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IHO Week 4 > CML Module > Flashcards

CML Module Flashcards

1
Q

Chronic Myeloproliferative Disorders:

Things you must know!

A
  • Malignant proliferation of myeloid cells in blood, bone marrow
  • Disorders of stem cells
  • Four disorders
    • CML (chronic myeloid leukemia)
    • PV (Polycythemia vera)
    • ET (Essential thrombocythemia)
    • MF (Myelofibrosis)
  • Only in adults
  • Long course
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2
Q

What is proliferating most in each disorder?

A

CML – neutrophils

PV – Red cells

ET – Platelets

MF – everything!

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3
Q

Common features in all 4 disorders?

A
  • Only in adults
  • Long clinical course
  • Increase WBC with left shift(mild/moderate)
  • Hypercellular marrow
  • Big spleen (extramedullary site)
  • May evolve into acute leukemia
  • Mutated tyrosine kinases
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4
Q

Chronic Myeloid Leukemia

Things you must know!

A
  • Neutrophilic leukocytosis
  • Basophilia
  • Philadelphia chromosome
  • 3 phases
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5
Q

Lab findings in CML

A

high WBC count

Neutrophilia w/ left shift

Basophilia

decreased hemoglobin = anemia

increased platelet count (at first) - increase in megakaryocytes

Decreased LAP

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6
Q

Clinical findings in CML?

Symptoms?

Signs?

A
  • Symptoms:
    • Slow onset
    • Fever, fatigue, night sweats
    • Abdominal fullness
  • Signs
    • Big spleen
    • Big liver
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7
Q

Phases of CML:

Chronic phase

Accelerated phase

Blast crisis

A
  1. Most pts present with Chronic phase
    * Stable counts, easily controlled, 3-4 yrs if untreated

50% go to Accelerated phase

  • Unstable counts, blast crisis within 6-12 months

50% go into Blast crisis

  • Acute leukemia, high mortality
  • Myeloid or lymphoid blast cells
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8
Q

3 types of remission:

  1. Hematologic
  2. Cytogenetic
  3. Molecular
A

1. Hematologic: – least sensitive

  • No spenomegaly
  • WBC <10,000, normal morphology
  • Normal Hgb, platelet count

2. Cytogenetic

  • No metaphases with t(9;22)

3. Molecular – most sensitive

  • No BCR/ABL transcripts by PCR
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9
Q

Polycythemia Vera

Things you must know!

A
  • High RBC (makes blood sludgy)
  • Different from secondary polycythemia
  • Thrombosis and hemorrhage
  • Jak-2 mutuation
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10
Q

Primary vs secondary polycythemia vera?

A
  • “Polycythemia” = increased RBC
  • Primary = intrinsic myeloid cell problem
  • Secondary = due to increased erythropoietin (smoking, high altitude…)
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11
Q

Clinical Findings of PV

Symptoms

Signs:

A
  • Symptoms:
    • Big spleen, liver
    • Plethora (flushing)
  • Signs:
    • Headache, pruritis, dizziness
    • Thrombosis, infarction
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12
Q

Jak-2 in PV

A
  • JAK-STAT pathway normally - cell signaling in many different cell types
  • Mutated in PV:
    • mutated Jak-2 --> increased activity –> cells grow on their own
  • Important for diagnosis and drug therapy
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13
Q

Treatment and Prognosis of PV

A

Treatment: Phlebotomy, maybe myelosuppressive drugs

Prognosis: median survival –> 9-14 years

Death from thrmobosis or hemorrhage

Leukemic transformation in some patients

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14
Q

Essential Thrombocythemia

Things you must know!

A
  • Very high platelet count in blood
  • Can occur in young women
  • Diagnosis of exculsion
  • Thrombosis and hemorrhage
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15
Q

Diagnostic Criteria for ET

A
  • Platelet count >600,000 (really high)
  • Make sure:
    • Normal Hgb <13 or RBC mass normal
    • No Philadelphia chromosome
    • No marrow fibrosis
    • No other reason for thrombocytosis
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16
Q

Clinical features of ET

Symptoms:

Signs:

A
  • Symptoms:
    • Bleeding and thrombosis
  • Signs:
    • Purpura, bruising
    • Pallor, tachycardia
    • Biggish spleen
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17
Q

Treatment and Prognosis of ET

A

Treatment:

  • Platelet pheresis
  • Maybe myelosuppressive drugs
  • Aspirin

Prognosis:

  • Median survival: 5-8 yrs
  • Death from thrombosis or hemorrhage
  • Leukemic transformation in some patients
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18
Q

Chronic Myelofibrosis

Things you must know!

A
  • Panmyelosis…
  • ….then marrow fibrosis
  • Massive Extramedullary hematopoiesis
  • Teardrop red cells
19
Q

Clinical findings in MF

Symptoms:

Signs:

A

Symptoms:

Left upper quadrant fullness

Weakness, fatigue, palpitations

Signs:

Huge spleen, pallor, tachycardia

20
Q

MF

Treatment:

Prognosis

A

Treatment:

  • Supportive
  • Maybe myelosuppressive drugs

Prognosis:

  • Median survival: 3-5 yrs
  • Death from marrow failure
  • Leukemia transformation in some patients
21
Q

Tyrosine Kinases Inhibitors: MOA

Bosutinib, Dasatinib, Imatinib, Nilotinib

A

Competitive antagoinists at the ATP-binding site of:

  1. bcr-abl

2. c-kit

3. PDGF

these are overexpressed in lots of epithelial derived cancers

22
Q

Tyrosine Kinase Inhibitor Drugs:

A

Bosutinib

Dasatinib

Imatinib

Nilotinib

Erlotinib

Gefitinib

23
Q

What does Dastainib also target?

