14 - Chronic Myeloproliferative Disorders

Question 1

Chronic MPDs - Overview

Answer 1

• Acquired clonal disorders of multipotential stem cells
• Proliferation of non-lymphoid cell lines
• Effective hematopoiesis (increased red cells,
  granulocytes, and/or platelets in blood)

Question 2

Chronic MPDs - Pathogenesis

Answer 2

• Genetic abnormality in stem cells
• Proliferation and expansion of “myeloid” cell lines
• Effective hematopoiesis
• Activation of tyrosine kinase and signal transduction
  pathways (BCR/ABL fusion, JAK-2 mutations)
• Secondary non-clonal fibrosis

Question 3

Chronic MPDs – Bcr-Abl

Answer 3

• Reciprocal translocation between chromosomes 9 and 22
  (Philadelphia chromosome)
• Abl (9q34) and Breakpoint cluster region (22q14)
• Creation of a fusion gene which yields a protein (210 kd) with
  tyrosine kinase activity
• Increased activity of other genes (myc, bcl-2)
• Cells have proliferative and survival advantages
• Diagnostic criteria for CML

Question 4

Chronic MPDs – JAK2 mutation

Answer 4

• Janus kinase (JAK2) gene mutation
• Activating mutation
• Dysregulation of erythropoiesis (erythropoietin-
  independent)
• Occurs in non-CML chronic MPDs

Question 5

Chronic MPDs – Clinical Features

Answer 5

Question 6

Chronic Myeloid Leukemia

Answer 6

• Predominant proliferation of granulocytes
• Defined by presence of Philadelphia chromosome
  (BCR/ABL fusion)
• Fusion product is p210 protein with increased tyrosine
  kinase activity (growth advantage)
• Increased transcription of MYC and BCL-2 (protection
  from apoptosis)

Question 7

CML – Philadelphia Chromosome

Answer 7

• 95% of cases due to balanced reciprocal translocation
  between chromosome 9 (ABL) and chromosome 22
  (BCR)
• 5% more cryptic BCR/ABL fusions
• Philadelphia chromosome is derivative chromosome
  22
• Additional chromosomal changes lead to progressive
  disease (accelerated/blast phase)

Question 8

CML - Overview

Answer 8

• Most common MPD (15-20% all leukemia)
• “Incidental” finding on routine blood work
• Symptoms related to leukocytosis and/or
  splenomegaly
• Most patients diagnosed in chronic phase of disease

Question 9

CML - Morphology

Answer 9

• Hypercellular marrow with increased M:E ratio (10-100 fold
  increase in granulocytes)
• Leukocytosis with myeloid cells in all stages of maturation
  (occasional blasts)
• Increased basophils and eosinophils
• Decreased leukocyte alkaline phosphatase (LAP)
• Thrombocytosis
• Splenic red pulp expansion

Question 10

CML – Clinical Course

Answer 10

• Chronic phase (2-8+ years)
• Transformation to accelerated/blast phase
  1) Increased blasts (blood, marrow, tissues)
  2) Increased basophils (>20%)
  3) Thrombocytopenia/thrombocytosis
  4) Increasing WBC/spleen size
  5) Clonal cytogenetic evolution

Question 11

CML - Treatment

Answer 11

• Control WBC/platelet counts (hydroxyurea)
• Eradicate Ph1-positive clone
  1) Tyrosine kinase inhibitors (imatinib)
  2) Allogeneic bone marrow transplant

Question 12

Polycythemia Vera - Overview

Answer 12

• Predominant proliferation of erythrocytes
• Erythropoietin-independent proliferation
• Increased red cell mass (HGB > 18.5 g/dl in men and >
  16.5 g/dl in women)
• JAK2 mutation
• Normal arterial oxygen saturation (no secondary
  cause for polycythemia)

Question 13

Causes of Polycythemia

Answer 13

• Spurious (dehydration, Gaisbock syndrome)
• Primary (polycythemia vera)
• Secondary
  1) Hypoxia (lung disease, altitude)
  2) Tumors (renal cell carcinoma)
  3) Renal disease
  4) Other causes

Question 14

PV - Clinical

Answer 14

• Insidious onset (mean age 60)
• Symptoms secondary to hyperviscosity (headache,
  dizziness, visual disturbances)
• Splenomegaly (left upper quadrant pain)
• Bleeding or thrombotic (DVT, acute MI, stroke)
  complications
• Ruddy complexion, brownish pigmentation

