BACKGROUND: The preplanned interim analysis of the COMMANDS trial showed greater efficacy of luspatercept than epoetin alfa for treating anaemia in erythropoiesis-stimulating agent (ESA)-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. In this Article, we report the results of the primary analysis of the trial. METHODS: COMMANDS is a phase 3, open-label, randomised, controlled trial conducted at 142 sites in 26 countries. Eligible patients were those aged 18 years or older, with myelodysplastic syndromes of very low risk, low risk, or intermediate risk (as defined by the Revised International Prognostic Scoring System), who were ESA-naive and transfusion dependent, and had a serum erythropoietin concentration of less than 500 U/L. Patients were stratified by baseline red blood cell transfusion burden, serum erythropoietin concentration, and ring sideroblast status, and randomly allocated (1:1) to receive luspatercept (1·0-1·75 mg/kg body weight, subcutaneously, once every 3 weeks) or epoetin alfa (450-1050 IU/kg body weight, subcutaneously, once a week; maximum total dose 80 000 IU) for at least 24 weeks. The primary endpoint was red blood cell transfusion independence lasting at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), evaluated in the intention-to-treat population. The safety population included all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT03682536; active, not recruiting). FINDINGS: Between Jan 2, 2019, and Sept 29, 2022, 363 patients were screened and randomly allocated: 182 (50%) to luspatercept and 181 (50%) to epoetin alfa. Median age was 74 years (IQR 69-80), 162 (45%) patients were female, and 201 (55%) were male. 289 (80%) were White, 44 (12%) were Asian, and two (1%) were Black or African American. 23 (6%) were Hispanic or Latino and 311 (86%) were not Hispanic or Latino. Median follow-up for the primary endpoint was 17·2 months (10·4-27·7) for the luspatercept group and 16·9 months (10·1-26·6) for the epoetin alfa group. A significantly greater proportion of patients in the luspatercept group reached the primary endpoint (110 [60%] vs 63 [35%]; common risk difference on response rate 25·4% [95% CI 15·8-35·0]; p<0·0001). Median follow-up for safety analyses was 21·4 months (IQR 14·2-32·4) for the luspatercept group and 20·3 months (12·7-30·9) for the epoetin alfa group. Common grade 3-4 treatment-emergent adverse events occurring among luspatercept recipients (n=182) were hypertension (19 [10%] patients), anaemia (18 [10%]), pneumonia (ten [5%]), syncope (ten [5%]), neutropenia (nine [5%]), thrombocytopenia (eight [4%]), dyspnoea (eight [4%]), and myelodysplastic syndromes (six [3%]); and among epoetin alfa recipients (n=179) were anaemia (14 [8%]), pneumonia (14 [8%]), neutropenia (11 [6%]), myelodysplastic syndromes (ten [6%]), hypertension (eight [4%]), iron overload (seven [4%]), and COVID-19 pneumonia (six [3%]). The most common serious treatment-emergent adverse events in both groups were pneumonia (nine [5%] luspatercept recipients and 13 [7%] epoetin alfa recipients) and COVID-19 (eight [4%] luspatercept recipients and ten [6%] epoetin alfa recipients). One death (due to acute myeloid leukaemia) considered to be luspatercept-related was reported at the interim analysis. INTERPRETATION: Luspatercept represents a new standard of care for ESA-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. Significantly more patients had red blood cell transfusion independence and haematological improvement with luspatercept than with epoetin alfa, with benefits observed across patient subgroups. FUNDING: Celgene and Acceleron Pharma.

• MeSH
• aktivinové receptory typu II terapeutické užití   MeSH
• anemie * farmakoterapie   etiologie   MeSH
• epoetin alfa * terapeutické užití   MeSH
• erythropoetin terapeutické užití   MeSH
• hematinika * terapeutické užití   MeSH
• hemoglobiny analýza   MeSH
• imunoglobuliny - Fc fragmenty terapeutické užití   škodlivé účinky   MeSH
• krevní transfuze statistika a číselné údaje   MeSH
• lidé středního věku MeSH
• lidé MeSH
• myelodysplastické syndromy * komplikace   farmakoterapie   MeSH
• rekombinantní fúzní proteiny * terapeutické užití   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

