Philadelphia-Negative Classical Myeloproliferative Neoplasms: Critical Concepts and Management Recommendations From European LeukemiaNet

Abstract

We present a review of critical concepts and produce recommendations on the management of Philadelphia-negative classical myeloproliferative neoplasms, including monitoring, response definition, first-and second-line therapy, and therapy for special issues. Key questions were selected according the criterion of clinical relevance. Statements were produced using a Delphi process, and two consensus conferences involving a panel of 21 experts appointed by the European LeukemiaNet (ELN) were convened. Patients with polycythemia vera (PV) and essential thrombocythemia (ET) should be defined as high risk if age is greater than 60 years or there is a history of previous thrombosis. Risk stratification in primary myelofibrosis (PMF) should start with the International Prognostic Scoring System (IPSS) for newly diagnosed patients and dynamic IPSS for patients being seen during their disease course, with the addition of cytogenetics evaluation and transfusion status. High-risk patients with PV should be managed with phlebotomy, low-dose aspirin, and cytoreduction, with either hydroxyurea or interferon at any age. High-risk patients with ET should be managed with cytoreduction, using hydroxyurea at any age. Monitoring response in PV and ET should use the ELN clinicohematologic criteria. Corticosteroids, androgens, erythropoiesis-stimulating agents, and immunomodulators are recommended to treat anemia of PMF, whereas hydroxyurea is the first-line treatment of PMF-associated splenomegaly. Indications for splenectomy include symptomatic portal hypertension, drug-refractory painful splenomegaly, and frequent RBC transfusions. The risk of allogeneic stem-cell transplantation-related complications is justified in transplantation-eligible patients whose median survival time is expected to be less than 5 years.

How to manage children and young adults with myeloproliferative neoplasms

“…However, familial clustering of PV, ET and PMF has been well described and patients should know that occasionally other members of the family may present these disorders. 16,17 In accordance with the European Leukemia Net (ELN) investigators, 18 in the absence of hematological or clinical abnormalities, I do not routinely genotype for JAK2 mutations or JAK2 46/1 (GGCC) haplotype the relatives of individuals with MPNs. 19 Patients should be notified that follow-up of PV, ET and to lesser extent early/prefibrotic PMF 20 is marked by thrombohemorrhagic complications, constitutional symptoms, such as pruritus, night sweats, fatigue and a propensity to transform into overt myelofibrosis (10 --25%), and acute leukemia (o5%), however, at different incidence concerning the disease entities.…”

“…Anagrelide is not licensed as first-line therapy for ET in Europe and the ELN group recommends this drug as second line therapy. 18 The use of aspirin (ASA) in children less than 12 years of age should be prescribed with caution because of the risk of Reye's syndrome. Overall, according to ELN experts, there are insufficient data to recommend a specific agent in children, and the choice should be individually tailored.…”

“…52 As suggested by the ELN, an alternative option as first line therapy in high-risk PV and ET is IFN-a. 18 This drug is known to be non-leukemogenic, but it is associated with side effects leading to withdrawn in about 20% of patients. Pegylated forms of IFN-a allow weekly administration, potentially improving compliance and possibly providing more effective therapy.…”

“…2 Long-term periodic transfusions can be complicated by hemosiderosis and may require the use of chelating agents. However, according to ELN, 18 iron-chelating therapy is not indicated except in allotransplantation. Unfortunately, results of any treatment for patients with blast phase of MPNs (median survival 6 months) are extremely poor.…”

Role of blood cells dynamism on hemostatic complications in low-risk patients with essential thrombocythemia

“…Patients with ET have a relatively benign prognosis [2], but thrombotic and hemorrhagic events may indeed occur over time, leading to severe morbidity [3][4][5]. Previous studies by Cortelazzo et al [6][7][8] showed that age [60 years and previous thrombotic or hemorrhagic events are strongly associated with a higher risk of developing further events. Conversely, the socalled low-risk ET group (young patients without previous vascular events), may also develop thrombotic or hemorrhagic events during follow-up.…”