Leukemia II Flashcards
1
Q
Chronic Lymphocytic
Leukemia/Small Cell Lymphoma
(CLL/SLL)
• Epidemiology
A
– Most common leukemia of adults in the Western World
• In contrast SLL accounts for only 4% of NHLs
– Twice as frequent in males as in females
– Typically occurs >50 yrs
2
Q
CLL/SLL
A
- Morphologically, phenotypically, and genotypically indistinguishable from small lymphocytic lymphoma (overlaps with SLL)
- Leukemia differs from lymphoma:
– In the degree of peripheral blood lymphocytosis - Most cases are of B cell origin
3
Q
CLL/SLL
A
• If the peripheral blood lymphocyte count exceeds 5,000 cells/μL
– Diagnosed with CLL
4
Q
CLL/SLL: Immunophenotype and
Genetics
A
- Express pan B cell markers
– CD19, CD20, and CD 23 - CD5, a T cell marker
- Low level Sig
- A small monoclonal Ig “spike” is present in the blood of some patients
- Most common chromosomal abnormalities
– Trisomy 12q, deletions of chromosomes 11q, 13q14, and 17p - Chromosomal translocation are rare
5
Q
CLL/SLL: Morphology
A
- Small round lymphocytes with scant cytoplasm with round to slightly irregular nuclei
- Smudge cells
- Diffuse effacement of lymph node architecture
- Bone marrow is almost always involved
6
Q
CLL/SLL: Laboratory
A
• WBC: usually elevated – lymphocytosis • Hypogammaglobulinemia • Increased susceptibility to infection • May have autoantibodies to RBC or platelets – Coombs test may be positive
7
Q
CLL/SLL: Clinical Presentation
• Often asymptomatic
A
- Symptoms, when present are often nonspecific
– Fatigue, weight loss, and anorexia - Generalized lymphadenopathy and hepatosplenomegaly
- Course and prognosis depend on stage
8
Q
CLL/SLL: Prognosis
• Median survival time ~4 to 6 years
A
• Prognosis correlates with size of the total lymphocyte pool and the presence of anemia or thrombocytopenia
• Trisomy 12 and deletions of 11q or 17p23
—worse prognosis
• CD38—worse prognosis
9
Q
CLL: Prognosis
A
- May transform to a more aggressive lymphocytic neoplasm
* Prolymphocytic transformation (most commonly) or Richter Syndrome
10
Q
CLL: Prognosis
A
- Due to hypogammaglobulinemia, increased incidence of bacterial infections
- Infection is a common cause of death
11
Q
Prolymphocytic Transformation
A
• Occurs in 15 – 30% of patients with CLL/SLL • Marked elevation of lymphocyte count – 10 – 50% prolymphocytes • Increased splenomegaly • Poor response to therapy • Less than 1 year survival
12
Q
CLL: Richter Syndrome
A
- Diffuse large B cell lymphoma
• Seen in ~10% of patients
• Rapid onset of fever, abdominal pain - Progressive lymphadenopathy
• Poor response to therapy
• Survival less than 1 year
13
Q
Chronic Lymphocytic Disorders
A
Chronic Lymphocytic Leukemia
Hairy Cell Leukemia
14
Q
Hairy Cell Leukemia
• Rare disorder
A
• middle age males
- M:F =4:1
- Caucasians
• ~2% of all leukemias
15
Q
Hairy Cell Leukemia:
Pathogenesis
A
• ~90% have activating point mutations in the serine/threonine kinase BRAF
– Positioned immediately downstream from RAS in the MAP kinase signaling cascade
16
Q
Hairy Cell Leukemia: Morphology and Immunotyping
A
- Bcell neoplasm
- Cells have fine hair-like projections visible in routine blood smears and in phase contrast microscopy
- Neoplastic cells demonstrate the presence of tartrate resistant acid phosphatase
- Express pan B-cell markers CD19 and CD20
- Monocyte associated antigen CD11c and CD103
- Surface IgH (usually IgG and either κ or λ)
17
Q
Hairy Cell Leukemia: Clinical Features
A
• Symptomatology results from tissue infiltration
– Splenomegaly: often massive
– Hepatomegaly: less common and not as marked
– Lymphadenopathy: rare
– Pancytopenia: resulting from marrow failure and splenic sequestration
18
Q
Hairy Cell Leukemia: Prognosis
A
- Indolent course
- Especially sensitive to certain chemotherapeutic regimens
- Long term remissions
– May relapse after 5 or more years, but generally respond well with re-treatment
19
Q
Chronic Myeloproliferative Disorders
A
Chronic Myelogenous Leukemia
Polycythemia Vera
Essential Thrombocytosis Primary Myelofibrosis (Myelofibrosis with Myeloid Metaplasia)
20
Q
Myeloproliferative Disorders
A
- Have a common pathogenic feature
- The presence of mutated, constitutively activated tyrosine kinases or other acquired aberrations in signaling pathways that lead to growth factor independence
