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INTRODUCTION: In recent years, there has been increased focus on individualizing treatment for persons with hemophilia including pharmacokinetic-guided (PK) dosing. AIMS: In this retrospective study clinical outcomes before and after PK-guided prophylaxis were examined. MATERIALS AND METHODS: Eight Haemophilia Treatment Centres from the United States participated in the study and included 132 patients classified into two cohorts: those undergoing a PK-assessment for product switch (switchers) or to optimize treatment (non-switchers). Subset analyses for the two most common products and patients with dosing per prescription label were included for annual bleeding rates (ABR), mean weekly consumption outcomes, and annualized cost of prophylaxis. RESULTS: The most common products before and after index date were octocog alfa, rurioctocog alfa pegol, and efmoroctocog alfa. Seventy-four (56%) patients were identified as switchers and 58 (44%) patients were classified as non-switchers. The majority of patients (78.0%) experienced either a decrease in ABR post-index or maintained 0 ABR during pre- and post-index time periods, with similar proportions identified in both switchers (77.0%) and non-switchers (79.3%) populations. Non-switchers were identified as having no significant change in cost of therapy, while switchers experienced increased cost of therapy driven by higher price of extended half-life products. Within subset analyses, patients receiving rurioctocog alfa pegol and efmoroctocog alfa had mean ABR under 1 after index date. CONCLUSION: PK-guided prophylaxis has the potential to improve clinical outcomes without increase in cost of therapy for patients maintaining product and can aid in maintaining effective protection against bleeds in those switching product.
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Hemofilia A , Humanos , Hemofilia A/tratamento farmacológico , Estudos Retrospectivos , Fator VIII/farmacologia , Hemorragia/prevenção & controle , Meia-Vida , PacientesRESUMO
Sickle cell disease (SCD) requires coordinated, specialized medical care for optimal outcomes. There are no United States (US) guidelines that define a pediatric comprehensive SCD program. We report a modified Delphi consensus-seeking process to determine essential, optimal, and suggested elements of a comprehensive pediatric SCD center. Nineteen pediatric SCD specialists participated from the US. Consensus was predefined as 2/3 agreement on each element's categorization. Twenty-six elements were considered essential (required for guideline-based SCD care), 10 were optimal (recommended but not required), and five were suggested. This work lays the foundation for a formal recognition process of pediatric comprehensive SCD centers.
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Anemia Falciforme , Criança , Humanos , Consenso , Anemia Falciforme/terapiaRESUMO
INTRODUCTION: Hemophilia A is a severe bleeding disorder affecting about 1 in 5,000 males. The gold standard for prophylaxis and treatment of acute bleeding has been factor (F) VIII concentrate. A multitude of treatment modalities are now available and under clinical investigation. AREAS COVERED: This review discusses ongoing/recently completed early-phase clinical trials registered on ClinicalTrials.gov in patients with hemophilia A through April 2022. These new pipeline therapies are focused on addressing the safety and efficacy of new factor-related products, non-factor related products, and gene therapy options for hemophilia. EXPERT OPINION: Current standard of care effectively prevents and treats acute bleeding and has significantly improved the quality of life in hemophilia. The biggest challenges in the improvement of care are treatment-related burden and the burden of cost in developing countries. New drugs under development are likely to enter practice by the end of this decade and address many of the unmet needs particularly of those with severe disease. Data is limited in unique populations (e.g. congenital/inherited FVIII inhibitors, non-severe hemophilia A, women/girls with hemophilia and children) which are important areas for future research; additional clinical trials and long-term outcome data are necessary prior to incorporating these new therapies in our treatment arsenal.
