Myelo- Syndromes

Question 1

Key myeloproliferative syndromes include:

Answer 1

Polycythemia vera

Essential Thrombocytosis

Myelofibrosis

CML

Question 2

Erythrocytosis:

Answer 2

An increase in the number of circulating RBCs per volume of blood.

Synonym: polycythemia

Question 3

What is hyperviscosity syndrome, and what symptoms are associated with it?

Answer 3

• Some pts with erythrocytosis (from whatever cause) develop this syndrome.
• Erythrocytosis with hyperviscosity symptoms should be treated with phlebotomy.
• Symptoms include:
• Headaches
• Visual changes
• Tinnitus
• Dizziness
• Paresthesias
• Decreased mental acuity

Question 4

Secondary erythrocytosis:

Answer 4

These conditions tend to lead to erythrocytosis because tissue hypoxia induces erythropoietin (epo) production by the kidney.

Other less common causes of increased erythropoietin levels include liver or kidney tumors which secrete erythropoietin, rare genetic disorders (eg a familial mutation in the epo receptor, making it constitutively active), and drug treatment with either androgens or erythropoietin.

Here, there is not a risk of blood clots, since the blood is being produced by a normal stimulus

Question 5

Erythrocytosis due to appropriate increases in EPO:

Answer 5

(These all include tissue hypoxia)

• Life at high altitude
• High affinity hemoglobins
• Cardiopulmonary disease leading to hypoxia
• Obesity-Hypoventilation syndrome

•Obstructive sleep apnea

•High carboxyhemoglobin levels

Question 6

Myeloproliferative disorders are _____ disorders leading to autonomous production of hematopoietic cells from ____ lineages.

Answer 6

Myeloproliferative disorders are stem cell disorders leading to autonomous production of hematopoietic cells from all three lineages. (red cells, white cells, platelets)

Question 7

All of the myeloproliferative disorders are ____

Answer 7

clonal

Question 8

What is Polycythemia vera?

Answer 8

• Definition: A neoplastic disorder arising from a pluripotent stem cell, generally characterized by erythrocytosis, with or without thrombocytosis and leukocytosis.
• Incidence 10 new cases per million
• Highest incidence in ages 50-75, but 5% occur in pts <40 y.o.

Question 9

•The erythroid progenitor cells of patients with P. vera, are capable of growing and dividing in the absence of _____

Answer 9

erythropoietin

Question 10

How is P vera diagnosed?

Answer 10

•Low or undetectable erythropoietin level

•JAK2 mutation

• JAK 2 is a tyrosine kinase which functions immediately downstream of the growth factor receptors. It is activated once the growth factor receptor gets turned on.
• In 2005, investigators found a mutation JAK2 V617F, which causes loss of auto-inhibition, leading to constitutive activation of JAK2, thus causing unregulated signaling thru growth factor receptors

Question 11

JAK2 V617F

Answer 11

JAK2 V617F has been found in

• 99% of P vera
• 60-65% of ET and myelofibrosis
• Some people with MDS and acute leukemia
• No normal patients

•Next steps:

• Determine causality and clinical implications
• Find effective inhibitors of JAK2

Question 12

Describe the progression of P vera if untreated:

Answer 12

•Latent phase - asymptomatic

•Proliferative phase - pts may be hypermetabolic or have sx of hyperviscosity or thrombosis

•Spent phase - anemia, leukopenia, secondary myelofibrosis, increasing liver and spleen size, fevers, weight loss

•Secondary AML

• 1-2% of pts treated with phlebotomy alone
• Certain drug therapies increase risk

Question 13

Symptoms associated with P vera

Answer 13

•Symptoms common to all erythrocytosis:

• Headache, decreased mental acuity, weakness

•Sx more specific to P vera and myeloproliferative diseases.

