RESUMEN
ABSTRACT: Children and adults with sickle cell disease (SCD) have increases in morbidity and mortality with COVID-19 infections. The American Society of Hematology Research Collaborative Sickle Cell Disease Research Network performed a prospective COVID-19 vaccine study to assess antibody responses and analyze whether messenger RNA (mRNA) vaccination precipitated any adverse effects unique to individuals with SCD. Forty-one participants received 2 doses of the Pfizer-BioNTech vaccine and provided baseline blood samples before vaccination and 2 months after the initial vaccination for analysis of immunoglobulin G (IgG) reactivity against the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike protein. Six-month IgG reactivity against the viral RBD was also available in 37 patients. Postvaccination reactogenicity was common and similar to the general population. There were no fevers that required inpatient admission. Vaso-occlusive pain within 2 to 3 days of first or second vaccination was reported by 5 participants (12%) including 4 (10%) who sought medical care. Twenty-seven participants (66%) were seropositive at baseline, and all 14 initially seronegative participants (34%) converted to seropositive after vaccination. Overall, mRNA vaccination had a good risk-benefit profile in individuals with SCD. This mRNA vaccine study also marks the first evaluation of vaccine safety and antibody response in very young children with SCD. This trial was registered at www.ClinicalTrials.gov as #NCT05139992.
Asunto(s)
Anemia de Células Falciformes , Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Vacunación , Humanos , Anemia de Células Falciformes/inmunología , Anemia de Células Falciformes/terapia , Masculino , Femenino , Adulto , COVID-19/prevención & control , COVID-19/inmunología , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , SARS-CoV-2/inmunología , Adolescente , Vacuna BNT162 , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Adulto Joven , Niño , Glicoproteína de la Espiga del Coronavirus/inmunología , Persona de Mediana Edad , Estudios Prospectivos , Vacunas de ARNmRESUMEN
ABSTRACT: Advanced practice providers (APPs) are critical to the hematology workforce. However, there is limited knowledge about APPs in hematology regarding specialty-specific training, scope of practice, challenges and opportunities in APP-physician interactions, and involvement with the American Society of Hematology (ASH). We conducted APP and physician focus groups to elucidate major themes in these areas and used results to inform development of 2 national surveys, 1 for APPs and 1 for physicians who work with APPs. The APP survey was distributed to members of the Advanced Practitioner Society of Hematology and Oncology, and the physician survey was distributed to physician members of ASH. A total of 841 APPs and 1334 physicians completed the surveys. APPs reported most hematology-specific knowledge was obtained via on-the-job training and felt additional APP-focused training would be helpful (as did physicians). Nearly all APPs and physicians agreed that APPs were an integral part of their organizations and that physician-APP collaborations were generally positive. A total of 42.1% of APPs and 29.3% of physicians reported burnout, and >50% of physicians felt that working with APPs had reduced their burnout. Both physicians and APPs reported interest in additional resources including "best practice" guidelines for APP-physician collaboration, APP access to hematology educational resources (both existing and newly developed resources for physicians and trainees), and greater APP integration into national specialty-specific professional organizations including APP-focused sessions at conferences. Professional organizations such as ASH are well positioned to address these areas.