A

Src

a tyrosinek inase that is upregulated in many cancers

24
Q

MOA of Erlotinib and Gefitinib?

A

-Competitive antagonists of ATP-binding site of epithelial growth factor receptor (EGFR) tyrosine kinase,

this is overexpressed in lots of epithelial-derived cancers

25
Q

Resistance of TK inhibitors?

A

-Change in target proteins

(mutation of ATP binding site that prevents drug binding)

Bosutinib, Dasatinib, Nilotinib were developed for cells that are resistant to Imatinib :)

26
Q

Pharmacokinetics of these drugs?

A
  • oral, good bioavailability
  • metabolized in liver, CYP3A4
27
Q

Toxicity of these drugs?

A
  • Relatively minor S.E. compared to other drugs we’ve learned
  • congestive heart failure
  • Myocardial infarction
  • Teratogenic
28
Q

Toxicity for:

Imatinib?

Erlotinib & Gefitinib?

A

Imatinib –> edema, BMS

Erlotinib & Gefitinib–> rare interstitial pneumonia

29
Q

Only curative therapy for CML?

A

Bone Marrow Transplant!

30
Q

Therapeutic Uses for:

Bosutinib

Imatinib

Dasatinib

Nalotinib

A

85-95% response in chronic phase of CML

delay death in 25% of patients in blast crisis

Gastrointestinal stromal tumors expressing c-kit

31
Q

Chromosomal translocation in CML?

What does it result in?

A

t(9;22) —> BCR-ABL fusion protein (Philadelphia chromosome)

creates new gene encoding constitutively active tyrosine kinase

32
Q

Neutrophil lineage:

  1. Stem Cell
  2. Progenitor cells
  3. Committed cells
A
  1. Stem Cell:
    • Undergo self renewal
    • Pluripotent
  2. Progenitor Cells:
    • Cabapble of proliferation but not self renewal
    • Multipotent
  3. Committed Cells:
    • Do not proliferate, only one fate
33
Q

Differentiation of neutophil:

Progenitor cell =

Cytokine =

Trascription factor =

Result =

A

Progenitor cell = GMP

Cytokine = G-CSF

Trascription factor = CEBP-alpha

Result = neutrophil differentiation

34
Q

What does BCR-ABL fusion protein do to neutrophil differentiation?

A

=constitutively active tyrosine kinase that activates proliferation and blocks apoptosis in absence of extracellular signals

-Mutations arise in hematopoietic stem cell but get passed down to all progeny

=disrupts normal neutrophil differentiation

35
Q

What is the benefit of BCR-ABL 1 progenitor cell for cancer cells?

A
  • proliferate more, survive longer
  • have opportunity to get more mutations –>more oncogenic
  • continue to differentiate and produce mature cells
  • But they do not self renew
36
Q

Blast phase of CML:

A
  • GMP acquires abililty to self renew
  • Acquires block to differentiation
  • ===huge expansion of blasts
    • 30% extramedullary
37
Q

What changes do you need to go from chronic to blast phase?

A
  • GMP acquired self renewal capability -Wnt-beta catenin signaling is activated
  • Differentiation is blocked - translation of CEBP-alpha is inhibited
  • Outcome
    • Extreme expansion of blasts
    • Production of functional mature cells blocked
    • Fatal disease
38
Q

Normal function of BCR and ABL1?

A
  • BCR: Ser/Thr kinase domain
    • role inhibition of some inflammatory responses
  • ABL1: tyrosine kinase domain
    • role in DNA repair, cytoskeletal organization
39
Q

Important differences between ABL1 and BCR-ABL1?

A
  1. ABL1 is inactivated unless activated by intracellular signaling
    * BCR-ABL1 = constitutively active
  2. ABL1 mainly nuclear
    * BCR-ABL1 = mainly cytoplasmic
  3. ABL1 and BCR-ABL1 activate different intracellular signaling pathways
40
Q

Activating/structural changes in BCR-ABL1?

A
  1. Coiled-coil domain: promotes dimerization (needed for activation)
  2. Myristate attachment site lost: necesary for autoinhibition
  3. Tyrosine-177 (Y-177): new binding site for intracellular signaling proteins
41
Q

CML treatment?

A
  • BCR-ABL specific TK inhibitors
  • Transition to blast phase can be blocked
  • Imatinib
42
Q

Imatinib MOA:

A
  • specifically inactivates ABL1 kinase by blocking ATP binding
  • Inactivation of BCR-ABL in mutant cells causes apoptosis
  • allows normal cells to repopulate
43
Q

Limitations of Imatinib

A
  1. Many develop secondary resistance due to mutations in BCR-ABL
  2. not effective against blast phase disease
  3. CML stem cells are resistant to tyrosine kinase inhibitors
  • Stem cells are quiescent, not strongly affected by inhibitors that block proliferation
  • Must be taken for life

IHO Week 4 (15 decks)

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