Myelo- Syndromes Flashcards
Key myeloproliferative syndromes include:
Polycythemia vera
Essential Thrombocytosis
Myelofibrosis
CML
Erythrocytosis:
An increase in the number of circulating RBCs per volume of blood.
Synonym: polycythemia
What is hyperviscosity syndrome, and what symptoms are associated with it?
- 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
Secondary erythrocytosis:
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
Erythrocytosis due to appropriate increases in EPO:
(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
Myeloproliferative disorders are _____ disorders leading to autonomous production of hematopoietic cells from ____ lineages.
Myeloproliferative disorders are stem cell disorders leading to autonomous production of hematopoietic cells from all three lineages. (red cells, white cells, platelets)
All of the myeloproliferative disorders are ____
clonal
What is Polycythemia vera?
- 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.
•The erythroid progenitor cells of patients with P. vera, are capable of growing and dividing in the absence of _____
erythropoietin
How is P vera diagnosed?
•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
JAK2 V617F
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
Describe the progression of P vera if untreated:
•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
Symptoms associated with P vera
•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
Physical exam findings in patients with P vera
•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
P. vera lab findings:
•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
P vera treatment:
•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
Pros/cons of P vera treatment with phlebotomy:
•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
Essential Thrombocytosis:
- 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
How is ET diagnosed?
•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
Complications of ET:
- 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
Symtoms of ET:
- Many patients are asymptomatic at time of diagnosis
- Digital ischemia from microvascular thrombi
- Erythromelalgia
- Pruritis
- Hemorrhage - seen in 40% of pts
Lab findings with ET:
- 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
ET treatment:
- 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.
Myelofibrosis is a ____ disorder affecting ____
Clonal stem cell disorder affecting megakaryocytes predominantly
All myeloproliferative disorders can result in a ___ phase which can be difficult to distinguish from primary ___
All myeloproliferative disorders can result in a spent phase which can be difficult to distinguish from primary MF
Myelofibrosis patient outcome
•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.
Myelofibrosis physical findings:
Massive splenomegaly
Hepatomegaly
Myelofibrosis lab findings:
- 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
What is shown in this smear?
This is a leukoerythroblastic smear
(seen in patients with myelofibrosis)
What is shown in this image?
This is a reticulin stain, which shows a ton of black-staining reticulin fibers.
This is a patient with myelofibrosis.
What is the treatment for myelofibrosis?
- 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.
A 65 y/o man presents with a platelet count of 600. What are his possible diagnoses?
P vera
Essential Thrombocytosis
Iron deficiency
Rheumatoid arthritis
What are myelodysplastic syndromes?
- 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
Myelodysplastic syndrome clinical features:
•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.
What are the lab findings in a patient with myelodysplastic features?
- 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
What are the findings of a bone marrow biopsy in a patient with myelodysplastic syndrome?
•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)
What cytogenic abnormalities are associated with MDS?
- 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
Treatment/prognosis of patients with MDS:
•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.
