Classical Philadelphia-negative myeloproliferative neoplasms (Ph-neg MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are characterized by uncontrolled clonal proliferation of multipotent bone marrow progenitors, sustained by acquired mutations in JAK2, CALR and MPL genes. Expansion of the mutated clone triggers an inflammatory response that influences the development of associated vascular complications and disease progression into MF and acute leukemia. This presentation will focus on the recent recommendations by ELN in low-risk PV patients.
According to ELN and NCCN patients with PV should be managed by the risk of thrombosis and cytoreductive drugs are recommended in high risk (over 60 y and/or prior thrombosis) while low-risk should be treated with low-dose aspirin and phlebotomy only. These guidelines have been reviewed by international recognized experts in the field of MPN. In January 2021, ELN promoted an international project specifically devoted to updating the clinical indications for using cytoreductive drugs in treating PV. The Expert Panel (EP), the chair and the methodologist were asked to grant the highest quality of the recommendations by adhering to standard methods for developing clinical practice guidelines, namely Grading of Recommendations Assessment, Development and Evaluation (GRADE) (WHO Handbook for Guideline Development, 2011).
These main questions will be presented and discussed. Question 1 - What benefits should be expected from cytoreductive drugs over phlebotomy in “low-risk” PV patients? Question 2 - Which “low-risk” PV patients might benefit from cytoreductive drugs? Question 3 - Which cytoreductive drugs should be preferred in “low-risk” patients? Question 4 - Which PV patients treated with HU should receive a different cytoreductive 223 drug? The results and recommendations were approved by Delphi consensus rounds and virtual meetings. The EP recommended that PV patients younger than 60 years old and/or free of prior thrombotic events start cytoreductive drug therapy if at least one of the criteria is fulfilled: 1) strictly-defined intolerance to phlebotomy, 2) symptomatic progressive splenomegaly, 3) persistent leukocytosis (> 20.000/mmc), 4) progressive leukocytosis 6) inadequate hematocrit control requiring phlebotomies, 7) persistently high cardiovascular risk, and 8) persistently high symptom burden. RopegIFN or pegylated IFN-alpha-2a was the recommended cytoreductive drug for the above patients. Finally, the EP suggested that either rIFNα or ruxolitinib should be considered for patients treated with hydroxyurea but requiring a therapy change.
The purpose of cytoreductive therapy is to obtain hematological responses, since normalizing blood counts with phlebotomy and/or cytoreductive drugs is thought fundamental to reduce the incidence of both arterial and venous thrombosis. However, despite achieving similar hematological responses, it is likely that the various cytoreductive drugs administered both in the first and second line do not have equal antithrombotic activity. In fact, for each of the three cytoreductive drugs currently used in clinical practice (Hydroxyurea [HU], Interferon [IFN], Ruxolitinib [Ruxo]), additional antithrombotic properties are recognized. For instance, HU is thought to have minimal antiinflammatory properties [19], whereas there is evidence that IFN and Ruxo can normalize inflammatory markers, further mitigating thrombotic risk [20, 21]. Unfortunately, clinical trials comparing head-to-head the standard HU with IFN or Ruxo did not provide solid evidence of superiority of the latter in terms of thrombosis reduction. It should be noted, however, that the design of these studies envisaged hematological responses as primary end-points and the trials were not powered to directly evaluate a decrease in thrombosis risk. On the other hand, it is not yet demonstrated that hematological response is a valid surrogate of thrombosis [22-24].
Both the National Comprehensive Cancer Network (NCCN) and the European Leukemia Net (ELN) recommend a risk-stratified approach to the treatment of an individual patient and in ET and PV patients are [Treatment focuses primarily on mitigation of thrombosis risk and most patients with ET and PV should receive low-dose aspirin
As the prognosis for ET and PV varies substantially between patients, both the National Comprehensive Cancer Network (NCCN) and the European Leukemia Net (ELN) recommend a risk-stratified approach to the treatment of an individual patient [4,8]. This is exemplified by two large retrospective studies evaluating prognostic factors and outcomes among patients with MPNs [9,10]. Conventionally, patients age ≥ 60 years or with prior thrombosis are classified as high-risk [4]. However, the association of a higher thrombosis risk with the presence of JAK2/MPL mutations in ET patients is increasingly recognized and included in the validated International Prognostic Score of Thrombosis in ET (IPSET) [5,11]. The impact of other factors such as leukocytosis in PV patients or the influence of co-mutations continues to evolve and is not part of the current guideline recommended approach to treatment selection [5,6,12–14]. Treatment focuses primarily on mitigation of thrombosis risk and most patients with ET and PV should receive low-dose aspirin [4,8,15].
prevention and treatment of major arterial and venous thrombosis in PV and ET with the aim to report: (i) quantitative estimates of major thrombosis incidence; (ii) rates of thrombosis under treatment with cytoreductive drugs; (iii) incidence of thrombosis under aspirin and oral anticoagulants.