Porphyria cutanea tarda (PCT) is the most common chronic porphyria, with approximate prevalence of 1:10,000. PCT is frequently associated with hepatitis C virus (HCV), malignant lymphoma and iron overload. Here, we present a case of PCT onset subsequent to hepatitis E virus infection (HEV), characterised by symptoms including skin fragility, haemorrhagic bullous skin exanthema, and onycholysis. The patient was successfully treated by erythrocytapheresis and hydroxychloroquine. After exclusion of other possible causes of PCT, HEV infection was identified as the likely trigger of the disease in this genetically predisposed individual, representing the first reported instance of such an association. Erythrocytapheresis emerged as a viable alternative to phlebotomy for PCT treatment. This case underscores the significance of considering HEV infection in the aetiology of PCT and highlights erythrocytapheresis as a promising therapeutic approach (Ref. 8).

Iron and copper chelation therapy plays a crucial role in treating conditions associated with metal overload, such as hemochromatosis or Wilson's disease. However, conventional chelators face challenges in reaching the core of iron and copper metabolism - the mitochondria. Mitochondria-targeted chelators can specifically target and remove metal ions from mitochondria, showing promise in treating diseases linked to mitochondrial dysfunction, including neurodegenerative diseases and cancer. Additionally, they serve as specific mitochondrial metal sensors. However, designing these new molecules presents its own set of challenges. Depending on the chelator's intended use to prevent or to promote redox cycling of the metals, the chelating moiety must possess different donor atoms and an optimal value of the electrode potential of the chelator-metal complex. Various targeting moieties can be employed for selective delivery into the mitochondria. This review also provides an overview of the current progress in the design of mitochondria-targeted chelators and their biological activity investigation.

• MeSH
• chelátory železa farmakologie   MeSH
• chelátory * terapeutické užití   metabolismus   MeSH
• chelátová terapie metody   MeSH
• lidé MeSH
• měď * metabolismus   MeSH
• mitochondrie * metabolismus   účinky léků   MeSH
• železo * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the standard-of-care treatment for anaemia in most patients with lower-risk myelodysplastic syndromes but responses are limited and transient. Luspatercept promotes late-stage erythroid maturation and has shown durable clinical efficacy in patients with lower-risk myelodysplastic syndromes. In this study, we report the results of a prespecified interim analysis of luspatercept versus epoetin alfa for the treatment of anaemia due to lower-risk myelodysplastic syndromes in the phase 3 COMMANDS trial. METHODS: The phase 3, open-label, randomised controlled COMMANDS trial is being conducted at 142 sites in 26 countries. Eligible patients were aged 18 years or older, had a diagnosis of myelodysplastic syndromes of very low risk, low risk, or intermediate risk (per the Revised International Prognostic Scoring System), were ESA-naive, and required red blood cell transfusions (2-6 packed red blood cell units per 8 weeks for ≥8 weeks immediately before randomisation). Integrated response technology was used to randomly assign patients (1:1, block size 4) to luspatercept or epoetin alfa, stratified by baseline red blood cell transfusion burden (<4 units per 8 weeks vs ≥4 units per 8 weeks), endogenous serum erythropoietin concentration (≤200 U/L vs >200 to <500 U/L), and ring sideroblast status (positive vs negative). Luspatercept was administered subcutaneously once every 3 weeks starting at 1·0 mg/kg body weight with possible titration up to 1·75 mg/kg. Epoetin alfa was administered subcutaneously once a week starting at 450 IU/kg body weight with possible titration up to 1050 IU/kg (maximum permitted total dose of 80 000 IU). The primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), assessed in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The COMMANDS trial was registered with ClinicalTrials.gov, NCT03682536 (active, not recruiting). FINDINGS: Between Jan 2, 2019 and Aug 31, 2022, 356 patients were randomly assigned to receive luspatercept (178 patients) or epoetin alfa (178 patients), comprising 198 (56%) men and 158 (44%) women (median age 74 years [IQR 69-80]). The interim efficacy analysis was done for 301 patients (147 in the luspatercept group and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier. 86 (59%) of 147 patients in the luspatercept group and 48 (31%) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26·6; 95% CI 15·8-37·4; p<0·0001). Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR 20-73]) versus epoetin alfa (27 weeks [19-55]). The most frequently reported grade 3 or 4 treatment-emergent adverse events with luspatercept (≥3% patients) were hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndromes, and syncope; and with epoetin alfa were anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia, and myelodysplastic syndromes. The most common suspected treatment-related adverse events in the luspatercept group (≥3% patients, with the most common event occurring in 5% patients) were fatigue, asthenia, nausea, dyspnoea, hypertension, and headache; and none (≥3% patients) in the epoetin alfa group. One death after diagnosis of acute myeloid leukaemia was considered to be related to luspatercept treatment (44 days on treatment). INTERPRETATION: In this interim analysis, luspatercept improved the rate at which red blood cell transfusion independence and increased haemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes. Long-term follow-up and additional data will be needed to confirm these results and further refine findings in other subgroups of patients with lower-risk myelodysplastic syndromes, including non-mutated SF3B1 or ring sideroblast-negative subgroups. FUNDING: Celgene and Acceleron Pharma.

