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Hematology

Myeloproliferative

Overview of Myeloproliferative Neoplasms (MPNs)

  • Definition: A group of clonal hematopoietic stem cell disorders characterized by increased proliferation of one or more myeloid cell lines in the bone marrow
  • Key Features:
    • Increased Blood Cell Counts: Elevated WBC count, RBC count, and/or platelet count
    • Extramedullary Hematopoiesis: Hematopoiesis (blood cell production) occurs outside the bone marrow, often in the spleen (leading to splenomegaly) and liver
    • Risk of Thrombosis and Bleeding: Due to abnormal platelet function and/or elevated blood cell counts
    • Risk of Transformation: Can progress to myelofibrosis (scarring of the bone marrow) or acute leukemia
  • Diagnostic Hallmark: MPNs are often characterized by specific genetic mutations that drive the increased proliferation
  • Classification:
    • Chronic Myeloid Leukemia (CML)
    • Polycythemia Vera (PV)
    • Essential Thrombocythemia (ET)
    • Primary Myelofibrosis (PMF)
    • Other, rarer MPNs

Chronic Myeloid Leukemia (CML)

  • Definition: A myeloproliferative neoplasm characterized by the presence of the BCR-ABL1 fusion gene, resulting from a reciprocal translocation between chromosomes 9 and 22 (t(9;22)(q34.1;q11.2))
  • Pathophysiology:
    • BCR-ABL1 Fusion Gene: The translocation creates the Philadelphia chromosome (Ph chromosome) and results in the fusion of the BCR gene on chromosome 22 with the ABL1 gene on chromosome 9
    • Constitutive Tyrosine Kinase Activity: The BCR-ABL1 fusion protein has constitutive (always “on”) tyrosine kinase activity, which drives uncontrolled proliferation of myeloid cells
  • Phases of CML:
    • Chronic Phase (CP):
      • Relatively indolent phase with increased WBC count, but <10% blasts in the bone marrow and peripheral blood
    • Accelerated Phase (AP):
      • Increasing WBC count, blasts between 10-19% in the bone marrow or peripheral blood, resistance to treatment, new cytogenetic abnormalities
    • Blast Phase (BP):
      • Transformation to acute leukemia (either myeloid or lymphoid) with ≥20% blasts in the bone marrow or peripheral blood
  • Clinical Features:
    • Chronic Phase:
      • Often asymptomatic
      • Fatigue
      • Splenomegaly
      • Night sweats
      • Weight loss
    • Accelerated Phase and Blast Phase:
      • Worsening symptoms
      • Fever
      • Bone pain
      • Bleeding
      • Infections
  • Laboratory Findings:
    • CBC:
      • Elevated WBC count (often > 25 x 10^9/L)
      • Neutrophilia with a “left shift” (increased band neutrophils, metamyelocytes, and myelocytes)
      • Basophilia
      • Eosinophilia
      • Anemia (variable)
      • Platelet count: Normal or elevated
    • Peripheral Blood Smear:
      • Increased granulocytes at various stages of maturation
      • Basophilia
      • Small number of blasts (in chronic phase)
      • Presence of blasts and promyelocytes (in accelerated and blast phases)
    • Bone Marrow Aspiration and Biopsy:
      • Hypercellular marrow with increased granulopoiesis
      • Myeloid:erythroid (M:E) ratio is increased
      • Blast percentage: <10% in chronic phase, 10-19% in accelerated phase, and ≥20% in blast phase
    • Cytogenetic Analysis:
      • Philadelphia chromosome (Ph chromosome): t(9;22)(q34.1;q11.2)
    • Molecular Testing:
      • BCR-ABL1 Fusion Gene: Detected by PCR or FISH (fluorescence in situ hybridization)
  • Treatment:
    • Tyrosine Kinase Inhibitors (TKIs):
      • Imatinib, dasatinib, nilotinib, bosutinib, ponatinib
      • Target the BCR-ABL1 tyrosine kinase activity, leading to apoptosis of leukemic cells
      • Highly effective in achieving and maintaining remission in most patients with chronic phase CML
    • Hematopoietic Stem Cell Transplantation (HSCT):
      • Potentially curative option
      • Typically reserved for patients who fail TKI therapy or who are in accelerated or blast phase
    • Interferon-alpha:
      • An older treatment option that is now less commonly used

Polycythemia Vera (PV)

