Stem Cell Disorders

Question 1

Aplastic Anemia

Overview

Answer 1

• A relatively uncommon disease
• Due to injury/destruction of the pluripotent stem cell
• Affects all subsequent cell populations ⇒ pancytopenia

Question 2

Aplastic Anemia

Etiologies

Answer 2

• 50% of cases have no identifiable cause
• Congenital
  
  • Fanconi’s anemia
• Immune
  
  • Ab that ⊗ hematopoiesis
• Drugs/Toxins
  
  • Predictable dose-related → idiosyncratic (unpredictable)
  • Usu. improves w/ withdrawal of the agent
  • Ex: chemotherapy, immunosuppressant drugs, XRT acute exposure – industrial accident benzene, gold, NSAIDS, neuroleptics
  • Chloramphenicol ⇒ both reversible dose-related and idiosyncratic rxns
    
    • Idiosyncratic rxn is irreversible and fatal
    • Occurs in 1 in 50K people who take the drug
• Viral
  
  • Hepatitis ⇒ usu. hep C; EBV
• Thymoma
• Pregnancy

Question 3

Fanconi’s Anemia

Answer 3

AR trait

Associated with:

• Hypoplasia or other abnormalities of the kidneys
• Hyperpigmentation of the skin
• Hypoplastic or absent thumbs and radii
• High risk of developing acute leukemia

Question 4

Aplastic Anemia

Clinical Manifestations

Answer 4

• Weakness, fatigue, high output failure
• Infection
• Bleeding

Question 5

Aplastic Anemia

Diagnosis

Answer 5

• Ultimately rests in the bone marrow interpretation
  
  • Must distinguish from hypoplastic myelodysplasia
• Peripheral blood – pancytopenia
• Bone marrow –aplasia; replaced w/ fat

Question 6

Aplastic Anemia

Treatment

Answer 6

• Supportive care
• Transfusions
• Abx
• Immunosuppressant agents
  
  • ATG; cyclosporine
  • 50% of pts respond
• Bone marrow transplant

Question 7

Pure Red Cell Aplasia

Answer 7

• Selective failure of the red cell precursors
• Other cellular elements are normal
• Associated w/ Parvo B19 infection

Question 8

Myelophthisic Anemia

Answer 8

• Infiltration of the bone marrow by tumor, fibrosis, granuloma
  
  • Most common malignancies ⇒ breast, prostate, lung, thyroid
• Thrombopoiesis is impaired but usu. not neutrophil production
  
  • Often see a left shift
• Severe normochromic, normocytic anemia w/ teardrop cells and nucleated red blood cells
• Bone marrow biopsy is diagnostic
• Treat the underlying disorder

Question 9

Myelodysplastic Syndromes (MDS)

Overview

Answer 9

• Clonal disorder in which the exact mechanism remains undefined
• Ineffective hematopoiesis ⇒ peripheral cytopenias and hypercellular marrow
• Chromosomal abnormalities seen in 50-60% of cases
• Complex cytogenetics
• Associated w/ rapid progression to acute leukemia

Question 10

Myelodysplastic Syndromes (MDS)

Secondary Causes

Answer 10

• Alkylating agents:
  
  • Cytoxan
  • Mustine
  • Nitrosureas
  • Procarbazine
  • Melphalan
  • Benzene
  • Insecticides
  • Pesticides
• Typically occur 2-3 years after exposure
• If d/t chemotherapy, can be up to 5-7 years

Question 11

Myelodysplastic Syndromes (MDS)

Clinical Manifestations

Answer 11

• Anemia: Pallor
• Thrombocytopenia: Bleeding
  
  • 60% of pts have thrombocytopenia
• Leukopenia: Fever, infection
  
  • 60% of pts neutropenic and cannot mount an inflammatory response to infection
  • Qualitative abnormality in neutrophils
• 10% of pts present initially w/ infection
• Cause of death in 21% of pts

Question 12

Myelodysplastic Syndromes (MDS)

Pathology

Answer 12

• Peripheral Blood ⇒ Macrocytic anemia (↑MCV)
  
  • Multinucleated primitive RBCs
  • Abnormal neutrophils
  • Hypolobulated PMNs ⇒ Pelger-Huet anomaly
  • Agranular PMNs
  • Abnormally large platelets
• Bone Marrow ⇒ Hypercellular
  
