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Flashcards in Myloproliferative diseases Deck (31):
1

CML is charecterized by

1. Philadelphia chromosome which is a 

2. shortened chromosome 22 resultant from 2

3. t(9,22) that consists of a mutant gene

4. the brc-able which produces a

5. p210 mutant tyrosine kinase that phosphorylates intracellular targets leading to proliferation of the clone

2

clonal disorders of hematopoiesis

1. acquired disorders

2. expansion of pluripotent hematopoietic stem cell

3. abnormal production of mature blood cells

4. predisposition to leukemia transformation

3

Chronic myeloproliferative disorders

charecterized by:

- hepatosplenomegaly

- hypermetabolism

- clonal increase in numbers of one or more circulating mature blood cell types

- clonal hematopoiesis without dysplasia

- predisposition to evolution to acute leukemia 

4

Hyperluekocytosis

- symptoms

- signs

SYMPTOMS: Dyspnea, Dizziness, Slurred  speech, Visual Blurriness, Diplopia,  Decreased Hearing, Tinnitus,  Confusion

SIGNS: Retinal Hemorrhages, Papilledema,
  Priapism, Neurologic Findings

5

clinical features of CML

symptoms:

signs:

symptoms: 

Fatigue
    Anorexia
    Abdominal Discomfort
    Early Satiety
    Weight Loss
    Diaphoresis
    Arthritis
    Leukostasis
    Abdominal Pain
    Urticaria
    
  SIGNS:

Pallor
    Splenomegaly
    Sternal Tenderness
    

6

lab findings for CML

1. hematologic

Neutrophilic Leukocytosis
    Anemia
    Thrombocytosis
    Myeloid Cells at All Stages of Development
    Basophilia
    Eosinophilia
    Hypersegmentation
    Decreased leukocyte Alkaline     Phosphatase
    Functional Abnormalities

7

lab findings for CML

2) marrow

Hypercellularity
    Increased Myelopoiesis
    Increased Megakaryocytes
    Reticulin Fibrosis
    Increased Progenitors
    Cytogenetics

8

Accelerated phase of CML

definition:

path:

clinical features:

DEFINITION:

Transformation to a More Malignant Phenotype

 

PATHOGENESIS:  

Additional Chromosomal abnormalities

Disordered Growth

     Diminished Maturation

 

CLINICAL FEATURES:

Fever, Diaphoresis,Weight Loss, Splenomegaly,     Adenopathy, Extramedullary     Blast Crisis

9

Accelerated phase of CML

- lab features

 Anemia
      Leukopenia or Leukocytosis
      Basophilia
      Thrombocytopenia
      Blasts (typically myloid blasts)

10

CML accelerated phase therapy

- Supportive Care
    - Chemotherapy
    - Interferons
    - Leukapheresis
    - Splenectomy
    - Radiotherapy
    - Bone Marrow Transplantation

11

predictors for adverse outcome after allogenic transplant for CML

Advanced age of recipient
Prolonged duration of CML
Advanced stage of CML
T-cell depletion
Persistence of molecular positivity after transplant
Absence of a/c GvHD

12

Mechanism of oncogenesis for CML

Constitutive activation of bcr-abl tyrosine kinase

-Intracellular signaling pathway activation
Altered proliferation, adhesion,  survival

13

Drug for CML

Imatinib mesylate

14

Therapeutic milestones in management of CML

Hematologic Remission
Cytogenetic Remission
Molecular Remission

Management of the sub-optimal response
- Timing of transplant viz. second-line therapy
 

15

therapeutic managment of CML-disease monitoring

Hematologic
- Weekly until stable, and thereafter every 2-4 weeks until complete cytogenetic response is achieved, then every 4-6 weeks until molecular response, and then every 6 weeks

Cytogenetic
- Every 3-6 months until CCyR, then every 12-18months
Histopathologic
Molecular
Every 3 months

histopathologic

molecular

- every 3 months

16

Polycythemia vera

def:

info:

DEFINITION:

Hematopoietic Stem Cell Disorder
    Sustained Erythrocytosis        

Increased RBC Mass

    Cellular Proliferation


PREVALENCE: 0.5-2.6 per 100,000
AGE:   Peak Onset Age 50-60
SEX:    Male > Female
Ethnic Predisposition: Less common in Asians,   more common in Ashkenazi Jews

17

Polycythemia vera

clinical features

symptoms

signs

SYMPTOMS: 

insidious:

Headache

Dizziness

Vertigo

Visual Disturbances

Angina

   Claudication

    Early Satiety

Abdominal  Pain
    Pruritus
    Thrombosis
    Hemorrhages

SIGNS: 

