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Myelodysplastic Syndromes Flashcards

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1
Q

Acute Leukemia: Etiology

A

Factors:
Clonal diseases = derived from a single, genetically aberrant cell that continues to change
• Critical genes are ones controlling proliferation, differentiation, epigenetic regulation

Host factors
• Increase susceptibility to accumulate genetic injury (Ex: Fanconi’s anemia)

Environment: drugs, chemicals, radiation, chemotherapy
• Ex: benzene in petroleum products and industrial solvents

Time (age): allows accumulation of events

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2
Q

Acute Leukemia: types

A

Normally = proliferation and differentiation
• If proliferation without differentiation → more undifferentiated cells (blasts) without “expiration” date → pancytopenia

Ex:
• Acute Myeloid Leukemia (AML) = accumulation of myeloid blasts
• Acute Lymphoblastic Leukemia (ALL) = accumulation of lymphoid blasts

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3
Q

Acute Leukemia: clinical features

A

Bone marrow failure
• Anemia → pallor, fatigue, dyspnea
• Neutropenia → fever, infections
• Thrombocytopenia → bruises, bleeding

Organ infiltration
• Bone pain, lymphadenopathy, meningeal signs (CNS problems) & intracerebral bleeding, testicular swelling, skin rash, pulmonary infiltrates

Emergencies:
• Coagulopathy (acute promyelocytic leukemia)
• Tumor lysis syndrome
• Hypercalcemia
• Neutropenic sepsis (susceptible to infections)
• Leukostasis (large dysfunctional cells clog small vessels)
• Pulmonary failure
• Severe pancytopenia

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4
Q

Acute Myeloid Leukemia (AML): Epidemiology

A
  • More common as people age (median age 67)

* 50% more common in men

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5
Q

Acute Myeloid Leukemia (AML): pathology

A
  • Auer rods = aggregates of myeloperoxidase-containing granules
  • Cell surface markers: CD13, CD33
  • Immunohistochemistry = express myeloperoxidase
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6
Q

Acute Myeloid Leukemia (AML): molecular pathophysiology

A

Ex: translocation between Chromosomes 8 and 21 [t(8;21)]
• “Core-binding factor (CBF)” leukemia
• Normally = TF’s CBFα and CBFβ bind → attract transcriptional activators → gene transcription (IL-3, GM-CSF, M-CSF) → neutrophil maturation
• With translocation = CBFα onto ETO gene on chromosome 8 → transcription of hybrid CBFα-ETO mRNA → chimeric TF → attracts repressor proteins → blocked myeloid differentiation
• Result: cell division and proliferation but no neutrophil maturation

Ex: Acute Promyelocytic Leukemia (APML)
• Translocation putting retinoic acid receptor alpha on chromosome 17 → PML gene on chromosome 15 [t(15;17)]
• Associated with severe DIC
• Favorable prognosis = responds to treatment with all trans retinoic acid → induces leukemic cell differentiation → remission

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7
Q

Acute Lymphoblastic Leukemia (ALL): epidemiology

A

• Childhood disease (median age 13)

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8
Q

Acute Lymphoblastic Leukemia (ALL): pathology

A 
Cell surface markers: 
•	B cell ALL = CD19, CD22, CD10
•	T cell ALL = CD7, CD3, CD2
•	Lymphoid lineage = TdT enzyme
Molecular analysis = clonal
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9
Q

Acute Myeloid Leukemia (AML): prognosis

A

Best:
t(8;21)
inv(16;16)
t(15;17)

Intermediate:
Normal Cytogenetics
Trisomy 8

Worst:
Chromosome 5, 7
11q23 abnl
Complex

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10
Q

Acute Lymphoblastic Leukemia (ALL): prognosis

A

Best: t(12;21)
Hyperdiploid

Worst:
t(9;22)
Hypodiploid
t(4;11)

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11
Q

Cytogenetic analysis: ALL vs. AML

A

AML:
CD 13/ CD33
Auer Rods (highly specific)
Germline Immunoglobulin/TCR genes

ALL:
B-ALL = CD19, CD22, CD10, TdT
T-ALL = CD7, CD3, CD2, TdT
Clonal Immunoglobulin/TCR genes

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12
Q

Describe the principles of treatment of acute leukemia.

A 
Supportive care: 
Maintain blood counts
•	Red cell and platelet transfusions
•	Cannot reliably transfuse neutrophils (because short survival)
Treat/Prevent infections
•	Bacterial and fungal infections common due to neutropenia (ANC below 500 cells/ul)
Control Coagulopathy 
Control metabolic problems
•	Tumor lysis syndrome

Treatment
Some = curative with aggressive, high-dose and extended chemotherapy
• More success in younger rather than older
• Treatment carries significant risks
Bone marrow transplantation
• May be curative
• Indicated for high risk and relapsed diseases

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13
Q

Chronic myelogenous leukemia (CML): etiology

A

o Most cases = unknown
o Increased risk with ionizing radiation and benzene exposure
o Most patients = 25-60 years old