Question 15

Polycythemia vera - Morphology

Answer 15

• Hypercellular marrow with panmyelosis
• Full maturation (no increase in blasts)
• Mild increase in reticulin fibers
• Absent stainable bone marrow iron
• Normal erythrocyte morphology
• Leukocytosis, thrombocytosis

Question 16

Polycythemia vera – Clinical Course

Answer 16

• Median survival 13 years
• Sustained polycythemic phase
• Spent phase (10%) - progressive marrow failure
• Myelofibrosis (10%)
• Acute leukemia transformation (5-10%)

Question 17

polycythemia vera - treatment

Answer 17

• Decrease blood viscosity (phlebotomy)
• Decrease bone marrow proliferation (hydroxyurea)
• Do not use antiplatelet agents (platelets are often
  dysfunctional), ? low-dose aspirin
• Ruxolitinib (JAK1/JAK2 inhibitor)
• Myelofibrosis or leukemic transformation associated with short survival

Question 18

Essential Thrombocythemia - Overview

Answer 18

• Predominant proliferation of megakaryocytes
  (platelets)
• Sustained elevation (> six months) of platelet count
  (> 600,000/ml)
• JAK2 mutation (50% of patients)
• No secondary cause of thrombocytosis

Question 19

Causes of Thrombocytosis

Answer 19

• Primary (essential thrombocythemia)
• Secondary
  1) Iron deficiency (chronic blood loss)
  2) Chronic inflammation/infection
  3) Asplenia, post-splenectomy
  4) Malignancy
  5) Myelodysplasia - del(5q)

Question 20

essential thrombocythemia - Clinical

Answer 20

• Bimodal incidence (age 55 and age 30)
• “Incidental” finding on routine blood work
• Symptoms related to abnormal platelet function in
  20-40% (mucosal bleeding, vascular occlusion - stroke,
  digital ischemia)
• Splenomegaly (50%)

Question 21

essential thrombocythemia - morphology

Answer 21

• Increased marrow cellularity with megakaryocytic
  hyperplasia
• No significant marrow fibrosis
• Stainable bone marrow iron (unless iron deficiency
  secondary to bleeding)
• Abnormal platelet morphology

Question 22

essential thrombocythemia - clinical course

Answer 22

• Median survival 10-15 years (longer for younger
  women)
• Occasional life-threatening thrombotic or
  hemorrhagic episode
• May develop fibrosis late in disease
• 5% transform to acute leukemia (secondary to
  therapy)

Question 23

essential thrombocythemia - treatment

Answer 23

• Decrease platelet count (hydroxyurea)
• Anti-platelet agents (anagrelide)
• Plateletpheresis (acute life-threatening hemostatic
  problems)

Question 24

Primary Myelofibrosis - Overview

Answer 24

• Predominant proliferation of megakaryocytes and
  granulocytes in marrow
• Progressive marrow fibrosis (reticulin, collagen)
  secondary to fibroblast growth factors secreted by
  neoplastic cells
• Extramedullary hematopoiesis (spleen, liver, lymph
  nodes)

Question 25

primary myelofibrosis - clinical

Answer 25

• Peak incidence in 7th decade
• May be asymptomatic (30%)
• Non-specific symptoms (weakness, fatigue, weight
  loss)
• Symptoms related to hypersplenism (left upper
  quadrant discomfort, early satiety)
• Symptoms related to cytopenias

Question 26

primary myelofibrosis - morphology

Answer 26

• Hypercellular marrow with increased, atypical
  megakaryocytes (early)
• Increased reticulin fibers with eventual collagen
  fibrosis and persistence of clustered atypical
  megakaryocytes
• Osteosclerosis (thickened bone trabeculae)
• Splenic extramedullary hematopoiesis with infarcts

Question 27

primary myelofibrosis - morphology (continued)

Answer 27

• Leukoerythroblastosis (circulating immature
  granulocytes and nucleated red blood cells)
• Anisopoikilocytosis with teardrop cells
• Abnormal platelets with occasional circulating
  megakaryocytes

Question 28

primary myelofibrosis - clinical course

Answer 28

• Median survival 3-5 years
• Causes of death include infection, hemorrhage,
  thromboembolic events, portal hypertension, heart
  failure
• Transformation to acute leukemia (5-10%)

Question 29

primary myelofibrosis - treatment

Answer 29

• Symptomatic therapy (hydroxyurea, less well
  tolerated than other MPDs)
• Transfusion support
• Splenectomy
• Ruxolitinib (JAK1/JAK2 inhibitor)
• Allogeneic bone marrow transplant (younger patients)