  • ↑ Cells in intermediate stages of maturation: ringed sideroblasts, micromegakaryocytes, multinucleated normoblasts
  • ↑ Iron stores

Question 13

Myelodysplastic Syndromes (MDS)

FAB Classification

Answer 13

• Refractory Anemia (RA) ⇒ < 5% blasts in marrow
• Refractory Anemia w/ Ringed Sideroblasts (RARS) ⇒ 15% sideroblasts in iron stains of the marrow
• Refractory Anemia w/ Excessive Blasts (RAEB) ⇒ Blasts of 5% to < 20%
• Refractory Anemia w/ Excessive Blasts in Transformation (RAEB-T) ⇒ > 20% blasts (now defined as acute leukemia)

Question 14

Chronic Myelomonocytic Leukemia (CMML)

Answer 14

• Peripheral monocytosis > 1,000/ul accompanied by other lineage cytopenia
• Peripheral blasts < 5%
• Dysplastic ∆ in the marrow
• Often see pleural/pericardial effusions from 3^rd spacing of fluids
• ± Hepatosplenomegaly
• Some feel that it belongs to the myeloproliferative disorders

Question 15

Myelodysplastic Syndromes (MDS)

Chromosomal Abnormalities

Answer 15

Most common:

• Trisomy 8, 5q
• Monosomy 7
• Complex (> 3)

Question 16

Myelodysplastic Syndromes (MDS)

Treatment

Answer 16

• Supportive Care
• Aggressive Chemotherapy ⇒ anti-leukemia drugs
• Experimental ⇒ monoclonal Ab, Arsenic
• Hypomethylating agents ⇒ help ∆ of marrow and ⊕ nl hematopoiesis
• Bone Marrow Transplant

Question 17

Myeloproliferative Neoplasms

(MPN)

Answer 17

• Neoplasms of the multipotent stem cell
• Diseases share features and overlap
• Often have cytogenetic abnormalities ⇒ can progress to acute leukemia
• Except CML, diseases run a chronic course over many years
• 4 main types are:
  
  • Polycythemia Vera
  • Essential thrombocytosis
  • Agnogenic Myeloid Metaplasia
    (also known as Primary Myelofibrosis)
  • Chronic Myelogenous Leukemia (CML)

Question 18

Polycythemia Vera

Answer 18

• Clonal disorder involving the hematopoietic stem cell
• Leads to autonomous proliferation of erythroid, myeloid, and megakaryocytic cell lines w/ red cells predominating
• Males > females
• Occurs in middle life
  
  • Average age @ dx is 60-65 years
• Must be distinguished from secondary polycythemia

Question 19

Secondary Polycythemia

Answer 19

Caused by ↑ erythropoietin

• Physiologic Secondary Polycythemia
  
  • High altitude
  • Right to left shunts
  • Chronic lung disease
  • Hemoglobin – oxygen dissociation abnormalities
• Pathologic Secondary Polycythemia
  
  • Kidney cysts or renal transplant
  • Neoplasms ⇒ renal cell, hepatoma, pheochromocytoma
  • Adrenal cortical hypersecretion
  • Exogenous androgens

Question 20

Polycythemia Vera

Criteria

Answer 20

• Category A:
  
  • Total RBC mass > 36 mg/kg (Male) / > 32 mg/kg (Female)
  • Arterial oxygen saturation > 92%
  • Splenomegaly
• Category B:
  
  • Thrombocytosis (> 400K)
  • Leukocytosis (> 12K)
  • ↑ LAP (leukocyte alkaline phosphatase) score
  • Serum B12 > 900 pg/ml or B12 binding capacity > 2200pg/ml
  • Polycythemia Vera dx is established by presence of certain combinations of these criteria

Question 21

Polycythemia Vera

Clinical Manifestations

Answer 21

• Ineffective hematopoiesis ⇒ anemia:
  
  • Fatigue
  • Pruritus (likely from hyper-catabolism)
  • Night sweats
  • Bone pain
  • Fever
  • Weight loss
• Sx that reflect ↑ plasma viscosity:
  