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14
Q

Chronic myelogenous leukemia (CML): pathophysiology

A

“Philadelphia chromosome”
• Reciprocal translocation between chromosome 9 and 22 → t(9;22)
Results: c-abl oncogene (from chromosome 9) next to bcr gene on chromosome 22
• Abl = cytoplasmic and nuclear tyrosine kinase
• Fusion of c-abl and bcr → new protein kinase that’s constitutively active

Note: t(9;22) also found in some cases of AML and ALL
o Poor prognosis

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15
Q

Chronic myelogenous leukemia (CML): pathology

A

Affects all 3 myeloid cell lines

Peripheral blood = granulocytic precursor cells in all levels of development
• Numerous eosinophils and basophils = distinguishes CML from reactive leukocytosis
• WBC count may be >300,000/μl
• Usually elevated platelets
• Hematocrit normal or low

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16
Q

Chronic myelogenous leukemia (CML): clinical features

A

Often asymptomatic → incidental diagnosis

Marked leukocytosis common:
•	Weight loss (hypermetabolic)
•	Massive splenomegaly 
•	Gout (hyperuricemia)
•	Anemia (pallor, fatigue, dyspnea)

Thrombocytosis → unusual clotting or bleeding

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17
Q

Chronic myelogenous leukemia (CML): clinical course

A

Chronic phase:
• Median 5-6 years stabilization
• Symptoms: fever, night sweats, fatigue (hypermetabolism), anorexia, abdominal pain from enlarged spleen

Accelerated phase:
• Transformation to more aggressive phase if not treated
• Median duration = 6-9 months
• Progressive block in differentiation

Blast crisis
• Disease = acute leukemia
• Median survival: 3-6 months
• Blasts replace WBCs in blood and marrow
• Can be myeloblastic (70%) or lymphoblastic (30%)
• Almost always fatal

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18
Q

Chronic myelogenous leukemia (CML): treatment

A

Imatinib mesylate = suppresses malignant clone
• Inhibits tyrosine kinase activity from fusion gene
• Reduces leukemic cell burden

Excellent survival and lower risk of developing blast crisis
o NOT a cure
HLA-matched stem cell transplantation curative

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19
Q

Be able to distinguish CML from benign causes of leukocytosis.

Study These Flashcards
A

CML:
o LAP (leukocyte alkaline phosphatase) negative
o Increased basophils
o Granulocytes with t(9;22) mutation

These features not present in reactive neutrophilic leukocytosis due to infection

20
Q

Define and list the Myeloproliferative Disorders

Study These Flashcards
A

From increased proliferation with differentiation
• Renewing stem cell with unrestrained proliferation → too many RBCs, WBCs, platelets, stroma

Ex:
• Chronic Myeloid Leukemia (too many myeloid cells)
• Polycythemia Vera (too many RBCs)
• Essential Thrombocythemia (too many platelets)
• Primary Myelofibrosis (marrow replaced by fibrous tissue)

21
Q

Polycythemia Vera: Description

Study These Flashcards
A

o Increased RBC volume
o 100% cases = JAK2 V617F mutation
o Important to distinguish from Secondary polycythemia or pseudopolycythemia

22
Q

Polycythemia Vera vs. Secondary Polycythemia

Study These Flashcards
A 
Causes of Secondary Polycythemia:
Diseases stimulating physiologic EPO:
o	Chronic hypoxia
o	CO poisoning
o	R to L shunts
o	High affinity Hgb
o	High altitudes 
Diseases causing inappropriate or ectopic EPO production:
o	Renal tumors
o	Liver tumors
o	Blood vessel tumors
Exogenous EPO

Secondary polycythemia vs. Polycythemia vera:
PV: Normal SaO2; decreased EPO
Reactive polycythemia (Physiologic EPO): Decreased SaO2; increased EPO
Reactive polycythemia (Inappropriate production of EPO): Normal SaO2; increased EPO

23
Q

Polycythemia Vera: Clinical features

Study These Flashcards
A
  • Hyperviscosity
  • Hypervolemia
  • Hypermetabolism
24
Q

Polycythemia Vera: symptoms & signs

Study These Flashcards
A 
Symptoms:
•	Headache
•	Weakness
•	Pruritis (aquagenic = brought on by showering)
•	Dizziness
•	Diaphoresis
•	Visual disturbance
•	Weight loss

