Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study
TL;DR: This phase 2, multicentre, open-label, dose-finding study aimed to assess the safety and efficacy of luspatercept in patients with anaemia due to lower-risk myelodysplastic syndromes and the proportion of patients achieving modified International Working Group-defined haematological improvement-erythroid (HI-E).
Abstract: Summary Background Myelodysplastic syndromes are characterised by ineffective erythropoiesis. Luspatercept (ACE-536) is a novel fusion protein that blocks transforming growth factor beta (TGF β) superfamily inhibitors of erythropoiesis, giving rise to a promising new investigative therapy. We aimed to assess the safety and efficacy of luspatercept in patients with anaemia due to lower-risk myelodysplastic syndromes. Methods In this phase 2, multicentre, open-label, dose-finding study (PACE-MDS), with long-term extension, eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low or intermediate 1 risk myelodysplastic syndromes or non-proliferative chronic myelomonocytic leukaemia (white blood cell count vs 0·75–1·75 mg/kg); pre-study transfusion burden (high transfusion burden vs low transfusion burden, defined as ≥4 vs 500 IU/L); presence of 15% or more ring sideroblasts; and presence of SF3B1 mutations. Efficacy analyses were carried out on the efficacy evaluable and intention-to-treat populations. This trial is currently ongoing. This study is registered with ClinicalTrials.gov, numbers NCT01749514 and NCT02268383. Findings Between Jan 21, 2013, and Feb 12, 2015, 58 patients with myelodysplastic syndromes were enrolled in the 12 week base study at nine treatment centres in Germany; 27 patients were enrolled in the dose-escalation cohorts (0·125–1·75 mg/kg) and 31 patients in the expansion cohort (1·0–1·75 mg/kg). 32 (63% [95% CI 48–76]) of 51 patients receiving higher dose luspatercept concentrations (0·75–1·75 mg/kg) achieved HI-E versus two (22% [95% CI 3–60]) of nine receiving lower dose concentrations (0·125–0·5 mg/kg). Three treatment-related grade 3 adverse events occurred in one patient each: myalgia (one [2%]), increased blast cell count (one [2%]), and general physical health deterioration (one [2%]). Two of these treatment-related grade 3 adverse events were reversible serious grade 3 adverse events: one patient (2%) had myalgia and one patient (2%) had general physical health deterioration. Interpretation Luspatercept was well tolerated and effective for the treatment of anaemia in lower-risk myelodysplastic syndromes and so could therefore provide a novel therapeutic approach for the treatment of anaemia associated with lower-risk myelodysplastic syndromes; further studies are ongoing. Funding Acceleron Pharma.
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TL;DR: Improved understanding of iron homeostasis and its regulation is leading to the development of targeted therapies for iron overload and inflammation, mainly centered on the manipulation of the hepcidin-ferroportin axis.
Abstract: Iron is biologically essential, but also potentially toxic; as such it is tightly controlled at cell and systemic levels to prevent both deficiency and overload. Iron regulatory proteins post-transcriptionally control genes encoding proteins that modulate iron uptake, recycling and storage and are themselves regulated by iron. The master regulator of systemic iron homeostasis is the liver peptide hepcidin, which controls serum iron through degradation of ferroportin in iron-absorptive enterocytes and iron-recycling macrophages. This review emphasizes the most recent findings in iron biology, deregulation of the hepcidin-ferroportin axis in iron disorders and how research results have an impact on clinical disorders. Insufficient hepcidin production is central to iron overload while hepcidin excess leads to iron restriction. Mutations of hemochro-matosis genes result in iron excess by downregulating the liver BMP-SMAD signaling pathway or by causing hepcidin-resistance. In iron-loading anemias, such as β-thalassemia, enhanced albeit ineffective ery-thropoiesis releases erythroferrone, which sequesters BMP receptor ligands, thereby inhibiting hepcidin. In iron-refractory, iron-deficiency ane-mia mutations of the hepcidin inhibitor TMPRSS6 upregulate the BMP-SMAD pathway. Interleukin-6 in acute and chronic inflammation increases hepcidin levels, causing iron-restricted erythropoiesis and ane-mia of inflammation in the presence of iron-replete macrophages. Our improved understanding of iron homeostasis and its regulation is having an impact on the established schedules of oral iron treatment and the choice of oral versus intravenous iron in the management of iron deficiency. Moreover it is leading to the development of targeted therapies for iron overload and inflammation, mainly centered on the manipulation of the hepcidin-ferroportin axis.
