Barbui, Tiziano

Abstract Disease Overview: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. Diagnosis: Bone marrow morphology remains the cornerstone of diagnosis. In addition, the presence of JAK2 mutation is expected in PV while approximately 90% of patients with ET express mutually exclusive JAK2, CALR, or myeloproliferative leukemia mutations. In ET, it is most important to exclude the possibility of prefibrotic myelofibrosis. Survival: Median survivals are 14 years for PV and 20 years for ET; the corresponding values for younger patients are 24 and 33 years. Certain mutations (mostly spliceosome) and abnormal karyotype might compromise survival in PV and ET. Life‐expectancy in ET is inferior to the control population. Driver mutations have not been shown to affect survival in ET. Risk of thrombosis is higher in JAK2‐mutated ET. Leukemic transformation rates at 10 years are estimated at <1% for ET and 3% for PV. Thrombosis Risk: In PV, 2 risk categories are considered: high (age > 60 years or thrombosis history present) and low (absence of both risk factors); in ET, 4 risk categories are considered: very low (age ≤ 60 years, no thrombosis history, JAK2 wild‐type), low (same as very low but JAK2 mutation present), intermediate (age > 60 years, no thrombosis history, JAK2 wild‐type) and high (thrombosis history present or age > 60 years with JAK2 mutation). Risk‐Adapted Therapy: The main goal of therapy in both PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once‐ or twice‐daily aspirin (81 mg), in the absence of contraindications. Very low‐risk ET might not require therapy while aspirin therapy is advised for low‐risk disease. Cytoreductive therapy is recommended for high‐risk ET and PV but it is not mandatory for intermediate‐risk ET. First‐line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second‐line drugs of choice are interferon‐α and busulfan. We do not recommend treatment with ruxolutinib in PV, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs.

AbstractObjectiveTo determine the financial and psycho‐social impact of participation in clinical trials of patients with BCR/ABL‐negative myeloproliferative neoplasms (MPN).MethodsAn international, observational cross‐sectional study was performed in 143 consecutive MPN patients (51% myelofibrosis, 36% polycythemia vera, 13% essential thrombocythemia), 68% from Italy, 17% from USA, and 15% from Spain.ResultsThirty‐five percent of patients reported having spent more money during the trial than in previous treatments and 21% having missed more workdays. Twelve percent replied that they would not have participated in the trial if the financial consequences would have been known beforehand. In 10% of the patients, the interpersonal relationships were more affected during the trial than in previous treatment but, overall, 91% subjects believed that participating in the clinical trial was worth the financial or emotional suffering. Concerning patients’ suggestions, 54% of them indicated that the number of visits required for the trial should be clearly specified in the informed consent, 60% recommended travel cost reimbursement, and 23% hotel cost reimbursement.ConclusionsPhysicians and pharmaceutical companies involved in clinical trials with patients with hematological diseases should be aware of these problems and make efforts to attenuate the socioeconomic burden of participation in the trials.

AbstractDisease overviewPolycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation.DiagnosisPV is defined by aJAK2mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely.JAK2,CALR, andMPLmutations are the mutually exclusive “driver” mutations in ET with respective incidences of 55%, 25%, and 3%; approximately 17% are triple‐negative. However, the same molecular markers might also be present in prefibrotic myelofibrosis, whose morphological distinction from ET is prognostically relevant.Survival and leukemic/fibrotic transformationMedian survivals are approximately 14 years for PV and 20 years for ET; the corresponding values for younger patients (age <60 years) are 24 and 33 years. Life‐expectancy in ET is inferior to the control population. Driver mutational status has not been shown to affect survival in ET whereas the presence ofJAK2/MPLmutations has been associated with higher risk of arterial thrombosis and that ofMPLwith higher risk of fibrotic progression. Risk factors for overall survival in both ET and PV include advanced age, leukocytosis and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Most recently,ASXL1,SRSF2, andIDH2mutations have been associated with inferior overall, leukemia‐free or fibrosis‐free survival in PV; similarly adverse mutations in ET includedSH2B3,SF3B1,U2AF1,TP53,IDH2, andEZH2.Thrombosis risk stratificationCurrent risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis. Accordingly, PV includes two risk categories: high‐risk (age >60 years or thrombosis history) and low‐risk (absence of both risk factors). In ET, risk stratification includes four categories: very low risk (age ≤60 years, no thrombosis history,JAK2/MPLun‐mutated), low risk (age ≤60 years, no thrombosis history,JAK2/MPLmutated), intermediate risk (age >60 years, no thrombosis history,JAK2/MPLun‐mutated), and high risk (thrombosis historyorage >60 years withJAK2/MPLmutation). In addition, presence of extreme thrombocytosis (platelets >1000 × 10(9)/L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding.Risk‐adapted therapyThe main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once‐daily aspirin (81 mg). In addition, high‐risk patients with PV require cytoreductive therapy. Very low risk ET patients might not require any form of therapy while low‐risk patients require at least once‐daily aspirin therapy. Cytoreductive therapy is also recommended for high‐risk ET patients but it is not mandatory for intermediate‐risk patients. First‐line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second‐line drugs of choice are interferon‐α and busulfan. We currently do not recommend treatment with ruxolutinib or otherJAK2inhibitors in PV or ET, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis. Am. J. Hematol. 92:95–108, 2017. © 2016 Wiley Periodicals, Inc.

In myeloproliferative neoplasms (MPNs), controversy persists regarding the usefulness and reproducibility of bone marrow (BM) features. Disagreements concerning the WHO classification are mainly focused on the discrimination between essential thrombocythemia (ET) and prefibrotic/early primary myelofibrosis (prePMF) and prodromal polycythemia vera (PV). Criticism mostly refers to lack of standardization of distinctive BM features precluding correct morphological pattern recognition. The distinction between WHO‐defined ET and prePMF is not trivial because outcome is significantly worse in prePMF. Morphology was generally considered to be non‐specific for the diagnosis of PV. Recent studies have revealed under‐diagnosis of morphologically and biologically consistent PV. Am. J. Hematol. 91:430–433, 2016. © 2015 Wiley Periodicals, Inc.

Purpose Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with disabling symptoms and a heightened risk of life-threatening complications. Recent studies have demonstrated the effectiveness of JAK inhibitor therapy in patients with PV patients who have a history of prior hydroxyurea (HU) use (including resistance or intolerance), phlebotomy requirements, and palpable splenomegaly. We aimed to determine how these features contribute alone and in aggregate to the PV symptom burden. Patients and Methods Through prospective evaluation of 1,334 patients with PV who had characterized symptom burden, we assessed patient demographics, laboratory data, and the presence of splenomegaly by disease feature (ie, known HU use, known phlebotomy requirements, splenomegaly). Results The presence of each feature in itself is associated with a moderately high symptom burden (MPN symptom assessment form [SAF] total symptom score [TSS] range, 27.7 to 29.2) that persists independent of PV risk category. In addition, symptoms incrementally increase in severity with the addition of other features. Patients with PV who had all three features (PV-HUPS) faced the highest total score (MPN-SAF TSS, 32.5) but had similar individual symptom scores to patients with known HU use (PV-HU), known phlebotomy (PV-P), and splenomegaly (PV-S). Conclusion The results of this study suggest that patients with PV who have any one of the features in question (known HU use, known phlebotomy, or splenomegaly) have significant PV-associated symptoms. Furthermore, it demonstrates that many PV symptoms remain severe independent of the number of features present.