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A. Disease Entities
[Figure] "Blood Cell Development" navigator

  1. Polycythemia Vera (PCV)
  2. Essential Thrombocythemia
  3. Idiopathic Myelofibrosis (Myeloid Metaplasia)
  4. Chronic Myeloid Leukemia (CML) - separate outline

B. Polycythemia [2] navigator

  1. Definitions
    1. Polycythemia: abnormally increased red blood cell mass
    2. RBC mass is determined by chromium-51 labelled RBC Scan
    3. Hematocrit (HCT) >52% usually corresponds to polycythemia
    4. Primary erythrocytosis - decreased erythropoietin (EPO) levels
    5. Secondary erythrocytosis - increased EPO
    6. Hereditary erythrocytosis - often due to mutations in EPO-receptor
  2. Secondary polycythemia is divided into normal and abnormal EPO responses
  3. Secondary Polycythemia with Appropriate EPO Increase
    1. Smoking (hypoxia) - due to carboxyhemoglobin
    2. Hypoxia (other causes) including high altitude [9]
    3. Congenital cyanotic heart disease
    4. Gross obesity
    5. High-affinity hemoglobin (familiial erythrocytosis) [14]
  4. Secondary Polycythemia with Abnormal EPO Increase
    1. Hypernephroma (renal carcinoma)
    2. Hydronephrosis
    3. Polycystic kidney disease
    4. Post-renal transplant
    5. Hepatoma
    6. Uterine leiomyoma
    7. Cerebellar hemangioblastoma

C. Polycythemia Vera (PCV) [2,3]navigator

  1. Epidemiology [7]
    1. Annual incidence is ~2.3 per 100,000 persons
    2. Median age at diagnosis ~60 years
    3. Slightly more common in men
    4. Bleeding complications less frequent and less severe than thromboses
  2. Pathogenesis [4,5]
    1. Clonal hemaopoietic stem cell disorder
    2. Bone marrow is hypercellular in all cell lines
    3. EPO levels are normal or low
    4. Erythroblasts in PCV can develop in the absence of Epo
    5. JAK2 (Janus Kinase 2, invovled in cell signaling) found on chromosome 9p [12]
    6. Mutations in JAK2 found in ~95% of PCV
    7. Expression of the anti-apoptosis protein Bcl-xL found in mature PCV erythroblasts [5]
    8. Erythroblasts do not normally express Bcl-xL, although EPO can induce Bcl-xL expression
    9. Reduced expression of thrombopoietin receptor Mpl has been found in PCV [6]
  3. JAK2 Mutations [12,18]
    1. JAK2 point mutation (V617F) found in ~95% of PCV [1]
    2. JAK2 V617F also found in 57% of myelofibrosis and 23% of essential thrombocythemia [12]
    3. JAK2 V617F mutation confers increased kinase activity and may be oncogenic
    4. Patients with thrombocythemia and JAK2 V617F had polycythemia, some with frank PCV [18]
    5. JAK V617F found in ~50% of patients with thrombocythemia or myelofibrosis
    6. JAK2 exon 12 gain-of-function mutations in 4 of 10 JAK2 V617F negative patients [21]
    7. JAK2 exon 12 mutations associated with isolated erythrocytosis
    8. JAK2 exon 12 erythrocyte colonies grew in absence of erythropoietin or IL3 [21]
  4. Symptoms
    1. Erythrocytosis 100%
    2. Thrombocytosis and granulocytosis in most cases
    3. Splenomegaly 75%
    4. Hepatomegaly 30%
    5. Pruritus 40%
    6. Thromboembolic and hemorrhagic events increased
    7. Transient ischemic attacks (TIA) and other infarctions (often prior to diagnosis)
  5. Complications of PCV
    1. Thrombosis - will often precede appearance of elevated hematocrit
    2. Iron deficiency
    3. Gout
    4. Splenomegaly
    5. Leukemia
    6. Myelofibrosis
  6. Classical Diagnostic Criteria for PCV [3]
    1. PCV diagnosis requires all three major criteria OR
    2. First two major criteria and any two minor criteria
    3. Major Criteria: increased red cell mass, normal arterial O2 saturation, splenomegaly
    4. Increased red cell mass: men 36mL/kg or higher, women 32mL/kg or higher
    5. Minor Criteria: platelets >400K/µL, leukocytes >12K/µL, elevated alkaline phosphatase
    6. Elevated alkaline phosphatase: level >100 IU/mL
    7. Vitamin B12 level >900pg/mL, or unbound vitamin B12 binding capacity >2200pg/mL is another minor criteria
  7. Diagnostic Criteria for JAK2 Mutant PCV [1]
    1. Elevated HCT (>52% men, >48% women) or RBC mass >25% above predicted value
    2. JAK2 mutation absent
    3. No causes of secondary erythrocytosis (normal O2 saturation, EPO level not elevated)
    4. One Major Criterion (i) or (ii) or 2 minor criteria: (i) Either palple splenomegaly (ii) Acquired genetic abnormality (excluding BCR-ABL) in hmatopoietic cells
    5. Minor Criteria: (i) Thrombocytosis (>450K/µL platelets) (ii) Neutrophilia (>10K/µL nonsmokers; >12.5K/µL smokers) (iii) Splenomegaly on radiography (iv) Endogenous erythroid colonies or low serum EPO
  8. Diagnostic Criteria for PCV without JAK2 mutations [1]
    1. Elevated HCT (>60% men, >56% women) or RBC mass >25% above predicted value
    2. JAK2 mutation present
    3. Cytogenetic studies and EPO levels of no diagnostic value
    4. Thrombocytosis is often present
  9. Treatment [3]
    1. Phlebotomize to HCT < 45% in men, < 42% in women
    2. Patients 50-70 years old receive phlebotomy ± hydroxyurea (HU)
    3. Patients >70 years old - 32P (radioactive phosphate) or phlebotomy + HU
    4. Alkylating agents are usually not recommended due to high rate of cancers [6]
    5. Chlorambucil or radioactive phosphorus reduces overall survival due to leukemia
    6. However, in persons with increased thrombosis risk, HU reduces risk and morbidity
    7. Interferon alpha 3MU sc 3X per week controls erythrocytosis in ~75% of patients
    8. Aspirin (ASA) 100mg po qd (low dose) reduced clinical thrombotic events >55% [15]
  10. Prognosis
    1. Risk of thrombosis is 2-5% (higher end in older persons) without ASA therapy
    2. Risk of thrombosis increased in persons with history of thrombosis
    3. No correlation yet demonstrated between thrombosis and platelet number or function
    4. Leukemia in <5% of patients treated with phlebotomy alone
    5. Median survival in patients receiving phlebotomy >12 years
    6. ASA reduces thrombotic events including fatal and near fatal events with minimal bleeding risk [15]

