Showing papers by "Giovanni Barosi published in 2015"
Salisbury District Hospital1, Austrian Academy of Sciences2, Academy of Athens3, University of Cambridge4, University of Florence5, St James's University Hospital6, Royal Bournemouth Hospital7, University of Southampton8, University of Oxford9, University of Birmingham10, Ludwig Maximilian University of Munich11, National Institutes of Health12, Medical University of Vienna13, University of Pavia14, Guy's and St Thomas' NHS Foundation Trust15, Wellcome Trust Sanger Institute16
TL;DR: It is demonstrated that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype and genome-wide significance in JAK2V617F-negative MPN.
Abstract: Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2(V617F)-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10(-10)) and rs2201862 (MECOM; meta-analysis P=1.96 × 10(-9)). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) P=7.3 × 10(-7)). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype.
145 citations
TL;DR: In this paper, the authors analyzed the prognostic impact of bone marrow fibrosis in 490 patients with primary myelofibrosis, evaluated at diagnosis, molecularly annotated and with extensive follow-up information, and found that fibrosis grade 2 and greater on a 0-3 scale was associated with clinical characteristics indicative of a more advanced disease.
Abstract: The prognostic significance of bone marrow (BM) fibrosis grade in patients with primary myelofibrosis (PMF) is still debated. A fibrosis grade greater than 1 was shown to associate with higher risk of death, and addition of fibrosis grade to IPSS score resulted in a more accurate prediction of survival. The aim of this study was to analyze the prognostic impact of BM fibrosis in 490 patients with PMF, evaluated at diagnosis, molecularly annotated and with extensive follow-up information. We found that fibrosis grade 2 and greater on a 0-3 scale was associated with clinical characteristics indicative of a more advanced disease, such as anemia, leukopenia, thrombocytopenia, constitutional symptoms, larger splenomegaly and a higher IPSS risk category. Patients with higher grade of fibrosis were also more likely to have additional somatic mutations in ASXL1 and EZH2, that are prognostically adverse. Median survival was significantly reduced in patients with grade 2 and 3 fibrosis as compared with grade 1; this effect was maintained when analysis was restricted to younger patients. In multivariate analysis, fibrosis grade independently predicted for survival regardless of IPSS variables and mutational status; the adverse impact of fibrosis was noticeable especially in lower IPSS risk categories. Overall, results indicate that higher grades of fibrosis correlate with unique clinical and molecular aspects and represent an independent adverse variable in patients with PMF; these observations deserve confirmation in prospectively designed series of patients. Am. J. Hematol. 91:918-922, 2016. © 2016 Wiley Periodicals, Inc.
46 citations
TL;DR: VEGF-induced Ca(2+) oscillations modestly stimulate PMF-ECFC growth and in vitro angiogenesis and may explain the modest effect of anti-VEGF therapies in PMF.
46 citations
TL;DR: The hypothesis that fibrosis in PMF results from an autoimmune process triggered by dead megakaryocytes was tested by determining that PMF patients expressed plasma levels of mitochondrial DNA and anti-mitochondrial antibodies greater than normal controls, identifying autoimmunity as a possible cause of marrow fibrosis.
Abstract: Primary myelofibrosis (PMF) is characterized by megakaryocyte hyperplasia, dysplasia and death with progressive reticulin/collagen fibrosis in marrow and hematopoiesis in extramedullary sites. The mechanism of fibrosis was investigated by comparing TGF-β1 signaling of marrow and spleen of patients with PMF and of non-diseased individuals. Expression of 39 (23 up-regulated and 16 down-regulated) and 38 (8 up-regulated and 30 down-regulated) TGF-β1 signaling genes was altered in the marrow and spleen of PMF patients, respectively. Abnormalities included genes of TGF-β1 signaling, cell cycling and abnormal in chronic myeloid leukemia (EVI1 and p21(CIP)) (both marrow and spleen) and Hedgehog (marrow only) and p53 (spleen only) signaling. Pathway analyses of these alterations predict an increased osteoblast differentiation, ineffective hematopoiesis and fibrosis driven by non-canonical TGF-β1 signaling in marrow and increased proliferation and defective DNA repair in spleen. Since activation of non-canonical TGF-β1 signaling is associated with fibrosis in autoimmune diseases, the hypothesis that fibrosis in PMF results from an autoimmune process triggered by dead megakaryocytes was tested by determining that PMF patients expressed plasma levels of mitochondrial DNA and anti-mitochondrial antibodies greater than normal controls. These data identify autoimmunity as a possible cause of marrow fibrosis in PMF.
