12-1: 1/10 - Myeloproliferative Disorders

Front 1

Myeloproliferative Disorders:
Cellularity
Onset (general)
Hallmark finding
End-result

Back 1

-Hypercellular (greater than 100%-age)
-Inc'd quantities of more than one cell lineage
-Asyx onset
-HALLMARK = Splenomegaly
-Terminate in acute leukemia or myelofibrosis

Front 2

JAK2 Mutation:
Which MPD is it found in?
Effect (biochemically)

Back 2

Philadelphia chromosome negative MPD

V617F: phenylalanine swapped for valine

Front 3

Polcythemia vera:
Propensity for JAK2 mutation
Hetero/Homozygous

Back 3

100%; homozygous

Front 4

Myelofibrosis:
JAK2 mutation--hetero/homozygous?

Back 4

Usually paired with an additional mutation; heterozygous

Front 5

JAK2:
Ligand
Effect of ligand binding
Effect of mutation

Back 5

Ligand = Epo
Effect: proliferation

JAK2-V617F-->constitutive autophosphorylation of JAK2 and thus constitutive proliferation:

-Inhibits apoptosis
-Promotes G1/S phase transition
-Promotes erythroid differentiation
-Promotes reticulin deposition

Front 6

MPDs are characterized by _______. Typically, more than one _______ is _________.

Why?

Back 6

MPDs char'd by disregulated, overproduction of cells. Typically more than one cell lineage overproduced.

This is bc clonal expansion occurs at pluripotent stem cell.

Front 7

MPD vs AML:
Cells involved
Ability to differentiate

Back 7

MPD: pluripotent SCs; multiple cell lineages affected.
cells maintain ability to differentiate.

AML: committed SCs; overproduciton of one cell lineage.
lack of differentiation.

Front 8

EPO Effects:
General
BFU-E
CFU-E

Back 8

CFU = colony forming units (early forms of RBCs); proliferate and differentiate

BFU = blast forming units; proliferation

Induces globin synthesis

Stimulates reticulocyte release

Front 9

Via what mechanism is EPO released by the kidneys?

Back 9

Kidney oxygen receptors determine low O2-->signal peritubular cells-->EPO release

Front 10

Causes of decreased O2 delivery to kidneys.

Back 10

i.e., causes of EPO release

-Dec'd Hgb concentration
-Dec'd atmospheric O2
-Cardiopulmonary dysfn
-Left shit of O2-dissocn curve

Front 11

How would you differentiate between a patient with erythrocytosis secondary to chronic hypoxia and a patient with polycythemia vera? Why is this possible?

Back 11

Erythrocytosis secondary to chronic hypoxia: normal to slightly elevated EPO levels, but EPO levels rise significantly if phlebotomized to nl HCTs

In PV, EPO levels remain low even when pts phlebotomized to normal HCTs bc of JAK mutations. Cells are EPO-independent.

Front 12

In P. Vera, what is the effect of the JAK mutation on EPO levels? On normal blood cell progenitors?

Back 12

Proliferation of robotic P. Vera clones decreases EPO levels and thus inhibits proliferation of normal EPO dependent progenitors.

Clone thus has greater competitive advantage.

Front 13

What is the diagnostic algorithm for P. Vera?

Back 13

Presence of JAK2 mutation leads to likelihood of disease

A low EPO makes P. Vera even more likely, but this is not always necessary.

Front 14

Signs of P. Vera in erythrocytotic phase.

Back 14

Splenomegaly (sometimes)

Erythrocytosis
Leukocytosis
Thrombocytosis
Thrombosis
Hemorrhage

Front 15

Signs of P. Vera in potpolycythemic myeloid metaplasia phase.

Back 15

Splenomegaly (common)
Anemia
Leukoerythroblastosis
Thrombocytopenia
Systemic Syptoms

BM IS FAILING

Front 16

In 40% patients with P. vera, this is the cause of death.

Where in the body does it occur?

Back 16

Thrombosis; occurs at unusual anatomic sites! Cavernous sinuses, renal vasculature.

Front 17

In P. Vera, what does risk of thrombosis correlate with?

Back 17

HCT > 50%

Front 18

Beyond thrombosis, what are other complications of P. vera?

Back 18

Hemorrhage: due to platelet dysfn, acq'd vWF defect

Potpolycythemic Myeloid Metaplasia: ~15 years of disorder; BM failure, splenomegaly, portal HTN, fevers, sweats

Acute Myeloid Leukemia: ~5%

Front 19

What is erythromelalgia? What might it indicate?