• MeSH
• anemie * farmakoterapie   etiologie   MeSH
• COVID-19 * MeSH
• dyspnoe farmakoterapie   MeSH
• epoetin alfa škodlivé účinky   MeSH
• erytropoéza MeSH
• hematinika * škodlivé účinky   MeSH
• hemoglobiny terapeutické užití   MeSH
• hypertenze * farmakoterapie   MeSH
• lidé MeSH
• myelodysplastické syndromy * komplikace   farmakoterapie   chemicky indukované   MeSH
• neutropenie * MeSH
• senioři MeSH
• tělesná hmotnost MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

INTRODUCTION: Pyruvate kinase (PK) deficiency is a rare, under-recognised, hereditary condition that leads to chronic haemolytic anaemia and potentially serious secondary complications, such as iron overload, cholecystitis, pulmonary hypertension and extramedullary haematopoiesis. It is an autosomal recessive disease caused by homozygous or compound heterozygous mutations in the PKLR gene. Due to its rarity and clinical heterogeneity, information on the natural history and long-term clinical course of PK deficiency is limited, presenting major challenges to patient management, the development of new therapies and establishing disease-specific treatment recommendations. The Pyruvate Kinase Deficiency Global Longitudinal (Peak) Registry is an initiative to address the gaps in the knowledge of PK deficiency. This manuscript describes the objectives, study design and methodology for the Peak Registry. METHODS AND ANALYSIS: The Peak Registry is an observational, longitudinal, global registry of adult and paediatric patients with a genetically confirmed diagnosis of PK deficiency. The Peak Steering Committee is composed of 11 clinicians and researchers with experience in the diagnosis and management of PK deficiency from 10 countries, a patient representative and representatives from the sponsor (Agios Pharmaceuticals). The registry objective is to foster an understanding of the longitudinal clinical implications of PK deficiency, including its natural history, treatments and outcomes, and variability in clinical care. The aim is to enrol up to 500 participants from approximately 60 study centres across 20 countries over 7 years, with between 2 and 9 years of follow-up. Data will include demographics, diagnosis history, genotyping, transfusion history, relevant clinical events, medications, emergency room visits and hospitalisations. ETHICS AND DISSEMINATION: Registry protocol and informed consent forms are approved by institutional review boards/independent ethics committees at each study site. The study is being conducted in accordance with the Declaration of Helsinki. Registry data will be published in peer-reviewed journal articles and conference publications. TRIAL REGISTRATION NUMBER: NCT03481738.

• MeSH
• dítě MeSH
• dospělí MeSH
• hemolytická nesférocytická kongenitální anemie * diagnóza   genetika   MeSH
• homozygot MeSH
• lidé MeSH
• pyruvátkinasa genetika   MeSH
• vrozené poruchy metabolismu pyruvátu * genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• alfa-talasemie MeSH
• chelátová terapie MeSH
• krevní transfuze MeSH
• management nemoci MeSH
• Publikační typ
• směrnice pro lékařskou praxi MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• hematologie a transfuzní lékařství
• genetika, lékařská genetika

• MeSH
• dietoterapie MeSH
• fyziologie výživy MeSH
• pyruvátkinasa nedostatek   MeSH
• talasemie dietoterapie   MeSH
• vrozené poruchy metabolismu pyruvátu dietoterapie   MeSH
• Publikační typ
• směrnice pro lékařskou praxi MeSH

• Konspekt
• Hygiena. Lidské zdraví
• NLK Obory
• nutriční terapie, dietoterapie a výživa
• hematologie a transfuzní lékařství

Mucormycosis is a rare invasive fungal disease diagnosed in immunocompromised patients, including those with diabetes or iron overload, and in patients treated for hematological malignancies or after transplantation. Isavuconazole is a triazole antifungal effective against Mucorales with good tolerability, but with potential for relatively high interindividual variability in pharmacokinetics. This report demonstrates the case of a lung transplant recipient treated with isavuconasole that exhibits a very long elimination half-life of 159 hours, and discusses the practical implications of this finding for dosage adjustment and need for therapeutic drug monitoring.

