From Palliation to Epigenetic Therapy in Myelofibrosis

Abstract Myelofibrosis shows a progressive clinical course and usually a poor, lethal prognosis. The molecular pathogenesis of this disease largely remains to be fully understood but the identification of the JAK2V617F mutation in more than half of patients was a major improvement in our understanding of the disease biology and may represent the first biologic marker useful for risk stratification, independently from conventional clinical predictors. After many elusive efforts, new effective treatment strategies are becoming available for this disease. Allogeneic transplantation following reduced-intensity conditioning programs, at least in some patients, may induce not only a hematologic response but also a molecular remission, thus supporting the hope of a possible, definitive eradication of the disease. Moreover, new innovative drugs, targeting either the JAK2V617F mutation or more general oncogenic mechanisms, may provide widely applicable, effective treatments to many patients for whom allogeneic transplantation is not feasible

Studies of the Site and Distribution of CD34+ Cells in Idiopathic Myelofibrosis

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Critical concepts, practice recommendations, and research perspectives of pixantrone therapy in non-Hodgkin lymphoma: a SIE, SIES, and GITMO consensus paper

Objectives: In this paper, we present a review of critical concepts and research perspectives and produce recommendations on the optimal use of pixantrone in non-Hodgkin lymphoma (NHL) by group discussion from an expert panel appointed by the Italian Society of Hematology and the affiliate societies, Societa Italiana di Ematologia Sperimentale and Gruppo Italiano Trapianto di Midollo Osseo. Methods: Recommendations were produced using the Delphi process. Scientific evidence on pixantrone efficacy was analyzed using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology in the areas where at least one randomized trial was published. The following key issues were addressed for practical recommendations: pixantrone monotherapy in aggressive relapsed or refractory non-Hodgkin B-cell lymphomas and toxicity risk management in patients candidates to pixantrone. Results and conclusions: After a balanced and value-oriented discussion, the panel agreed that the benefit/risk profile was in favor of pixantrone in the treatment of adult patients with multiply relapsed or refractory aggressive NHL B-cell lymphomas. Pixantrone was deemed to be contraindicated in patients with uncontrolled cardiovascular disease. Despite a low rate of cardiotoxicity of pixantrone reported in clinical trials, the panel recommended that all patients receiving pixantrone should undergo periodical cardiac monitoring

A sensitive detection method for MPLW515L or MPLW515K mutation in chronic myeloproliferative disorders with locked nucleic acid-modified probes and real-time polymerase chain reaction.

Acquired mutations in the juxtamembrane region of MPL (W515K or W515L), the receptor for thrombopoietin, have been described in patients with primary myelofibrosis or essential thrombocythemia, which are chronic myeloproliferative disorders. We have developed a real-time polymerase chain reaction assay for the detection and quantification of MPL mutations that is based on locked nucleic acid fluorescent probes. Mutational analysis was performed using DNA from granulocytes. Reference curves were obtained using cloned fragments of MPL containing either the wild-type or mutated sequence; the predicted sensitivity level was at least 0.1% mutant allele in a wild-type background. None of the 60 control subjects presented with a MPLW515L/K mutation. Of 217 patients with myelofibrosis, 19 (8.7%) harbored the MPLW515 mutation, 10 (52.6%) with the W515L allele. In one case, both the W515L and W515K alleles were detected by real-time polymerase chain reaction. By comparing results obtained with conventional sequencing, no erroneous genotype attribution using real-time polymerase chain reaction was found, whereas one patient considered wild type according to sequence analysis actually harbored a low W515L allele burden. This is a simple, sensitive, and cost-effective procedure for large-scale screening of the MPLW515L/K mutation in patients suspected to have a myeloproliferative disorder. It can also provide a quantitative estimate of mutant allele burden that might be useful for both patient prognosis and monitoring response to therapy

Hydroxyurea in essential thrombocythemia: rate and clinical relevance of responses by European LeukemiaNet criteria

Abstract A definition of response by cytoreductive therapy in essential thrombocythemia was recently provided by the European LeukemiaNet (ELN). Complete, partial, or no clinicohematologic responses were defined on the bases of platelet count, disease-related symptoms, spleen size, and white blood cell count. To provide estimates and clinical correlation of responses according to these criteria, we retrospectively examined 416 essential thrombocythemia patients treated with hydroxyurea for at least 12 months. Complete response, partial response, and no response were 25%, 58%, and 17%, respectively. Age more than 60 years and JAK2V617F mutation were significant predictors of response. After a median follow-up of 3.9 years, we registered 23 deaths, 16 hematologic transformations, and 27 thrombotic events (rate, 1.66% patients/year). Age, previous thrombosis, leukocytosis (white blood cell count > 10 × 109/L), but not ELN responses, were independently associated with higher risk of thrombosis. The actuarial probability of thrombosis was significantly influenced by leukocytosis (P = .017) and not by platelet count, indicating that platelet number does not seem of prime relevance in the definition of ELN response

Allogeneic hsct with reduced intensity conditioning regimens in high risk patients with myelofibrosis

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Evidence that Prefibrotic Myelofibrosis Is Aligned along a Clinical and Biological Continuum Featuring Primary Myelofibrosis

PURPOSE: In the WHO diagnostic classification, prefibrotic myelofibrosis (pre-MF) is included in the category of primary myelofibrosis (PMF). However, strong evidence for this position is lacking. PATIENTS AND METHODS: We investigated whether pre-MF may be aligned along a clinical and biological continuum in 683 consecutive patients who received a WHO diagnosis of PMF. RESULTS: As compared with PMF-fibrotic type, pre-MF (132 cases) showed female dominance, younger age, higher hemoglobin, higher platelet count, lower white blood cell count, smaller spleen index and higher incidence of splanchnic vein thrombosis. Female to male ratio and hemoglobin steadily decreased, while age increased from pre-MF to PMF- fibrotic type with early and to advanced bone marrow (BM) fibrosis. Likely, circulating CD34+ cells, LDH levels, and frequency of chromosomal abnormalities increased, while CXCR4 expression on CD34+ cells and serum cholesterol decreased along the continuum of BM fibrosis. Median survival of the entire cohort of PMF cases was 21 years. Ninety-eight, eighty-one and fifty-six percent of patients with pre-MF, PMF-fibrotic type with early and with advanced BM fibrosis, respectively, were alive at 10 years from diagnosis. CONCLUSION: Pre-MF is a presentation mode of PMF with a very indolent phenotype. The major consequences of this contention is a new clinical vision of PMF, and the need to improve prognosis prediction of the disease