Back 19

Erythromelalgia = burning sensation in digits, relieved by cooling

Seen in P. vera

Can lead to acrocyanosis; tx w/anti-platelet tx

Front 20

P. vera:
Therapy

Back 20

-Prevent thrombosis:
Phlebotomize
Hydroxyurea
Anti-platelet tx w/low dose ASA

-Allogenic BM transplant (curative):
Young pts
HLA-matched donor

Front 21

When is inappropriate EPO secretion seen in secondary erythrocytosis?

Back 21

Kidney tumors

Front 22

P. Vera vs Secondary Erythrocytosis:
RBC Mass
Splenomegaly
ALtered O2 Delivery
Thrombocytosis
BM Quality
EPO Levels
JAK2 Mutation

Back 22

P Vera:
RBC Mass inc'd
Splenomegaly v. common
Altered O2 delivery absent
Thrombocytosis present (pluripotent HSC involvement)
BM has panyhyperplasia
EPO levels dec'd
JAK2 Mutation PRESENT

Secondary erythrocytosis:
RBC Mass inc'd
Splenomegaly absent
Altered O2 delivery often present
Thrombocytosis Absent
BM has erythroid hyperplasia
EPO levels inc'd
JAK2 mutation ABSENT

Front 23

Most common cause of impaired O2 transport in blood in the US. Why?

Back 23

Smoking:
CO binds to Hgb-->impaired O2 transport

Front 24

What is spurious erythrocytosis?

Causes?

Back 24

Erythrocytosis secondary to diminished plasma volume rather than inc'd RBC mass.

Causes:
Volume depletion, diuretics, stress

Front 25

Leukoerythroblastosis:
Histologic features
Indicative of?

Back 25

tear drop cells: myelofibrosis (fibers in BM) squeezes RBCs into tear drop shape

Nuc’d RBC is indicative of BM crowding

Leukoerythroblastosis-->myelofibrosis

Front 26

Utility of reticulin stain in BM.

Back 26

Detects deposition of fibers in BM in myelofibrosis.

Front 27

How does idiopathic myelofibrosis result in fibrosis?

Back 27

JAK2 mutation signals colony forming megakaryocyte units to proliferate into megak's and form Platelet-Derived GF (and platelets)

Platelet-Dertived GF stimulates fibroblasts-->collagen production; inhibition of collagenase

Front 28

Idiopathic Myelofibrosis:
Clinical Presentation
Lab presentation
Radiologic findings

Back 28

Splenomegaly****** due to extramedullary hematopoiesis (IN ALL PATIENTS)

-Almost all patients are anemic (as opposed to P. Vera, where pts have erythrocytosis)

-Leukocytosis, thrombocytosis common at onset, nbut pancytopenia develops as marrow fibrosis progresses

-JAK2 MUTATION

-Osteosclerosis on imaging

Front 29

What is essential thrombocytosis?

Back 29

Least common myeloprolif disorer; platelet count >600,000

Major complication is thrombosis

Tx = anti-platelet therapy
Hydroxyurea
Anegrelide

Front 30

Essential vs Reactive Thrombocytosis:
Chronic platelet increases
Thrombosis
Abnormal platelet function
BM fibrosis
Splenomegaly
Ferritin

Back 30

Essential Thrombocytosis:
Chronic platelet inc: Yes
Thrombosis: Yes
Abnl platelet fn: Yes
BM fibrosis: Yes
Splenomeg: Sometimes
Ferritin:Normal

Reactive thrombocytosis:
Thrombosis: No
Abnl platelet fn: No
BM fibrosis: No
Splenomeg: No
Ferritin: ABNRML

Front 31

Chronic Myelogenous Leukuemia:
Cell lines affected
Defining Feature

Back 31

Expansion of all hematopoietic lineages with myeloid lineage most affected

Transformation to acute leukemia without therapy.

Front 32

Philadelphia Chromosome:
Translocation
Present in which diseases?
Effects (protein formed, result)

Back 32

t(9;22)

95% of chronic myelogenous leukemia
20% of ALL
2% AML

Effects:
Forms hybrid BCR-ABL gene, which is a constitutively active tyrosine kinase.

Front 33

Role of BCR.

Back 33

Unclear, but does increase oxidative burst in nphils.

Front 34

ABL and BCR are prone to have breakpoints.

What role does this play in the diseases translocations can cause? Provide 3 examples.

Back 34

ABL has one breakpoint
BCR has three breakpoints

Where break occurs determines disease.