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Hemofilia A , Masculino , Criança , Humanos , Feminino , Hemofilia A/tratamento farmacológico , Qualidade de Vida , HemorragiaRESUMO
Evidence suggests neuropathic pain (NP) develops over time in sickle cell disease (SCD), contributing to a complex, difficult-to-treat phenotype, with management based on scant evidence. One characteristic of NP found is hyperalgesia caused by nervous system sensitization, but risk factors for this have not been identified within the SCD population, as exact mechanisms leading to its development are not well defined. The SPICE (Sickle cell Pain: Intervention with Capsaicin Exposure) trial was a pilot safety and feasibility trial of high-dose (8%) topical capsaicin for patients with SCD and recurrent/chronic pain with neuropathic features, aimed at exploring capsaicin's utility as a mechanistic probe and adjunctive pain treatment for this population. Ten participants identifying "target" sites of pain with NP-type qualities consented to treatment. The primary endpoint was safety/tolerability. The novel Localized Peripheral Hypersensitivity Relief score (LPHR) was developed to determine improvement in sensitivity attributable to TRPV1 neutralization. There were no severe treatment-related adverse events. Higher baseline pain sensitivity at a given body site was associated with self-reported history of more frequent localized vaso-occlusive pain episodes at that site. There was a statistically significant improvement in the mean LPHR, evidencing TRPV1's importance to the development of hypersensitivity and a potential therapeutic benefit of capsaicin for SCD.
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Background: Bleeding in people with hemophilia A can be life threatening, and intra-articular bleeds can result in joint damage. Most clinical studies focus on treated bleeds, while bleeds not treated with coagulation factor(s) (untreated bleeds) are underreported. Objectives: We assessed the incidence of untreated bleeds during a noninterventional study (NIS) wherein people with hemophilia A, with or without factor VIII (FVIII) inhibitors, were managed according to standard practice. Patients/Methods: Using the Bleed and Medication Questionnaire, we prospectively collected data from three cohorts: Cohort A, adults/adolescents (age ≥12 years) with FVIII inhibitors; Cohort B, children (aged <12 years) with FVIII inhibitors; Cohort C, adults/adolescents without FVIII inhibitors. Untreated bleeds were analyzed for site, frequency, and etiology of bleeding and compared with those during emicizumab prophylaxis in the same individuals after transferring to a Phase III HAVEN trial. Results: In the 221 participants enrolled in the NIS (Cohort A, n = 103; Cohort B, n = 24; Cohort C, n = 94), the incidence of untreated bleeds was approximately 40% of all bleeds in people with FVIII inhibitors and 26.2% in adolescents/adults without inhibitors. Approximately 70% of treated bleeds and approximately 54% of untreated bleeds in adults/adolescents were in joints. Untreated joint bleeds were less common (7.1%) in children. Overall, intra-individual comparisons showed reduced treated/untreated bleeds following transition from standard to emicizumab prophylaxis. Conclusion: A significant proportion of bleeding events are untreated in people with hemophilia A. There is a need to further understand why bleeds remain untreated and to capture such events in clinical studies.
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Sickle cell disease (SCD) increases the incidence of childhood stroke eighty-fold. Stroke risk can be estimated by measurement of the blood velocity through the middle cerebral artery (MCA) using transcranial doppler ultrasound (TCD). A high MCA blood velocity indicates increased stroke risk due to cerebral vasculopathy, and first-line treatment to prevent primary or recurrent strokes in high-risk children with SCD has classically been chronic blood transfusions. Research has more recently shown that many of these patients may safely transition from transfusions to oral hydroxyurea (HU) treatment while maintaining a decreased risk of stroke. However, the effect on stroke risk of truly prophylactic HU treatment beginning in infancy, prior to the onset of cerebral vasculopathy, is less well understood. Our retrospective study aimed to document the long-term effects of HU treatment compared with no HU treatment in children with SCD, using TCD measurements as our primary outcome and a surrogate marker of stroke risk. Our results showed that when accounting for age-related variability and duration of treatment, prophylactic HU treatment was independently associated with lower TCD MCA velocities compared with no HU treatment, providing further evidence supporting its early initiation for patients with SCD.
