BACKGROUND: Myelodysplastic neoplasms (MDS) are heterogeneous hematopoietic disorders characterized by ineffective hematopoiesis and genome instability. Mobilization of transposable elements (TEs) is an important source of genome instability leading to oncogenesis, whereas small PIWI-interacting RNAs (piRNAs) act as cellular suppressors of TEs. However, the roles of TEs and piRNAs in MDS remain unclear. METHODS: In this study, we examined TE and piRNA expression through parallel RNA and small RNA sequencing of CD34+ hematopoietic stem cells from MDS patients. RESULTS: Comparative analysis of TE and piRNA expression between MDS and control samples revealed several significantly dysregulated molecules. However, significant differences were observed between lower-risk MDS (LR-MDS) and higher-risk MDS (HR-MDS) samples. In HR-MDS, we found an inverse correlation between decreased TE levels and increased piRNA expression and these TE and piRNA levels were significantly associated with patient outcomes. Importantly, the upregulation of PIWIL2, which encodes a key factor in the piRNA pathway, independently predicted poor prognosis in MDS patients, underscoring its potential as a valuable disease marker. Furthermore, pathway analysis of RNA sequencing data revealed that dysregulation of the TE‒piRNA axis is linked to the suppression of processes related to energy metabolism, the cell cycle, and the immune response, suggesting that these disruptions significantly affect cellular activity. CONCLUSIONS: Our findings demonstrate the parallel dysregulation of TEs and piRNAs in HR-MDS patients, highlighting their potential role in MDS progression and indicating that the PIWIL2 level is a promising molecular marker for prognosis.

• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Progressing myelodysplastic syndrome (MDS) into acute myeloid leukemia (AML) is an indication for hypomethylating therapy (HMA, 5-Azacytidine (AZA)) and a BCL2 inhibitor (Venetoclax, VEN) for intensive chemotherapy ineligible patients. Mouse models that engraft primary AML samples may further advance VEN + AZA resistance research. METHODS: We generated a set of transplantable murine PDX models from MDS/AML patients who developed resistance to VEN + AZA and compared the differences in hematopoiesis of the PDX models with primary bone marrow samples at the genetic level. PDX were created in NSGS mice via intraosseal injection of luciferase-encoding Lentivirus-infected MDS/AML primary cells from patient bone marrow. We validated the resistance of PDX-leukemia to VEN and AZA and further tested candidate agents that inhibit the growth of VEN/AZA-resistant AML. RESULTS AND DISCUSSION: Transplantable PDX models for MDS/AML arise with 31 % frequency. The lower frequency of transplantable PDX models is not related to peritransplant lethality of the graft, but rather to the loss of the ability of short-term proliferation of leukemic progenitors after 10 weeks of engraftment. There exist subtle genetic and cytological changes between primary and PDX-AML samples however, the PDX models retain therapy resistance observed in patients. Based on in vitro testing and in vivo validation in PDX models, Panobinostat and Dinaciclib are very promising candidate agents that overcome dual VEN + AZA resistance.