Signs:
•	Splenomegaly 
•	Skin plethora
•	Hepatomegaly 
•	Conjunctival plethora 
•	Systolic HT
25
Polycythemia Vera: disease course
* Increased risk of thromboembolic complications (31%): MI, stroke, deep venous thrombosis (especially portal vein thrombosis) * Progression to AML (19%) * Other cancer (15%) * Hemorrhage (6%) * Myelofibrosis (4%)
26
Polycythemia Vera: treatment
Reduce hematocrit | • Phlebotomy: goal <400/μl
27
Polycythemia Vera: prognosis
* Long natural history | * Years to decades = slow growing
28
Essential Thrombocythemia: description
Increased platelet count (>600,000/μl) | • Often also leukocytosis, but hematocrit is not increased
29
Essential Thrombocythemia: causes
* Clonal stem cell disorder | * JAK2, CaIR, MPL gene mutations
30
Essential Thrombocythemia: clinical features
* Most = asymptomatic * Abnormal clotting or bleeding * Erythromelalgia (burning in hands and feet)
31
Essential Thrombocythemia vs. Secondary thrombocytosis
``` Secondary thrombocytosis due to: • Iron deficiency • Chronic infections/inflammation • Acute hemorrhage • Malignancy • Connective tissue diseases (ex: rheumatoid arthritis) • Post-splenectomy ```
32
Essential Thrombocythemia: treatment
Evaluate risk for clotting because treatment risk may be greater than disease risk Prevent thrombosis • Reduce risk factors (smoking, HT) • Aspirin Prevent bleeding • High platelets sequester clotting factors Reduce platelet count • Hydroxyurea
33
Essential Thrombocythemia: prognosis
* Long natural history (years to decades) | * Increased risk of developing marrow fibrosis and AML
34
Myelofibrosis: description
o Fibrosis of the bone marrow often with atypical appearing megakaryocytes o Growth factors abnormally shed from clonally expanded megakaryocytes → Nonclonal fibroblastic proliferation and hyperactivity → Bone marrow fibrosis • Fibroblasts are NOT the malignant cells (just proliferate in response to abnormal growth factors from neoplastic hematopoietic stem cells) • JAK 2 V617F mutation in about 50% of cases
35
Myelofibrosis: clinical presentation
* Often with massive splenomegaly * Early = Anemia, elevated WBC and platelets * Late = Anemia, lower WBC and platelets due to marrow failure and splenomegaly
36
Myelofibrosis: pathology
Blood smear is characteristic • “Teardrop” RBC • Precursor cells (nucleated RBCs, giant platelets, megakaryocytes, neutrophil precursors) Marrow biopsy = fibrotic (staining for reticulin) • Shows dense CT and trapped megakaryocytes
37
Myelofibrosis: treatment
Palliative Control spleen size • Ruxolitinib (to inhibit JAK2), hydroxyurea, radiation, surgery Control inflammatory symptoms • Ruxolitinib Cure • Hematopoietic cell transplantation
38
Myelofibrosis: prognosis
* Worst prognosis of the 3 MPDs | * Median survival 3.5 years
39
Describe the role of the JAK2 mutation in the pathophysiology of the chronic myeloproliferative disorders.
JAK2 = on chromosome 9 o Signal transduction protein used by EPO receptor Normally = binding EPO to receptor → dimerization of receptors → JAK2 phosphorylation o Enters nucleus o Generates growth and survival signals In polycythemia vera (and others) = valine replaced by phenylalanine at position 617 (JAK2 V617F mutation) o Constitutively active → promotes RBC production • Also involved in regulating platelet and granulocyte production
40
Define “myelodysplasia.”
• Under-production of one or more cell lines in conjunction with ineffective erythropoiesis and abnormal cell differentiation o Self-renewing cells but damaged → poor proliferation and differentiation control with cell death (apoptosis) occurring = bone marrow filled with cells but being killed → pancytopenia • Ex: Myelodysplastic syndromes
41
Myelodysplastic syndromes: Epidemiology
Causes: anything interfering with normal hematopoietic cell differentiation • Ex: ionizing radiation and cytotoxic chemotherapy • MDS = long term complication of treating cancer • But most cases = unknown cause Older patients = median age 65-70 years
42
Myelodysplastic syndromes: clinical presentation
Pancytopenia (diverse presentation) • Anemia (usually macrocytic), thrombocytopenia, neutropenia Ineffective hematopoiesis • Paradox of hyper cellular marrow, but low blood counts Potential evolution to AML • For many but not all • Higher risk if have higher proportion of blast cells in marrow
43
Myelodysplastic syndromes: pathology
Pseudo Pelger-Huet cells (hypolobated neutrophils) Ring Sideroblast • Iron deposition around nucleus with Prussian blue stain • From iron accumulation in mitochondria • Indicates disordered heme synthesis Cytogenic analysis = often shows chromosome 5 or 7 abnormalities
44
Myelodysplastic syndromes: prognosis
International Prognostic Scoring System (IPSS) “Risk” (death or AML) – predicted by: 1) Proportion of blasts in the bone marrow • High blast count is bad (greater than 5%) 2) Cytogenetics • Normal is good • Loss of chromosome 7 is bad • Loss of chromosome 5 short arm (q) = long survival 3) Severity of pancytopenia • Just anemia is good • All counts down is bad
45
Myelodysplastic syndromes: treatment
High risk MDS: median survival of months • Chemotherapy • Bone marrow transplant ``` Low risk: median survival 6-8 years • Improve counts (EPO) • Quality of life • Prevent iron overload • Lenalidomide (better response if MDS due to 5q deletion) ```

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