Asunto(s)
Hematología , Médicos , Humanos , Grupos Focales , Oncología Médica , Recursos HumanosRESUMEN
The Blood and Marrow Transplant Clinical Trials Network (BMT CTN), funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute for more than 2 decades, is focused on improving the outcomes of hematopoietic cell transplantation (HCT) and other cellular therapies. It answered critical questions about conditioning intensity, donor choice, graft-versus-host disease prevention and treatment, and relapse mitigation strategies in a manner made possible by an extensive network of centers that have enrolled more than 16,000 patients to more than 55 trials. Although the BMT CTN has engaged patients in a variety of ways since its establishment, there is a growing realization that increasing that engagement and including caregivers offers many additional benefits to patients and investigators alike. Bringing the voice of patients and caregivers to clinical trial design is likely to enhance trial participation and reduce barriers to recruitment/retention. Unless clinical trials are designed with unique considerations of patients who have socioeconomic and access challenges, these populations will remain under-represented in HCT trials with limited generalizability of results. The next main frontier in our field is patient and caregiver access to high-quality HCT facilities coupled with the opportunity to participate in relevant, meaningful clinical research. In 2021, the BMT CTN Executive Committee convened a Patient and Caregiver Advocacy Task Force with a diverse membership representing a variety of stakeholders. The charge to the Task Force was to provide achievable recommendations for incorporating patient input at all steps of clinical trial development from initial concept to dissemination of results. Four focus areas were identified: (1) patient and caregiver input in research portfolio; (2) patient engagement in informed consent, protocol development and trial conduct; (3) communication to patients about trial progress, primary outcomes and secondary analyses; and (4) increased awareness among patients who may be considering BMT or cell therapy about BMT CTN trials. Three specific initiatives were considered as high priority by the Task Force: Fostering patient and caregiver engagement in development of the research portfolio and protocols; Developing communication plans for ongoing studies; and Simplifying the process for informed consent to make it more patient friendly. The BMT CTN has established a patient and caregiver advocacy committee that is tasked with developing concrete steps to incorporate recommendations of the BMT CTN Task Force in its current and future work. The BMT CTN recognizes patient and caregivers are valuable partners whose voice will enhance the conduct of impactful trials in BMT and cell therapy.
Asunto(s)
Cuidadores , Trasplante de Células Madre Hematopoyéticas , Humanos , Médula Ósea , Trasplante de Médula Ósea/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Consentimiento Informado , Ensayos Clínicos como AsuntoRESUMEN
BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82â×â10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING: National Heart, Lung, and Blood Institute, National Institutes of Health.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/uso terapéutico , Transfusión Sanguínea/métodos , Hidroxiurea/uso terapéutico , Adolescente , Anemia de Células Falciformes/fisiopatología , Velocidad del Flujo Sanguíneo , Circulación Cerebrovascular/fisiología , Niño , Preescolar , Terapia Combinada , Sustitución de Medicamentos , Femenino , Humanos , Masculino , Accidente Cerebrovascular/etiología , Resultado del Tratamiento , Ultrasonografía Doppler TranscranealRESUMEN
Serial phlebotomy was performed on sixty children with sickle cell anaemia, stroke and transfusional iron overload randomized to hydroxycarbamide in the Stroke With Transfusions Changing to Hydroxyurea trial. There were 927 phlebotomy procedures with only 33 adverse events, all of which were grade 2. Among 23 children completing 30 months of study treatment, the net iron balance was favourable (-8·7 mg Fe/kg) with significant decrease in ferritin, although liver iron concentration remained unchanged. Therapeutic phlebotomy was safe and well-tolerated, with net iron removal in most children who completed 30 months of protocol-directed treatment.