31 citations
TL;DR: The Italian Society of Hematology and affiliate societies reviewed the evidence regarding the management of these lymphomas to produce evidence-based recommendations aimed at contributing to therapy optimization and standardization.
Abstract: Indolent nonfollicular B-cell lymphoma (INFBCL) has been classified in the World Health Organization 2008 system among the mature B-cell neoplasms and includes nodal and extranodal marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), and small lymphocytic lymphoma (SLL). Recently, the array and sequencing technologies have provided new insights into their molecular pathogenesis; the molecular discoveries, however, have not yet translated into consistent changes in their management. Thus, the therapy for INFBCL remains challenging. To promote widespread adoption of appropriate clinical practice, the Italian Society of Hematology and affiliate societies (Italian Society of Experimental Hematology and Italian Group for Bone Marrow Transplantation) reviewed the evidence regarding the management of these lymphomas to produce evidence-based recommendations aimed at contributing to therapy optimization and standardization. We used the Grades of Recommendation, Assessment, Development, and Evaluation system, which is based on a sequential assessment of the quality of evidence, followed by an analysis of the benefit/risk balance and subsequent judgment about the strength of recommendations. For issues without consistent evidence, we used the consensus technique. We have provided separate recommendations for diagnostic and staging requirements, first-line therapy, and postinduction therapy for the most frequent INFBCLs (ie, LPL, SLL, and nodal, splenic, and gastric MZL).
27 citations
TL;DR: This work systematically reviewed the literature and analyzed the risk of biases in the two randomized studies (COMFORT I and COMFORT II) on which FDA and EMA approval was based to critically analyze data supporting use of ruxolitinib in the clinical settings approved by the US and Europe.
Abstract: The recent approval of molecular-targeted therapies for myeloproliferative neoplasm-associated myelofibrosis (MPN-MF) has dramatically changed its therapeutic landscape. Ruxolitinib, a JAK1/JAK2 tyrosine kinase inhibitor, is now widely used for first- and second-line therapy in persons with MPN-MF, especially those with disease-related splenomegaly, intermediate- or high-risk disease, and constitutional symptoms. The goal of this work is to critically analyze data supporting use of ruxolitinib in the clinical settings approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). We systematically reviewed the literature and analyzed the risk of biases in the two randomized studies (COMFORT I and COMFORT II) on which FDA and EMA approval was based. Our strategy was to apply the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach by evaluating five dimensions of evidence: (1) overall risk of bias, (2) imprecision, (3) inconsistency, (4) indirectness, and (5) publication bias. Based on these criteria, we downgraded the evidence from the COMFORT I and COMFORT II trials for performance, attrition, and publication bias. In the disease-associated splenomegaly sphere, we upgraded the quality of evidence because of large effect size but downgraded it because of comparator choice and outcome indirectness (quality of evidence, low). In the sphere of treating persons with intermediate- or high-risk disease, we downgraded the evidence because of imprecision in effect size measurement and population indirectness. In the sphere of disease-associated symptoms, we upgraded the evidence because of the large effect size, but downgraded it because of comparator indirectness (quality of evidence, moderate). In conclusion, using the GRADE technique, we identified factors affecting the quality of evidence that were otherwise unstated. Identifying and evaluating these factors should influence the confidence with which physicians use ruxolitinib in persons with MPN-MF.
17 citations
TL;DR: Recommendations on the use of BV are issued during a consensus project, sponsored by the Italian Society of Hematology and its affiliate societies, and Società Italiana di Ematologia Sperimentale and Gruppo Italiano Trapianto di Midollo Osseo.