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Hemophilia A is the most common severe inherited bleeding disorder in males. Initial treatment strategies focused on the use of factor concentrates to prevent joint bleeding and the development of long-term crippling arthropathy. The current standard of care has evolved from regular replacement of factor VIII concentrates which has significantly improved the quality of life for those with severe disease to include and consider novel therapies that augment or bypass the hemostatic pathway (ie, emicizumab, Mim8). Other pipeline therapies that suppress specific natural anticoagulant pathways (ie, antithrombin, TFPI) to reestablish hemostatic balance are under Phase 3 trial investigation. These novel therapeutics have allowed providers more variety in dosing regimens and ease of administration while also maintaining effective bleeding prevention. The possibility of "curative" gene therapy is under exploration, with ongoing clinical trials in adult males.
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Sickle cell disease (SCD) is characterized by frequent and unpredictable vaso-occlusive crises (VOCs). Sickle erythrocytes (SSRBCs) contribute to VOCs by participating in a series of adhesive events with blood cells and the vascular endothelium. Adhesion assays have been used to evaluate the relationship between SSRBC adhesion and SCD severity. We developed a standardized, clinical flow adhesion assay of whole blood to vascular cell adhesion molecule (FA-WB-VCAM). The objective of this study was to assess the variability and clinical predictive value of FA-WB-VCAM in a six-month longitudinal, observational study (ELIPSIS) in SCD subjects during at-home, steady-state and self-reported VOCs, and following VOC resolution. We observed a strong relationship between FA-WB-VCAM and SCD severity. Adhesion indices were significantly lower in SCD subjects on hydroxycarbamide and increased during VOCs; at-home VOCs had significantly higher FA-WB-VCAM than steady-state and contact VOCs. SCD subjects with a high frequency of self-reported VOCs had a pro-adhesive phenotype at steady state and were stratified into a high-adhesive phenotype cohort; two years prospectively we observed a higher frequency of VOCs in the high-adhesion cohort. This study supports stratifying SCD subjects based on steady-state FA-WB-VCAM and suggests that FA-WB-VCAM may be a plausible surrogate end-point for SCD severity.
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Anemia Falciforme/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo , Estudos de Casos e Controles , Humanos , Estudos LongitudinaisRESUMO
Blood cell adhesion to P-selectin and vascular cell adhesion molecule-1 (VCAM-1) contributes to the pathophysiology of vaso-occlusion crisis (VOC) events in individuals with sickle cell disease (SCD). We evaluated the use of standardized flow adhesion biomarkers in a six-month, 35-subjects longitudinal study (ELIPSIS). Flow adhesion of whole blood on P-selectin (FA-WB-Psel) and VCAM1 (FA-WB-VCAM), and of isolated white blood cells on P-selectin (FA-WBC-Psel) and VCAM-1 (FA-WBC-VCAM) were elevated on VOC days compared with non-VOC days, but only FA-WB-Psel reached statistical significance (P = 0·015). Optimal cut-off values were established with Cox regression models for FA-WB-Psel [46 cells/mm²; hazard ratio (HR): 2·3; 95% confidence interval (CI):1·4-4·0; P = 0·01] and FA-WB-VCAM (408 cells/mm², HR:1·8; 95% CI: 0·9-3·45; P = 0·01). A combined (FA-WB-Psel and FA-WB-VCAM) multimarker risk score was also significantly (P = 0·0006) correlated with VOC risk that was two-fold higher for intermediate and 5·64-fold higher for high score. The concordance (C)-index for the multimarker score was 0·63 in the six-month period (95% CI: 0·56-0·70), indicating a better ability to distinguish patient risk of VOC, compared to individual biomarkers FA-WB-VCAM (C-index: 0·57; 95% CI: 0·49-0·65) or FA-WB-Psel (C-index: 0·58; 95% CI: 0·53-0·62). The presented multimarker score can be used to risk-stratify individuals with SCD during their steady state into low, intermediate, and high-risk strata for self-reported VOCs. Such risk stratification could help focus healthcare resources more efficiently to maintiain health, personalize treatment selection to each patient's individual needs, and potentially reduce healthcare costs.