Asunto(s)
Anemia de Células Falciformes/complicaciones , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/terapia , Flebotomía , Adolescente , Anemia de Células Falciformes/terapia , Niño , Preescolar , Femenino , Ferritinas/metabolismo , Humanos , Hierro/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Flebotomía/efectos adversos , Flebotomía/métodos , Reacción a la Transfusión , Resultado del Tratamiento , Adulto JovenRESUMEN
Hydroxyurea has proven efficacy in children and adults with sickle cell anemia (SCA), but with considerable inter-individual variability in the amount of fetal hemoglobin (HbF) produced. Sibling and twin studies indicate that some of that drug response variation is heritable. To test the hypothesis that genetic modifiers influence pharmacological induction of HbF, we investigated phenotype-genotype associations using whole exome sequencing of children with SCA treated prospectively with hydroxyurea to maximum tolerated dose (MTD). We analyzed 171 unrelated patients enrolled in two prospective clinical trials, all treated with dose escalation to MTD. We examined two MTD drug response phenotypes: HbF (final %HbF minus baseline %HbF), and final %HbF. Analyzing individual genetic variants, we identified multiple low frequency and common variants associated with HbF induction by hydroxyurea. A validation cohort of 130 pediatric sickle cell patients treated to MTD with hydroxyurea was genotyped for 13 non-synonymous variants with the strongest association with HbF response to hydroxyurea in the discovery cohort. A coding variant in Spalt-like transcription factor, or SALL2, was associated with higher final HbF in this second independent replication sample and SALL2 represents an outstanding novel candidate gene for further investigation. These findings may help focus future functional studies and provide new insights into the pharmacological HbF upregulation by hydroxyurea in patients with SCA.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/genética , Exoma/genética , Hemoglobina Fetal/metabolismo , Genómica , Hidroxiurea/farmacología , Análisis de Secuencia de ADN , Anemia de Células Falciformes/metabolismo , Niño , Estudios de Cohortes , Proteínas de Unión al ADN , Relación Dosis-Respuesta a Droga , Exoma/efectos de los fármacos , Humanos , Hidroxiurea/efectos adversos , Hidroxiurea/uso terapéutico , Dosis Máxima Tolerada , Sistemas de Lectura Abierta/genética , Fenotipo , Estudios Prospectivos , Factores de Transcripción/genética , Resultado del TratamientoRESUMEN
Newborn screening (NBS) provides early diagnosis of sickle hemoglobinopathies. After Hb S [ß6(A3)GluâVal, GAG>GTG], Hb C [ß6(A3)GluâLys, GAG>AAG] is the most common hemoglobin (Hb) abnormality identified in the United States (1,2). Published data regarding children with Hb C disease are limited. This study was conducted to summarize a single institution's clinical and laboratory data for patients with Hb C disease, specifically homozygous Hb CC and its variants over a 10-year period. Forty-seven patients, whose mean age at diagnosis was 2.9 years (range 0.04 to 23 years), were identified. Twenty-nine had Hb CC and the remainder had compound heterozygous variants [10 Hb C/ß(+)-thalassemia (ß(+)-thal), four Hb C/ß(0)-thal, and one each with Hb C/Hb Hope or ß136(H14)GlyâAsp (GGT>GAT), Hb C/Hb Lepore (a hybrid δß-globin gene), Hb C/HPFH (hereditary persistence of fetal Hb) [probably a (G)γ HPFH-2 (the Ghanaian type)], and Hb C/Osu-Christiansborg or ß52(D3)AspâAsn (GAT>AAT)]. All patients had mild microcytic anemia with reticulocytosis and frequent target cells on peripheral smear. Splenomegaly or cholelithiasis occurred in 2.6% of patients <8 years of age, however, these symptoms were more common (71.0%) in patients >8 years of age. No patient had serious infections or painful events resembling vasoocclusion. Accurate diagnosis and understanding of Hb C-related disorders helped to avoid confusion with sickle hemoglobinopathies and aided in proper clinical management.