Plethora
    Retinal Hemorrhages
    Splenomegaly
    Hepatomegaly

18

Polycythemia vera

Other lab findings

Normal Arterial O2 Saturation (Normal FiO2)

Elevated B12 and B12- Binding Capacity

Hyperuricemia

Decreased Erythropoietin Level

Evidence of Clonality

- G6PD isoenzyme analysis
- JAK2 mutation

19

Established criteria for P.vera

Elevated RCM
Absence of secondary causes
Splenomegaly-palp.
Clonality
Thrombocytosis
Neutrophilia
Splenomegaly-other
Low Epo/EEC growth

20

Treatment for P. vera

 Phlebotomy-
  

Goals are PCV (packed cell volume) of 45 in men, 42 in women, and 37 in late pregnancy

   Radioactive Phosphorus
  

Other Myelosuppressive Agents
  

Antihistamines
 

  Allopurinol
  

Aspirin, 100 mg daily is routine

21

Other therapies for P. vera

Hydroxyurea
- Leukemogenic potential, cytopenias, mucositis

Alpha-Interferon
- Cost, inconvenience, toxicity

Anagrelide
- Mixed results on bleeding, vascular, erythromelalgia features; uncertain value viz. thrombosis.  Vasodilatory effects may dissipate

- Conventional alkylators

- Piprobroman
 

22

Course and prognosis for p. vera

Acute leukemia (1%)


   “Spent Phrase” of Polycythemia   Vera
  

Thrombosis
  

Special issues:
    Pregnancy
    Evolution to Acute Leukemia

23

Primary thrombocythemia

definition

clinical features

DEFINITION:

- Clonal Disorder of Platelet Production
   -  Persistent Elevation in Platelet Count
  -  Exclusion of Other Myeloproliferative Diseases

CLINICAL FEATURES:
   Age 50-70
   M=F
   Usually Asymptomatic
  

Occasionally:

Hemorrhagic Manifestations
                  Erythromelalgia
        Neurologic Manifestations
         Thrombosis

24

Lab findings in thrombocythemia

 

hematologic:

 increased Hematocrit

 increased RBC Mass

    Normal to Increased Plasma volume

    Occasionally Microcytosis
    

Neutrophilia

    Thrombocytosis

Marrow:

Hypercellular
    Increased Megakaryocytes
    Myeloid and Erythroid Hyperplasia
    Absent Stainable Iron
     

25

Thrombocythemia

lab features:

hematologic:

Thrombocytosis > 600 x 109/Liter
          Neutrophilia
        Basophilia 

marrow:

Hypercellularity
         Increase in All Cell Lines 

26

Pathophysiology of essential thrombocythemia

Clonality is evident by G6PD isoenzyme analysis

JAK2 mutation is seen in 30-50%

EEC growth is noted

Hypersensitivity to thrombopoietic agents

Acquired MPL 515 mutation is seen in 1% of patients, often coexisting with JAK2 mutation

27

Clinical course of essential thrombocythemia

Predictors of adverse events
- Age over 60, Leukocytosis, smoking, DM

Thrombohemorrhagic risk
- Age over 60, platelets > 1500K, cardiovascular risk factors
- Anagrelide/ASA associ with greater risk of arterial thrombosis, but lower risk of venous when compared to HU/ASA

- Risk of AML transformation

28

Other myeloproliferative diseases

Chronic idiopathic myelofibrosis

Hypereosinophilic syndrome

Chronic eosinophilic leukemia

Mastocytosis
- Cutaneous mastocytosis
- Systemic mastocytosis
- Aggressive systemic mastocytosis

29

Hypereosinophilic syndrome

Sustained eosinophilia > 1500/cu.mm

End-organ manifestations of tissue infiltration

Absence of secondary causes of eosinophila
- Allergy
- Metazoan parasitic infection/chronic infection
- Hypersensitivity pneumonitis
- Collagen vascular disease
- Neoplasia
- CML, Mastocytosis, AML, other MPD

30

hypereosiniphilc syndrome

molecular path

- Interstitial deletion of chromosome 4q12
- FIP1L1-PDGFRα fusion tyrosine kinase
- This fusion typically confers sensitivity to imatinib
- Other partner genes may be PDGFRβ or c-kit, or KIF5b-PDGFRα

31

Mastocytosis

Distinguished by site and degree of involvement
- Cutaneous
- Systemic
- Aggressive systemic

Somatic clonal mutations may involve c-kit(D816V) of FIP1L1-PDGFRα

Elevated serum tryptase