Barbara Mora

Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-2 cohorts

The international prognostic scoring system (IPSS) provides reliable risk assessment in patients with primary myelofibrosis (PMF). Recent clinical trials in PMF patients with intermediate-2 or high IPSS risk have shown a survival advantage of ruxolitinib over placebo (COMFORT-1) or best available therapy (COMFORT-2). Because crossover was allowed in these studies, we analyzed the cohort of ruxolitinib-naive patients used for developing the dynamic IPSS (DIPSS). By adopting ad hoc statistical analyses, we compared survival from diagnosis of 100 PMF patients receiving ruxolitinib within COMFORT-2 with that of 350 patients of the DIPSS study. Subjects were properly matched, and both left-truncation and right-censoring were accounted in order to compare higher IPSS risks exclusively. Patients receiving ruxolitinib had longer survival (5 years, 95% confidence interval [CI]: 2.9-7.8 vs 3.5 years, 95% CI: 3.0-3.9) with a hazard ratio of 0.61 (95% CI: 0.41-0.91; P = .0148). This observation suggests that ruxolitinib may modify the natural history of PMF.

A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms with variable risk of evolution into post-PV and post-ET myelofibrosis, from now on referred to as secondary myelofibrosis (SMF). No specific tools have been defined for risk stratification in SMF. To develop a prognostic model for predicting survival, we studied 685 JAK2, CALR, and MPL annotated patients with SMF. Median survival of the whole cohort was 9.3 years (95% CI: 8-not reached-NR-). Through penalized Cox regressions we identified negative predictors of survival and according to beta risk coefficients we assigned 2 points to hemoglobin level <11 g/dl, to circulating blasts ⩾3%, and to CALR-unmutated genotype, 1 point to platelet count <150 × 109/l and to constitutional symptoms, and 0.15 points to any year of age. Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) allocated SMF patients into four risk categories with different survival (P<0.0001): low (median survival NR; 133 patients), intermediate-1 (9.3 years, 95% CI: 8.1-NR; 245 patients), intermediate-2 (4.4 years, 95% CI: 3.2–7.9; 126 patients), and high risk (2 years, 95% CI: 1.7–3.9; 75 patients). Finally, we found that the MYSEC-PM represents the most appropriate tool for SMF decision-making to be used in clinical and trial settings.

Driver mutations' effect in secondary myelofibrosis: An international multicenter study based on 781 patients.

Driver mutations’ effect in secondary myelofibrosis: an international multicenter study based on 781 patients

New molecular genetics in the diagnosis and treatment of myeloproliferative neoplasms.

Purpose of reviewMyeloproliferative neoplasms (MPN) are conditions of great interest because of the identification of their molecular basis and of the entering of new small molecules into clinical practice. The aim of this review is to report the role of mutations in the diagnosis, prognosis, and in the prediction of response to JAK inhibitors in MPN. Recent findingsNew mutations of the CALR gene have been discovered in patients without JAK2 or MPL mutations and are now included in the World Health Organization classification system. The role of ASXL1 and SRSF2 together with the driver mutations is emerging in the prognostication of myelofibrosis. SummaryA wide mutational analysis of MPN helps to define diagnosis and prognosis. In the future, clinical trials based on a robust valuation of mutations will guide treatment decision-making towards precision medicine.

Involvement of MAF/SPP1 axis in the development of bone marrow fibrosis in PMF patients