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Anemia Falciforme/metabolismo , Selectina-P/metabolismo , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/diagnóstico , Anemia Falciforme/patologia , Adesão Celular , Progressão da Doença , Feminino , Humanos , Leucócitos/metabolismo , Leucócitos/patologia , Estudos Longitudinais , Masculino , Prognóstico , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
INTRODUCTION: Severe haemophilia A (HA) has a major impact on health-related quality of life (HRQoL). AIM: Assess the impact of emicizumab on HRQoL in persons with severe HA (PwHA) without factor VIII (FVIII) inhibitors in the phase 3 HAVEN 3 and 4 studies. METHODS: This pooled analysis examines the HRQoL of PwHA aged ≥ 18 years treated with emicizumab prophylaxis via Haemophilia-Specific Quality of Life Questionnaire for Adults (Haem-A-QoL) and EuroQoL 5-Dimensions 5-levels (EQ-5D-5L). In particular, changes from baseline in Haem-A-QoL 'Physical Health' (PH) domain and 'Total Score' (TS) are evaluated. RESULTS: Among 176 evaluable participants, 96 (55%) had received prior episodic treatment and 80 (45%) prophylaxis; 70% had ≥ 1 target joint and 51% had experienced ≥ 9 bleeds in the previous 24 weeks. Mean Haem-A-QoL PH and TS improved after emicizumab initiation. Mean (standard deviation) -12.0 (21.26)- and -8.6 (12.57)-point improvements were observed in PH and TS from baseline to Week 73; Week 73 scores were 27.9 (24.54) and 22.0 (14.38), respectively. Fifty-four percent of participants reported a clinically meaningful improvement in PH scores (≥ 10 points) by Week 73. Subgroups with poorer HRQoL prior to starting emicizumab (i.e. receiving episodic treatment, ≥ 9 bleeds, target joints) had the greatest improvements in PH scores, and corresponding reductions in missed workdays; change was not detected among those previously taking prophylaxis. No change over time was detected by the EQ-5D-5L questionnaire. CONCLUSIONS: Emicizumab prophylaxis in PwHA without FVIII inhibitors resulted in persistent and meaningful improvements in Haem-A-QoL PH and less work disruption than previous treatment.
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Hemofilia A , Adulto , Anticorpos Biespecíficos , Anticorpos Monoclonais Humanizados , Fator VIII/uso terapêutico , Hemofilia A/complicações , Hemofilia A/tratamento farmacológico , Humanos , Qualidade de Vida , AutorrelatoRESUMO
We aimed to identify predictors of outcomes and survival in patients living in 4 major metropolitan areas who had sickle cell disease (SCD) and COVID-19 to inform best approaches to prevention and care. Data were collected at baseline and during the clinical course in SCD patients diagnosed with COVID-19 in four COVID-19 epicenters. Patients were followed up posthospital discharge for up to 3 months. Of sixty-six SCD patients with COVID-19, fifty patients (75%) required hospitalization, and seven died (10.6%). Patients with preexisting kidney disease (chronic kidney disease) were more likely to be hospitalized. The most common presenting symptom was vaso-occlusive pain. Acute chest syndrome occurred in 30 (60%) of the 50 hospitalized patients and in all who died. Older age and histories of pulmonary hypertension, congestive heart failure, chronic kidney disease, and stroke were more prevalent in patients who died, as were higher creatinine, lactate dehydrogenase, and D-dimer levels. Anticoagulation use while inpatient was twice less common in patients who died. All deaths occurred in individuals not taking hydroxyurea or any other SCD-modifying therapy. Patients with SCD and COVID-19 exhibited a broad range of disease severity. We cannot definitively state that the overall mortality is higher in patients with SCD, although our case fatality rate was â¼10% compared with â¼3% in the general population, despite a median age of 34 years. Individuals with SCD aged >50 years, with preexisting cardiopulmonary, renal disease, and/or stroke not receiving hydroxyurea, who present with high serum creatinine, lactate dehydrogenase, and D-dimer levels, are at higher risk of death, irrespective of genotype or sex.
