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

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