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by hyperplastic megakaryopoiesis and myelofibrosis. We recently described the upregulation of MAF (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog) in PMF CD34+ hematopoietic progenitor cells (HPCs) compared to healthy donor. Here we demonstrated that MAF is also upregulated in PMF compared with the essential thrombocytemia (ET) and polycytemia vera (PV) HPCs. MAF overexpression and knockdown experiments shed some light into the role of MAF in PMF pathogenesis, by demonstrating that MAF favors the megakaryocyte and monocyte/macrophage commitment of HPCs and leads to the increased expression of proinflammatory and profibrotic mediators. Among them, we focused our further studies on SPP1 and LGALS3. We assessed SPP1 and LGALS3 protein levels in 115 PMF, 47 ET and 24 PV patients plasma samples and we found that SPP1 plasma levels are significantly higher in PMF compared with ET and PV patients. Furthermore, in vitro assays demonstrated that SPP1 promotes fibroblasts and mesenchymal stromal cells proliferation and collagen production. Strikingly, clinical correlation analyses uncovered that higher SPP1 plasma levels in PMF patients correlate with a more severe fibrosis degree and a shorter overall survival. Collectively our data unveil that MAF overexpression contributes to PMF pathogenesis by driving the deranged production of the profibrotic mediator SPP1.

A new acute myeloid leukemia case with STAT5B-RARA gene fusion due to 17q21.2 interstitial deletion

Chiara Pessina , Claudia Basilico , Angelo Genoni, Emanuela Meroni, Lorenzo Elli, Paola Granata, Rossana Righi, Francesco Pallotti, Barbara Mora, Andrea Ferrario, Francesco Passamonti and Rosario Casalone SMeL Citogenetica e Genetica Medica, ASST Sette Laghi, Varese, Italy; Dipartimento di Medicina Specialistica, Ematologia, ASST Sette Laghi, Varese, Italy; Dipartimento di Scienze Chirurgiche e Morfologiche, Universit a degli Studi dell’Insubria, Varese, Italy; Dipartimento di Medicina Clinica e Sperimentale, Ematologia, Universit a degli Studi dell’Insubria, Varese, Italy

Value of cytogenetic abnormalities in post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a study of the MYSEC project

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN)[1][1] that can progress to blast phase[2][2] and to post-PV (PPV) myelofibrosis (MF) and post-ET (PET) MF,[3][3] from now on referred to as secondary myelofibrosis (SMF). Progression may depend on many

Post-ET and Post-PV Myelofibrosis: Updates on a Distinct Prognosis from Primary Myelofibrosis

Purpose of ReviewThe purpose of this review is to help doctors in the management of patients with post-polycythemia (PPV) and post-essential thrombocythemia (PET) myelofibrosis (MF) facing diagnostic criteria, prognostication, and treatment possibilities.Recent FindingsDiagnostic criteria of primary myelofibrosis (PMF) have been recently updated from the WHO classification. A clear-cut distinction between pre-fibrotic and overt PMF has been done. Concerning PPV and PET MF, the criteria come from 2008. Prognostication of PMF has been well established on clinical criteria, but recent molecular acquisitions will improve the strategy. For PPV and PET MF, the new MYSEC-PM is helpful for prediction of survival. JAK2-inhibitors and stem cell transplant are the two critical therapeutic approaches in myelofibrosis.SummaryDifferences between PMF and SMF substantiate the efforts underway to adequately stratify SMF patients with ad hoc prognostic tools and to use such categorization to evaluate available treatment modalities.

Gender effect on phenotype and genotype in patients with post-polycythemia vera and post-essential thrombocythemia myelofibrosis: results from the MYSEC project

Gender effect on phenotype and genotype in patients with post-polycythemia vera and post-essential thrombocythemia myelofibrosis: results from the MYSEC project Daniela Barraco, Barbara Mora, Paola Guglielmelli , Elisa Rumi, Margherita Maffioli, Alessandro Rambaldi , Marianna Caramella, Rami Komrokji, Jason Gotlib, Jean Jacques Kiladjian, Francisco Cervantes, Timothy Devos, Francesca Palandri, Valerio De Stefano , Marco Ruggeri, Richard T. Silver, Giulia Benevolo, Francesco Albano, Michele Merli, Daniela Pietra, Tiziano Barbui, Giada Rotunno, Mario Cazzola, Toni Giorgino , Alessandro Maria Vannucchi and Francesco Passamonti