21
Q
Myeloproliferative Disorders
• Common features:
A
– Increased proliferative drive in the bone marrow
– Homing of the neoplastic stem cells to secondary hematopoietic organs (extramedullary hematopoiesis)
– Variable transformation to a spent phase characterized by marrow fibrosis and peripheral blood cytopenias
– Variable transformation to acute leukemias
22
Q
Chronic Myelogenous Leukemia
A
CML
23
Q
CML: Epidemiology
A
- Primarily a disease of adults (25 – 60)
* Peak incidence in the fourth and fifth decades
24
Q
CML: Pathogenesis and Genetics
• Etiologyisunknown
A
- Arises by neoplastic transformation and clonal expansion of pluripotent stem cell
– Granulocytic precursors are the dominant cell line involved, all hematopoietic lineages can be involved - Associated with the presence of a distinctive chromosomal abnormality—the Philadelphia chromosome
25
Philadelphia Chromosome
t(9;22) present in 90% (Ph1)
The BCR-cABL fusion gene results in production of a fusion protein with tyrosine kinase activity
Ph1 negative CML have rearrangements of BCR-cABL
– Normal myeloid progenitors depend on signals generated by growth factors and their receptors for growth and survival
– Growth factor dependence of CML progenitors is greatly decreased by signals generated by BCR- cABL
26
Nomenclature
* BCR-ABL
• BCR-cABL
• t(9;22)
• Philadelphia Chromosome
| * Ph1
27
CML: Pathogenesis
* The cell of origin is a pluripotent hematopoietic stem cell
* For unknown reasons, BCR-ABL preferentially drives the proliferation of granulocytic and megakaryocytic progenitors
* It also causes the abnormal release of immature granulocytic forms from the marrow into the peripheral blood
28
CML: Laboratory Findings
• PeripheralBlood
– Anemia and thrombocytosis
– Leukocytosis : markedly increased, often exceeding
100,000 cells/mm3
– Blasts usually make up
29
CML: Laboratory Findings
• BoneMarrow
– Markedly hypercellular with granulocytic proliferation
– M:E ratio increased 10 to 20 fold
– Decreased normoblasts
30
CML: Clinical Features
| • Onset slow, insidious
• Symptoms non specific
• Extreme splenomegaly (dragging sensation in abdomen)
• Fatigue malaise exercise intolerance, fever, sweating, weight loss, anorexia
• Mild to moderate anemia
31
CML: Course
• Slow progression
• Drugs which target BCR-AB
– Treatment with BCR-ABL inhibitors results in sustained hematologic remissions in > 90% of patients
– Do not get rid of the CML stem cell
– Now have resistance to 1st generation BCR- ABL inhibitors
• nowhave2ndand3rdgenerationinhibitors
32
CML: Course
* Terminal Phases:
– Accelerated phase (subacute transformation)
* Progressive splenomegaly, refractory to therapy, increased anemia, additional chromosomal abnormalities
– Blast crisis
* Increased blasts in bone marrow and peripheral blood (myeloid or lymphoid)
* 50% occur without going through accelerated phase
• 30% have cells resembling precursor B-cells
33
Leukocyte Alkaline Phos (LAP)
In CML
Decreased or absent
34
Leukocyte Alkaline Phos (LAP)
In leukamoid
increased
35
Basophilia
In CML
present
36
Basophilia
In leukamoid
absent
37
Thrombocytosis
In CML
Present
38
Thrombocytosis
In leukamoid
Absent
39
Toxic Granulation
In CML
Absent
40
Toxic Granulation
In leukamoid
Present
41
anemia
In CML
Present
42
anemia
In leukamoid
Absent
43
Ph1
In CML
Present
44
Ph1
In leukamoid
Absent
45
CML: Prognosis
* Targeted therapy
– Inhibitors of the BCR-cABL tyrosine kinase induce complete remission in a high fraction of patients
* Allogenic bone marrow transplant
46
PCV: Epidemiology
* Late middle age (median age of onset 60 yrs)
| * M>F
47
PCV: Pathophysiology
* Panmyelosis with erythroid percursors dominant
– Absolute increase in red cell mass (RBC 6 – 12million/μL)
– Hematocrit 60% or greater
– Granulocytosis (as high as 50,000/ μL)
– Thrombocytosis
– Basophilia
* Erythropoietin decreased
48
PCV: Genetics
• Strongly associated with activating mutations in JAK2
– A tyrosine kinase that acts in the signaling pathways downstream from the erythropoietin receptor
– Participates in the JAK/ STAT pathway
– Lies downstream from multiple hematopoietic growth factor receptors, including erythropoietin
49
PCV: Genetics
• The transformed progenitor cells have markedly decreased requirements for erythropoietin and other hematopoietic growth factors