  • Definition: A myeloproliferative neoplasm characterized by increased production of red blood cells (erythrocytosis), often accompanied by increased production of white blood cells and platelets
  • Diagnostic Criteria:
    • Elevated hemoglobin and hematocrit
    • Presence of the JAK2 V617F mutation (or other JAK2 exon 12 mutation)
    • Bone marrow showing erythroid, granulocytic, and megakaryocytic proliferation
  • Pathophysiology:
    • JAK2 Mutation: A mutation in the JAK2 gene (Janus kinase 2), most commonly the V617F mutation
      • JAK2 is a tyrosine kinase involved in signal transduction for several growth factors, including erythropoietin (EPO)
      • The JAK2 mutation leads to constitutive activation of the EPO receptor signaling pathway, resulting in uncontrolled RBC production, independent of EPO levels
    • Erythroid Progenitor Hypersensitivity: Erythroid progenitors become hypersensitive to growth factors
  • Clinical Features:
    • Elevated red cell mass is what causes:
      • Headache
      • Dizziness
      • Fatigue
      • Blurred Vision
      • Pruritus (itching, especially after a warm bath)
      • Erythromelalgia (burning pain and redness in the extremities)
      • Thrombosis: Increased risk of blood clots (stroke, heart attack, pulmonary embolism, DVT)
      • Bleeding: Paradoxically, some patients may experience bleeding due to abnormal platelet function
      • Splenomegaly: Enlarged spleen
  • Laboratory Findings:
    • CBC:
      • Elevated HGB and HCT
      • Elevated RBC count
      • WBC count: May be normal or elevated
      • Platelet count: May be normal or elevated
    • Peripheral Blood Smear:
      • May show erythrocytosis (increased RBCs)
      • May see some granulocytosis and thrombocytosis
    • Serum Erythropoietin (EPO) Level:
      • Low or Normal
    • JAK2 Mutation Analysis:
      • Positive for JAK2 V617F mutation (or other JAK2 mutation)
    • Bone Marrow Examination (not always required):
      • Hypercellular marrow with increased erythroid, granulocytic, and megakaryocytic lineages
  • Treatment:
    • Phlebotomy:
      • To reduce HCT to <45%
      • Mainstay of therapy
    • Low-Dose Aspirin:
      • To reduce the risk of thrombosis
    • Cytoreductive Therapy:
      • Hydroxyurea: To suppress bone marrow proliferation
      • Ruxolitinib: A JAK2 inhibitor used in patients who are resistant to or intolerant of hydroxyurea
    • Interferon-alpha:
      • May be used in younger patients or pregnant women

Essential Thrombocythemia (ET)

  • Definition: A myeloproliferative neoplasm characterized by sustained thrombocytosis (elevated platelet count)
  • Diagnostic Criteria:
    • Sustained Platelet Count ≥450 x 10^9/L
    • Bone Marrow Showing Increased Numbers of Megakaryocytes
    • Exclusion of Other MPNs: Absence of criteria for PV, PMF, or CML
    • Presence of a Clonal Marker (e.g., JAK2, CALR, or MPL mutation) or Evidence of Clonal Hematopoiesis in the Absence of Other Causes of Thrombocytosis
  • Pathophysiology:
    • Mutations in JAK2, CALR, or MPL genes lead to increased megakaryocyte proliferation and platelet production
      • JAK2 mutation (Janus kinase 2): Affects signal transduction
      • CALR mutation (calreticulin): Affects protein folding and calcium signaling
      • MPL mutation (thrombopoietin receptor): Affects thrombopoietin signaling
  • Clinical Features:
    • Often asymptomatic
    • Thrombosis: Increased risk of blood clots (stroke, heart attack, DVT, pulmonary embolism)
    • Bleeding: Paradoxically, some patients may experience bleeding due to abnormal platelet function
    • Erythromelalgia: Burning pain and redness in the extremities
    • Splenomegaly: Enlarged spleen (less common than in PV or PMF)
  • Laboratory Findings:
    • CBC:
      • Elevated platelet count (≥450 x 10^9/L)
      • WBC count: May be normal or slightly elevated
      • RBC count: Usually normal
    • Peripheral Blood Smear:
      • Thrombocytosis: Increased number of platelets
      • Large platelets (megathrombocytes)
      • Abnormal platelet morphology (e.g., hypogranular platelets)
    • Bone Marrow Examination (not always required):
      • Increased numbers of megakaryocytes with abnormal morphology
    • Molecular Testing:
      • Positive for JAK2, CALR, or MPL mutation (in most cases)
  • Treatment:
    • Low-Dose Aspirin:
      • To reduce the risk of thrombosis
    • Cytoreductive Therapy:
      • Hydroxyurea: To lower the platelet count
      • Anagrelide: Inhibits platelet production
      • Interferon-alpha: May be used in younger patients or pregnant women