P210-BCR-ABL leads to 95% of Chronic Myelogenous Leukemia

P190: leads to ALL; rare CML with monocytosis

P230: rare CML variant with thrombocytosis

Front 35

BCR-ABL effects.

Back 35

Expression of B1 integrin inhibits cell adhesion

Activates mitogenic PW's: RAS, MAP kinase, Jak-Stat, P13 kinase, and Myc

Shift towards anti-apoptosis

Degrades inhibitory proteins

CELLS CAN STILL DIFFERENTIATE

Front 36

ABL gene:
Role

Back 36

Produces tyrosine kinase; plays role in signal transduction and regulation of cell growth

Front 37

How does the P210BCR-ABL mutation differ from normal ABL activity?

Effects of this?

Back 37

YOU GUYS, P210 BCR-ABL = PHILADELPHIA CHROMOSOME!!!!

Has much higher tyrosine kinase activity

leads to proliferation signals independent of GFs

Suppression of apoptosis

Feedback mechs that suppress growth of normal cells allowing malignant cells to dominate

Front 38

Why is chronic myelogenous leukemia considered chronic?

Back 38

Because without treatment, patients can survive about 5 years. As opposed to acute leukemia, where patients would live about 6 months.

Front 39

CML:
PE Findings
Lab findings (General and smear findings)
LAP Score

Back 39

Splenomegaly****
Fatigue (due to anemia)
Weight loss
Sternal tenderness

Lab findings:
Leukocytosis including nphils of all stages of development, myelocytes, basophilia (!!!)

Thrombocytosis
Anemia
Leukocyte alkaline phosphae score is low (normally found in nphils; low in clones, high in inflammatory states like pnuemonia)

Front 40

CML:
Histologic findings of peripheral smear
Histologic findings of BM aspirate

Back 40

Smear:
CML Chronic PhasePeripheral Smear: Diff stages of differentiation of nphils (metamyelocytes, blasts) in periphery. ABNORMAL. Should be bands or PMNs in periphery!!

BM: hypercellular (near 100%), predominance of myeloid precursors

Front 41

When is there a risk for hypserviscosity syndrome of CML?

Back 41

WBC > 200K

Can lead to cerebrovascular, cardio ischemia, priapism. It's a perfusion problem.

Front 42

Why does CML fail to remain in indolent chronic phase?

Back 42

Clonal evolution (to a BM failure disorder)
Myelofibrosis

Front 43

What is clonal evolution?

Back 43

It's not BCR-ABL protein causing AML; aging DNA acquires another mutation and then can become AML. This is clonal evolution.

Front 44

CML:
Therapy

Back 44

Supportive care

Reduce number of WBCs:
Leukophoresis
Hydroxyurea
Cytarabine

Front 45

Interferon Alfa:
Use
MOA
Compare use with Hydroxyurea

Back 45

Use in CML

Note: IFNs are produced in response to antigens, such in infection or neoplasm

IFN-alfa has a direct antiproliferative effect on CML progenitor cells via an unk mech

Higher rate of cytogenetic response than hydroxyurea (can no longer detect Philadelphia chromosome); improvement in survival rates.

Front 46

Why is allogeneic transplant superior to IFN-alfa in treating CML?

Back 46

80% patients with remissions after transplant have negative PCR for BCR-ABL protein. Rarely achieved w/IFN-alfa.

Transplantation involves high doses of chemotherapy followed by transplant.

Front 47

BM Transplant Disadvantages.

Back 47

Available to limited number of pts

Considerable M&M

Less effective in pts in accelerated or blast phases

Front 48

Imatinib:
Use
MOA
Conerns

Back 48

Use in CML

TARGETED TX!

MOA: occupies kinase pocket of BCR-ABL protein; prevents access to ATP, preventing phosphorylation of any substrate and downstream signaling.

Concerns: Resistance! Especially in blastic phases.

Front 49

What is a cytogenetic response in treating CML?

Back 49

-Undetectable BCR-ABL

Front 50

Why does resistance develop against imatinib?

Back 50

Heterogeneous mechs:
-Spontaneous mutation of tyrosine kinase binding domain
-Numeric or structural cytogenetic abnlts
-Overexpression of BCR-ABL

Front 51

What is the T3151 Mutant BCR-ABL?

Back 51

Mutation making CML resistant to imatinib and second-generation treatments.

Front 52

How are patients with CML treatment resistance treated?

Back 52

Dose escalation of imatinib
2nd generation kinase inhibitors
SC transplant