Myelodysplastický syndrom (MDS) je heterogenní skupina onemocnění myeloidní řady. S ohledem na výběr terapie se pacienti s MDS dělí na nemocné s nižším a vyšším rizikem, přičemž téměř tři čtvrtiny nemocných s MDS jsou klasifikovány jako pacienti s nižším rizikem. U těchto nemocných je dominujícím problémem anemie, která má významný dopad na kvalitu života pacientů a jejich prognózu. Standardem terapie symptomatické anemie u nemocných s MDS nižšího rizika jsou látky stimulující erytropoezu (ESA), mnoho pacientů však na tuto terapii nereaguje a u většiny nemocných, kteří na ni reagují, dojde k relapsu a závislosti na transfuzích. V poslední době se však objevují nové možnosti léčby anemie, mezi něž patří i luspatercept. Luspatercept je rekombinantní fúzní protein, který váže vybrané ligandy superrodiny TGF-β. Tím inhibuje signalizaci SMAD2/3, což vede k potenciaci diferenciace a proliferace buněk červené řady v pozdních fázích erytropoezy. V klinických studiích byla léčba luspaterceptem spojena se zvýšením podílu pacientů s nezávislostí na transfuzích a s hematologickým zlepšením a rovněž naše zkušenosti s luspaterceptem u prvních 34 takto léčených nemocných jsou velmi dobré.

Myelodysplastic syndrome (MDS) is a heterogeneous group of diseases of the myeloid lineage. With respect to the choice of therapy, MDS patients are divided into a lower- and higher-risk group, with nearly three-quarters of MDS patients classified as lower-risk. In these patients, anaemia is the main issue as it has a significant impact on the quality of life and prognosis of the patients. Erythropoiesis-stimulating agents (ESAs) are the standard therapy for symptomatic anaemia in lower-risk MDS patients, but many of them do not respond to this therapy, and those who do respond relapse and become transfusion- -dependent. Recently, new treatment options for anaemia have emerged, including luspatercept. Luspatercept is a recombinant fusion protein that binds specific ligands from the TGF-β family. This inhibits SMAD2/3 signalling, leading to the potentiation of differentiation and proliferation of the red lineage cells in the late stages of erythropoiesis. In clinical trials, treatment with luspatercept has been associated with an increase in the proportion of patients with transfusion independence and haematological improvement, and our experience with luspatercept in the first 34 patients treated has also been very good.

• Klíčová slova
• Luspatercept,
• MeSH
• aktivinové receptory typu II aplikace a dávkování   terapeutické užití   MeSH
• erythropoetin terapeutické užití   MeSH
• imunoglobuliny - Fc fragmenty aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• myelodysplastické syndromy * farmakoterapie   MeSH
• rekombinantní fúzní proteiny aplikace a dávkování   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

Myelodysplastický syndrom (MDS) představuje klonální poruchu krvetvorby. Léčebnou strategii volíme podle rizika onemocnění na základě revidovaného Mezinárodního prognostického systému (revised International Prognostic Scoring System, IPSS-R). Pro pacienty s nižším rizikem je doporučena podpůrná, stimulační nebo imunomodulační terapie. Jako velmi nadějný lék pro pacienty s myelodysplastickým syndromem nízkého rizika a s transfuzní dependencí se jeví luspatercept. Přípravek byl s úspěchem zkoumán v rámci randomizovaných multicentrických klinických studií. Připojená kazuistika ilustruje léčebný potenciál luspaterceptu.

Myelodysplastic syndrome (MDS) is a clonal hematopoietic disorder. We choose the treatment strategy on the basis of the risk of the disease according to the revised International Prognostic Scoring System (IPSS-R). For patients at lower risk, the recommended therapy is supportive, stimulating or immunomodulatory. Luspatercept appears to be a very promising drug for patients with low-risk myelodysplastic syndrome and transfusion dependence. The drug has been successfully investigated in randomized multicenter clinical trials. The attached case report illustrates the potential of luspatercept.

• Klíčová slova
• Luspatercept,
• MeSH
• aktivinové receptory typu II aplikace a dávkování   terapeutické užití   MeSH
• chelátová terapie MeSH
• erythropoetin terapeutické užití   MeSH
• imunoglobuliny - Fc fragmenty aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• myelodysplastické syndromy * farmakoterapie   MeSH
• rekombinantní fúzní proteiny aplikace a dávkování   terapeutické užití   MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• kazuistiky 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

Myelodysplastický syndrom je klonální onemocnění hemopoézy. U nemocných s nízkým rizikem progrese choroby či přechodu do akutní myeloidní leukemie je dominantním problémem cytopenie, a to především anemie. Ta se vyskytuje až u 90 % nemocných. Hlubší anemie, zvláště u transfuzně závislých nemocných, významně snižuje kvalitu života, zvyšuje morbiditu, ale i mortalitu. Dosud jsme byli odkázáni u většiny nemocných (s výjimkou nemocných s 5q-syndromem, kteří jsou výbornými respondenty terapie lenalidomidem) na transfuze či podávání erytropoetinů. Erytropoetiny ale nejsou příliš účinné právě u nemocných s již vyvinutou závislostí na transfuzích. Proto je velkým přínosem v léčbě těchto nemocných nový přípravek luspatercept, inhibitor dráhy TGF-β, který vede až u 50 % nemocných k eliminaci transfuzní potřeby, výraznému zlepšení kvality života, a jak bylo recentně prokázáno, i k prodloužení doby přežívání. Prezentujeme kazuistiku nemocné, u níž byl tento přípravek úspěšně použit, a to i jako lék čtvrté linie terapie.