  • Headaches
  • Dizziness
  • Blurred vision
  • Chest pain
  • Thrombosis
  • Bleeding
• Extramedullary hematopoiesis ⇒ splenomegaly
• Consider PV in people who develop unprovoked thrombo-embolic event and in unusual sites such as dural sinuses

Question 22

Polycythemia Vera

Prognosis

Answer 22

• Without therapy, median survival is 2 years
• W/ phlebotomy alone, survival is 10-12 years
• 10% have progressive fibrosis and anemia ⇒ spent phase

Question 23

Polycythemia Vera

Complications

Answer 23

• Clonal Evolution
  
  • Can transform to MDS and/or AML
  • 10% risk w/ PV at 10 years of follow-up
  • Highest w/ CML (90%)
  • Lowest w/ Essential Thrombocytosis (5%)
• Bleeding
  
  • Usu. mild and occurs at high platelet counts
• Thrombosis
  
  • Arterial and venous thrombosis
  • Microcirculatory d/o like erythromelagia (episodes of pain, redness, and swelling in various parts of the body)

Question 24

Polycythemia Vera

Treatment

Answer 24

• Mild symptoms ⇒ phlebotomy
• More significant sx ⇒ myelo-suppressant agents (Busulfan)
• Goal of tx is to achieve a nl HCT

Question 25

Essential Thrombocytosis Overview

Answer 25

* Clonal disorder of the hematpoietic stem cell * **Leads to autonomous proliferation of all cell lines w/ platelets predominating** * Platelet count can be as high as 3 to 4 million * An overproduction of platelets in the absence of stimulus * Must rule out reactive thrombocytosis which can be caused by: * Inflammation, Bleeding, Iron deficiency, Hemolysis, Malignancy, Post-splenectomy * **Usu. occurs in age \> 60 years**

Question 26

Essential Thrombocytosis Clinical Manifestations

Answer 26

Sx are linked to platelet dysfunction and aggregation in the microvasculature: * **Thrombosis** * **Bleeding** * **Headaches** * **Amaurosis fugax** (blindness due to a lack of blood flow) * **Pruritis** * **Claudication** * **Early satiety** 2/2 hepatomegaly and/or splenomegaly

Question 27

Essential Thrombocytosis Laboratory Findings

Answer 27

* Laboratory Findings * **Sustained platelet count \> 450K** * Peripheral blood: **platelets of different morphologies** * Large platelets * Hypogranular platelets * **Abnormal platelet aggregation studies**

Question 28

Essential Thrombocytosis Course and Prognosis

Answer 28

* Median survival better than PV * \< 10% transform to acute leukemia * Death due to hemorrhage or fatal thrombosis

Question 29

Essential Thrombocytosis Treatment

Answer 29

* **Plateletpheresis** ⇒ used to emergently drop the platelet count * More significant sx ⇒ **add myelosuppressant agent** * Busulfan, Hydroxyurea, Agrylin * Goal platelet count 300K – 400K

Question 30

Agnogenic Myeloid Metaplasia Overview

Answer 30

**“Primary Myelofibrosis”** Characterized by: * **Progressive fibrosis of the bone marrow** * **↑ Proliferation of granulocytes and platelets** * Development of **extramedullary hematopoiesis** * Usu. occurs in **age \> 60 years**

Question 31

Agnogenic Myeloid Metaplasia “Primary Myelofibrosis” Differential Diagnosis

Answer 31

* Metastatic cancer to the bone * Infections and granulomas * Hairy cell leukemia

Question 32

Agnogenic Myeloid Metaplasia “Primary Myelofibrosis” Clinical Manifestations

Answer 32

* Early satiety and weight loss * Massive spleen * Abdominal pain * Anemia * Bone pain

Question 33

Agnogenic Myeloid Metaplasia “Primary Myelofibrosis” Pathology

Answer 33

* _Peripheral Blood:_ * **Anemia w/ pancytopenia** * **Tear drop cells** * Abnormal large platelets * Presence of precursor WBCs and nucleated RBCs * _Bone Marrow:_ * **“Dry tap”** ⇒ difficult to aspirate * ↑ megakaryocytes * **\> ⅓ myelofibrosis w/ ↑ reticulin + collagen** * **Extramedullary hematopoiesis** ⇒ spleen, kidneys, liver, lungs, adrenal glands