• MeSH
• aspergilóza * farmakoterapie   MeSH
• lidé MeSH
• monitorování léčiv MeSH
• mukormykóza * diagnóza   farmakoterapie   MeSH
• plíce MeSH
• příjemce transplantátu MeSH
• triazoly terapeutické užití   farmakokinetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

BACKGROUND: Dysmetabolic iron overload syndrome (DIOS) is characterized by hyperferritinemia and normal transferrin saturation level with components of metabolic syndrome (MS). Among cases of MS, we determined those with DIOS and their characterizations, then we evaluated the association between plasma catecholamines status and hypertension in DIOS. METHODS: We compared 101 hypertensive patients with 50 healthy participants (control group). Iron (iron, transferrin, and ferritin), insulin, and plasma catecholamine (adrenaline, noradrenaline, and dopamine), profiles were measured for both groups. Homeostasis model assessment of insulin resistance index and transferrin saturation were also calculated. RESULTS: Out of 101 hypertensive patients, 64 were diagnosed with MS, and 6 of the latter met the DIOS diagnostic criteria. Significantly, DIOS patients were older and had lower body mass index (BMI) compared with hypertensive non-DIOS patients with p-values of (0.026), and (0.033), respectively. Adrenaline, noradrenaline, and dopamine levels did not differ significantly between DIOS and non-DIOS patients. CONCLUSIONS: Of the MS patients, 9.3% were diagnosed with DIOS. Accordingly, complete iron profiling should be performed routinely in the cases of MS for early diagnosis of DIOS, to prevent future complications. Further studies are required to test the hypothesis linking older age and lower BMI with the pathogenesis of DIOS.

• MeSH
• adrenalin MeSH
• dopamin MeSH
• katecholaminy MeSH
• lidé MeSH
• metabolický syndrom * diagnóza   komplikace   metabolismus   MeSH
• noradrenalin MeSH
• přetížení železem * diagnóza   komplikace   MeSH
• transferin metabolismus   MeSH
• železo metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Labile redox-active iron ions have been implicated in various neurodegenerative disorders, including the Parkinson's disease (PD). Iron chelation has been successfully used in clinical practice to manage iron overload in diseases such as thalassemia major; however, the use of conventional iron chelators in pathological states without systemic iron overload remains at the preclinical investigative level and is complicated by the risk of adverse outcomes due to systemic iron depletion. In this study, we examined three clinically-used chelators, namely, desferrioxamine, deferiprone and deferasirox and compared them with experimental agent salicylaldehyde isonicotinoyl hydrazone (SIH) and its boronate-masked prochelator BSIH for protection of differentiated PC12 cells against the toxicity of catecholamines 6-hydroxydopamine and dopamine and their oxidation products. All the assayed chelating agents were able to significantly reduce the catecholamine toxicity in a dose-dependent manner. Whereas hydrophilic chelator desferrioxamine exerted protection only at high and clinically unachievable concentrations, deferiprone and deferasirox significantly reduced the catecholamine neurotoxicity at concentrations that are within their plasma levels following standard dosage. SIH was the most effective iron chelator to protect the cells with the lowest own toxicity of all the assayed conventional chelators. This favorable feature was even more pronounced in prochelator BSIH that does not chelate iron unless its protective group is cleaved in disease-specific oxidative stress conditions. Hence, this study demonstrated that while iron chelation may have general neuroprotective potential against catecholamine auto-oxidation and toxicity, SIH and BSIH represent promising lead molecules and warrant further studies in more complex animal models.

• MeSH
• buňky PC12 MeSH
• chelátory železa * farmakologie   MeSH
• deferasirox farmakologie   MeSH
• deferipron farmakologie   MeSH
• deferoxamin farmakologie   MeSH
• dopamin farmakologie   MeSH
• katecholaminy farmakologie   MeSH
• krysa rodu rattus MeSH
• oxidační stres MeSH
• oxidopamin farmakologie   MeSH
• přetížení železem * MeSH
• železo farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH