Polycythemia Vera and Other Myeloproliferative Neoplasms¶
Chapter 108 | Harrison's 22e · Part 4 – Oncology: Hematologic Malignancies · Chapter 108
Key Clinical Points¶
- Polycythemia vera (PV) is characterized by erythrocytosis, leukocytosis, and thrombocytosis with JAK2 V617F mutation in >95% of cases.
- Diagnostic criteria for PV include hemoglobin >18.5 g/dL (men) or >16.5 g/dL (women), elevated hematocrit (>52% men, >48% women), and bone marrow fibrosis.
- Primary myelofibrosis (PMF) is characterized by splenomegaly (>90%), leukoerythroblastosis, and reticulin fibers in the marrow.
- Essential thrombocythemia (ET) is defined by platelet count >450 × 10⁹/L without other MPN features.
- Distinguish between relative erythrocytosis (e.g., dehydration) and absolute erythrocytosis (e.g., hypoxia, renal disease).
- Ruxolitinib is a primary treatment for PMF-related splenomegaly and constitutional symptoms.
- PMF has a poor prognosis with median survival of 5-7 years.
- JAK2 V617F mutation is present in >95% of PV cases and 50-60% of PMF.
- CALR mutations occur in ~30% of ET/PMF without JAK2 mutation; MPL in 5-10% of MPNs.
- Thrombocytosis can be caused by inflammation, malignancy, infection, or myeloproliferative disorders (Table 108-6).
1. DEFINITION & CLASSIFICATION¶
The World Health Organization (WHO) classifies chronic myeloproliferative neoplasms (MPNs) as disorders characterized by:
• Overproduction of one or more blood cell lineages without significant dysplasia • Extramedullary hematopoiesis • Myelofibrosis • Risk of transformation to acute leukemia
Key MPN subtypes include: • Polycythemia vera (PV) • Primary myelofibrosis (PMF) • Essential thrombocythemia (ET) • Chronic myeloid leukemia (CML) • Chronic neutrophilic leukemia (CNL) • Chronic eosinophilic leukemia • Mastocytosis • MPNs, unclassifiable
Table 108-1 provides the official WHO classification of these disorders.
TABLE 108-1 World Health Organization Classification of Chronic Myeloproliferative Neoplasms
- Disorder
- Chronic myeloid leukemia, BCR-ABL–positive
- Chronic neutrophilic leukemia
- Chronic eosinophilic leukemia, not otherwise specified
- Polycythemia vera
- Primary myelofibrosis
- Essential thrombocytosis
- Mastocytosis
- Myeloproliferative neoplasms, unclassifiable
1.1 Molecular Pathogenesis¶
Key mutations associated with MPNs:
• JAK2 V617F: Present in >95% of PV cases and 50-60% of PMF. • CALR (calreticulin): Found in ~30% of ET/PMF without JAK2 mutation. • MPL (thrombopoietin receptor): Found in ~5-10% of MPNs. • Advanced disease markers: TET2, ASXL1, and EZH2 mutations.
2. EPIDEMIOLOGY¶
• PV: Incidence 1-2 per 100,000; median age at diagnosis 60 years. • PMF: Incidence ~1.5 per 100,000; median age 65 years. • ET: Incidence 0.3-0.5 per 100,000; affects women more frequently than men.
Risk Factors: • Genetic predisposition (JAK2, CALR, MPL mutations) • Environmental factors (radiation exposure) • Age-related clonal hematopoiesis
3. CLINICAL FEATURES¶
Polycythemia Vera (PV) features:
• Constitutional symptoms: Fatigue, pruritus, night sweats. • Cardiovascular complications: Thrombosis (stroke, MI), hypertension. • Splenomegaly: Present in 20-30% of cases. • Hemorrhagic diathesis: Due to platelet dysfunction.
Primary Myelofibrosis (PMF) features:
• Constitutional symptoms: Weight loss, fever. • Splenomegaly: >90% of cases. • Hepatomegaly and Lymphadenopathy.
Laboratory Findings:
PV: • Hemoglobin: >18.5 g/dL (men) or >16.5 g/dL (women). • Hematocrit: >52% (men) or >48% (women). • Platelet count: 450-1,100 × 10⁹/L. • White blood cell count: 7-15 × 10⁹/L.
PMF: • Anemia: Hb <12 g/dL in 80% of cases. • Leukoerythroblastosis: Observed on peripheral smear. • Platelet count: >450 × 10⁹/L in 60-70% of cases.
Thrombocytosis (Table 108-6) can be caused by: • Tissue inflammation (e.g., IBD, collagen vascular disease). • Malignancy or Infection. • Myeloproliferative disorders (PV, PMF, ET, CML). • Myelodysplastic disorders (5q- syndrome, refractory sideroblastic anemia). • Postsplenectomy or hyposplenism.
TABLE 108-6 Causes of Thrombocytosis
| Cause Category | Specific Conditions |
|---|---|
| Tissue inflammation | collagen vascular disease, inflammatory bowel disease |
| Malignancy | N/A |
| Infection | N/A |
| Myeloproliferative disorders | polycythemia vera, primary myelofibrosis, essential thrombocytosis, chronic myelogenous leukemia |
| Myelodysplastic disorders | 5q– syndrome, idiopathic refractory sideroblastic anemia |
| Other | Postsplenectomy or hyposplenism, Hemorrhage, Surgery, Hemolysis |
4. DIFFERENTIAL DIAGNOSIS¶
Secondary Erythrocytosis (Table 108-2):
• Relative Erythrocytosis: → Hemoconcentration due to dehydration, diuretics, ethanol abuse, androgens, or tobacco. • Absolute Erythrocytosis: → Hypoxia (Carbon monoxide intoxication, High altitude, Pulmonary disease). → High-oxygen-affinity hemoglobin. → Right-to-left cardiac/vascular shunts. → Adrenal tumors, Sleep apnea syndrome, Hepatopulmonary syndrome. → Renal Disease (Renal artery stenosis, SGLT2 inhibitors, Focal sclerosing or membranous glomerulonephritis, Postrenal transplantation, Renal cysts, Bartter’s syndrome). → Erythropoietin receptor mutations or VHL mutations (Chuvash polycythemia). → 2,3-BPG mutation, PHD2 (EGLN1) and HIF2α (EPAS1) mutations, LNK mutations.
Myelophthisis: • Metastatic cancer (breast, lung). • Infections (tuberculosis, HIV). • Gaucher disease.
TABLE 108-2 Causes of Erythrocytosis
| Type | Causes |
|---|---|
| Relative Erythrocytosis | Hemoconcentration secondary to dehydration, diuretics, ethanol abuse, androgens, or tobacco abuse |
| Absolute Erythrocytosis | Hypoxia (Carbon monoxide intoxication, High-oxygen-affinity hemoglobin, High altitude, Pulmonary disease), Right-to-left cardiac or vascular shunts, Adrenal tumors, Sleep apnea syndrome, Hepatopulmonary syndrome, Renal Disease (Renal artery stenosis, SGLT2 inhibitors, Focal sclerosing or membranous glomerulonephritis, Postrenal transplantation, Renal cysts, Bartter’s syndrome), Erythropoietin receptor mutations, VHL mutations (Chuvash polycythemia), 2,3-BPG mutation, PHD2 (EGLN1) and HIF2α (EPAS1) mutations, LNK mutations |
5. DIAGNOSTIC APPROACH¶
Algorithm for evaluating suspected erythrocytosis:
- Initial Assessment: Determine if erythrocytosis is relative (e.g., dehydration) or absolute.
- Molecular Testing: Perform JAK2 mutation testing.
- Bone Marrow Biopsy: Assess for marrow cellularity and fibrosis.
- Exclusion of Secondary Causes: Rule out hypoxia, renal disease, and other non-hematologic causes.
Polycythemia Vera (PV) Diagnosis:
- Assess Hemoglobin: >18.5 g/dL (men) or >16.5 g/dL (women).
- Test for Mutations: JAK2 V617F (>95% cases) or other MPN-associated mutations.
- Bone Marrow Biopsy: Look for hypercellularity with fibrosis.
- Exclusion: Rule out secondary erythrocytosis (e.g., hypoxia, renal disease).
Primary Myelofibrosis (PMF) Diagnosis:
- Clinical signs: Splenomegaly and constitutional symptoms.
- Bone Marrow Biopsy: Identify reticulin fibers (score ≥2) and CD34+ fibroblasts.
- Peripheral Smear: Look for leukoerythroblastosis.
- Rule out other causes of myelofibrosis (Table 108-3): → Malignant: Acute leukemia, CML, Hairy cell, Hodgkin's, Lymphoma, Myelodysplasia, Metastatic carcinoma, PV, Mastocytosis. → Nonmalignant: HIV, Hyperparathyroidism, Renal osteodystrophy, SLE, Tuberculosis, Vitamin D deficiency, Thorium exposure, Gray platelet syndrome.
TABLE 108-3 Disorders Causing Myelofibrosis
| Category | Disorders |
|---|---|
| MALIGNANT | Acute leukemia (lymphocytic, myelogenous, megakaryocytic), Chronic myeloid leukemia, Hairy cell leukemia, Hodgkin’s disease, Primary myelofibrosis, Lymphoma, Multiple myeloma, Myelodysplasia, Metastatic carcinoma, Polycythemia vera, Systemic mastocytosis |
| NONMALIGNANT | HIV infection, Hyperparathyroidism, Renal osteodystrophy, Systemic lupus erythematosus, Tuberculosis, Vitamin D deficiency, Thorium dioxide exposure, Gray platelet syndrome |
6. MANAGEMENT & TREATMENT¶
Polycythemia Vera (PV) Management:
- Phlebotomy: Maintain Hb <16.5 g/dL (women) or <18.5 g/dL (men).
- Hydroxyurea: 5-20 mg/kg PO daily for leukocytosis/thrombocytosis.
- Interferon-alpha: Alternative for young patients with contraindications to hydroxyurea.
- Ruxolitinib: First-line for resistant cases or splenomegaly.
Primary Myelofibrosis (PMF) Management:
- Ruxolitinib: 10-25 mg BID for constitutional symptoms and splenomegaly.
- Fedratinib (Jakavi): Alternative if ruxolitinib is not tolerated.
- Allogeneic Stem Cell Transplant: Curative option for fit patients <65 years.
Monitoring: • CBC every 2-4 weeks during initial treatment. • JAK2 mutation monitoring. • Liver function tests (ALT/AST, bilirubin). • Bone marrow biopsy annually.
6.1 Clinical Monitoring¶
• CBC: Every 2-4 weeks during initial treatment. • JAK2 mutation status monitoring. • Liver function tests (ALT/AST, bilirubin). • Bone marrow biopsy: Annually.
7. COMPLICATIONS & PROGNOSIS¶
Polycythemia Vera (PV):
• Median survival: >15 years with treatment. • 10-year overall survival: ~80%. • Thrombosis risk: 10-20% annual incidence.
Primary Myelofibrosis (PMF):
• Median survival: 5-7 years. • Prognostic Factors: → Age, WBC count, LDH, and bone marrow fibrosis grade.
Risk Stratification for PMF (Tables 108-4 & 108-5):
• IPSS (2009) Risk Factors: Anemia (<10 g/dL), Leukocytosis (>25,000/μL), Blasts (≥1%), Constitutional symptoms, Age (>65), Unfavorable karyotype, Platelet count (<100,000/μL). • DIPSS (2010) Risk Factors: Anemia, Blasts, Age, Platelet count.
Risk Categories: • Low: IPSS 0; DIPSS 0. • Intermediate-1: IPSS 1-2; DIPSS 1-2; DIPSS PLUS 1. • Intermediate-2: [No IPSS]; DIPSS 3-4. • High: IPSS ≥3; DIPSS >4; DIPSS PLUS 4-6.
TABLE 108-4 Three Current Scoring Systems for Estimating Prognosis in PMF Patients
| Risk Factor | IPSS (2009) | DIPSS (2010) | DIPSS PLUS (2011) |
|---|---|---|---|
| Anemia (<10 g/dL) | X | X | X |
| Blasts (≥1%) | X | X | X |
| Age (>65 years) | X | X | X |
| Platelet count (<100,000/μL) | X |
TABLE 108-5 IPSS and DIPSS Risk Stratification Systems
| Risk Categories | Number of Factors | IPSS | DIPSS | DIPSS PLUS |
|---|---|---|---|---|
| Low | 0 | 0 | 0 | |
| Intermediate-1 | 1 | 1-2 | 1-2 | 1 |
| Intermediate-2 | 3-4 | |||
| High | ≥3 | ≥3 | >4 | 4-6 |
8. KEY PEARLS & HIGH-YIELD POINTS¶
• JAK2 V617F is the hallmark of PV (>95%) and a major marker in PMF (50-60%). • Dacrocytes (teardrop cells) and nucleated RBCs on peripheral smear are key indicators of extramedullary hematopoiesis. • Reticulin score ≥2 in bone marrow is required for the diagnosis of myelofibrosis. • Distinguish between absolute erythrocytosis (e.g., renal disease, hypoxia) and relative erythrocytosis (e.g., dehydration) to avoid treating a secondary condition as an MPN. • Ruxolitinib is the primary targeted therapy for managing splenomegaly and constitutional symptoms in PMF.
Reference Tables¶
TABLE 108-1 World Health Organization Classification of Chronic Myeloproliferative Neoplasms Chronic myeloid leukemia…¶
Harrison's 22e, p.818
- Chronic myeloid leukemia, BCR-ABL–positive
- Chronic neutrophilic leukemia
- Chronic eosinophilic leukemia, not otherwise specified
- Polycythemia vera
- Primary myelofibrosis
- Essential thrombocytosis
- Mastocytosis
- Myeloproliferative neoplasms, unclassifiable
TABLE 108-2 Causes of Erythrocytosis Relative Erythrocytosis Hemoconcentration secondary to dehydration, diuretics…¶
Harrison's 22e, p.820
| Relative Erythrocytosis | |
|---|---|
| Hemoconcentration secondary to dehydration, diuretics, ethanol abuse, androgens, or tobacco abuse |
|
| Absolute Erythrocytosis | |
| Hypoxia | Tumors |
| Carbon monoxide intoxication | Hypernephroma |
| High-oxygen-affinity hemoglobin | Hepatoma |
| High altitude | Cerebellar hemangioblastoma |
| Pulmonary disease | Uterine myoma |
| Right-to-left cardiac or vascular shunts | Adrenal tumors |
| Sleep apnea syndrome | Meningioma |
| Hepatopulmonary syndrome | Pheochromocytoma |
| Renal Disease | Drugs |
| Renal artery stenosis | Androgens SGLT2 inhibitors |
| Focal sclerosing or membranous glomerulonephritis |
Recombinant erythropoietin Familial (with normal hemoglobin function) |
| Postrenal transplantation | |
| Renal cysts | Erythropoietin receptor mutations |
| Bartter’s syndrome | VHL mutations (Chuvash polycythemia) |
| 2,3-BPG mutation | |
| PHD2 (EGLN1) and HIF2α (EPAS1) mutations LNK mutations |
|
| Polycythemia vera |
TABLE 108-3 Disorders Causing Myelofibrosis MALIGNANT Acute leukemia (lymphocytic, myelogenous, megakaryocytic) Chronic…¶
Harrison's 22e, p.821
| MALIGNANT | NONMALIGNANT |
|---|---|
| Acute leukemia (lymphocytic, myelogenous, megakaryocytic) |
HIV infection Hyperparathyroidism Renal osteodystrophy Systemic lupus erythematosus Tuberculosis Vitamin D deficiency Thorium dioxide exposure Gray platelet syndrome |
| Chronic myeloid leukemia | |
| Hairy cell leukemia | |
| Hodgkin’s disease | |
| Primary myelofibrosis | |
| Lymphoma | |
| Multiple myeloma | |
| Myelodysplasia | |
| Metastatic carcinoma | |
| Polycythemia vera | |
| Systemic mastocytosis |
TABLE 108-4 Three Current Scoring Systems for Estimating Prognosis in PMF Patients¶
Harrison's 22e, p.822
| RISK FACTOR | IPSS (2009)a | DIPSS (2010)b | DIPSS PLUS (2011)c |
|---|---|---|---|
| Anemia (<10 g/dL) | X | X | X |
| X | X | ||
| Peripheral blood blasts (≥1%) | X | X | X |
| X | X | ||
| Age (>65 years) | X | X | X |
| Platelet count (<100,000/μL) | X |
TABLE 108-5 IPSS and DIPSS Risk Stratification Systems¶
Harrison's 22e, p.822
| RISK CATEGORIESa | NUMBER OF RISK FACTORS | ||
|---|---|---|---|
| IPSS | DIPSS | DIPSS PLUS | |
| 0 | 0 | ||
| Intermediate-1 | 1 | 1–2 | 1 |
| 2 | 3–4 | ||
| High | ≥3 | >4 | 4–6 |
TABLE 108-6 Causes of Thrombocytosis Tissue inflammation: collagen vascular disease, inflammatory bowel disease…¶
Harrison's 22e, p.823
| Tissue inflammation: collagen vascular disease, inflammatory bowel disease |
Hemorrhage |
|---|---|
| Infection | Surgery |
| Myelodysplastic disorders: 5q– syndrome, idiopathic refractory sideroblastic anemia |
Hemolysis |