Infectious complications are an important cause of morbidity and mortality in patients with myelodysplastic syndromes (MDS). Preventing infections could significantly improve both survival and quality of life. Unfortunately, both infections and antimicrobial prophylaxis in patients with MDS are incompletely assessed due to the heterogeneity of disorders included in each publication, changing definitions over time, and lack of standardized prophylaxis practices. Despite these limitations, some basic statements can be made. Infections in MDS are associated with neutropenia. Patients with lower-risk (LR) MDS tend to have fewer infections compared to patients with higher-risk (HR) MDS, which may be related to the different prevalence of neutropenia in the 2 groups. Pneumonia is the most common infection, and bacteria are the most common pathogens. Invasive fungal infections (IFI) are uncommon. Reactivation of latent viruses are rare. With the limited data available, we agree that antibacterial prophylaxis can be considered in patients with HR-MDS during severe neutropenia and early cycles of therapy when infections are most likely to occur. Given the low prevalence of IFI and viral reactivation, antimicrobial prophylaxis for these pathogens is less likely to be advantageous for most patients, although antifungal prophylaxis with activity against mold is commonly used in patients with persistent, profound neutropenia. Ultimately, improved data collection regarding infections and antimicrobial prophylaxis is needed to improve care for patients with MDS.
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
Preparát CPX-351, marketingovým označením Vyxeos liposomal, je nově schváleným léčivem určeným k terapii vysoce rizikových forem akutní myeloidní leukemie (AML) vzniklých na podkladě předchozího myelodysplastického syndromu či v souvislosti s předchozí protinádorovou terapií. Preparát je v České republice hrazen u nemocných s uvedenými typy AML pro pacienty ve věku od 60 let. Následující práce popisuje ve svém úvodu indikaci a dávkovací schéma CPX-351, dále jeho mechanizmus účinku a ve stručnosti také zmiňuje terapeutické výsledky a bezpečnostní profil CPX-351, zjištěné v registrační studii produktu. V hlavní části článek popisuje aktuální klinické zkušenosti s CPX-351 získané od roku 2022 na ÚHKT Praha a detailně rozebírá kazuistiky dvou pacientů léčených na ÚHKT v uplynulých měsících. Terapie CPX-351 představuje dle dosavadních zkušeností ÚHKT poměrně efektivní možnost léčby vysoce rizikových AML, u nichž léčba standardní chemoterapií často selhává.
The therapeutic agent CPX-351, Vyxeos liposomal, is a newly approved drug intended for therapy of high-risk subtypes of acute myeloid leukaemia (AML) such as AML arising from antecedent myelodysplastic syndrome or associated with previous anticancer therapy. In the Czech Republic, CPX-351 is reimbursed for patients aged 60 and over with the above-mentioned AML subtypes. The following paper describes the indication and dosage schedule of CPX-351, its mechanism of action and also briefly mentions the therapeutic results and safety profile of CPX-351 according to the product registration study. The article then focuses on current clinical experience with CPX-351 since 2022 at the UHKT Prague and analyses in detail the case reports of two patients treated at the UHKT in the last months. CPX-351 therapy represents, according to our experience so far, a relatively effective option for treating high-risk AML in which treatment with standard chemotherapy often fails.
