Department of Hematology and Oncology R3 Joonbeom Shin Polycythemia Vera Department of Hematology and Oncology R3 Joonbeom Shin

Physiology of Erythropoiesis Pluripotent hematopoietic stem cell → Erythroid progenitor cell : Erythropoietin (EPO) stimulating the hierarchical process of lineage-commitment and differentiation. Erythropoietin (EPO) : 90% synthesized by the kidneys, response to hypoxemia, anemia, oxygen release (high oxygen-affinity hemoglobinopathies), oxygen delivery (vascular occlusion). Negative feedback of erythropoiesis : down-regulating EPO production with increasing oxygen delivery → suppresses renal EPO production.

Approach to Polycythemia Hematocrit > 48 or > 52 % in women and men. Hemoglobin concentration > 16.5 or > 18.5 g/dL in women and men. RBC count : above 3 test are all concentrations, so → dependent upon the plasma volume as well as the RBC mass. Relative polycythemia : reduced plasma volume → Gaisbock’s disease, spurious polycythemia, stress erythrocytosis, pseudopolycythemia. Absolute polycythemia : absolute increase in RBC mass, erythrocytosis 1. Primary polycythemia : acquired or inherited mutation of erythroid progenitors itself, polycythemia vera or rare familial variants. 2. Secondary polycythemia : increased erythropoietin activity, hypoxia induced EPO response or EPO-secreting tumor.

Major Causes of Erythrocytosis

Approach to Polycythemia M/C cause of polycythemia : hypoxia → living at high altitude, home O2 therapy or respiratory assist devices, intracardiac or intrapulmonary shunts, or renal transplantation. Anabolic steroids, erythropoietin or stored RBCs, especially in athletes. Smoking or inhaling smoke & chronic exposure to carbon monoxide. Rare genetic causes : high oxygen-affinity hemoglobinopathies, hereditary hemorrhagic telangiectasia, pulmonary AV malformations. Hemorrhagic or thrombotic events, or post-bath pruritus, plethoic faces, dilated lingual or retinal veins, or areas of painful erythema → suspicion of polycythemia vera. Total WBC and/or platelet count, with or without a reduction in the MCV

Disease Incidence of Polycythemia Vera 1.9/100,000 (Olmsted County, Minnesota during the period from 1935 through 1989) : approximately one-half that for multiple myeloma in the same population. Slightly higher in men than women (2.8 versus 1.3 cases per 100,000 per year). Highest for men aged 70 to 79 years (24 cases per 100,000 persons per year).

Approach to Polycythemia Vera Polycythemia Vera : one of the chronic myeloproliferative disorders. Median survival of untreated symptomatic patients : 6 to 18 months from the time of diagnosis, but current survival of treated patients is 10 years or more. Survival threatening factors 1. Fatal thrombotic complications due to increased whole blood viscosity : reducing the venous hematocrit to levels of 45 percent or less via phlebotomy. 2. Tranformation into Myelofibrosis with myeloid metaplasia and/or Acute myeloid leukemia.

Approach to Polycythemia Vera Polycythemia Vera Study Group (PVSG) : Cause of Death 1. Thrombosis (29 percent) 2. Hematologic malignancies (23 percent) 3. Nonhematologic malignancies (16 percent) 4. Hemorrhage (7 percent) 5. MMM (3 percent)

Clinical Presentations Non-specific complaints : headache (48%), weakness (47%), dizziness (43%), and excessive sweating (33%), acute gouty arthritis (5 to 20%). Pruritus : especially following vigorous rubbing of the skin after a warm bath or shower (“ Aquagenic pruritus ”) (43%). – unclear cause, suggested that cutaneous mast cell degranulation, histamine and prostaglandin hypothesis. Erythromelalgia : burning pain in the feet or hands accompanied by erythema, pallor, or cyanosis, in the presence of palpable pulses, associated acral paresthesia. - pathognomonic microvascular thrombotic complications in PV and essential thrombocythemia, platelet counts > 400,000/μL. → respond dramatically to low dose aspirin. Thrombosis : blood viscosity, platelet number and activity increased. → CVA, AMI, thrombophlebitis, DVT, PTE and Budd-Chiari syndrome.

Clinical Presentations G-I symptoms : PUD, gastroduodenal erosions. → alterations in mucosal blood flow due to viscosity. Physical examination : Splenomegaly (70%), facial plethora (67%), and hepatomegaly (40%), Stigmata of gouty arthritis may be present. Lab findings : Increased Hct and RBC mass in virtually all patients Platelet count over 400,000/μL in 60% WBC count over 12,000/μL in 40% Bone marrow cellularity increase in 90% Absent storage iron from the marrow in 95%

Diagnostic Criteria Polycythemia Vera Study Group (PVSG) criteria (1974) : “ Gold Standard ” - Developed prior to the general availability of assays for erythropoietin, endogenous erythroid colony formation, and specific karyotypic and clonal analyses. - Should only be applied to populations in which other causes have been excluded. - Practicing hematologist sees 10 cases of relative or secondary polycythemia for every new patient with PV. - Despite these concerns, it has been estimated that the false positive rate using the PVSG criteria is only about 0.5 percent.

PVSG Criteria

Newer Diagnostic Criteria Increased RBC mass : International Council for Standardization in Hematology (ICSH) – Should be normalized by body surface area, especially in obese patients. : Hemoglobin concentration > 16.5 g/dL in women and > 18.5 g/dL in men (with Hematocrit > 50% in women and > 56% in men → Hematocrit > 55% in women and > 60% in men). Palpable splenomegaly : Splenomegaly may not be detectable by P/E → Non-palpable but enlarged spleen on imaging test. Total WBC count : Lymphocytes or monocytes are not increased in PV → ANC > 10,000/μL LAP score and serum B12 : neither sensitive nor specific → not included in newer algorithms.