D. Myeloproliferative (Essential) Thrombocythemia [7,8] navigator

  1. Characteristics
    1. Platelet counts increased, often >1 million / µL
    2. Elevated platelet counts lead to increased viscosity and capillary clogging (thrombosis)
    3. Bleeding diathesis also occurs, because platelets are dysfunctional
    4. High risk of spontaneous abortion in women with clonal thrombocythemia
    5. JAK2 V617F mutation in 23% of cases who also had chromosome 9p LOH [12]
    6. Overall, JAK2 V617F mutation found in ~50% of essential thrombocythemia [1,18]
    7. JAK2 V617F patients with thrombocythemia have signs of polycythemia, some with frank PCV [18]
  2. Epidemiology
    1. Incidence ~2.5 per 100,000 persons
    2. Prevalence ~35 in 100,000 persons
    3. ~1% of patients with platelet count >400K/µL develop ET over 5 years
    4. Very low progression or risk of transformation to either myelofibrosis or metaplasia
    5. Very low incidence of progression to acute leukemia
    6. Essentially normal lifespan compared with age matched controls
  3. Differential of High Platelets (>450K/µL)
    1. Reactive thrombocythemia - infection or other inflammation
    2. Hemoconcentration
    3. Iron deficiency
    4. Essential thrombocythemia
    5. Myeloproliferative Disease (with accompanying thrombocythemia)
    6. Thrombopoietin, C reactive protein (CRP), and IL6 levels are useful for differential
  4. Diagnosis
    1. Rule out reactive thrombocytosis as well as other causes of clonal thrombocytosis
    2. Patients with myeloproliferative thrombocythemia have elevated thrombopoietin levels [6] and low Interleukin 6 and CRP levels
    3. This contrasts with patients with inflammatory (reactive) thrombocytosis
    4. Leukocyte alkaline phosphatase level to rule out chronic myelogenous leukemia (CML)
    5. Bone marrow examination is crticial
  5. Diagnosis of JAK2 Mutant ET [1]
    1. Platelet count >450K/µL
    2. Mutation in JAK2
    3. No other myeloid cancer, especially JAK2+ PCV, myelofibrosis, or myelodysplasia (MDS)
  6. Diagnosis of JAK2 Normal ET [1]
    1. Platelet count >450K/µL
    2. Normal JAK2
    3. No reactive cause for thrombocytosis
    4. Normal ferritin (>20µg/L)
    5. No other myeloid cancer, especially CML, myelofibrosis, PCV, or MDS
  7. Risks for Clinical Events
    1. Age >60 years
    2. Previous vascular episodes
    3. Hemorrhagic episodes associated with higher platelet counts
    4. In general, persons with >1.5 million/µL should be treated with cytoreductive therapy
    5. Intermediate risk may include platelets >1.0 million/µL with other risk for vascular disease
  8. Treatment
    1. Maintain platelets < 1million/µL (goal <400K/µL in high risk patients)
    2. If platelets are lower than 1 million/µL and there are no symptoms, then no therapy
    3. Hydroxyurea superior to anagrelide in high risk essential thrombocythemia with higher risk of vascular events and transformation to myelofibrosis in anagrelide group [17]
    4. JAK2 V617F patients with essential thrombocythemia have a better response to hydroxyurea but not anagrelide compared with patients without mutation [18]
    5. No difference in platelet counts or leukemogenesis in hydroxyrea versus anagrelide [17]
    6. Intensified chemotherapy in patients with symptoms and poor response to HU or anagrelide
    7. Aspirin - for very high risk thrombosis, vasomotor symptoms
    8. Typically, low doses of aspirin (75-100mg/d) recommended [3,7]
    9. Interferon alpha 3MU sc 3X per week controls platelet counts in >80% of patients
    10. In young persons, course is usually benign
    11. Standard of care is now hydroxyurea + low dose aspirin [8,17]
  9. Hydroxyurea (Hydrea®) [19]
    1. Myelosuppressive therapy
    2. Dose is 10-15mg/kg/day
    3. Very effective for reduction of platelet counts, maintain <600K/µL
    4. Overall well tolerated, and significantly decreases risk for recurrent events
    5. Reduces risk of thrombosis in high risk patients from ~24% to <4%
    6. Hydroxyurea confers increased late risk of leukemia
    7. Other side effects: mucocutaneous lesions, neutropenia (reversible), GI complaints
  10. Anagrelide (Agrylin®) [20]
    1. Reasonable alternative for patients resistant or intolerant to HU
    2. Blocks maturation of megakaryocytes and decreases platelet production
    3. Inhibits platelet cyclic AMP phosphodiesterase
    4. Hepatic metablism, excreted in urine, elimination half-life 76 hours
    5. Dose is 0.5mg po qid or 1mg bid; maximum is 2.5mg qid
    6. Responses within 7-14 days; effects are reversible within a few days
    7. Patients do not become refractory to this agent
  11. Alkylating Agents
    1. Melphalan or chlorambucil
    2. Busulfan
    3. Generally reserved for refractory disease
  12. Dipyridamole (Persantine®)
    1. Coronary vasodilator at high doses
    2. Also inhibits platelet function
    3. Questionable efficacy; safe as adjunctive therapy

