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Heme > Myelodysplastic Syndromes > Flashcards

Myelodysplastic Syndromes Flashcards

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.

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

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

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

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

A
  • Hyperviscosity
  • Hypervolemia
  • Hypermetabolism
24
Q

Polycythemia Vera: symptoms & signs

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
Q

Polycythemia Vera: disease course

A
  • 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
Q

Polycythemia Vera: treatment

A

Reduce hematocrit

• Phlebotomy: goal <400/μl

27
Q

Polycythemia Vera: prognosis

A
  • Long natural history

* Years to decades = slow growing

28
Q

Essential Thrombocythemia: description

A

Increased platelet count (>600,000/μl)

• Often also leukocytosis, but hematocrit is not increased

29
Q

Essential Thrombocythemia: causes

A
  • Clonal stem cell disorder

* JAK2, CaIR, MPL gene mutations

30
Q

Essential Thrombocythemia: clinical features

A
  • Most = asymptomatic
  • Abnormal clotting or bleeding
  • Erythromelalgia (burning in hands and feet)
31
Q

Essential Thrombocythemia vs. Secondary thrombocytosis

A 
Secondary thrombocytosis due to:
•	Iron deficiency 
•	Chronic infections/inflammation 
•	Acute hemorrhage
•	Malignancy 
•	Connective tissue diseases (ex: rheumatoid arthritis)
•	Post-splenectomy
32
Q

Essential Thrombocythemia: treatment

A

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
Q

Essential Thrombocythemia: prognosis

A
  • Long natural history (years to decades)

* Increased risk of developing marrow fibrosis and AML

34
Q

Myelofibrosis: description

A

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
Q

Myelofibrosis: clinical presentation

A
  • Often with massive splenomegaly
  • Early = Anemia, elevated WBC and platelets
  • Late = Anemia, lower WBC and platelets due to marrow failure and splenomegaly
36
Q

Myelofibrosis: pathology

A

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
Q

Myelofibrosis: treatment

A

Palliative

Control spleen size
• Ruxolitinib (to inhibit JAK2), hydroxyurea, radiation, surgery

Control inflammatory symptoms
• Ruxolitinib

Cure
• Hematopoietic cell transplantation

38
Q

Myelofibrosis: prognosis

A
  • Worst prognosis of the 3 MPDs

* Median survival 3.5 years

39
Q

Describe the role of the JAK2 mutation in the pathophysiology of the chronic myeloproliferative disorders.

A

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
Q

Define “myelodysplasia.”

A

• 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
Q

Myelodysplastic syndromes: Epidemiology

A

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
Q

Myelodysplastic syndromes: clinical presentation

A

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
Q

Myelodysplastic syndromes: pathology

A

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
Q

Myelodysplastic syndromes: prognosis

A

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
Q

Myelodysplastic syndromes: treatment

A

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)

Heme (15 decks)

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