- Klíčová slova
- CPX-351,
- MeSH
- akutní myeloidní leukemie * farmakoterapie MeSH
- cytarabin farmakologie terapeutické užití MeSH
- daunomycin farmakologie terapeutické užití MeSH
- homologní transplantace metody MeSH
- léková dermatitida etiologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- myelodysplastické syndromy komplikace MeSH
- sekundární malignity komplikace radioterapie MeSH
- seminom radioterapie MeSH
- senioři MeSH
- transplantace hematopoetických kmenových buněk metody MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky 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
- Klíčová slova
- luspatercept,
- MeSH
- aktivinové receptory typu II farmakologie terapeutické užití MeSH
- anemie etiologie farmakoterapie krev MeSH
- antianemika * farmakologie terapeutické užití MeSH
- imunoglobuliny - Fc fragmenty farmakologie terapeutické užití MeSH
- klinické zkoušky, fáze II jako téma MeSH
- lidé MeSH
- myelodysplastické syndromy * komplikace MeSH
- randomizované kontrolované studie jako téma MeSH
- rekombinantní fúzní proteiny farmakologie terapeutické užití MeSH
- transfuze erytrocytů metody škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Klíčová slova
- luspatercept,
- MeSH
- aktivinové receptory typu II farmakologie terapeutické užití MeSH
- anemie etiologie farmakoterapie krev MeSH
- antianemika * farmakologie terapeutické užití MeSH
- imunoglobuliny - Fc fragmenty farmakologie terapeutické užití MeSH
- lidé MeSH
- myelodysplastické syndromy * komplikace MeSH
- rekombinantní fúzní proteiny farmakologie terapeutické užití MeSH
- transfuze erytrocytů metody škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- MeSH
- akutní myeloidní leukemie farmakoterapie mortalita MeSH
- analýza přežití MeSH
- azacytidin aplikace a dávkování terapeutické užití MeSH
- faktor stimulující kolonie granulocytů aplikace a dávkování terapeutické užití účinky léků MeSH
- fixní kombinace léků MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- myelodysplastické syndromy * farmakoterapie komplikace MeSH
- Check Tag
- lidé MeSH
While in vivo T-cell depletion (TCD) is widely used, its benefit in patients with MDS still remains a matter of debate. This study evaluates the impact of TCD on outcomes, and compares ATG and alemtuzumab, in patients with MDS. 1284 patients from the EBMT registry were included in this study with 470 patients in the no-TCD group and 814 in the TCD group (alemtuzumab N = 168; ATG N = 646). At 6 months, aGVHD III-IV cumulative incidences (CI) for no-TCD, ATG or alemtuzumab groups were 13% vs 14% vs 11% (ns), respectively. At 5 years, CI of chronic GVHD were 64% vs 52% vs 51% (p < 0.00017); and CI of relapse was 23% vs 25% vs 39% (p < 0.0001) for no TCD, ATG and alemtuzumab respectively; OS was 47% vs 46% vs 34% (p = 0.009) respectively; and GRFS was 21% vs 28% and 20% (p = 0.045) respectively. In multivariable analysis, ATG improved GRFS, and alemtuzumab decreased OS. Both ATG and alemtuzumab decreased risk of chronic GVHD, but the increased risk of relapse with alemtuzumab is associated with a poor GRFS and suggest to not use alemtuzumab in the setting of allo-SCT for high risk disease.
- MeSH
- alemtuzumab terapeutické užití MeSH
- homologní transplantace škodlivé účinky MeSH
- lidé MeSH
- myelodysplastické syndromy * komplikace terapie MeSH
- nádory * komplikace MeSH
- nemoc štěpu proti hostiteli * etiologie MeSH
- příprava pacienta k transplantaci škodlivé účinky MeSH
- recidiva MeSH
- registrace MeSH
- retrospektivní studie MeSH
- T-lymfocyty MeSH
- transplantace hematopoetických kmenových buněk * škodlivé účinky MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- myelodysplastické syndromy komplikace MeSH
- následné studie MeSH
- pancytopenie etiologie patologie MeSH
- paroxysmální hemoglobinurie etiologie patologie MeSH
- předškolní dítě MeSH
- prognóza MeSH
- receptory antigenů T-buněk alfa-beta genetika MeSH
- refrakterní anemie etiologie patologie MeSH
- retrospektivní studie MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- dopisy MeSH
- práce podpořená grantem MeSH
- Klíčová slova
- Luspatercept,
- MeSH
- aktivinové receptory farmakologie terapeutické užití MeSH
- imunoglobuliny - Fc fragmenty farmakologie terapeutické užití MeSH
- kongresy jako téma MeSH
- krevní nemoci * diagnóza terapie MeSH
- lenalidomid terapeutické užití MeSH
- lidé MeSH
- mnohočetný myelom terapie MeSH
- myelodysplastické syndromy diagnóza komplikace terapie MeSH
- rekombinantní fúzní proteiny farmakologie terapeutické užití MeSH
- senioři * MeSH
- Check Tag
- lidé MeSH
- senioři * MeSH
- Publikační typ
- novinové články MeSH