E. Idiopathic Myelofibrosis (Myeloid Metaplasia) [16]navigator

  1. Group of clonal stem-cell disorders with ineffective myeloid differentiation
    1. Ineffective erythropoiesis
    2. Dysplastic-megakaryocyte hyperplasia
    3. Increase in ratio of immature to total granulocytes
    4. Myeloproliferation is accompanied by reactive bone marrow (myelo-) fibrosis
  2. Types of Myeloid Metaplasia
    1. Agnogenic myeloid metaplasia - idiopathic myelofibrosis, no known precursor disease
    2. Post-polycythemic myeloid metaplasia - progression from PCV (above)
    3. Separated into JAK2 mutant (JAK2+) and JAK2 normal myeloid metaplasia
    4. Mutations in JAK2 occur in ~60% of myeloid metaplasia
  3. Epidemiology
    1. Occurs median age ~60-65 years
    2. Overall, indicence is ~1 per 100,000
    3. Male = Female
    4. Increased prevalence among Ashkenazi Jews
  4. Pathogenesis
    1. Clonal disorder which affects stem cells; 60% with JAK2 mutations
    2. These stem cells are trilineage precursors (granulocytic, erythroid, megakaryocytic)
    3. Resident fibroblasts which mediate fibrosis are polyclonal
    4. Thus, the stromal cell component is a reactive process
    5. Megakaryocytes and/or monocytes produce pro-fibrotic cytokines
    6. These cytokines include platelet-derived growth factor and TGF-ß
    7. In addition, angiogenic factors (VEGF) and basic FGF are produced
    8. Underexpression of thrombopoietin receptor Mpl has been documented [4]
    9. Overall, moderate rate of progression to true leukemia
  5. Clinical Symptoms
    1. Marrow fibrosis (myelofibrosis) with extramedullary hematopoiesis
    2. Weight loss and night sweats may occur
    3. Splenomegaly - may include pain and splenic infarction (hematopoiesis)
    4. Mass effects from organomegaly can lead to peripheral edema (portal hypertension 7%)
    5. Bone pain can be major symptom (increased hematopoiesis in non-long bones)
  6. Laboratory
    1. Mean WBC ~40K/µL, mainly granulocytes
    2. Neutropenia in ~15% of patients
    3. Platelet count elevated in ~30% of patients; 50-125K/µL in ~30% of patients
    4. Anemia due to ineffective hematopoiesis
    5. Presence of tear-drop shaped and/or nucleated red cells in blood
    6. Presence of immature granulocytes in the blood
    7. Bone marrow analysis should be done to rule out CML (see above)
  7. Diagnostic Criteria for JAK2+ Idiopathic Myelofibrosis [1]
    1. Reticulin grade 3 or higher (on 0-4 scale) on bone marrow biopsy
    2. Mutation in JAK2
    3. Two of the following "minor" criteria are required:
    4. Otherwise unexplained anemia (Hb <11.5g/L men, <10g/L women)
    5. Teardrop RBC on peripheral blood film
    6. Palpable splenomegaly
    7. Leukoerthryoblastic blood film: >1 nucleated RBC or immature myeloid cell in blood film)
    8. Systemic symptoms: night sweats, weight loss >10% in 6 months, diffuse bone pain
    9. Histologic evidence of extramedullar hematopoiesis
  8. Diagnostic Criteria for Idiopathic Myelofibrosis with Normal JAK2 [1]
    1. Reticulin grade 3 or higher (on 0-4 scale) on bone marrow biopsy
    2. Absence of mutation in JAK2
    3. Absence of BCR-ABL fusion gene
    4. Two of the following "minor" criteria are required:
    5. Otherwise unexplained anemia (Hb <11.5g/L men, <10g/L women)
    6. Teardrop RBC on peripheral blood film
    7. Palpable splenomegaly
    8. Leukoerthryoblastic blood film: >1 nucleated RBC or immature myeloid cell in blood film)
    9. Systemic symptoms: night sweats, weight loss >10% in 6 months, diffuse bone pain
    10. Histologic evidence of extramedullar hematopoiesis
  9. Treatment
    1. Androgen therapy with Danazol may improve anemia
    2. Glucocorticoids may sometimes be helpful
    3. Hydroxyurea - to reduce (extramedullary) hematopoiesis
    4. Splenectomy (see below)
    5. Interferons
    6. Radiotherapy - splenic pain, infarctions, bone pain, extramedullary tumors
    7. Transfusions as needed
    8. Thalidomide, with anti-angiogenic activity, is being studied
    9. Allogeneic stem-cell transplantation - may have benefit, mainly in young persons
  10. Indications for Splenectomy
    1. Hydroxyurea-resistant pain
    2. Hemolytic anemia or thrombocytopenia requiring transfusions
    3. Portal hypertension
    4. Splenic irradiation may be beneficial, usually only initial course

References navigator

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