• Publikační typ
• časopisecké články MeSH

BACKGROUND: Unmet medical needs remain in patients with red blood cell transfusion-dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) who are not responding to or are ineligible for erythropoiesis-stimulating agents (ESAs). Imetelstat, a competitive telomerase inhibitor, showed promising results in a phase 2 trial. We aimed to compare the RBC transfusion independence (RBC-TI) rate with imetelstat versus placebo in patients with RBC-TD LR-MDS. METHODS: In phase 3 of IMerge, a double-blind, placebo-controlled trial conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients (aged ≥18 years) with ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per International Prognostic Scoring System [IPSS] criteria) were randomly assigned via a computer-generated schedule (2:1) to receive imetelstat 7·5 mg/kg or placebo, administered as a 2-h intravenous infusion, every 4 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and IPSS risk group. Patients, investigators, and those analysing the data were masked to group assignment. The primary endpoint was 8-week RBC-TI, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anti-cancer therapy, if any. Primary efficacy analyses were performed in the intention-to-treat population, and safety analyses were conducted in patients who received at least one dose of trial medication or placebo. This trial is registered with ClinicalTrials.gov (NCT02598661; substudy active and recruiting). FINDINGS: Between Sept 11, 2019, and Oct 13, 2021, 178 patients were enrolled and randomly assigned (118 to imetelstat and 60 to placebo). 111 (62%) were male and 67 (38%) were female. 91 (77%) of 118 patients had discontinued treatment by data cutoff in the imetelstat group versus 45 (75%) in the placebo group; a further one patient in the placebo group did not receive treatment. Median follow-up was 19·5 months (IQR 12·0-23·4) in the imetelstat group and 17·5 months (12·1-22·7) in the placebo group. In the imetelstat group, 47 (40% [95% CI 30·9-49·3]) patients had an RBC-TI of at least 8 weeks versus nine (15% [7·1-26·6]) in the placebo group (rate difference 25% [9·9 to 36·9]; p=0·0008). Overall, 107 (91%) of 118 patients receiving imetelstat and 28 (47%) of 59 patients receiving placebo had grade 3-4 treatment-emergent adverse events. The most common treatment-emergent grade 3-4 adverse events in patients taking imetelstat were neutropenia (80 [68%] patients who received imetelstat vs two [3%] who received placebo) and thrombocytopenia (73 [62%] vs five [8%]). No treatment-related deaths were reported. INTERPRETATION: Imetelstat offers a novel mechanism of action with durable transfusion independence (approximately 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs. FUNDING: Janssen Research & Development before April 18, 2019, and Geron Corporation thereafter.

• MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• erytropoéza MeSH
• lidé MeSH
• mladiství MeSH
• myelodysplastické syndromy * farmakoterapie   MeSH
• oligonukleotidy * MeSH
• protokoly protinádorové kombinované chemoterapie MeSH
• trombocytopenie * farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH

Myelodysplastický syndrom je klonální onemocnění hemopoezy. 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 nemocných závislých na transfuzích významně snižuje kvalitu života, zvyšuje morbiditu i mortalitu. Dosud jsme byli odkázáni u většiny nemocných (s výjimkou nemocných s 5q-syndromem, kteří jsou výbornými respondenty na terapii lenalidomidem) na transfuze či podání 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 transformujícího růstového faktoru β (transforming growth factor β, TGF – β), který vede až u 50 % nemocných k eliminaci transfuzní potřeby, výraznému zlepšení kvality života, a jak bylo recentně prokázáno, i k prodloužení přežívání. Prezentujeme zde kazuistiku nemocné, kde byl tento přípravek úspěšně použit v kombinaci s erytropoetinem a v dlouhodobé léčbě vysokou dávkou.

Myelodysplastic syndrome (MDS) is a clonal disease of the hemopoesis. 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 erythropoetins for most patients (except for patients with 5q-syndrome, who are excellent responders to lenalidomide therapy). However, erythropoetins are not very effective in patients with already developed transfusion dependence. Therefore, the new drug luspatercept,an inhibitor of the transforming growth factor p 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 in combination with erythropoietin and in long-term high-dose therapy.

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

• Publikační typ
• komentáře MeSH

Our observational study analysed fungal infection frequency within cohorts with versus without antifungal prophylaxis (AFP) among newly diagnosed first-line venetoclax and azacitidine (VEN + AZA)-treated acute myeloid leukaemias in Czech, Austrian and Slovak haematology centres. Among 186 patients, 85 (46%) received antifungal prophylaxis, while 101 (54%) received no prophylaxis. Fungal infections occurred in 1/85 patients with prophylaxis (1%) and 5/101 patients without prophylaxis (5%) (p = 0.222). No significant difference was recorded between cohorts with and without AFP in terms of death rate (p = 0.296) and overall survival (p = 0.844). In conclusion, most infections were not severe, developing during the first treatment-cycle and did not affect patients' overall outcome.

• MeSH
• akutní myeloidní leukemie * farmakoterapie   komplikace   MeSH
• antifungální látky * terapeutické užití   aplikace a dávkování   MeSH
• azacytidin * aplikace a dávkování   terapeutické užití   MeSH
• bicyklické sloučeniny heterocyklické * aplikace a dávkování   terapeutické užití   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mykózy * prevence a kontrola   etiologie   MeSH
• protokoly protinádorové kombinované chemoterapie * škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sulfonamidy * aplikace a dávkování   terapeutické užití   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie 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

• Publikační typ
• úvodníky MeSH