Question 34

Agnogenic Myeloid Metaplasia “Primary Myelofibrosis” Diagnosis

Answer 34

**Via bone marrow biopsy ⇒ see fibrosis and osteosclerosis** Megakaryocytes release platelet derived growth factor (PDGF) ⇒ ⊕ fibroblasts ⇒ fibrosis

Question 35

Agnogenic Myeloid Metaplasia “Primary Myelofibrosis” Course and Prognosis

Answer 35

* **Usu. asymptomatic for the first 1- 2 years** * Median survival 5 years * Some may live up to 15 years * Those w/ platelet counts \< 100K and hemoglobin \< 10 g have a worse prognosis * **Death due to infection, CHF, bleeding, portal HTN**

Question 36

Agnogenic Myeloid Metaplasia “Primary Myelofibrosis” Treatment

Answer 36

* **Supportive care** * **Chemotherapy** * **Splenectomy** ⇒ for severe cytopenias or severe sx * **Bone Marrow Transplant** ⇒ may reverse fibrosis

Question 37

Chronic Myelogenous Leukemia (CML) Overview

Answer 37

* **Myeloproliferative disorder** * **↑ proliferation of granulocytes w/o loss of their capacity to differentiate** * Dx is often made incidentally on routine CBC * CML encompasses **15-20% of adult leukemias** * Seen mainly in **ages 25-60 years** * Usu. there are no predisposing factors in pts presenting w/ the disease * ↑ incidence seen in persons exposed to atomic bombs in Hiroshima and Nagasaki * ↑ incidence seen in pts who had radiation for Ankylosing Spondylitis or cervical cancer

Question 38

Chronic Myelogenous Leukemia (CML) Chromosomal Abnormalities

Answer 38

* **The Philadelphia Chromosome** * Translocation b/t chromosomes 9 and 22 * c-abl oncogene from chromosome 9 → bcr breakpoint on chromosome 22 * Aberrant **bcr/abl** transcript ⇒ **tyrosine kinase gene product w/ enhanced activity** * ⊕ Cell division much greater than normal c-abl gene product * ⊗ Apoptosis * Unregulated myeloproliferation * **JAK2** * Located on short arm of chromosome 9 * Mutations ⇒ constitutive tyrosine kinase phosphorylation activity ⇒ **hypersensitivity to cytokines** * **Most abundant in RBCs and myeloid cells** * Dysregulated TK activity ⇒ possible tx approaches such as in CML

Question 39

Chronic Myelogenous Leukemia (CML) Pathology

Answer 39

* _Peripheral Blood:_ * **↑ in granulocytes** w/ presence of immature or intermediate stage cells of myeloid series * **± ↑ Basophils** * **↑ Platelets** * **↓ (zero) in LAP score** * _Bone Marrow:_ * **Hypercellular w/ ↑ in myeloid elements**

Question 40

Chronic Myelogenous Leukemia (CML) Clinical Course

Answer 40

* **_Chronic Phase_** * Most pts are asymptomatic * **Peripheral blood leukocytosis \> 25K**, can be up to 300K * Mild splenomegaly and anemia * Thrombocytosis * Lasts 2-3 years * **_Accelerated Phase_** * Usu. 3-4 years after presentation * **↑ Resistance to therapy** * **↑ Marrow and peripheral blasts** * Splenomegaly despite therapy * ± Extramedullary disease * Cytogenetic evolution * Median survival 8-18 months * **_Blast Crisis (Acute leukemia)_** * Develops in 75-85% of pts * **Can be AML or ALL** * Survival 3-6 months * **20% blasts or blasts + promyelocytes in blood/marrow** * Constitutional sx (fever, sweats) * Infection * Anemia * Thrombocytopenia * Extramedullary disease

Question 41

Chronic Myelogenous Leukemia (CML) Treatment

Answer 41

* **Hydroxyurea** * Still occassionally used until dx established ⇒ ↓WBCs while awaiting genetics * **Interferon-α** * Hematologic control in 70-80% * **Imatimib (Gleevac) STI571** * ⊗ ATP receptor preventing phosphorylation * Tyrosine kinase gene product cannot be made * **Bone Marrow Transplant** should be performed within one year of dx for best results