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Tefferi A.,Mayo Medical School | Cervantes F.,Institute dInvestigacions Biomediques August Pi i Sunyer | Mesa R.,Mayo Medical School | Passamonti F.,Ospedale di Circolo e Fondazione Macchi | And 11 more authors.
Blood | Year: 2013

The current document is a revision of the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria for treatment response in my-elofibrosis (MF) and represents a collaborative effort by the IWG-MRT and the European LeukemiaNet to objectively assess the value of new drugs in inducing morphologic remission or improvement in MF-associated symptomatic burden (MF-SB). Some of the changes in the current revision include stricter definitions of red cell transfusion dependency and independency and consideration of the Myeloproliferative Neoplasm Symptom Assessment Form as a tool to quantify meaningful changes in disease-related symptoms. Six response categories are listed: complete remission (CR) and partial remission signify treatment effects that are consistent with disease modification, whereas drug-induced improvements in MF-SB were annotated as clinical improvement, anemia response, spleen response, orsymptoms response. Additional criteria are provided for progressive disease, stable disease, and relapse. The document also includes recommendations for assessing cytogenetic and molecular remissions, without mandating their inclusion for CR assignment. © 2013 by The American Society of Hematology. Source

Cervantes F.,Institute dInvestigacio Biomedica August Pi i Sunyer | Vannucchi A.M.,University of Florence | Kiladjian J.-J.,Assistance Publique Hopitaux de Paris | Al-Ali H.K.,University of Leipzig | And 11 more authors.
Blood | Year: 2013

Ruxolitinib is a potent Janus kinase (JAK)1/JAK2 inhibitor that has demonstrated rapid reductions in splenomegaly and marked improvement in disease-related symptoms and quality of life in patients with myelofibrosis (MF). The present analysis reports the 3-year follow-up (median, 151 weeks) of the efficacy and safety of Controlled Myelofibrosis Study With Oral Janus-associated Kinase (JAK) Inhibitor Treatment-II (the COMFORT-II Trial), comparing ruxolitinib with the best available therapy (BAT) in 219 patients with intermediate-2 and high-risk MF. In the ruxolitinib arm, with continued therapy, spleen volume reductions of ≥35% by magnetic resonance imaging (equivalent to approximately 50% reduction by palpation) were sustained for at least 144 weeks, with the probability of 50% (95% confidence interval [CI], 36-63) among patients achieving such degree of response. At the time of this analysis, 45% of the patients randomized to ruxolitinib remained on treatment. Ruxolitinib continues to be well tolerated. Anemia and thrombocytopenia were the main toxicities, but they were generally manageable, improved over time, and rarely led to treatment discontinuation (1% and 3.6% of patients, respectively). No single nonhematologic adverse event led to definitive ruxolitinib discontinuation inmore than 1 patient. Additionally, patients randomized to ruxolitinib showed longer overall survival than those randomized to BAT (hazard ratio, 0.48; 95% CI, 0.28-0.85; log-rank test, P = .009). This trial was registered at clinicaltrials. © 2013 by The American Society of Hematology. Source

Barosi G.,Center for the Study of Myelofibrosis
Best Practice and Research: Clinical Haematology | Year: 2014

Essential thrombocythemia (ET) and primary myelofibrosis (PMF), together with polycythemia vera (PV) are Phildelphia-negative (Ph-neg) classical myeloproliferative neoplasms (MPN). ET has been traditionally identified by thrombocytosis and absence of relevant bone marrow (BM) fibrosis, while PMF by BM reticulin or collagen fibrosis with megakaryocyte hyperplasia and dysplasia, and extramedullary hematopoiesis. These diagnostic profiles have been challenged since 2001 when the World Health Organization (WHO) has included in the domain of PMF a new category of patients, namely early/prefibrotic MF, characterized by the absence of relevant reticulin fibrosis in BM, dual megakaryocyte and granulocyte proliferation, and megakaryocyte dysplasia. This review is focused on summarizing the diagnostic uncertainties of early/ prefibrotic myelofibrosis, recent advances in our understanding of the biology of the variant, and the accompanying translational implications. © 2014 Elsevier Ltd. All rights reserved. Source

Barosi G.,Center for the Study of Myelofibrosis
Expert Review of Hematology | Year: 2012

Conventional drugs for myelofibrosis are driven by clinical needs, primarily anemia and splenomegaly. With these therapies, stem cell transplantation remains the only potentially curative approach. The discovery that mutations affecting JAK2 or MPL lead to activation of the intracellular JAK-STAT signaling pathway, and that other mutations (TET2, EZH2, ASXL1, IDH1 and IDH2) interfere with the normal machinery of epigenetics, has prompted to the development of therapies targeted at controling the major disease mechanisms. JAK2 ATP competitive inhibitors (ruxolitinib, lestaurtinib, SAR302503, SB1518 and CYT387) or drugs that indirectly inhibit the JAK-STAT pathway (everolimus) have documented major effects on splenomegaly and its constitutional symptoms. Epigenetic drugs (demethylating agents and histone deacetylase inhibitors) have displayed only minor effects on the disease symptoms. Relenting disease progression remains an unmet clinical need. © 2012 Expert Reviews Ltd. Source

Barbui T.,Ospedali Riuniti di Bergamo | Carobbio A.,Ospedali Riuniti di Bergamo | Cervantes F.,University of Barcelona | Vannucchi A.M.,University of Florence | And 6 more authors.
Blood | Year: 2010

We assessed frequency and predictive factors for major cardiovascular (CV) events in 707 patients with primary myelo-fibrosis (PMF) followed in 4 European institutions. A total of 236 deaths (33%) were recorded for an overall mortality of 7.7% patient-years (pt-yr). Fatal and nonfatal thromboses were registered in 51 (7.2%) patients, with a rate of 1.75% pt-yr. If deaths from non-CV causes were considered as competing events, we estimated that the adjusted rate of major thrombotic events would have been 2.2% pt-yr. In a multivariable model, age older than 60 years (hazard ratio [HR], 2.34; 95% confidence interval [CI], 1.24-4.39, P = .01) and JAK2 mutational status (HR, 1.92; 95% CI, 1.10-3.34; P = .02) were significantly associated with thrombosis, whereas the strength of the association between leukocyte count higher than 15 x 109/L and CV events was of borderline significance (HR, 1.72; 95% CI, 0.97-2.72; P = .06). The highest incidence of fatal and nonfatal thrombosis was observed when the mutation was present along with leukocytosis (3.9% pt-yr; HR, 3.13; 95% CI, 1.26-7.81). This study is the largest hitherto carried out in this setting and shows that the rate of major CV events in PMF is comparable with that reported in essential thrombocythemia, and it is increased in aged patients and those with JAK2 V617F mutation and leukocytosis. © 2010 by The American Society of Hematology. Source

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