Myelodysplastic syndrome is a clonal disease of the hemopoiesis. In patients with a low risk of disease progression or transition to acute myeloid leukemia, cytopenia, especially anemia, is the dominant problem. It occurs in up to 90% of patients. Deeper anemia, especially in transfusion-dependent patients, significantly reduces quality of life, increases morbidity and mortality. So far, we could use as a treatment only transfusions or erythropoietins for most patients (except for patients with 5q-syndrome, who are excellent responders to lenalidomide therapy). However, erythropoietins are not very effective in patients with already developed transfusion dependence. Therefore, the new drug luspatercept, an inhibitor of the TGF-β pathway, is of great benefit in the treatment of these patients, resulting in the elimination of the need for transfusions in up to 50% of patients, a significant improvement in quality of life and, as recently demonstrated, prolonged survival. We present a case report of a patient where this agent was successfully used as a fourth line therapy.

• Publikační typ
• zprávy MeSH

BACKGROUND: Luspatercept, an inhibitor of the transforming growth factor beta (TGF-β) pathway, is a novel treatment for anemic patients with lower-risk myelodysplastic syndromes (MDS) with transfusion dependence (TD) who do not respond to erythropoiesis-stimulating agents (ESA) therapy or are not suitable candidates for this treatment. We present real-world experience with luspatercept therapy from two hematology centers in the Czech Republic. METHODS: By January 2024, 54 MDS patients (33 men, 21 women) with a median age of 74 years (range, 55-95) were treated with luspatercept ± ESA at two Charles University hematology centers in Prague and Hradec Králové. According to the WHO 2016 classification, the cohort included 32 MDS-RS-MLD, seven MDS-MLD, two patients with 5q- + ring sideroblasts (RS), 12 RARS-T, and 1 patient with CMML-0 + RS. SF3B1 mutation data were available for 45 patients. All patients were in the IPSS-R and IPSS-M lower-risk groups (except four IPSS-M high). The median follow-up was 17 months (range, 1-54). All patients were transfusion-dependent. Thirty-five (64.8%) patients had a high transfusion burden (HTB) with ≥ 4 transfusion units (TU)/8 weeks, and 19 (35.2%) had a low transfusion burden (LTB) (< 4 TU/8 weeks). The median time between diagnosis and initiation of luspatercept was 27 months (range, 4-156). ESA were used prior to luspatercept in 45 patients, and luspatercept was used as first-line treatment in nine patients. Thirty-one (61%) patients were treated simultaneously with ESA. RESULTS: Only patients who received luspatercept for ≥ 8 weeks (51 patients) were assessed. We evaluated the achievement of transfusion independence (TI) lasting 8, 12, 16, and 24 weeks. Thirty-two (62.7%) patients achieved TI for ≥ 8 weeks, 31 (60.7%) for ≥ 12 weeks, 29 (56.8%) for ≥ 16 weeks, and 25 (49%) for ≥ 24 weeks. Hematologic improvement (HI) without TI was achieved in six patients (11.7%). Overall, HI + TI was achieved in 38 patients (74.5%). Epoetin alfa was used simultaneously in 31 patients (60.7%). In 21 (55.2%) of all responding patients, concomitant therapy with epoetin alfa led to an improved response, with 16 reaching TI. Thirteen (25.5%) patients were nonresponders. Eight (21%) patients experienced therapy failure and became transfusion-dependent again. Optimal response required a gradual increase in the luspatercept dose to 1.75 mg/kg in up to 35 patients, with 23 responders (TI + HI). Response rates varied by transfusion burden: 79% in LTB and 50% in HTB reached TI. Of RS+ patients, 70% reached TI, while only one out of five RS- patients achieved TI. Among 39 SF3B1-positive patients, 61.6% achieved TI. In the low and very low IPSS-M groups, 86% of patients responded (TI + HI), compared to 62% in the moderate-low group. Luspatercept was well-tolerated, with no adverse events higher than grade II toxicity. CONCLUSION: We have demonstrated in real-world clinical practice that luspatercept is a very effective agent, even in an unselected, pretreated, significantly TD MDS population. The effect was particularly high in the IPSS-M low and very low groups. We believe that the relatively high response rate in our patients was influenced by the frequent use of a higher dose (1.75 mg/kg) and especially by adding ESA to luspatercept in poorly responding patients.

• Publikační typ
• časopisecké články MeSH

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

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