• Pruritis after bathing (super itchy)
• Erythromelalgia (palms/soles of hands and feet burning)
• Hypermetabolic symptoms
• Thrombosis (arterial or venous)
• Budd-Chiari syndrome (thrombosis of the hepatic vein) is associated with P vera and other MPNs (It’s also associated with PNH)
• Hemorrhage

Question 14

Physical exam findings in patients with P vera

Answer 14

•Facial plethora (fullness and redness in the face)

•Splenomegaly (gets worse with time)

• found in 70% of pts

•Hepatomegaly

• 40% of pts

•Distension of retinal veins

Question 15

P. vera lab findings:

Answer 15

•CBC:

• ­elevated Hgb/Hct
• ­elevated WBC in 45%
• ­elevated Plts (in 65% of patients)
• Basophilia (can be seen in all MPDs)

•­Elevated uric acid (can lead to gout) and B12

•Low EPO levels

•Positive JAK2 V617F

Question 16

P vera treatment:

Answer 16

•Phlebotomy

•Myelosuppressive agents:

• Hydroxyurea
• Alkylating agents such as busulfan
• 32P

•Interferon alpha

•Low dose aspirin has been found to decrease the risk of thrombosis in PV, and should be given to almost all patients

Question 17

Pros/cons of P vera treatment with phlebotomy:

Answer 17

•Generally, the best initial treatment for P vera

• No increase in progression to AML
• Rapid onset
• No marrow suppression
• Remove 500 cc blood 1-2x/wk to target Hct 45%, then maintain
• Downsides:
• Increased risk of thrombosis
• No effect on progression to spent phase
• May be insufficient to control disease

Question 18

Essential Thrombocytosis:

Answer 18

• Incidence is similar to P vera
• 20% of pts are <40 y.o.
• Exact pathophysiology is unclear
• 90% have a somatically acquired driver mutation in either JAK2, CALR, or MPL
  
  • •JAK2 V617F
  • •CALR (calreticulin)—mutated protein will activate MPL
  • •MPL—the thrombopoietin receptor—when mutated, is constitutively active

Question 19

How is ET diagnosed?

Answer 19

•First, rule out secondary causes of thrombocytosis:

• cancer
• Infection
• inflammation
• bleeding
• iron deficiency
• Platelet count should be >450 on 2 separate occasions, at least 1 month apart
• Exclude CML by absence of Philadelphia chromosome
• JAK2 is positive 60-65% of the time
• Abnormal bone marrow biopsy

Question 20

Complications of ET:

Answer 20

• Rarely progresses to AML (progression in <1% of pts)
• May progress to secondary myelofibrosis
• Major complication is thrombosis
• Occurs in 20-30% of patients
• Clots may be arterial or venous

Question 21

Symtoms of ET:

Answer 21

• Many patients are asymptomatic at time of diagnosis
• Digital ischemia from microvascular thrombi
• Erythromelalgia
• Pruritis
• Hemorrhage - seen in 40% of pts

Question 22

Lab findings with ET:

Answer 22

• Iron studies should be normal, as should the sedimentation rate, which is a measure of inflammation.
• Platelets can be very large and bizarrely shaped
• Marrow shows clusters of abnormal megakaryocytes.
• 60-65% may have JAK2 mutation
• CALR or MPL may be mutated

Question 23

ET treatment:

Answer 23

• Use hydroxyurea, anagrelide, or interferon alpha
• Treatment targeted at reducing the platelet count.
• Whom to treat is controversial.
• In general, treat those who have had or are at risk for thrombosis, those >65 y.o
• Why treat?
• In pts at risk for thrombosis, Rx reduces risk of thrombosis and maybe secondary myelofibrosis.

