Disease overview
Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) respectively characterized by clonal 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 MPL mutations (so called driver mutations). In ET, it is most important to exclude the possibility of prefibrotic myelofibrosis.
Survival
Median survivals are approximately 15 years for PV and 18 years for ET; the corresponding values for patients age 40 or younger were 37 and 35 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 but risk of thrombosis is higher in JAK2 mutated cases. Leukemic transformation rates at 10 years are estimated at <1% for ET and 3% for PV.
Thrombosis risk
In PV, two risk categories are considered: high (age > 60 years or thrombosis history present) and low (absence of both risk factors). In ET, four 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‐daily 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.
New treatment directions
Controlled studies are needed to confirm the clinical outcome value of twice‐daily vs once‐daily aspirin dosing and the therapeutic role of pegylated interferons and direct oral anticoagulants.
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.
Polycythemia vera (PV) is a relatively indolent myeloid neoplasm with median survival that exceeds 35 years in young patients, but its natural history might be interrupted by thrombotic, fibrotic, or ...leukemic events, with respective 20-year rates of 26%, 16%, and 4%. Current treatment strategies in PV have not been shown to prolong survival or lessen the risk of leukemic or fibrotic progression and instead are directed at preventing thrombotic complications. In the latter regard, two risk categories are considered: high (age >60 years or thrombosis history) and low (absence of both risk factors). All patients require phlebotomy to keep hematocrit below 45% and once-daily low-dose aspirin, in the absence of contraindications. Cytoreductive therapy is recommended for high-risk or symptomatic low-risk disease; our first-line drug of choice in this regard is hydroxyurea but we consider pegylated interferon as an alternative in certain situations, including in young women of reproductive age, in patients manifesting intolerance or resistance to hydroxyurea therapy, and in situations where treatment is indicated for curbing phlebotomy requirement rather than preventing thrombosis. Additional treatment options include busulfan and ruxolitinib; the former is preferred in older patients and the latter in the presence of symptoms reminiscent of post-PV myelofibrosis or protracted pruritus. Our drug choices reflect our appreciation for long-term track record of safety, evidence for reduction of thrombosis risk, and broader suppression of myeloproliferation. Controlled studies are needed to clarify the added value of twice- vs once-daily aspirin dosing and direct oral anticoagulants. In this invited review, we discuss our current approach to diagnosis, prognostication, and treatment of PV in general, as well as during specific situations, including pregnancy and splanchnic vein thrombosis.
Major causes of morbidity and mortality in myeloproliferative neoplasms are represented by arterial and venous complications, progression to myelofibrosis, and transformation to acute leukemia. The ...pathogenesis of thrombosis results from a complex interplay of clinical and disease-related factors. Abnormalities of blood cells arising from the clonal proliferation of hematopoietic stem cells involve not only quantitative changes but also qualitative modifications that characterize the switch of these cells from a resting to a procoagulant phenotype. According to age and previous thrombosis, patients are classified in a “high risk” or “low risk”. Novel disease-related determinants such as leukocytosis and JAK2V617F mutational status and/or mutational burden are now under active investigation. In low-risk polycythemia vera patients, only phlebotomy and primary antithrombotic prophylaxis with aspirin is recommended, while in high-risk patients cytotoxic therapy is considered. Whether novel drugs targeting the constitutively active JAK2/STAT pathway will improve the management of thrombosis is a challenge for future studies.
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 aspirinAs 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.
The new edition of the 2016 World Health Organization (WHO) classification system for tumors of the hematopoietic and lymphoid tissues was published in September 2017. Under the category of ...myeloproliferative neoplasms (MPNs), the revised document includes seven subcategories: chronic myeloid leukemia, chronic neutrophilic leukemia, polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), chronic eosinophilic leukemia-not otherwise specified and MPN, unclassifiable (MPN-U); of note, mastocytosis is no longer classified under the MPN category. In the current review, we focus on the diagnostic criteria for JAK2/CALR/MPL mutation-related MPNs: PV, ET, and PMF. In this regard, the 2016 changes were aimed at facilitating the distinction between masked PV and JAK2-mutated ET and between prefibrotic/early and overtly fibrotic PMF. In the current communication, we (i) provide practically useful resource tables and graphs on the new diagnostic criteria including outcome, (ii) elaborate on the rationale for the 2016 changes, (iii) discuss the complementary role of mutation screening, (iv) address ongoing controversies and propose solutions, (v) attend to the challenges of applying WHO criteria in routine clinical practice, and (vi) outline future directions from the perspectives of the clinical pathologist.
Treatment options for myelofibrosis are limited. We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as compared with the best available ...therapy, in patients with myelofibrosis.
We assigned 219 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis to receive oral ruxolitinib or the best available therapy. The primary end point and key secondary end point of the study were the percentage of patients with at least a 35% reduction in spleen volume at week 48 and at week 24, respectively, as assessed with the use of magnetic resonance imaging or computed tomography.
A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy (P<0.001); the corresponding percentages at week 24 were 32% and 0% (P<0.001). At 48 weeks, the mean palpable spleen length had decreased by 56% with ruxolitinib but had increased by 4% with the best available therapy. The median duration of response with ruxolitinib was not reached, with 80% of patients still having a response at a median follow-up of 12 months. Patients in the ruxolitinib group had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. The most common hematologic abnormalities of grade 3 or higher in either group were thrombocytopenia and anemia, which were managed with a dose reduction, interruption of treatment, or transfusion. One patient in each group discontinued treatment owing to thrombocytopenia, and none discontinued owing to anemia. Nonhematologic adverse events were rare and mostly grade 1 or 2. Two cases of acute myeloid leukemia were reported with the best available therapy.
Continuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects. An influence on overall survival has not yet been shown. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00934544.).
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