13 - Stem Cell Disorders

Question 1

Hematopoietic Stem Cells

Answer 1

• Multipotential
• Capable of self-renewal
• Capable of differentiation
• Give rise to all normal hematopoietic cells

Question 2

Stem Cell Disorders

Answer 2

• Cell line(s) involved reflect the level of the stem cell
  defect
• May be clonal or not
• Most are acquired, but occasionally congenital

Question 3

Stem cell disorder classification

Answer 3

• Aplastic Anemia (bone marrow failure)
• Paroxysmal Nocturnal Hemoglobinuria
• Myelodysplastic Syndromes
• Chronic Myeloproliferative Disorders
• Acute Leukemias

Question 4

Aplastic Anemia - Pathophysiology

Stem cell disorders

Answer 4

• Quantitative or qualitative abnormality of pluripotent
  stem cells
• Immunologic suppression of hematopoiesis
• Abnormalities in the hematopoietic microenvironment
• Abnormalities in humoral or cellular control of cell
  proliferation or cell death.

Question 5

Aplastic Anemia - Pathophysiology - Causes

Stem cell disorders

Answer 5

• Immune-mediated injury - idiosyncratic, dose-
  independent (most common mechanism)
• idiopathic cases (most common), certain drugs
  (e.g. chloramphenicol, sulfa drugs), viral infections
• Toxic injury - predictable, dose-dependent
  (chemotherapeutic drugs, ionizing radiation,
  benzene)

Question 6

Aplastic Anemia - Clinical Presentation

Stem cell disorders

Answer 6

• Median age of onset – 25 years
• Symptoms and physical related to cytopenias
  1) Weakness, fatigue (anemia)
  2) Infections (neutropenia)
  3) Bleeding (thrombocytopenia)
  4) No organomegaly
• Increased marrow fat may be detected by imaging
  studies

Question 7

Fanconi Anemia

Stem cell disorders

Answer 7

• Congenital form of aplastic anemia
• Most forms autosomal recessive
• Fanconi Anemia Complementation genes
• Patients often present in first decade of life
• Chromosomal instability with exposure to alkylating
  agents or radiation (increased risk of malignancies)
• Dysmorphic features (skeletal, skin, renal)

Question 8

Aplastic Anemia – Diagnostic Criteria

Stem cell disorders

Answer 8

• Hypocellular bone marrow (<25%)
• Peripheral pancytopenia
  1) absolute neutrophils:
• severe <500/μl
• very severe: <200/μl
  2) platelet count: <20,000/μl
  3) anemia with low reticulocytes: <40,000/μl

Question 9

Aplastic Anemia - Morphology

Answer 9

• Bone marrow hypocellularity (often <5%)
• Absence of normal maturing hematopoietic elements
• Pancytopenia
• Often macrocytic red cells
• Increased fetal hemoglobin levels
• Elevated erythropoietin levels

Question 10

Aplastic Anemia - Therapy

Stem cell disorders

Answer 10

• Removal of suspected
  etiologic factors
• Supportive care
• packed RBCs
• platelets
• antibiotics
• Restore hematopoiesis
• Immunotherapy with
  Anti-thymocyte globulin
  (ATG), cyclosporin
• Stem cell transplant

Question 11

Aplastic Anemia - Prognosis

Answer 11

• Untreated - 20% survival at 1 year
• Supportive care results in 25% survival at 2 years
• Immunosuppression results in 50-70% survival at 5
  years
• > 85% long term survival for young patients with HLA-
  matched donor

Question 12

Aplastic Anemia – Clinical Course

Answer 12

• Patients die from complications related to cytopenias
  or definitive therapy (graft versus host disease,
  infections)
• Some patients evolve into clonal disorders
  (paroxysmal nocturnal hemoglobinuria,
  myelodysplasia, acute myeloid leukemia)

Question 13

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Stem cell disorders

Answer 13

• Acquired clonal multipotential stem cell disorder
• Impaired production of all non-lymphoid
  hematopoietic cells (pancytopenia)
• Increased susceptibility to complement (intravascular
  hemolytic anemia with hemoglobinuria)