Newer Diagnostic Criteria Bone marrow aspiration and biopsy : Absence of Iron in 94% : Cellularity - 36 to 100% (mean 82%, normal 35 to 50%) : Megakaryocytes and amount Reticulin – variable but generally increased. BM Clonal markers : deletion of the long arm of chromosome 20, chromosome 8 or 9 trisomy, loss of heterozygosity on the short arm of chromosome 9 → up to 30% of previously untreated PV patients, helped to establish the malignant character of PV. JAK2 (V617F) Serum EPO : remainded low after the enough phlebotomy. Endogenous erythroid colony (EEC) formation : 100% of untreated PV patients and 50% of treated PV patients with chemotherapy.

Newer Diagnostic Stratigies 1. Additional presence of either a low serum EPO concentration or spontaneous EEC formation. 2. Addition of either palpable splenomegaly or abnormal bone marrow karyotype. If neither of these is present, the diagnosis can be made in the presence of two or more of the following: • Platelet count >400,000/microL • Absolute neutrophil count >10,000/microL • Splenic enlargement on a scanning procedure • Low serum EPO or spontaneous EEC 3. The WHO criteria, when one of the following is present: splenomegaly, a clonal genetic abnormality other than the Philadelphia chromosome (or BCR-ABL fusion gene), or spontaneous EEC. If these are not present, the diagnosis can be made in the presence of two or more of the following: • White blood cell count >12,000/microL • Bone marrow showing panmyelosis • Low serum EPO 4. Upon the presence of four or more of the following: • Increased RCM (>36 mL/kg for men and >32 mL/kg for women) • Normal arterial O2 saturation (> or =92 percent) with an increased RCM • Splenomegaly • Bone marrow hypercellularity with megakaryocytic hyperplasia and absent iron stores • Increased platelet (>400,000/microL) and total white blood cell (> or =12,000/microL) counts • Spontaneous EEC formation • Decreased serum EPO in the presence of an elevated RCM

Diagnostic Recommendations Low EPO level : highly specific for PV (specificity of 92 to 99 %). If a single EPO test is normal ; the second value will be low in more than one-quarter of these patients. If repeated values are normal, should undergo BM aspiration and biopsy with cytogenetic studies. If non-diagnostic BM, should undergo EEC assay, if not available, or repeat Hb and EPO test in 3 months.

Diagnostic Recommendations

Diagnostic Recommendations

Treatment Strategy PVSG Conclusions – The following conclusions were drawn from the PVSG major trial : 1. Phlebotomy treatment yielded the best overall survival, but at the cost of increased thrombotic events during the first three years. 2. Myelosuppressive therapy reduced the incidence of thrombosis, but increased the risk of AML, lymphoma, gastrointestinal, and skin malignancies. Life threatening and Non-life threatening Polycythemia vera

Phlebotomy Used as treatment of PV was recommended by Osler in the first decade of the 20th century. The mainstay of therapy for all patients with PV is phlebotomy to keep the hematocrit level below 45%. Progressive increase in the incidence of vascular occlusive episodes at hematocrit levels higher than 44%. With appropriate and monitored fluid replacement to avoid both hypotension and fluid overload.

Low dose of aspirin High-dose aspirin (900 mg/d) and dipyridamole (225 mg/d) : increased incidence of G-I bleeding. Low dose of aspirin (40~100 mg/d) : no increased bleeding diathesis. : significantly lowered the combined risk of cardiovascular death, myocardial infarction, stroke, pulmonary embolism, or major venous thrombosis. : significantly reduced the combined rate of major or minor thrombosis.

Risk Stratification in Polycythemia Vera Risk category Risk factors Low risk Age younger than 60 y and no history of thrombocytosis and platelet count lower than 1500 × 109/L Indeterminate risk thrombocytosis and either platelet count higher than 1500 × 109/L or the presence of cardiovascular risk factors High risk Age 60 y or older or a positive history of thrombosis

Treatment of Polycythemia Vera Risk category Age <60 y Age ≥60 y Women of childbearing age Low risk Phlebotomy alone ± low-dose aspirin Not applicable Indeterminate risk Phlebotomy alone High risk Phlebotomy + hydroxyurea or interferon α + low-dose aspirin Phlebotomy + hydroxyurea + low-dose aspirin Phlebotomy + interferon α + low-dose aspirin

Cytoreductive Agents Hydroxyurea : Antimetabolite, 500 mg twice/d → Neutropenia, mucocutaneous change, hyperpigmentation, nail change, and even leukemogenic. Busulfan Chlorambucil Radioactive phophorus 32 (32P)

Newer Drugs Anagrelide : Platelet function inhibitor, reducing the platelet count in more than 80%. → fluid retention, renal insufficiency, and CHF. Interferon α : Control erythrocytosis in 76% of the patients. → confusion, depression, autoimmunity to drug, hyperlipidemia. Pipobroman : Alkylating agent, incidence of AML of 10 % at a mean follow-up period of 13 years. → Nausea, rash, diarrhea, abdominal cramps, hemolysis.

Treatment of Non–Life Threatening Complications Microvascular Disturbances Including Erythromelalgia : light-headedness, transient neurologic or ocular disturbances, tinnitus, atypical chest discomfort, paresthesias. : low-dose aspirin produces prompt alleviation of symptoms. : normalization of platelet count with cytoreductive therapy may be necessary in certain patients who do not respond well to aspirin therapy. Management of Pruritus in PV : conventional treatment with antihistamines. : paroxetine or fluoxetine, a selective serotonin reuptake inhibitor. : PUVA

Treatment Recommendations Aggressive phlebotmy and generalized supportive care. Low dose of aspirin. Cytoreductive agents. Antihistmines and SSRI.