Asunto(s)
Hemoglobina C/genética , Hemoglobinopatías/genética , Hemoglobinopatías/patología , Adolescente , Niño , Preescolar , Índices de Eritrocitos , Eritrocitos/metabolismo , Eritrocitos/patología , Femenino , Hemoglobinas Anormales/genética , Heterocigoto , Homocigoto , Humanos , Lactante , Masculino , Mutación Puntual , Adulto Joven , Talasemia beta/genética , Talasemia beta/patologíaRESUMEN
Glomerular hyperfiltration and microalbuminuria/proteinuria are early manifestations of sickle nephropathy. The effects of hydroxyurea therapy on these renal manifestations of sickle cell anemia (SCA) are not well defined. Our objective was to investigate the effects of hydroxyurea on glomerular filtration rate (GFR) measured by (99m)Tc-DTPA clearance, and on microalbuminuria/proteinuria in children with SCA. Hydroxyurea study of long-term effects (HUSTLE) is a prospective study (NCT00305175) with the goal of describing the long-term cellular, molecular, and clinical effects of hydroxyurea therapy in SCA. Glomerular filtration rate, urine microalbumin, and serum cystatin C were measured before initiating hydroxyurea therapy and then repeated after 3 years. Baseline and Year 3 values for HUSTLE subjects were compared using the Wilcoxon Signed Rank test. Associations between continuous variables were evaluated using Spearman correlation coefficient. Twenty-three children with SCA (median age 7.5 years, range, 2.5-14.0 years) received hydroxyurea at maximum tolerated dose (MTD, 24.4 ± 4.5 mg/kg/day, range, 15.3-30.6 mg/kg/day). After 3 years of treatment, GFR measured by (99m)Tc-DTPA decreased significantly from 167 ± 46 mL/min/1.73 m² to 145 ± 27 mL/min/1.73 m² (P = 0.016). This decrease in GFR was significantly associated with increase in fetal hemoglobin (P = 0.042) and decrease in lactate dehydrogenase levels (P = 0.035). Urine microalbumin and cystatin C levels did not change significantly. Hydroxyurea at MTD is associated with a decrease in hyperfiltration in young children with SCA.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/uso terapéutico , Glomerulonefritis/prevención & control , Hidroxiurea/uso terapéutico , Glomérulos Renales/efectos de los fármacos , Adolescente , Albuminuria/etiología , Albuminuria/prevención & control , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/fisiopatología , Anemia de Células Falciformes/orina , Antidrepanocíticos/administración & dosificación , Antidrepanocíticos/efectos adversos , Niño , Preescolar , Estudios de Cohortes , Cistatina C/sangre , Monitoreo de Drogas , Femenino , Hemoglobina Fetal/análisis , Tasa de Filtración Glomerular/efectos de los fármacos , Glomerulonefritis/etiología , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/efectos adversos , Glomérulos Renales/fisiopatología , Masculino , Pentetato de Tecnecio Tc 99m , Factores de TiempoRESUMEN
Sickle cell anaemia (SCA) is a severe debilitating haematological disorder associated with a high degree of morbidity and mortality. The level of fetal haemoglobin (HbF) is well-recognized as a critical laboratory parameter: lower HbF is associated with a higher risk of vaso-occlusive complications, organ damage, and early death. Hydroxycarbamide treatment can induce HbF, improve laboratory parameters, and ameliorate clinical complications of SCA but its mechanisms of action remain incompletely defined and the HbF response is highly variable. To identify pathways of hydroxycarbamide activity, we performed microarray expression analyses of early reticulocyte RNA obtained from children with SCA enrolled in the HydroxyUrea Study of Long-term Effects (NCT00305175) and examined the effects of hydroxycarbamide exposure in vivo. Hydroxycarbamide affected a large number of erythroid genes, with significant decreases in the expression of genes involved in translation, ribosome assembly and chromosome organization, presumably reflecting the daily cytotoxic pulses of hydroxycarbamide. Hydroxycarbamide also affected expression of numerous genes associated with HbF including BCL11A, a key regulator of baseline HbF levels. Together, these data indicate that hydroxycarbamide treatment for SCA leads to substantial changes in erythroid gene expression, including BCL11A and other potential signalling pathways associated with HbF induction.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/metabolismo , Antidrepanocíticos/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , Hidroxiurea/efectos adversos , Adolescente , Antidrepanocíticos/administración & dosificación , Proteínas Portadoras/biosíntesis , Niño , Preescolar , Femenino , Hemoglobina Fetal/biosíntesis , Perfilación de la Expresión Génica , Humanos , Hidroxiurea/administración & dosificación , Lactante , Masculino , Proteínas Nucleares/biosíntesis , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Represoras , Transducción de Señal/efectos de los fármacosRESUMEN
Chronic transfusion reduces the risk of recurrent stroke in children with sickle cell anemia (SCA) but leads to iron loading. Management of transfusional iron overload in SCA has been reported as suboptimal [1], but studies characterizing monitoring and treatment practices for iron overload in children with SCA, particularly in recent years with the expansion of chelator options, are lacking. We investigated the degree of iron loading and treatment practices of 161 children with SCA receiving transfusions for a history of stroke who participated in the Stroke with Transfusions Changing to Hydroxyurea (SWiTCH) trial. Data obtained during screening, including past and entry liver iron concentration (LIC) measurements, ferritin values, and chelation were analyzed. The mean age at enrollment was 12.9 ± 4 years and the mean duration of transfusion was 7 ± 3.8 years. Baseline LIC (median 12.94 mg/g dw) and serum ferritin (median 3,164 ng/mL) were elevated. Chelation therapy was initiated after a mean of 2.6 years of transfusions. At study entry, 137 were receiving chelation, most of whom (90%) were receiving deferasirox. This study underscores the need for better monitoring of iron burden with timely treatment adjustments in chronically transfused children with SCA.
Asunto(s)
Anemia de Células Falciformes/terapia , Benzoatos/uso terapéutico , Terapia por Quelación , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/metabolismo , Hierro/metabolismo , Accidente Cerebrovascular/prevención & control , Triazoles/uso terapéutico , Adolescente , Anemia de Células Falciformes/metabolismo , Anemia de Células Falciformes/patología , Benzoatos/farmacología , Niño , Deferasirox , Femenino , Ferritinas/sangre , Humanos , Quelantes del Hierro/farmacología , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/patología , Hígado/metabolismo , Masculino , Prevención Secundaria , Reacción a la Transfusión , Triazoles/farmacología , Adulto JovenRESUMEN
Hydroxyurea has been shown to be efficacious for the treatment of sickle cell anemia (SCA), primarily through the induction of fetal hemoglobin (HbF). However, the exact mechanisms by which hydroxyurea can induce HbF remain incompletely defined, although direct transcriptional effects and altered cell cycle kinetics have been proposed. In this study, we investigated potential epigenetic and alternative molecular mechanisms of hydroxyurea-mediated HbF induction by examining methylation patterns within the (G)γ-globin promoter and miRNA expression within primary CD71(+) erythrocytes of patients with SCA, both at baseline before beginning hydroxyurea therapy and after reaching maximum tolerated dose (MTD). Using both cross-sectional analysis and paired-sample analysis, we found that the highly methylated (G)γ-globin promoter was inversely correlated to baseline HbF levels, but only slightly altered by hydroxyurea treatment. Conversely, expression of several specific miRNAs was significantly increased after hydroxyurea treatment, and expression of miR-26b and miR-151-3p were both associated with HbF levels at MTD. The significant associations identified in these studies suggest that methylation may be important for regulation of baseline HbF, but not after hydroxyurea treatment, whereas changes in miRNA expression may be associated with hydroxyurea-mediated HbF induction. This study was registered at ClinicalTrials.gov (NCT00305175).
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/genética , Epigénesis Genética/efectos de los fármacos , Células Eritroides/efectos de los fármacos , Hemoglobina Fetal/genética , Hidroxiurea/uso terapéutico , Adulto , Antidrepanocíticos/uso terapéutico , Niño , Islas de CpG/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Eritrocitos/efectos de los fármacos , Eritrocitos/fisiología , Hemoglobina Fetal/metabolismo , Perfilación de la Expresión Génica , Humanos , MicroARNs/genética , Estudios Prospectivos , Reticulocitos/efectos de los fármacos , Reticulocitos/fisiologíaRESUMEN
Hydroxyurea therapy has proven laboratory and clinical efficacies for children with sickle cell anemia (SCA). When administered at maximum tolerated dose (MTD), hydroxyurea increases fetal hemoglobin (HbF) to levels ranging from 10% to 40%. However, interpatient variability of percentage of HbF (%HbF) response is high, MTD itself is variable, and accurate predictors of hydroxyurea responses do not currently exist. HUSTLE (NCT00305175) was designed to provide first-dose pharmacokinetics (PK) data for children with SCA initiating hydroxyurea therapy, to investigate pharmacodynamics (PD) parameters, including HbF response and MTD after standardized dose escalation, and to evaluate pharmacogenetics influences on PK and PD parameters. For 87 children with first-dose PK studies, substantial interpatient variability was observed, plus a novel oral absorption phenotype (rapid or slow) that influenced serum hydroxyurea levels and total hydroxyurea exposure. PD responses in 174 subjects were robust and similar to previous cohorts; %HbF at MTD was best predicted by 5 variables, including baseline %HbF, whereas MTD was best predicted by 5 variables, including serum creatinine. Pharmacogenetics analysis showed single nucleotide polymorphisms influencing baseline %HbF, including 5 within BCL11A, but none influencing MTD %HbF or dose. Accurate prediction of hydroxyurea treatment responses for SCA remains a worthy but elusive goal.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/genética , Hidroxiurea/farmacocinética , Hidroxiurea/uso terapéutico , Farmacogenética , Adolescente , Biomarcadores Farmacológicos/análisis , Biomarcadores Farmacológicos/metabolismo , Niño , Preescolar , Análisis Mutacional de ADN , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/farmacología , Masculino , Dosis Máxima Tolerada , Farmacogenética/métodos , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Stroke occurs in 5-10% of children with sickle cell anemia (SCA) and has a high (>50%) risk of recurrence without therapy. Chronic monthly erythrocyte transfusions effectively prevent recurrent stroke, but their long-term use is limited by serious side effects, including iron overload. An alternative to transfusion for secondary stroke prevention in SCA is needed, especially one that also improves the management of iron overload. METHODS: Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) is an NHLBI-sponsored Phase III multicenter randomized controlled clinical trial for children with SCA, stroke, and iron overload (NCT00122980). The primary goal of SWiTCH is to compare 30 months of alternative therapy (hydroxyurea and phlebotomy) with standard therapy (transfusions and chelation) for the prevention of secondary stroke and reduction of transfusional iron overload. DISCUSSION: SWiTCH has several distinctive study features including novel methodological and design components: (1) composite primary endpoint including both stroke recurrence rate and iron burden; (2) non-inferiority design with an "acceptable" increased stroke risk; (3) transfusion goals based on current academic community practices; (4) special oversight for the enrollment and randomization process; (5) overlap treatment period within the alternative treatment arm; (6) masking of the overall trial Principal Investigator to treatment results; (7) inclusive independent stroke adjudication process for all suspected new neurological events; and (8) periodic therapeutic phlebotomy program to alleviate iron overload. CONCLUSION: Investigation of alternative treatments in SWiTCH could lead to changes in the management of cerebrovascular disease for selected patients with SCA, stroke, and iron overload.
Asunto(s)
Anemia de Células Falciformes/terapia , Transfusión de Eritrocitos , Hidroxiurea/uso terapéutico , Sobrecarga de Hierro/terapia , Accidente Cerebrovascular/terapia , Adolescente , Adulto , Anemia de Células Falciformes/complicaciones , Terapia por Quelación , Niño , Preescolar , Transfusión de Eritrocitos/efectos adversos , Humanos , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/prevención & control , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Adulto JovenRESUMEN
Early manifestations of sickle nephropathy include glomerular hyperfiltration and proteinuria, typically microalbuminuria. Over time, a subset of patients develops histologic changes, decreased glomerular filtration, and ultimately renal failure. This study was designed to determine the rate of glomerular hyperfiltration and prevalence of albuminuria in a cross-sectional analysis of untreated children with sickle cell anemia (SCA), and to identify correlates of both complications. Measured glomerular filtration rate (GFR) by plasma clearance of 99-technetium diethylenetriaminepentaacetate was compared to GFR estimates calculated from published formulas. Eighty-five children (mean age 9.4 ± 4.8 years) were studied; 76% had glomerular hyperfiltration with mean GFR = 154 ± 37 ml/min/1.73 m(2). GFR declined in teenage years and was significantly correlated with increased serum cystatin C levels and higher systolic blood pressure. Measured GFR had only modest correlations with GFR estimates (Pearson correlation coefficients ≤0.5). Albuminuria, usually microalbuminuria, occurred in 15.9% and was associated with higher diastolic blood pressure and lower white blood cell and absolute neutrophil counts. Cystatin C levels inversely reflect GFR changes and are associated with albuminuria; serial monitoring may provide a sensitive and accurate marker of nephropathy in children with SCA.
Asunto(s)
Albuminuria/etiología , Anemia de Células Falciformes/complicaciones , Enfermedades Renales/etiología , Adolescente , Niño , Estudios Transversales , Tasa de Filtración Glomerular , HumanosRESUMEN
Stroke is a devastating complication of sickle cell anemia (SCA), affecting 5% to 10% of patients before adulthood. Several candidate genetic polymorphisms have been proposed to affect stroke risk, but few have been validated, mainly because previous studies were hampered by relatively small sample sizes and the absence of additional patient cohorts for validation testing. To verify the accuracy of proposed genetic modifiers influencing stroke risk in SCA, we performed genotyping for 38 published single nucleotide polymorphisms (SNPs), as well as α-thalassemia, G6PD A(-) variant deficiency, and ß-globin haplotype in 2 cohorts of children with well-defined stroke phenotypes (130 stroke, 103 nonstroke). Five polymorphisms had significant influence (P < .05): SNPs in the ANXA2, TGFBR3, and TEK genes were associated with increased stroke risk, whereas α-thalassemia and a SNP in the ADCY9 gene were linked with decreased stroke risk. Further investigation at these genetic regions may help define mutations that confer stroke risk or protection in children with SCA.
Asunto(s)
Anemia de Células Falciformes/genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Accidente Cerebrovascular/genética , Adolescente , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/diagnóstico , Niño , Preescolar , Estudios de Cohortes , Femenino , Marcadores Genéticos/fisiología , Glucosafosfato Deshidrogenasa/genética , Deficiencia de Glucosafosfato Deshidrogenasa/complicaciones , Deficiencia de Glucosafosfato Deshidrogenasa/diagnóstico , Deficiencia de Glucosafosfato Deshidrogenasa/genética , Humanos , Masculino , Polimorfismo de Nucleótido Simple/fisiología , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/etiología , Globinas beta/genéticaRESUMEN
Autoimmune hemolytic anemia (AIHA) is characterized by the presence of autoantibodies, most frequently of the IgG isotype, directed against erythrocyte surface antigens. The direct antiglobulin test (DAT) is the critical laboratory test for the diagnosis of AIHA, but is negative in 3-11% of cases. In these cases of DAT negative AIHA, a wider spectrum of clinical data including more specialized testing for erythrocyte autoantibodies may be required. We describe the unique and challenging case of an infant with corticosteroid-responsive, DAT negative AIHA, in which specialized gel card testing identified an isolated IgA autoantibody on the erythrocyte surface.
Asunto(s)
Anemia Hemolítica Autoinmune/inmunología , Anticuerpos Antiidiotipos/inmunología , Autoanticuerpos/inmunología , Membrana Eritrocítica/inmunología , Corticoesteroides/uso terapéutico , Prueba de Coombs , Femenino , Humanos , LactanteRESUMEN
Unstable hemoglobin variants represent a rare etiology of congenital hemolytic anemia. Without a high index of suspicion, plus proper laboratory testing and interpretation, the correct diagnosis can be elusive. We report on five children who were initially thought to have other congenital disorders such as hereditary spherocytosis or thalassemia, before ß-globin gene sequencing led to the definitive diagnosis. Recognizing the variable clinical presentation and laboratory data reported will aid clinicians in diagnosis of unstable hemoglobins variants in children with atypical forms of hemolytic anemia, particularly those with low pulse oximetry values or whose hemoglobin electrophoresis suggest ß-thalassemia trait.
Asunto(s)
Anemia Hemolítica Congénita/diagnóstico , Hemoglobinas Anormales/análisis , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Masculino , Análisis de Secuencia de ADN , Globinas beta/genéticaRESUMEN
Hydroxyurea induces fetal hemoglobin, improves laboratory parameters, and ameliorates clinical complications of sickle cell anemia (SCA), but its long-term efficacy and safety in this patient population remain incompletely defined. Although generally considered non-DNA reactive, an important safety concern is that hydroxyurea may indirectly cause genotoxic damage. To better address this safety issue of hydroxyurea in patients with SCA, we measured the production of micronuclei (MN) in red blood cells (RBCs) as a marker of genotoxicity. Blood samples were collected from children with SCA enrolled in the Hydroxyurea Study of Long-term Effects (ClinicalTrials.gov NCT00305175). Flow cytometry quantified circulating MN-containing erythrocyte sub-populations before and during hydroxyurea exposure. The frequency of micronucleated reticulocytes (MN-CD71(+)) and micronucleated mature erythrocytes (MN-RBC) was then tested for associations with laboratory and clinical data. In cross-sectional analysis of 293 blood samples from 105 children with SCA and a median of 2 years of hydroxyurea therapy, exposure to hydroxyurea was associated with significantly increased frequencies of MN-CD71(+) and MN-RBC compared to baseline. The increases were evident by 3 months of therapy, and did not escalate further with up to 12 years of continuous drug exposure. In prospective longitudinal analysis, substantial inter-individual variation in the effect of hydroxyurea on %MN-CD71(+) was observed that was associated with the expected laboratory effects of hydroxyurea. In conclusion, clinically relevant exposure to hydroxyurea is associated with increased MN production consistent with erythroblast genotoxicity but with substantial inter-patient variability. Associations between increased %MN-CD71(+) and laboratory benefits suggest that hydroxyurea effects on MN production may be related to individual patient sensitivity to hydroxyurea within the bone marrow.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/efectos adversos , Daño del ADN , Hidroxiurea/efectos adversos , Micronúcleos con Defecto Cromosómico , Adolescente , Niño , Preescolar , Humanos , Pruebas de Micronúcleos , Mutación , TiempoRESUMEN
Acute splenic sequestration crisis (ASSC) is a hematological emergency in young children with sickle cell disease (SCD), characterized by worsening anemia and splenomegaly, usually with reticulocytosis and thrombocytopenia. Transient aplastic crisis (TAC) due to parvovirus B19 infection occurs in older children with SCD, and typically manifests as worsening anemia with reticulocytopenia and no splenomegaly. Five older children with SCD (4 HbSC, 1 HbSS on hydroxyurea) developed ASSC concurrent with TAC and had a severe clinical course. Our cases suggest that older children with SCD and acute parvovirus infection should be monitored closely for splenomegaly and multi-system dysfunction.
Asunto(s)
Anemia Aplásica/etiología , Anemia de Células Falciformes/complicaciones , Esplenomegalia/etiología , Enfermedad Aguda , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , ReticulocitosRESUMEN
BACKGROUND: Hydroxyurea improves laboratory parameters and prevents acute clinical complications of sickle cell anemia (SCA) in children and adults, but its effects on organ function remain incompletely defined. METHODS: To assess the safety and efficacy of hydroxyurea in young children with SCA and to prospectively assess kidney and brain function, 14 young children (mean age 35 months) received hydroxyurea at a mean maximum tolerated dose (MTD) of 28 mg/kg/day. RESULTS: After a mean of 25 months, expected laboratory effects included significant increases in hemoglobin, MCV and %HbF along with significant decreases in reticulocytes, absolute neutrophil count, and bilirubin. There was no significant increase in glomerular filtration rate by DTPA clearance or Schwartz estimate. Mean transcranial Doppler (TCD) velocity changes were -25.6 cm/sec (P < 0.01) and -26.8 cm/sec (P < 0.05) in the right and left MCA vessels, respectively. At study exit, no child had conditional or abnormal TCD values, and none developed brain ischemic lesions or vasculopathy progression by MRI/MRA. Growth and neurocognitive scores were preserved and Impact-on-Family scores improved. CONCLUSIONS: These pilot data indicate hydroxyurea at MTD is well-tolerated by both children and families, and may prevent chronic organ damage in young children with SCA.