Question 14

Paroxysmal Nocturnal Hemoglobinuria (PNH) - Pathophysiology

Answer 14

• Mutation in PIG-A gene (phosphatidyl inositol glycan
  class A)
• Absence of glycosyl phosphatidylinositol (GPI) in cell
  membranes
• Loss of additional GPI-anchored proteins (CD55, CD59
• degrade complement)
• May arise from aplastic anemia (escape from T cell
  immunosuppression)

Question 15

Paroxysmal Nocturnal Hemoglobinuria (PNH) - Clinical Presentation

Answer 15

• Complement-mediated intravascular hemolysis
• Anemia
• Hemoglobinuria
• Iron deficiency
• Complement-mediated destruction of stem cells
• Pancytopenia
• Neutropenia and infection
• Platelet-activation and clotting
• Venous thrombosis (e.g. Budd-Chiari syndrome)

Question 16

Paroxysmal Nocturnal Hemoglobinuria (PNH) - Laboratory Findings

Answer 16

• Hemolytic anemia (reticulocytosis, decreased
  haptoglobin, increased LD, hemoglobinuria)
• May become iron deficient over time
• Granulocytopenia, thrombocytopenia
• Flow cytometry (diagnostic)
• Sucrose hemolysis, acid hemolysis

Question 17

Paroxysmal Nocturnal Hemoglobinuria (PNH) - Treatment

Answer 17

• Transfusion as necessary, iron replacement (if
  deficient)
• Anticoagulation for thrombosis (major cause of death)
• Eculizumab (anti-C5 humanized monoclonal antibody)
• Stem cell transplant (severe cases)

Question 18

Myelodysplastic Syndromes (MDS)

Stem cell disorders

Answer 18

• Group of acquired clonal multipotential stem cell
  disorders
• Ineffective hematopoiesis (similar to megaloblastic
  anemia, but secondary to abnormal stem cell)
• Blood cytopenias

Question 19

Myelodysplastic Syndromes (MDS) - Etiology/Pathophysiology

Answer 19

• Most cases are idiopathic
• May be secondary to previous chemical exposure
  (pesticides, benzene) or chemotherapy (alkylating
  agents)
• Clonally abnormal stem cell, which is incapable of
  proper maturation (increased apoptosis)
• All non-lymphoid cell lines may be affected

Question 20

MDS – Epidemiology

Answer 20

• 15,000 new cases/year in US (adults)
• Median age > 70 (incidence increases with age)
• Greater incidence in males than females
• More common than AML
• Median survival 1-3 years

Question 21

MDS - Classification

Answer 21

• Number of cell lines involved (by dysplasia)
• Ringed sideroblasts
• Number of blasts (<20%)
• Chromosomal abnormalities (5q-)
• Previous therapy

Question 22

MDS – Blood Morphology

Answer 22

• Pancytopenia
• Macrocytic red cells
• Dimorphic red cell population
• No reticulocytosis
• Dysplastic morphology
• Cytogenetic findings: del(5q)/-5, del(7q)/-7, +8,
  complex karyotype

Question 23

MDS – Bone Marrow Morphology

Answer 23

• Hypercellular bone marrow
• Maturation abnormalities
  Erythroid - hyperplasia, megaloblastoid features,
  binucleation, dysplastic nuclei, ringed sideroblasts

Myeloid - hypogranularity, pseudo Pelger-Huet
anomaly, increased blasts

Megakaryocytic - mononuclear, dwarf, abnormal
nuclei

Question 24

MDS – Prognosis Scoring

Answer 24

• Consensus based on International MDS Risk Analysis
  Workshop
• Effort to better predict outcome
• Scoring based on the following
• Cytogenetics
• % bone marrow blasts
• Number and degree of cell lines affected
• Transformation to acute leukemia (20-40%)

Question 25

MDS - Treatment

Answer 25

• Supportive therapy – transfusions, antibiotics, growth
  factors
• Non-curative goals - decrease bone marrow blasts,
  transfusion requirements, infections
• Lower score (5q-) - lenalinomide (40-80% response)
• Higher score – azacytadine (20- 40% response),
  delay in transformation to acute leukemia
• Bone marrow transplant – 40% cure (most patients not
  eligible), high transplant mortality (age >55)