Abstract: Brentuximab vedotin (BV) is approved for the treatment of patients with relapsed or refractory CD30-positive Hodgkin lymphoma, and relapsed or refractory systemic anaplastic large-cell lymphoma. Several uncertainties remain regarding the optimal use of the drug in its approved indications as well as outside them. This article reports recommendations on the use of BV issued during a consensus project, sponsored by the Italian Society of Hematology (SIE) and its affiliate societies, Societa Italiana di Ematologia Sperimentale (SIES) and Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Scientific evidence on BV was evaluated by a panel of experts, and consensus was developed by group discussion for key questions selected according to the clinical relevance. The following key issues were addressed: testing CD30 positivity to assess eligibility to BV; assessing practice indications of BV in Hodgkin lymphoma and systemic anaplastic large-cell lymphoma; providing pretreatment evaluation of patients candidates to BV; monitoring the response to BV; managing patients treated with BV; and assessing the role of BV in other CD30-positive lymphomas.
15 citations
TL;DR: Bioinformatic analysis indicates the possibility that the G>T transversion may interfere with the correct splicing of exon 14 by modifying a splicing regulatory sequence, which is associated with the JAK2-V617F allele burden in PMF granulocytes.
Abstract: Background Primary myelofibrosis (PMF) is an acquired clonal disease of the hematopoietic stem cell compartment, characterized by bone marrow fibrosis, anemia, splenomegaly and extramedullary hematopoiesis. About 60% of patients with PMF harbor a somatic mutation of the JAK2 gene (JAK2-V617F) in their hematopoietic lineage. Recently, a splicing isoform of JAK2, lacking exon 14 (JAK2Δ14) was described in patients affected by myeloproliferative diseases.
8 citations
Mayo Clinic1, Paris Diderot University2, Peking Union Medical College3, VU University Medical Center4, Vanderbilt University Medical Center5, Hospital Universitario La Paz6, Guy's and St Thomas' NHS Foundation Trust7, University of Barcelona8, University of Grenoble9, University of Puerto Rico10, Celgene11, Erasmus University Rotterdam12, Leiden University Medical Center13, Maastricht University14, University Medical Center Freiburg15, University Hospital of Basel16, University of Pavia17
TL;DR: The results of this study suggest that patients with thrombocytopenia will benefit from aggressive symptomatic control, potentially from targeted agents.
4 citations
Oregon Health & Science University1, Mayo Clinic2, Guy's and St Thomas' NHS Foundation Trust3, Paris Diderot University4, VU University Medical Center5, Peking Union Medical College6, Vanderbilt University Medical Center7, Hospital Universitario La Paz8, University of Barcelona9, Heidelberg University10, University of Grenoble11, University of Puerto Rico12, Celgene13, Erasmus University Rotterdam14, Leiden University Medical Center15, Maastricht University16, University Hospital of Basel17, University of Florence18, University of Pavia19
TL;DR: Overall, significant worsening in symptom burden can be recognized over time for individuals diagnosed with MPNs and disease duration should be investigated as an alternative marker of burden in future survival studies.
2 citations
TL;DR: Improvement in the documentation of responsiveness of patient-reported outcomes will allow to use them as a critical endpoint of new trials, and exploiting the clinical utility of biomarkers should become a major goal of future clinical experimentation in MF.
Abstract: New targeted therapies administered in phase II and phase III studies have produced substantial improvements in outcomes of myelofibrosis (MF). However, strong documentation that the new agents modify the natural history of the disease is lacking, and a number of therapeutic indications of new drugs remain unaddressed. Overall survival (OS) improvement is the major goal of next-generation clinical trials in MF. This may be attained if an adequate population of patients and an unambiguous design of the trial will be selected. Another goal is preventing disease progression in early MF: this requires a controlled clinical trial with an accessible endpoint and a clinically relevant definition of disease progression. Improvement in the documentation of responsiveness of patient-reported outcomes (PROs) will allow to use them as a critical endpoint of new trials. Finally, exploiting the clinical utility of biomarkers should become a major goal of future clinical experimentation in MF.