289 citations
University of Paris1, University of La Réunion2, Leipzig University3, University of London4, University of Texas System5, Sunnybrook Research Institute6, University of Florence7, University of Bologna8, University of Pavia9, Ankara University10, Cleveland Clinic11, University of Oxford12, University of Leeds13, Johns Hopkins University14, Columbia University15, University of Düsseldorf16, Technische Universität München17, university of lille18, University of Rome Tor Vergata19, Ghent University Hospital20, Stanford University21, Karolinska Institutet22, Yale University23, Albert Einstein College of Medicine24, Vanderbilt University25, Celgene26
TL;DR: Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event.
Abstract: Background Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusio...
278 citations
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University of Pavia1, Harvard University2, Memorial Sloan Kettering Cancer Center3, University of California, San Diego4, University of Oxford5, Leeds Teaching Hospitals NHS Trust6, Wellcome Trust Sanger Institute7, University of Paris8, Hannover Medical School9, Radboud University Nijmegen10, University of South Florida11, Cleveland Clinic12, Washington University in St. Louis13, Paris Descartes University14, University of Texas MD Anderson Cancer Center15, University of British Columbia16, Vanderbilt University17, University of Dundee18, University of Amsterdam19, University of Göttingen20, Stanford University21, Kyoto University22, Karolinska University Hospital23
TL;DR: In patients with clonal cytopenia of undetermined significance, SF3B1 mutation is almost invariably associated with subsequent development of overt MDS with RS, suggesting that this genetic lesion might provide presumptive evidence of MDS in the setting of persistent unexplained cy topenia.
152 citations
TL;DR: The myelodysplastic syndromes are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML).
Abstract: Disease overview The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older males and in individuals with prior exposure to cytotoxic therapy. Diagnosis Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry or molecular genetics is usually complementary and may help refine diagnosis. Risk-stratification Prognosis of patients with MDS can be calculated using a number of scoring systems. In general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow and cytogenetic characteristics. The most commonly used system is probably the International Prognostic Scoring System (IPSS). IPSS is now replaced by the revised IPSS-R score. Although not systematically incorporated into new validated prognostic systems, somatic mutations can help define prognosis and should be considered as new prognostic factors. Risk-adapted therapy Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts and cytogenetic and mutational profiles. Goals of therapy are different in lower risk patients than in higher risk. In lower risk, the goal is to decrease transfusion needs and transformation to higher risk disease or AML, as well as to improve survival. In higher risk, the goal is to prolong survival. Current available therapies include growth factor support, lenalidomide, hypomethylating agents, intensive chemotherapy and allogeneic stem cell transplantation. The use of lenalidomide has significant clinical activity in patients with lower risk disease, anemia and a chromosome 5 alteration. 5-azacitidine and decitabine have activity in both lower and higher-risk MDS. 5-azacitidine has been shown to improve survival in higher risk MDS. A number of new molecular lesions have been described in MDS that may serve as new therapeutic targets or aid in the selection of currently available agents. Additional supportive care measures may include the use of prophylactic antibiotics and iron chelation. Management of progressive or refractory disease At the present time there are no approved interventions for patients with progressive or refractory disease particularly after hypomethylating based therapy. Options include participation in a clinical trial or cytarabine based therapy and stem cell transplantation.
145 citations
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TL;DR: An overview of the current therapeutic landscape in MDS focusing on recent advances in clinical and translational research is provided, with a particularly urgent medical need in patients failing current first-line therapies, such as with erythropoiesis-stimulating or hypomethylating agents.
135 citations
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Stanford University1, University of Göttingen2, University of Texas MD Anderson Cancer Center3, University of Rochester Medical Center4, St James's University Hospital5, University of Paris6, University of Düsseldorf7, University of Pavia8, Medical University of Vienna9, University of Chicago10, Quest Diagnostics11, University of Freiburg12, Cleveland Clinic13, Federal University of Ceará14, Nagasaki University15, University of Dundee16, VU University Medical Center17
TL;DR: This revised IPSS-R comprehensively integrated the numerous known clinical features into a method analyzing MDS patient prognosis more precisely than the initial IPSS and should prove beneficial for predicting the clinical outcomes of untreated MDS patients and aiding design and analysis of clinical trials in this disease.
2,310 citations