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Anemia Falciforme/complicações , COVID-19/complicações , Síndrome Torácica Aguda/sangue , Síndrome Torácica Aguda/complicações , Síndrome Torácica Aguda/mortalidade , Síndrome Torácica Aguda/terapia , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/mortalidade , Anemia Falciforme/terapia , Antidrepanocíticos/uso terapêutico , COVID-19/sangue , COVID-19/mortalidade , COVID-19/terapia , Progressão da Doença , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Hidroxiureia/uso terapêutico , Masculino , Fatores de Risco , SARS-CoV-2/isolamento & purificação , Adulto JovemRESUMO
Prophylaxis with emicizumab, a subcutaneously administered bispecific humanized monoclonal antibody, promotes effective hemostasis in persons with hemophilia A (PwHAs). The primary efficacy, safety, and pharmacokinetics of emicizumab were reported previously, but long-term data were limited. Here, data from 401 pediatric and adult PwHAs with/without factor VIII (FVIII) inhibitors who were enrolled in the phase 3 HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4 studies (NCT02622321, NCT02795767, NCT02847637, NCT03020160) have been pooled to establish a long-term efficacy, safety, and pharmacokinetics profile. Across a median efficacy period of 120.4 weeks (interquartile range, 89.0-164.4) (data cutoff 15 May 2020), the model-based treated annualized bleed rate (ABR) was 1.4 (95% confidence interval [CI], 1.1-1.7). ABRs declined and then stabilized at <1 in an analysis of 24-week treatment intervals; at weeks 121 to 144 (n = 170), the mean treated ABR was 0.7 (95% CI, 0-5.0). During weeks 121 to 144, 82.4% of participants had 0 treated bleeds, 97.6% had ≤3 treated bleeds, and 94.1% reported no treated target joint bleeds. Bleeding into target joints decreased substantially. Emicizumab was well tolerated, and no participant discontinued because of adverse events beyond the 5 previously described. This data cutoff includes the previously reported 3 thrombotic microangiopathies (one in the PwHA with fatal rectal hemorrhage) and 2 thromboembolic events, all associated with activated prothrombin complex concentrate use, as well as a myocardial infarction and a venous device occlusion. With 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in PwHAs of all ages with/without FVIII inhibitors and remains well tolerated, with no new safety concerns identified.
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Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Hemofilia A/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/farmacocinética , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Criança , Fator VIII/antagonistas & inibidores , Feminino , Seguimentos , Hemofilia A/complicações , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
Reversible cerebral vasoconstriction syndrome (RCVS), is rare in the pediatric population and is characterized by severe headaches and other neurologic symptoms. We present a case of RCVS occurring concomitantly with posterior reversible encephalopathy syndrome in an 8-year-old African American child with sickle cell disease (HbSS). Imaging studies including computed tomography, magnetic resonance imaging and cerebral angiography of the brain showed acute hemorrhagic stroke and a beaded appearance of peripheral cerebral vessels. In this report, we focus on the typical features of RCVS and discuss the underlying risk factors that may increase the risk in patients with HbSS disease.