Question 24

Myelofibrosis is a ____ disorder affecting ____

Answer 24

Clonal stem cell disorder affecting megakaryocytes predominantly

Question 25

All myeloproliferative disorders can result in a ___ phase which can be difficult to distinguish from primary \_\_\_

Answer 25

All myeloproliferative disorders can result in a **spent** phase which can be difficult to distinguish from primary **MF**

Question 26

Myelofibrosis patient outcome

Answer 26

•Natural History * Median survival is 5 yrs * Transforms into AML in 5-20% •Symptoms * \>50% pts present with sx of anemia and thrombocytopenia * Pts may have fever, sweats, wt loss * As spleen enlarges (from EMH), pts may have abdominal pain, early satiety.

Question 27

Myelofibrosis physical findings:

Answer 27

Massive splenomegaly Hepatomegaly

Question 28

Myelofibrosis lab findings:

Answer 28

* Early on, pts may have high­ platelets and normal Hgb and WBC. * Anemia, and low Plts and low WBC seen as disease progresses * Peripheral smear shows **leukoerythroblastic** picture, with **teardrops, NRBC and early granulocytes** * “Dry tap” or inability to aspirate liquid marrow frequently seen * Increased collagen and reticulin fibrosis on bone marrow biopsy

Question 29

What is shown in this smear?

Answer 29

This is a leukoerythroblastic smear | (seen in patients with myelofibrosis)

Question 30

What is shown in this image?

Answer 30

This is a reticulin stain, which shows a ton of black-staining reticulin fibers. This is a patient with myelofibrosis.

Question 31

What is the treatment for myelofibrosis?

Answer 31

* There is no definitive therapy * If patient is young, BM transplant can be done, but older patients have too high mortality * Rx is supportive, with transfusions * Splenectomy can be done for sx of abdominal pain, but frequent complications of thrombosis, hemorrhage, and infection.

Question 32

A 65 y/o man presents with a platelet count of 600. What are his possible diagnoses?

Answer 32

P vera Essential Thrombocytosis Iron deficiency Rheumatoid arthritis

Question 33

What are myelodysplastic syndromes?

Answer 33

* Definition: Conditions in which there is **disordered maturation** in 1 or more cell lines, usually producing cytopenias * Population of dysplastic cells represent an **abnormal clone of cells.** With time, the clone can remain stable or progress, generating further clones with worsening cytopenias and further cytogenetic abnormalities

Question 34

Myelodysplastic syndrome clinical features:

Answer 34

•This is a disease of the elderly. In pts older than 60, incidence is 1 in 1500 •Some pts are diagnosed because of abnormal CBC findings (low counts). Some present because of symptomatic anemia or thrombocytopenia.

Question 35

What are the lab findings in a patient with myelodysplastic features?

Answer 35

* Any cell line or combination of cell lines can be affected. * Peripheral cell abnormalities * **Macrocytosis of RBCs** (with a normal B12/folate) * **Neutrophils can be hypogranular or bi-lobed.** * Can have **monocytosis**

Question 36

What are the findings of a bone marrow biopsy in a patient with myelodysplastic syndrome?

Answer 36

**•Megaloblastic erythropoeisis** **•Ringed sideroblasts** •Abnormal nucleus of RBC precursors (**dyserythropoiesis**) **•Small megakaryocytes** with abnormally hypolobated nuclei **•Blast cells should account for \<20% of marrow cells** (if above 20%, is considered AML)

Question 37

What cytogenic abnormalities are associated with MDS?

Answer 37

* Monosomy 5, 7, or 8 can be seen * Deletion of the long arm of 5 is associated with a better prognosis * Complex cytogenetics (many many abnormalities) has a very bad prognosis

Question 38

Treatment/prognosis of patients with MDS:

Answer 38

**•Treatment is usually supportive** **•Transfusions of RBCs and platelets** as necessary **•Growth factors** (epo and G-CSF) can help with some of the cytopenias * Thalidomide and derivatives may help relieve some transfusion dependence in a subset of pts. * Certain agents which cause **DNA hypomethylation** can lead to remission. **•Once the patient develops AML, the chances of achieving remission are decreased, and the duration of any remission is much shorter.**