Essential Thrombocythemia (ET): - Incidence - Presentation

- Bimodal (peaks at age 30 and 60) - Isolated Thrombocytosis

MPNs: CML, PV, ET, PMF, CEL Flashcards by Filip Garrett

Which MPN has the longest survival and lowest transformation (5%) to Acute Leukemia?

Essential Thrombocythemia (ET)

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What is the Diagnostic Criteria for ET? (4)

Aimed at excluding secondary thrombocytosis and other MPNs

Sustained Thrombocytosis (>450)
BM w/ Megakaryocytic Hyperplasia w/O panmyelosis (no significant increase in granulocytic/erythroid precursors)
Fails to meet criteria for PV, PMF, CML, or MDS
JAK2 B617F mutation (or no evidence for reactive thromobocytosis)

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CML Imatinib Resistance:

-% Initially present

-5% of cases initially (emerges during treatment in many more)

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Philadelphia Chromosome:

-Most commonly occurs where and with what?

In major breakpoint cluster (M-BCR)

-w/ p210 fusion protein

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Essential Thrombocythemia (ET):
-Bone Marrow findings (4)

Large, Hyperlobated Megs
Paratrabecular
Emperipolesis
Stainable Iron Present

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Most common cause of death in PV?

-2nd

Thrombosis

-Acute Leukemia

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Mutations in what, produce a small subset of ET and PMF but are NOT seen in PV?

MPL mutations

-MPL W515L or W515K

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What is the Philadelphia Chromosome?

Reciprocal Translocation of chromosomes 9 and 22

-t(9;22)(q34;q11)

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Primary Myelofibrosis (PMF) - Cellular (Prefibrotic) Stage:
-Presentation (3)

Anemia
Mild Leukocytosis
Thrombocytosis

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Polycythemia Vera (PV) - Diagnostic Criteria:
-General (2)

Both Major + 1 Minor

- 1st Major + 2 Minor

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What is the Jak-2 protein involved in?

Stimulating the STAT pathway

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CML Imatinib Resistance:

-Result of what?

Mutations within the BCR-ABL gene

Tyrosine Kinase Domain
P-loop (so-called)

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CML is defined by the presence of what?

Philadelphia Chromosome

-t(9;22) - BCR/ABL

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Essential Thrombocythemia (ET):

Incidence
Presentation

Bimodal (peaks at age 30 and 60)

- Isolated Thrombocytosis

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CML - Blast Phase manifests as what types of acute leukemia? (2)
-Percentages

AML (70%)

- ALL (30%)

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CML - Chronic Phase:

-Peripheral Blood (6)

Leukocytosis with:
-Neutrophilia
-Monocytosis
-Basophilia
-Eosinophilia
Thrombocytosis

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What is the most powerful Prognostic Factor in CML?

Response to Tyrosine Kinase Inhibitor (TKI) therapy as measured by Quantitative RT-PCR.

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Chronic Eosinophilic Leukemia (CEL):

-Must exclude other hematolymphoid neoplasms w/ eosinophilia (3)

Rearrangements of:

PDGFRa
PDGFRb
FGFR1

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CML - Accelerated Phase criteria:

-1 or more of the following (4)

Progressive Basophilia (>20%)
Progressive Thrombocytopenia (<100) or Thrombocytosis (>1,000)
Clonal Cytogenetic Progression (+8,i17q,+19,2ndPhChr)
Increasing Blasts (>10% but <20%)

Polycythemia Vera (PV) - Proliferative (Chronic) Phase:
-Peripheral Blood (4)

Erythrocytosis - sometimes w/:

-Neutrophilia, Basophilia, and/or Thrombocytosis

Which uncommon breakpoint/fusion protein is associated with marked thrombocytosis and relatively mature leukemic neutrophils?

u-BCR breakpoint

-p230 fusion protein

Which uncommon breakpoint/fusion protein is associated with CML with marked monocytosis and Ph+ ALL?

m-BCR breakpoint

-p190 fusion protein

What is the most common JAK-2 Mutation?

G to T substitution at nucleotide 1849

-Val to Phe substitution at codon 617 (Val617Phe)

CML - Chronic Phase:

-Bone Marrow (5)

Hypercellular BM
High M:E ratio
Small,Hypolobated (“Dwarf”) Megs
Mild Reticulin Fibrosis
Thickening of Paratrabecular generative cuffs

Chronic Eosinophilic Leukemia (CEL): | -Common tissue sites (4)

- Heart - GI tract - Lung - CNS

Chronic Eosinophilic Leukemia (CEL) must have evidence of clonality, such as increased blasts or clonal cytogenetic abnormalities; lack this and the diagnosis is?

