3.26 NIELL Myeloproliferative Diseases

Question 1

Myeloid Neoplasms Def and Types

Answer 1

Def: arise from hematopoietic progenitors and typically give rise to clonal proliferations that replace BM
AML: Blast accumulation >20-30% in BM and Replace Normal Elements
Myeloid Proliferative disorders: see terminal diff. but exhibits increase or dysregulated growth.
-Usually see increase in formed elements in peripheral blood

Question 2

Chronic Myelogenous Leukemia

Answer 2

• Usually Presents 45-55 age
• 9:22 Philadelphia Chromo: present in 100% of RBC, WBC, Monocytes and platelets
• -See cont activation of Tyrosine Kinase
• PB: WBC precursors present
• Basophilia is common
• Elevated Uric Acid: Excess purine breakdonw
• Increased B12 b/c increased Transcobalamine 1

Question 3

Phases of CML

Answer 3

Chronic Phase (5-6yrs)
Accelerated Phase (6-9 months)
-Anemia, thrombocytopenia and increased blast cells
Blast Crisis (3-6 months)
-20% or more blasts in the marrow (decreased diff)

Question 4

Older Treatments for CML

Answer 4

Busulfan
Hydroxyurea: maintains WBC in chronic phase but does not decrease % of BCR-ABL cells
Interferon: Replaced by Imatinib
BM transplant (not available with all pts)

Question 5

Targeted Therapies

Answer 5

Imatinib: takes up ATP binding site
-!st line therapy (1st gen) May see Neutropenia and Thrombocytopenia
-Good response in Chronic Phase, some response in blast phase
Dasatinib and Nilotinib (2nd Gen)
-Both faster remission than Imatinib (less info known)
-higher affinity for BCR-ABL, Kinase and can be useful in imatinab resistance

Question 6

JAK-2 Mutations

Answer 6

-MPD-associated mutation in JAK-2
V617F-JAK2 is a common mutation seen
-PV, ET and MF

Question 7

Idiopathic Myelofibrosis (PMF)
-Causes

Answer 7

Occurs around 65
Causes:
-Myeloproliferation with granulocytic hyperplasia and megakaryocytosis
-Marrow fibrosis with increased collagen Type I, III, IV, and V in marrow (mostly III)
-Fibrosis closely coorelates with increased dysmorphic megakaryocytes in the marrow
-Fibrosis is the result of release of cytokines from the abnormal megakaryocytes

Question 8

Clinical and Physical findings of PMF

Answer 8

Fatigue, weakness, shortness of breath, bone pain
Physical Findings:
-Hepatomegally (75%) Splenomegally (100%)
-Muscle wasting, pheripheral edema, purpura, bone tenderness

Question 9

PMF labs

Answer 9

-Early: Thrombocytosis
-Bizarre changes in megs (peripheral and BM)
-Aniso and poikliocytosis
-TEAR DROPS
–Happen anytime there is a problem with BM architecture
-Nucleated RBCs and WBCs
BASOPHILIA
Marrow: increased fibrosis and abnormal megs

Question 10

Other Important Symptoms of PMF

Answer 10

Portal Hypertension: resulting in ascites, esophageal and gastric varices
Osteosclerosis: prox femur & humerus pelvis, vertebral bodies, ribs and skull

Question 11

Treatment of PMF

Answer 11

• Not very good at treating, give transfusions
• Lenalidamide may achieve remission
• Radiation used to manage symptoms
• BM transplant is curative but most pts are too old (high mortality rate)
• Roxolitinib: Jak2 inhibitor, some results but not great

Question 12

Causes of Secondary Thrombocytosis

Answer 12

• Acute and transient: trauma, Major surgery and acute bleeding
• More sustained thrombocytosis: inro def, chronic infection, chronic inflamm disease, neoplasia
• Lifelong thrombocytosis: splenectomy or asplenic pts

Question 13

Characteristics of Secondary Thrombocytosis

Answer 13

• Generally, no splenomegally
• no extreme plt elevations
• morphology and func is normal
• Thrombosis and bleeding is rare
• Usually see elevated levels of thrombopoetin that coorelates with the plt count

Question 14

Essential Thrombocytosis

Answer 14

Least common of MPDs

Diagnosed age 50-60

Question 15

ET Clinical Features

Answer 15

Splenomegally in 40% of pts

• Aortic and mitral valvular leaflet thickening or vegetations
• Leukemic transformation is less than othe other MPDs
• Serum Thrombopoetin levels are normal or elevated and does not coorelate with the platelet count**

Question 16

Risks of ET

Answer 16

-Some pts with only bleeding or thrombosis
–risk for thrombosis: previous, older age and ass CV risk factors (smoking)
Bleeding is >1,500,000 plts, b/c plts are not func normally
-Arterial Thrombosis is more common than venous

Question 17

Treatment of ET

Answer 17

Hydroxyurea: brings down plt #

-Anagrelide: interferes with terminal differentiation of megas and also decreases # of ptls

Question 18

Polycythemia

Answer 18

Increase in total # of RBC or decrease in plasma volume making the blood more viscous
-Appropriate if in response to Hypoxia, inappropriate if not hypoxic

Question 19

Secondary Polycythemia

Answer 19

• Can be due to increase in alititude, is a response to hypoxic state
• Increase in Epo leading to increased synthesis of RBC
• Can also be caused by localized hypoxia of the kidney

Question 20

Polycythemia Rubra Vera (PRV)

Answer 20

Myeloproliferative disease involving stem cells that are neoplastic w/ loss of all control of proliferation, nothing will inhibit
Common in 50-60yr olds
-Pruritus (itching) is a major symptom
-Thrombosis is a major concern, usually put on low dose aspirin to try and help

Question 21

4H’s of PRV (Goljan)

Answer 21

-Hyperviscosity: increase in peripheral resistance b/c of increase viscosity leads to sluggish circulation
–main cause of thrombosis (biggest problem)
–Why phlebotomies are done
-Hypervolemia: increase in plasma volume that matches increase in RBC syn
-Histonemia: All cells are increased (RBCs, WBC, Plts, Mast and basophils)
–Itching***:cause by increase in mast cells
-Hyperuriacemia: b/c hematopoietic cells are increased and when they die purine is breakdown and uric acid is increased
RBC mass: up, plasma volume: up, Oxygen saturation is Normal, Epo: low

Question 22

Spent Phase of PRV

Answer 22

Eventually may develop:

• Anemia, Leucocyosis, marrow fibrosis, enlarging spleen
• Mimics Myeloidfibrosis at this stage