– Due to constitutive JAK2 signaling
50
PCV: Morphology
* Hypercellular marrow with some residual fat
* Increase in red cell progenitors is subtle
– Can be increase in granulocytic and megakaryocytic progenitors as well
* In the spent phase
– Late in the course
– Extensive marrow fibrosis
– Increased extramedullary hematopoiesis (spleen and liver)
51
PCV: Clinical Presentation
• Uncommon: 1-3 per 100,000 per year
* Insidious onset
* Late middle age
52
PCV: Clinical Presentation
• Symptoms due to increased red cell mass and hematocrit
– Increased viscosity
– Vascular stasis
– Thrombotic tendency
– Hemorrhagic diathisis
53
PVC: Clinical Presentation
• Headache
• Dizziness
• GI symptoms
• Cyanosis
• Hypertension
• Thrombotic complications
54
PCV: Prognosis and Treatment
* Treatment: phlebotomy
* Can enter a spent phase
– `with clinical and anatomic features of primary myelofibrosis
• May develop terminal AML (~1%)
55
Primary Myelofibrosis (Myelofibrosis with Myeloid Metaplasia)
• Definition: A chronic progressive panmylosis with:
– Bone marrow fibrosis
– Splenomegaly with extramedullary hematopoiesis
– Leukoerythroblastic anemia
56
Primary Myelofibrosis: Epidemiology
• Uncommon in individuals younger than 60 years
57
Primary Myelofibrosis: Genetics
• Activating JAK2 mutations are present in 50 -60%
• Activating MPL mutations in an additional 1-5%
• Most of the remaining cases have calreticulin that is hypothesized to give incrased JAK-STAT signaling
58
Myelofibrosis: Laboratory
• Moderate to severe normochromic normocytic anemia
• Marked poikilocytosis
• Nucleated RBC
• Teardrop shaped erythrocytes
• Basophilic stippling
• WBC: increased, decreased, or normal
59
Myelofibrosis: Marrow Findings
* Hypocellular marrow with dense fibrosis
* Marrow fibrosis appears to be the result of inappropriate release of PDGF and TFG-β from neoplastic megakaryocytes
– This causes deposition of collagen by non- neoplastic fibroblasts
* Extramedullary hematopoiesis
60
Primary Myelofibrosis: Clinical Course
• Comes to attention because of anemia or splenomegaly
• Fatigue, night sweats, and weight loss
• Left upper quadrant fullness (splenomegaly)
• Secondary gout
61
Primary Myelofibrosis: Treatment
• Difficult to treat
• Variable course
• Median survival 4 to 5 years
• In 5 – 20% of cases, transformation to AML
62
Essential Thrombocytosis: Genetics
• Often associated with activating point mutations in JAK2 (501%) or MPL (5 – 10%)
– MPL is a receptor tyrosine kinase that is normally activated by thrombopoietin
– Most fo the remaining cases have mutations in calreticulin (a protein with several described functions in the endoplasmic reticulum and cytoplasm
63
Essential Thrombocytosis: Genetics
• Progenitors are therefore thrombopoietin independent
• The JAK2 mutation is the same as seen in PCV
– Unclear as to why some patients get PCV and others get ET
– ? Iron deficiency
64
Essential Thromocytosis: Clinical Presentation
• Elevated platelet counts
– PCV and primary myelofibrosis are ruled out due to absence of:
• Polycythemia
• Marrow fibrosis
65
ET: Laboratory Findings
| • Platelets> 1x 1012/L
• Abnormal and giant platelets
* Neutrophilic leukocytosis
* Marrow
– Megakaryocytic markedly hyperplasic
– Bone marrow cellularity overall is only mildly
increasee
– Features of other MPDs are absent
66
ET: Clinical Course
* Bleeding, thrombosis
* Splenomegaly (50%)
* Can transform into AML
* Can transform into another myeloproliferative disorder
67
ET: Clinical Course
• Indolent, with a long asymptomatic period
* Median survival time 12-15 years
* Erythromelalgia
– A throbbing, burning of the hands and feet caused by occlusion of small arterioles by platelet aggregates
68
Myelodysplastic Syndromes
• A group of clonal stem cell disorders characterized by maturation defects resulting in ineffective hematopoiesis and an increased risk of developing AML
• Arises in two settings:
– Idiopathic
– Therapy related
69
Myelodysplastic Syndromes
* Idiopathic
– > 50 years of age – Insidious
| * Therapy Related
– Complication of previous genotoxic drug or radiation therapy
70
Myelodysplastic Syndromes
* All forms can transform to AML
* Presents with weakness, infections, and hemorrhages
* Pancytopenia
* Median survival 9 - 29 months
