of efficacy in the lumasiran clinical trials.
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Ácido Oxálico , Espectrometria de Massas em Tandem , Humanos , Cromatografia Líquida/métodos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Ensaios Clínicos como AssuntoRESUMO
Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with age could guide clinical management, but data are limited for this rare disease. We conducted a cohort study of 153 subjects from 143 families with confirmed biallelic SBDS mutations enrolled on the North American Shwachman Diamond Registry or Bone Marrow Failure Registry. The SBDS c.258 + 2T>C variant was present in all but 1 patient. To evaluate the association between blood counts and age, 2146 blood counts were analyzed for 119 subjects. Absolute neutrophil counts were positively associated with age (P < .0001). Hemoglobin was also positively associated with age up to 18 years (P < .0001), but the association was negative thereafter (P = .0079). Platelet counts and marrow cellularity were negatively associated with age (P < .0001). Marrow cellularity did not correlate with blood counts. Severe marrow failure necessitating transplant developed in 8 subjects at a median age of 1.7 years (range, 0.4-39.5), with 7 of 8 requiring transplant prior to age 8 years. Twenty-six subjects (17%) developed a myeloid malignancy (16 myelodysplasia and 10 acute myeloid leukemia) at a median age of 12.3 years (range, 0.5-45.0) and 28.4 years (range, 14.4-47.3), respectively. A lymphoid malignancy developed in 1 patient at the age of 16.9 years. Hematologic complications were the major cause of mortality (17/20 deaths; 85%). These data inform surveillance of hematologic complications in SDS.
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Doenças da Medula Óssea , Insuficiência Pancreática Exócrina , Doenças Hematológicas , Adolescente , Adulto , Doenças da Medula Óssea/complicações , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/patologia , Criança , Pré-Escolar , Estudos de Coortes , Insuficiência Pancreática Exócrina/complicações , Insuficiência Pancreática Exócrina/genética , Doenças Hematológicas/complicações , Humanos , Lactente , Pessoa de Meia-Idade , Síndrome de Shwachman-Diamond , Adulto JovemRESUMO
Introduction: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate, leading to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. In the 6-month double-blind period (DBP) of ILLUMINATE-A, a phase 3, randomized, placebo-controlled trial in patients with PH1 ≥6 years old, treatment with lumasiran, an RNA interference therapeutic, led to substantial reductions in urinary oxalate (UOx) levels. Methods: We report data to month 12 in the extension period (EP) of ILLUMINATE-A, including patients who continued lumasiran (lumasiran/lumasiran) or crossed over from placebo to lumasiran (placebo/lumasiran). Results: In the lumasiran/lumasiran group (n = 24), the reduction in 24-hour UOx level was sustained to month 12 (mean reduction from baseline, 66.9% at month 6; 64.1% at month 12). The placebo/lumasiran group (n = 13) had a similar time course and magnitude of 24-hour UOx reduction (mean reduction, 57.3%) after 6 months of lumasiran. Kidney stone event rates seemed to be lower after 6 months of lumasiran in both groups compared with the 12 months before consent, and this reduction was maintained at month 12 in the lumasiran/lumasiran group. At study start, 71% of patients in the lumasiran/lumasiran group and 92% in the placebo/lumasiran group had nephrocalcinosis. Nephrocalcinosis grade improved after 6 months of lumasiran in the lumasiran/lumasiran and placebo/lumasiran groups (13% and 8% of patients, respectively). After an additional 6 months of lumasiran, 46% of patients had improvement in nephrocalcinosis grade within the lumasiran/lumasiran group. Estimated glomerular filtration rate (eGFR) remained stable during the course of lumasiran treatment. The most common adverse events (AEs) related to lumasiran were mild, transient injection-site reactions (ISRs). Conclusion: Long-term lumasiran treatment enabled sustained lowering of UOx levels with acceptable safety and encouraging results on clinical outcomes.
RESUMO
To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.
Assuntos
Hematopoiese Clonal/genética , Hematopoiese Clonal/fisiologia , Síndrome de Shwachman-Diamond/genética , Síndrome de Shwachman-Diamond/metabolismo , Adolescente , Adulto , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/metabolismo , Criança , Pré-Escolar , Fatores de Iniciação em Eucariotos/genética , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Ribossomos/genética , Proteína Supressora de Tumor p53/genética , Adulto JovemRESUMO
Catastrophic antiphospholipid antibody syndrome (CAPS) and macrophage activation syndrome (MAS) are both life-threatening hematologic disorders that infrequently afflict patients with rheumatologic disease. CAPS is characterized by fulminant multiorgan damage related to small vessel thrombosis in the setting of persistent antiphospholipid antibodies. It can occur in patients with rheumatologic diseases such as systemic lupus erythematosus but can also affect patients who do not have rheumatologic disease. By contrast, the term MAS is applied when patients with rheumatologic disease develop hemophagocytic lymphohistiocytosis (HLH); therefore, patients with MAS have an underlying rheumatologic disease by definition. Similar to CAPS, HLH/MAS can have a fulminant presentation, but the pathogenesis and manifestations are different. In both CAPS and MAS, management generally includes but is not limited to immunosuppression with steroids. Fatalities are relatively common and morbidity is often significant. Early recognition of these disorders and initiation of timely treatment are important. More effective therapies for both syndromes are urgently needed.