Primary Myelofibrosis (PMF)

  • Definition: A myeloproliferative neoplasm characterized by progressive bone marrow fibrosis (scarring), splenomegaly, and extramedullary hematopoiesis
  • Diagnostic Criteria:
    • Megakaryocyte proliferation and dysplasia in the bone marrow
    • Reticulin and/or collagen fibrosis
    • Exclusion of Other MPNs: Absence of criteria for PV, ET, or CML
    • Presence of a Clonal Marker (e.g., JAK2, CALR, or MPL mutation) or Evidence of Clonal Hematopoiesis in the Absence of Other Causes of Myelofibrosis
  • Pathophysiology:
    • Mutations in JAK2, CALR, or MPL genes lead to:
      • Abnormal megakaryocyte proliferation and activation
      • Release of cytokines (e.g., TGF-β, PDGF, VEGF) that stimulate fibroblast proliferation and collagen deposition in the bone marrow
    • Progressive bone marrow fibrosis impairs normal hematopoiesis, leading to:
      • Cytopenias (anemia, thrombocytopenia)
      • Extramedullary hematopoiesis (blood cell production in the spleen, liver, and other organs)
  • Clinical Features:
    • Anemia: Fatigue, weakness
    • Splenomegaly: Abdominal discomfort, early satiety
    • Constitutional Symptoms: Fatigue, weight loss, night sweats, fever
    • Bone Pain
    • Thrombosis and Bleeding: Due to abnormal platelet function
  • Laboratory Findings:
    • CBC:
      • Anemia (usually present)
      • Thrombocytopenia or thrombocytosis (variable)
      • Leukoerythroblastosis: Presence of immature granulocytes and nucleated RBCs in the peripheral blood
    • Peripheral Blood Smear:
      • Teardrop cells (dacrocytes): Abnormally shaped RBCs that are characteristic of PMF
      • Leukoerythroblastosis: Immature granulocytes and nucleated RBCs
      • Large, abnormal platelets
    • Bone Marrow Aspiration and Biopsy:
      • Hypercellular marrow (early stages)
      • Increased megakaryocytes with abnormal morphology
      • Reticulin and/or collagen fibrosis (graded on a scale of 0-3)
    • Molecular Testing:
      • Positive for JAK2, CALR, or MPL mutation (in most cases)
  • Treatment:
    • Supportive Care:
      • Transfusions to manage anemia and thrombocytopenia
      • Ruxolitinib: A JAK2 inhibitor that reduces spleen size, improves constitutional symptoms, and may prolong survival
      • Danazol or thalidomide: May improve anemia or thrombocytopenia
      • Hydroxyurea: To manage thrombocytosis or leukocytosis
    • Splenectomy: May be considered for symptomatic splenomegaly or refractory cytopenias, but carries significant risks
    • Hematopoietic Stem Cell Transplantation (HSCT):
      • The only potentially curative option
      • Reserved for younger patients with high-risk disease

Key Terms

  • Myeloproliferative Neoplasm (MPN): A clonal hematopoietic stem cell disorder with increased production of myeloid cells
  • Chronic Myeloid Leukemia (CML): MPN with the BCR-ABL1 fusion gene
  • Polycythemia Vera (PV): MPN with increased red blood cell production; often associated with JAK2 V617F mutation
  • Essential Thrombocythemia (ET): MPN with increased platelet production; associated with JAK2, CALR, or MPL mutations
  • Primary Myelofibrosis (PMF): MPN characterized by bone marrow fibrosis and extramedullary hematopoiesis; associated with JAK2, CALR, or MPL mutations
  • Extramedullary Hematopoiesis: Blood cell production outside the bone marrow (e.g., in the spleen and liver)
  • Splenomegaly: Enlargement of the spleen
  • Thrombosis: Formation of blood clots
  • Hepatomegaly: Enlargement of the liver
  • Leukoerythroblastosis: Presence of immature granulocytes and nucleated RBCs in the peripheral blood
  • Teardrop Cells (Dacrocytes): Abnormally shaped RBCs seen in primary myelofibrosis
  • Hydroxyurea: A chemotherapeutic drug used to suppress bone marrow proliferation
  • Ruxolitinib: A JAK2 inhibitor used to treat MPNs