Polycythaemia vera D45

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 13.09.2021

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Synonym(s)

polcythemia vera (engl.); polycythaemia vera rubra; Polycythemia; polycythemia vera; primary red blood cellosis

Definition
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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.

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

Etiopathogenesis
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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.

Manifestation
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> 60 years

Clinical features
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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

Diagnosis
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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.

Differential diagnosis
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Secondary erythrocytosis (old name polyglobulia) with increase in HB, erythrocytes and hematocrit. Secondary erythrocytosis is often due to erythropoietin(EPO) proliferation, e.g. exogenous as a result of hypoxia at altitude; also endogenous in connection with chronic lung disease (COPD), heart disease, kidney dysfunction. Artificial erythrocytosis is induced in athletes by various doping agents, with EPO playing a special role.

Congenital primary erythrocytosis is rare.

Complication(s)
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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
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Cytoreductive therapy aimed at reducing PV-associated potentially life-threatening thromboembolic and bleeding complications, as well as any nonspecific symptoms that may occur. These include:

Phlebotomy (bloodletting): Because increasing hematocrit greatly increases blood viscosity and thus the risk of thrombosis, the main goal is to permanently lower the hematocrit to < 45% in men and < 40% in women.

Alternative (or complementary): cytoreductive therapy with phosphor-32, chlorambucil, busulphan, hydroxyurea.

Note: Iron removed by phlebotomy leads to secondary iron deficiency, which limits erythropoiesis and may lead to fatigue and decrease in performance.

Anti-aggregant therapy: Platelets may also be involved in the development of thrombosis in PV patients. Daily intake of 100 mg ASA is recommended.

Drug cytoreductive therapy: Drug therapy is indicated only when adequate hematocrit reduction cannot be achieved by phlebotomy or when a thromboembolic complication has occurred despite low-dose ASA administration with normalized hematocrit. Other indications are increasing splenomegaly or phlebotomy-refractory aquagenic pruritus. Only hydroxycarbamide and interferon-a are now used for treatment. Hydroxycarbamide lowers erythrocytes, granulocytes and platelets (dosage: 500mg to 2. 500 mg daily).

Interferon-alpha: Conventional interferon-alpha and pegylated interferon-alpha combine high efficacy with lack of leukemogenic and oncogenic risk (dosage between 3 × 3 and 5 × 5 million IU interferon-alpha s.c., or 40 µg pegylated interferon-alpha). Therapy limiting factors are the side effects of the interferons. Hydroxycarbamide is generally preferred because of its oral availability and much better tolerability.

Anagrelide an imidazolidine preparation is the drug of choice for targeted platelet reduction (mean dosage 2 mg daily). This drug acts selectively on megakaryocytes and is not leukemogenic.

Therapy of aquagenic pruritus: Water-induced pruritus is the chronic symptom of PV that has a lasting impact on the quality of life. It is caused by water of different temperatures, sometimes already by heavy sweating or hand washing. The best treatment is consistent cytoreductive therapy of PV. In case of persistent pruritus, some authors recommend the addition of bicarbonate or starch to the bath water, although their effect is unclear. In case of non-response, antihistamines, serotonin reuptake inhibitors (e.g. fluoxetine, paroxetine) or the topical application of a capsaicin are available. In addition, phototherapy can be used.

Progression/forecast
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According to various retrospective studies on patients under 50 years of age, mean life expectancy is > 23 years (2 years without therapy). 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 post-polycythemic myelofibrosis is expected in about 10 % of patients.

Note(s)
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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.

Literature
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  1. Barbui T et al. (2016) The 2016 revision of WHO classification of myeloproliferative neoplasms: Clinical and molecular advances. Blood Rev 30:453-459.
  2. Castellanos-González M et al (2013) Eosinophilic fasciitis as a manifestation of a cutaneous T-cell lymphoma not otherwise specified. Am J Dermatopathol 35:666-670.
  3. Cerquozzi S et al (2017) Risk factors for arterial versus venous thrombosis in polycythemia vera: a single center experience in 587 patients. Blood Cancer Journal 7: 662.
  4. Collie AM et al.(2013) Cutaneous intravascular extramedullary hematopoiesis in a patient with post-polycythemia vera myelofibrosis. J Cutan Pathol 40:615-620.
  5. DGHO (2019) Onkopedia Guideline: Polycythaemia vera, available at: https://www.onkopedia.com/de/onkopedia/guidelines/polycythaemia-vera-pv/@@view/html/index.html (accessed 9/13/2021).
  6. Gómez M et al.(2016) Risk factors for non-melanoma skin cancer in patients with essential thrombocythemia and polycythemia vera. Eur J Haematol 96:285-290.
  7. Griesshammer M et al (2019) Thromboembolic events in polycythemia vera. Annals of Hematology 2019; 98(5): 1071-1082.
  8. Kettle JG et al.(2016) Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 1. Expert Opin Ther Pat 7:1-17.
  9. Le Gall-Ianotto C et al. (2016) Clinical characteristics of aquagenic pruritus in patients with myeloproliferative neoplasms. Br J Dermatol doi: 10.1111/bjd.14809.
  10. Lozano-Masdemont B et al.(2016) Granulomatous Dermatitis as a Cutaneous Manifestation of Hematologic Disorders: The First Case Associated With Polycythemia Vera and a New Case Associated With Myelodysplasia. Actas Dermosifiliogr 107:e27-32.
  11. Parnes A et al (2016)Polycythemia and Thrombocytosis. Prim Care 43:589-605.
  12. Pecci A et al.(2014) Cutaneous involvement by post-polycythemia vera myelofibrosis. Am J Hematol 89:448.
  13. Shanmugam VK et al (2013) Chronic leg ulceration associated with polycythemia vera responding to ruxolitinib (Jakafi(®)).J Foot Ankle Surg 52:781-785.
  14. Uzuncakmak TK et al.(2015) Lentiginoses in polycythemia vera patient: Is there a role for JAK2 (V617F) mutation? JAKSTAT. 4(1):e1071000.
  15. Yamamoto T et al.(2014) Cutaneous invasion of leukemia cells during blastic transformation in a post polycythemia vera myelofibrosis patient. Int J Hematol 100:525-526.

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Last updated on: 13.09.2021