Polycythaemia veraD45

Polycythaemia vera is an autonomous red cell proliferation. Together with primary essential thrombocythaemia and primary myelofibrosis, it belongs to the Philadelphia chromosome-negative chronic myeloproliferative diseases. There is an increase in erythrocytes, and in some cases granulocytes and/or platelets. The resulting increase in hematocrit leads to an increased risk of thromboembolic complications (see thrombosis below).

According to a Swedish study, PV patients have a 3-fold increased risk of arterial thrombosis and a 13-fold increased risk of venous thrombosis in the first 3 months of therapy after diagnosis compared with the control group of the same sex and age (Griesshammer M et al. 2019). Generic risk factors such as immobile lifestyle, diabetes mellitus and nicotine abuse further increase the risk of thrombosis during the course of polycythaemia vera (Cerquozzi S et al 2017). Thromboembolism (TE) occurs in atypical vessels in more than 55 % of cases and may therefore only be detected late.

0.7/ 100 000 inhabitants. m:w=1.2:1.0; a family cluster is described.

The etiology is unknown.

Genetics: Presence of a somatic mutation of the JAK2 gene(JAK2V617F) in exon 14 (about 95% of patients) or the rare somatic JAK2 mutation in exon 12 (about 5% of PV patients). The risk of thrombosis is favored by JAK2-induced alterations of erythrocyte surface proteins. In addition, functionally altered platelets can lead to bleeding and thrombosis. Since erythrocytes do not have a nucleus, the mutation is detected in peripheral blood via granulocyte DNA.

Pathogenesis of PV: present is a transformation of a hematopoietic stem cell leading to hyperplasia of all 3 rows of cells in the bone marrow. The erythrocyte progenitors of the bone marrow of patients with PV proliferate spontaneously in vitro without the addition of erythropoietin. EPO levels are decreased in most patients.

Comment: JAK2 is a cytoplasmic tyrosine kinase involved in signal transduction of various cytokines (including the EPO receptor). The mutation enhances the activity of the JAK2 tyrosine kinase, leading to EPO-independent growth. The JAK2 gene mutation is a somatic mutation which is therefore not detectable in the germ line.

> 60 years

Because of the slow onset, the first symptoms can often be traced back 2-3 years after diagnosis.

Headaches, weakness, itching, dizziness: 40-50

tendency to sweat, visual disturbances, tinnitus, weight loss, tingling paraesthesia in the acra: 30-40%.

Dyspnea, joint problems, upper abdomen problems: 20-30%.

Furthermore, hypertension occurs in about 70-80% of patients; splenomegaly can be detected in 50% of patients, hepatomegaly in 40%.

PV and skin changes:

• In about 40% of the patients aquagenic pruritus occurs.
• Squamous cell carcinomas (actinic keratoses): predisposes age (>50 years), female sex, long-term therapy with busulphan or hydroxycarbamide.
• Skin ulcers (mostly occurring as ulcus cruris): Stubborn and therapy-resistant ulcers of the lower extremity are found under or following therapy with hydroxyurea (seeskin ulcer). In this case a change in therapy to Ruxolitinib (Jakafi®) is recommended.
• Erythema: Extensive deep red reddening of the skin (face - apparently healthy appearance) and mucous membranes (lips blue-red cyanotic) is found in 60-70% of patients.
• Less frequent are ecchymoses, eczema, urticarial efflorescences and urticarial vasculitis,
• also: nodular, blue-red, painful infiltrates of the skin (extramedullary haematopoiesis)
• In individual cases described are: Eosinophilic fasciitis, Sweet syndrome, erythromelalgia

In case of a permanently elevated hematocrit (52 % for men, 48 % for women) with normal oxygen saturation, an erythropoietin determination and a JAK2V617F mutation analysis must be performed. If the mutation is homozygous and the erythropoietin level is reduced, PV is assured.

If the JAK2V617F mutation is not present and the EPO level is reduced, the JAK2 mutation should be detected in exon 12.

If the JAK2-specific mutations are not detected and the EPO level is normal or increased, PV is unlikely.