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Anemia Falciforme/complicações , Transfusão de Sangue/métodos , Transtornos Cerebrovasculares/patologia , Síndrome da Leucoencefalopatia Posterior/patologia , Vasoconstrição , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/terapia , Criança , Humanos , Masculino , Síndrome da Leucoencefalopatia Posterior/etiologia , Síndrome da Leucoencefalopatia Posterior/terapia , PrognósticoRESUMO
Emicizumab, a bispecific monoclonal antibody, bridges activated factor IX (FIXa) and FX, replacing the function of missing FVIIIa to restore effective hemostasis in persons with hemophilia A (PwHA). Here we assess pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers in PwHA with FVIII inhibitors in the Phase III HAVEN 1 study (NCT02622321). Blood samples from 112 PwHA receiving 1.5 mg/kg once-weekly subcutaneous emicizumab were analyzed at central laboratories. Emicizumab concentrations for PK analysis were measured via validated immunoassay. PD effects were assessed using FVIII chromogenic activity assay containing human factors (Hyphen Biophen FVIII:C), and by FXIa-triggered thrombin generation (TG). Activated partial thromboplastin time (aPTT), prothrombin time (PT), antigen levels of FIX and FX, fibrinogen, D-dimer, and prothrombin fragment 1.2 (PF1.2) levels were determined. Emicizumab trough concentrations ≥ 50 µg/mL were maintained throughout the study. FVIII-like activity and TG (peak height) correlated with emicizumab concentrations and remained above 20 U/dL and 100 nM, respectively, with a weekly maintenance dose, theoretically converting persons with severe hemophilia A to a mild disease phenotype. aPTT was normalized at subtherapeutic concentrations of emicizumab. Plasma concentrations of target antigens FIX and FX were not significantly affected by emicizumab treatment; nor were fibrinogen, PT (international normalized ratio), D-dimer, or PF1.2. The PK profile of once-weekly emicizumab in HAVEN 1 provides sustained therapeutic plasma levels, consistent with population PK models. Both the PK profile and the PD and safety biomarkers are consistent with the established efficacy of emicizumab prophylaxis in PwHA with FVIII inhibitors.
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Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Hemofilia A/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Biespecíficos/farmacocinética , Anticorpos Biespecíficos/farmacologia , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Criança , Fator VIII/antagonistas & inibidores , Hemofilia A/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
Clinical trials in sickle cell disease (SCD) often focus on health care utilization for painful vaso-occlusive crises (VOCs). However, no objective, quantifiable pain biomarkers exist, pain is not specific to VOCs, health care utilization varies between patients, unreported at-home VOCs likely contribute to long-term outcomes, and patient-reported outcomes are seldom considered. This noninterventional, longitudinal, 6-month study aimed to develop tools to identify VOCs in SCD patients with or without health care utilization. Participants wore an actigraph device, tracking sleep and activity. Patients with SCD used an electronic patient-reported outcome (ePRO) tool to collect data on pain, medication, fatigue, and daily function. Patients self-reported when they experienced VOC pain (VOC day). Biomarkers were collected every 3 weeks (non-VOC). Self-reported VOCs triggered at-home or in-hospital blood collection. The study enrolled 37 participants with SCD; 35 completed the study. Participants reported 114 VOC events and 346 VOC days, of which 62.3% and 78.3%, respectively, were self-treated at home. The ePRO and actigraphy captured end points of pain, functionality, fatigue, activity, and sleep; each was significantly altered on VOC days compared with non-VOC days. Biomarkers collected at home or in the hospital on VOC days were significantly altered compared with non-VOC baseline values, including leukocyte-platelet aggregates, microfluidic-based blood cell adhesion, interleukin-6, C-reactive protein, interleukin-10, tumor necrosis factor-α, and thrombin-antithrombin. The Evaluation of Longitudinal Pain Study in Sickle Cell Disease (ELIPSIS) trial shows the feasibility of accurately monitoring out-of-hospital pain by using patient-reported VOC days as potential end points for clinical trials in SCD; it describes the changes in biomarkers and activity measured by actigraphy that may enable improved identification and assessment of VOCs.