Hypereosinophilic Syndrome (HES)

Primary Myelofibrosis (PMF) - Cellular (Prefibrotic) Stage: -Bone Marrow finding (1) -Megakaryocyte morphology/chromatin/distribution -

-Hypercellular BM Megakaryocytes: - Lobulated (aberrantly) - Clumped, Hyperchromatic, and Inky Chromatin - Clusters adjacent to sinuses and trabeculae

CML - Chronic Phase: - Splenomegaly (+/-) - Leukocyte Alkaline Phosphatase (LAP) score - Vit. B12 level

CML - Chronic Phase: - Splenomegaly is Common - LOW Leukocyte Alkaline Phosphatase (LAP) score - Elevated Vit. B12 level (markedly)

``` Polycythemia Vera (PV) - Diagnostic Criteria: -Minor Criteria (3) ```

- BM panmyelosis (megs,grans,erythroids) - Endogenous Erythroid Colony Formation (in vitro) - Normal serum EPO

Chronic Eosinophilic Leukemia (CEL): | -Must exclude secondary eosinophila causes (4)

- Allergic reaction - Parasitic infection - Collagen Vascular Disease - Mastocytosis

``` Polycythemia Vera (PV) - Diagnostic Criteria: -Major Criteria (2) ```

First Major: - Hgb >18.5 (Men) - Hgb >16.5 (Female) - or Increased RBC Mass Second Major: - JAK2 B617F - or functionally similar JAK2 mutation

``` Polycythemia Vera (PV): -Signs/Symptoms (7) ```

- HTN - Thrombosis - Pruritus - Plethora - Erythromelalgia - Headache - Splenomegaly

CML - Blast Phase criteria. (3)

- >20% Blasts in Blood or BM - Tissue infiltrate of Blasts (Chloroma) - Accumulation of Blasts in BM filling an Intertrabecular Space)

Chronic Eosinophilic Leukemia (CEL): | -Diagnostic Criteria

Eosinophilia (>1.5) with tissue infiltration and damage

What mutation is present in the majority of non-CML MPNs? | -Percentages

JAK2 (Janus Kinase 2) Mutation - PV (>90%) - ET/PMF (>50%)

``` Primary Myelofibrosis (PMF) - Fibrotic Stage: -Peripheral blood (1) ```

Leukoerythroblastic pattern

``` Primary Myelofibrosis (PMF) - Fibrotic Stage: -Bone Marrow (4) ```

- Bone Marrow is Inaspirable - Reticulin Fibrosis - Intrasinusoidal Hematopoiesis - Abnormal, Clustered Megs

Chronic Eosinophilic Leukemia (CEL): - Gender - Age

- M>F (9:1) | - 25-45 y/o

What are the Myeloproliferative Neoplasms? (5)

``` -Chronic Myelogenous Leukemia (CML) Non-CML MPNs -Polycythemia Vera (PV) -Essential Thrombocythemia (ET) -Primary Myelofibrosis (PMF) -Chronic Eosinophilic Leukemia (CEL) ```

``` Polycythemia Vera (PV) - Spent Phase: -AKA ```

Postpolycythemic Myelofibrosis with Myeloid Metaplasia (PPMM)

``` Polycythemia Vera (PV) - Spent Phase: -Findings (3) ```

- Peripheral Myelophthisic Pattern - BM Reticulin Fibrosis - Extramedullary Hematopoiesis

Chronic Eosinophilic Leukemia (CEL): | -Eosinophil characteristics (2)

- Hypogranular | - Cyanide Resistant MPO stain highlights granules

A second activating mutation involving what, produces a small proportion of cases?

JAK2 exon 12

``` Polycythemia Vera (PV) - Proliferative (Chronic) Phase: -Bone Marrow (3) ```

- Hypercellular BM - Megakaryocyte Hyperplasia (Prominent) - Decreased/Absent Stainable Iron

Philadelphia Chromosome: - ABL locus - BCR locus - Result

- ABL locus - 9q34 - BCR locus - 22q11 - Chimeric Bcr-Abl protein with enhanced Tyrosine Kinase Activity

CML - Chronic Phase: | -Neutrophils

- Immature Neutrophils | - High proportion of Myelocytes (Myelocyte "Bulge")