WHO criteria of PV

• A1: erythrocyte count > 5.5 mill/ul (>5.0 mill/ul) or Hb > 18.5g/dl (16.5g/dl) or haematocrit >52% (49%) in men (women)
• A2: exclusion of secondary erythrocytosis or congenital primary erythrocytosis
• A3: JAK2 mutation in nuclear blood or bone marrow cells or PRV1 expression in mature neutrophils or clonal cytogenetic aberration in bone marrow cells other than Ph chromosome
• A4: Formation of erythropoietic colonies in an EPO-free environment
• A5: Splenomegaly
• B1:Platelet count > 45,000/ul
• B2: Leukocyte count >12,000/ul
• B3: Proliferation of myelopoietic cells in bone marrow with prominence of erythroblasts and megakaryocytes
• B4: Reduced or low-normal blood concentration of EPO.
• Diagnosis: is confirmed when A1+A2 (or A3) + one more A (or 2 more B) are detected.

Differentiation of PV has to be made from other MPNs with increased red cell counts and from reactive (secondary) erythrocytoses. Transitions between entities of MPN are possible. Congenital (sporadic or familial) forms of primary erythrocytosis are extremely rare.

Cases of PV with pure erythrocytosis (characterized by mutations in exon 12 of the JAK2 gene) are important with regard to their differential diagnostic need from secondary erythrocytoses.

Myeloproliferative neoplasms

Essential thrombocythemia (especially in JAK2 V617F-positive forms, elevated levels of hemoglobin and hematocrit may be present).

Primary myelofibrosis: in the early hyperproliferative stage, proliferation of all three cell series including erythrocytosis may be present.

Reactive erythrocytosis

Erythrocytosis due to decrease of plasma volume

Pseudopolyglobulia with increase in erythrocyte count in stress or severe exsiccosis

Erythrocytosis due to heavy nicotine consumption triggered by increased levels of carbon monoxide hemoglobin

Acquired secondary erythrocytosis due to arterial hypoxia in chronic heart and lung diseases, in sleep apnea syndrome or in tumor diseases with paraneoplastic EPO production and in drug-induced polyglobulia (e.g. testosterone), condition after kidney transplantation, doping

Rare congenital causes of erythrocytosis:

• Erythropoietin receptor mutations leading to increased EPO sensitivity of erythroid progenitors;
• VHL mutation with impaired EPO gene regulation (Chuvash polycythemia),
• EGLN1 (PHD2)-EPAS1 (HIF2A) mutations.
• Hemoglobinopathy with increased oxygen affinity or 2,3-DPG deficiency (e.g., 2,3-DPG mutase deficiency)
• Disorders of hemoglobin formation with normal O2 affinity of hemoglobin (heterozygous beta-thalassemia, alpha-thalassemia minor, mild iron deficiency anemias; hemoglobin concentration, hematocrit, and mean red cell volume are decreased in these cases)

Transition to acute leukemia or transition to post-polycythemic myelofibrosis. The leukaemia risk averages 7.4 % of patients. The risk increases from 2.4 % (for bloodletting, anagrelide, interferon-alpha) to 16.7 % when treated with at least 2 cytotoxic drugs.

Therapy stratification is based on the risk of thrombosis and is primarily aimed at preventing arterial or venous vascular occlusion. Good symptom control is usually associated with an improvement in quality of life. All currently available drug therapy options are non-curative. Main therapeutic goals are:

• Reduction of the risk of thromboembolism.
• Control of clinical symptoms
• Postponement or prevention of late complications (myelofibrosis and MDS/acute leukemia).

The recommended therapy for all patients is a combination of phlebotomy with low-dose acetylsalicylic acid (ASA). Cytoreductive therapy is recommended for high-risk patients and for low-risk patients with significant disease progression during progression (Barbui T et al 2011).

Primary therapy

• Bloodletting
• ASA 100 mg/day

During progression, if progression of myeloproliferation or increasing risk of thrombosis/bleeding or phlebotomy therapy not feasible or uncontrollable symptoms if appropriate initially or during progression, regardless of eventual progression (preferably within therapy trials or as an individual therapy decision):

• Hydroxyurea+ IFN alpha2

Second-line therapy:

• Ruxolitinib+IFN alpha 2b+ hydroxyurea+ busulfan
• and/or acetylsalicylic acid, IFN: interferon.

General therapeutic measures

• Weight normalization, regular exercise, avoidance of desiccation and prolonged sitting (compression stockings if necessary, especially during travel), reduction of vascular risk factors and effective treatment of cardiovascular disease, no nicotine use.
• Bloodletting: Bloodletting is the fastest and easiest measure to lower hematocrit and eliminate hyperviscosity. Isovolemic phlebotomies of 500 ml (possibly 300 ml at the beginning) are recommended once or twice a week, depending on individual tolerance, until the hematocrit (regardless of gender) is adjusted below 45%. A significant reduction in the thromboembolism rate can be achieved by a good adjustment of the hematocrit value < 45% and a control of the leukocyte count. This is also associated with a reduction in cardiovascular mortality and mortality caused by other major thrombotic events. The phlebotomy frequency should be individually adjusted to the hematocrit values. Occasional phlebotomies may be required in addition to cytoreductive therapy to maintain the hematocrit within the desired range if a change in cytoreductive therapy does not seem possible or warranted. The iron deficiency that always occurs is "desired" and is not substituted. In exceptional cases, by no means routinely, cautious oral iron substitution may be given for symptomatic iron deficiency under strict indication and close laboratory control. Increasing iron deficiency is not infrequently accompanied by a secondary platelet increase.
• Erythrocytapheresis: This procedure is only available at facilities equipped for it. It is considered an alternative procedure to phlebotomy.
• Antiplatelet agents: Low dose acetylsalicylic acid ('low dose' aspirin, ASA/ 100 mg/day, is indicated for primary prophylaxis of thrombosis in patients without contraindications to the drug (history of ulcers, previous bleeding complications, etc.). Cave: Contraindications. With a platelet count > 1 million/µl, ASA should be administered only after a drug-induced reduction in the platelet count (<600 000/µl) because of the increased risk of bleeding, since the frequently observed loss of high-molecular-weight von Willebrand factor multimers can lead to an increased bleeding tendency. ASA should not be prescribed below a level of 30% of vWF activity.
• Alternative: other antiplatelet agents (e.g., ADP antagonists). Confirmed data on this are not available.

Cytoreductive therapy: In case of risk factors(thromboembolism, and older age ≥60 years), there is an indication to initiate cytoreductive therapy (high-risk patients). In low-risk patients, cytoreductive therapy in case of progression of myeloproliferation, increasing risk of thromboembolism and bleeding, and otherwise uncontrollable distressing clinical symptoms. Signs of progression of myeloproliferation include:

• Increase in spleen size or symptomatic splenomegaly.
• Platelet increase to >1 000 000/µl (secondary platelet increase due to iron deficiency under phlebotomy should be considered).
• Leukocyte increase to >15 000/µl or higher
• Frequent or increasing phlebotomy frequency
• Increased/increased risk of thromboembolism and bleeding and uncontrollable distressing clinical symptoms
• New onset of thromboembolism during the course of the disease
• Hemorrhagic complications
• Microcirculatory disturbances despite ASA
• Limited feasibility of phlebotomies
• Symptomatic iron deficiency that does not allow continuation of phlebotomies
• Uncontrolled hematocrit increase if iron substitution is unavoidable
• Severe or distressing disease-related symptoms.

Primary therapy:

Hydroxyurea (hydroxycarbamide): Hydroxyurea (initial dose: 15-20 mg/kg bw/day). Individual adjustment to blood values must be made. Caveat (young patients): The increase in the risk of secondary leukemia, which cannot be excluded with certainty during hydroxyurea treatment, suggests the cautious use of this substance in young patients. The continuation of phlebotomy therapy, if necessary, should be made dependent on individual blood values.

Resistance or intolerance to hydroxyurea (HU) in PV is given in:

• Need for phlebotomy after 3 months of therapy with at least 2g HU/day to keep the hematocrit below 45%, or
• Uncontrolled myeloproliferation (i.e. platelets >400 000/µl or leukocytes >10 000/µl) after 3 months of therapy with at least 2g HU/day or
• Spleen size reduction below 50% with massive1 splenomegaly (assessed by palpation) or incomplete disappearance of symptoms due to splenomegaly after 3 months of therapy with at least 2g HU/day or
• Absolute neutrophil count <1 000/µl or platelet count <100 000/µl or hemoglobin <10g/dl with the lowest dose of HU required to achieve a complete2 or partial3 clinical hematologic response; or
• Leg ulcers or other unacceptable HU-related non-hematologic toxicities, such as other skin or mucosal manifestations, gastrointestinal symptoms, pneumonitis, or fever regardless of HU dosage (Barosi G et al 2010).

Alternative: interferon alpha (Barbui T et al. 2018). Pegylated interferon-alpha is much better tolerated than conventional interferon-alpha in terms of side effects and efficacy spectrum (currently no longer used!). The conventional form of pegylated IFN is administered once a week (IFN alfa-2a, average dosage 90µg per week). A new pegylated form (ropeginterferon alfa-2b) approved for PV patients (without symptomatic splenomegaly) with longer duration of action allows application at 14-day intervals. Comment: Results of the randomized pivotal trial in untreated or hydroxyurea-pretreated high-risk patients showed significant superiority of ropeginterferon over hydroxyurea or best available therapy. In a clinical control study, low-risk PV showed superiority of ropeginterferon (100 µgalle 14 days) over standard therapy (phlebotomy plus low-dose ASA).Hematocrit was more stable below 45% with IFN (Barbui T et al.2021). Further studies demonstrate the positive effect of using IFN as early as possible even in low-risk PV (Abu-Zeinah G 2021).

Second-line therapy: In case of resistance or intolerance to the primary therapy, but also in case of severe clinical symptoms that cannot be controlled by the primary therapy (e.g. persistent pruritus and others), a change of therapy (second-line therapy) is indicated. Hydroxyurea or IFN (depending on first-line therapy) and the tyrosine kinase inhibitor (TKI) ruxolitinib are available for this purpose.

Ruxolitinib: For ruxolitinib, the initial dose is 2x10 mg/day. Ruxolitinib results in control of increased myeloproliferation, particularly hematocrit and splenomegaly with overall good tolerability. Other beneficial effects include regression of fatigue and pruritus and other PV-associated symptoms with significant improvement in quality of life. The effect occurs in the majority of patients within the first 4 weeks. Attention must be paid to the possible occurrence of skin tumors and infections (especially herpes zoster) (Kiladjian JJ et al.(2020).

Busulfan: Busulfan (Cave: leukemogenic potential) should be considered as an alternative therapy in patients of advanced age when no other therapeutic options are available.

Radiophosphorus and the use of chlorambucil are now considered obsolete.

Anagrelide (1 to 2 mg/day) is aimed exclusively at reducing platelet production and is therefore unsuitable as monotherapy for PV. Anagrelide may be used in combination (off-label) with other drugs (e.g., hydroxyurea or IFN-alpha) if necessary in cases of severely elevated platelet counts, if a satisfactory reduction in platelet count cannot be achieved with monotherapy alone. Anagrelide in combination with ASA leads to an increased risk of bleeding.

Splenic irradiation and splenectomy: Splenic irradiation in low, fractionated doses and splenectomy (high risk of morbidity and mortality) are reserved for individual cases with splenomegaly-related problems and predominantly involve patients transitioning to myelofibrosis. They are to be performed only under very strict indications.

Allogeneic bone marrow or peripheral blood stem cell transplantation: The only curative treatment options for PV. Due to the favorable prognosis of PV, it is indicated only in isolated cases. The indication should be considered especially in children, adolescents and young adults with complications.

Prophylaxis of rethrombosis: If thrombosis has already occurred (risk factor for rethrombosis), permanent prophylaxis with vitamin K antagonists is recommended. Alterants: Direct oral anticoagulants (DOAK; factor Xa and thrombin inhibitors); they are considered to be equieffective.

Late complications (post-PV myelofibrosis, MDS/acute leukemia): In post-PV MF, the indication for allogeneic transplantation is usually made according to the recommendations for primary myelofibrosis (see below PMF).

Life expectancy in completely untreated PV is massively limited due to vascular complications (median survival time approx. 1½ years). With good control of the disease, the median survival probability in a retrospective analysis of 1545 PV patients was just under 19 years (Chiewitz E et al. (1962). Confirmed risk factors for thromboembolism and main stratification parameters are older age (≥60 years, although biological age is also considered in clinical practice) and previous arterial or venous thrombosis.

Low risk

• Age <60 years, no thromboembolism (in the overall course).

High risk

• Age ≥60 years and/or thromboembolism (overall).

Median life expectancy is >23 years (2 years without therapy) according to various retrospective studies of patients younger than 50 years. The 20-year risk of transition to acute leukemia is 15%. The use of cytoreductive drugs with a leukemogenic risk profile should be avoided, especially in young patients.

The 20-year risk of transition to postpolycythemic myelofibrosis is expected in about 10% of patients.

Clinical examination and blood count: intervals depend on the form of therapy and the therapy phase as well as the individual course of the disease. In the initial phase of the therapy and in the case of therapy changes at short notice, after reaching a stable phase usually once a month. Occasionally there are long phlebotomy-free phases in which an extension of the control intervals is possible. A sonographic control of the spleen once a year is recommended.

The disease of PV does not exclude pregnancy. Increased risk of thrombosis for the patient and the fetus (increased spontaneous abortion rate, placental infarction/insufficiency)! Intensive interdisciplinary care necessary.

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