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Anemia Falciforme/complicações , Dor/etiologia , Actigrafia , Adolescente , Adulto , Anemia Falciforme/diagnóstico , Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Biomarcadores/análise , Feminino , Humanos , Hidroxiureia/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Dor/diagnóstico , Medidas de Resultados Relatados pelo Paciente , Adulto JovemRESUMO
Gene therapy has the potential to overcome many of the limitations of prophylactic hemophilia therapies. Several clinical trials evaluate investigational adeno-associated virus (AAV)-mediated gene transfer approaches for the treatment of hemophilia A and B. The practical application of these approaches is nuanced by differences in AAV serotypes, transgene modifications, manufacturing, dosing, administration, and approach to follow-up. This guide explores mechanisms of AAV gene transfer, identification of appropriate candidates for clinical trial participation, anticipated trial events that follow infusion of an investigational gene therapy including outcomes to be monitored, and future considerations. Patient-accessible infographic summaries of these topics are included to serve as potential visual aids that healthcare providers may choose to utilize or adapt to guide informed consultation. The fundamentals of AAV-mediated, liver-directed gene transfer for hemophilia are reviewed, to facilitate discussion between healthcare providers, patients, and their families and advocates if considering a trial of investigational gene therapy.
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Dependovirus , Terapia Genética , Vetores Genéticos , Hemofilia A , Hemofilia B , Transdução Genética , Ensaios Clínicos como Assunto , Hemofilia A/genética , Hemofilia A/terapia , Hemofilia B/genética , Hemofilia B/terapia , HumanosRESUMO
Treatment of refractory Evans syndrome (ES) remains a challenge in hematology practice. Due to rarity of this condition, evidence-based approaches are limited and often treatment choices stem from small case series or anecdotal experiences. There is mounting evidence that some patients have genetic defects that could be targeted with promising preliminary results. Here, we describe three very refractory pediatric ES cases treated on bortezomib without adverse effects. Two of the three patients had dramatic and long-lasting recovery that started following the initial doses of the drug. Clinical trials to assess the role of bortezomib in ES treatment are warranted.
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Anemia Hemolítica Autoimune/tratamento farmacológico , Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Esteroides/farmacologia , Trombocitopenia/tratamento farmacológico , Adolescente , Anemia Hemolítica Autoimune/patologia , Criança , Humanos , Lactente , Masculino , Prognóstico , Trombocitopenia/patologiaRESUMO
Evans syndrome is defined by bilineal autoimmune cytopenia, typically coombs positive hemolytic anemia and thrombocytopenia. Corticosteroids are the mainstay of treatment, with rituximab and/or mycophenolate mofetil often used in steroid-refractory cases. However, no treatment methodology has ever evaluated by a randomized clinical trial. We present a 15-year-old boy with Evans syndrome and common variable immunodeficiency who experienced a severe, refractory flare 16 months postsplenectomy. After failing to respond to multiple other agents, he achieved a durable response to a bortezomib-based regimen. Bortezomib may be a reasonable second or third line option, especially before high-morbidity therapies such as splenectomy or stem cell transplantation.
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Anemia Hemolítica Autoimune/cirurgia , Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Complicações Pós-Operatórias/tratamento farmacológico , Esplenectomia/efeitos adversos , Trombocitopenia/cirurgia , Adolescente , Anemia Hemolítica Autoimune/patologia , Humanos , Masculino , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/patologia , Prognóstico , Recidiva , Trombocitopenia/patologiaRESUMO
Venous thromboembolism has increasing significance in hospitalized pediatric patients. Patients who have life-threatening or limb-threatening thrombotic events require thrombolysis in addition to anticoagulation. In patients who show signs of heparin resistance or heparin-induced thrombocytopenia, it is imperative to identify alternative therapeutic options. We present a child in whom bivalirudin was used for systemic anticoagulation during catheter-directed thrombolysis along with tissue plasminogen activator (Alteplase® ) for the treatment of a near-occlusive organ-threatening thrombus. We also review the currently available literature on the use of combination therapy of an intravenous direct thrombin inhibitor with alteplase.