8/13- Erythrocytosis and Myeloproliferative Disorders Flashcards
What are the myeloproliferative neoplasms (list) and their defining characteristics?
- Chronic Myelogenous Leukemia -increased leukocytes
- Polycythemia Vera- increased erythrocytes
- Essential Thrombocythemia- increased platelets
- Idiopathic Myelofibrosis (Agnogenic Myeloid- -Metaplasia with Myelofibrosis)-variable increased or decreased blood cells
For the following conditions, describe relative numbers of RBCs, WBCs, Megakaryocytes, and fibroblasts:
- Polycythemia vera
- Essentail thrombocythemia
- Idiopathic myelofibrosis
- Chronic myelogenous leukemia
Most common myeloproliferative neoplasm?
Polycythemia vera (?)
TEST TEST TEST TEST
Common Features of myeloproliferative disorders?
TEST TEST TEST TEST
- Acquired mutation in a hematopoietic stem cell
- Clonal hematopoiesis
- Proliferation of granulocytes, red cells and/or platelets
- Splenomegaly (variable)
- Bone marrow fibrosis (variable)
- Possibility of transforming to acute leukemia
Myeloid stem cells give rise to what cells?
- RBCs
- Megakaryocytes/platelets
- Monocytes/macrophages
- Neutrophils
- Eosinophils
- Basophils
What is the evidence for clonality of myeloproliferative disorders?
1. Women with Myeloproliferative disease who are heterozygous for X-linked genes like G6PD express only one isoenzyme in their hematopoietic cells
—T lymphocytes are very long lived, thus T cells (and NK cells) may not be part of th eP vera (or other MPD) clone
2. Philadelphia Chromosome in CML
3. Evolution acute leukemia (usually myeloid, sometimes lymphoid, suggesting SC defect may be pluripotent in SC)
4. To some extent, each of the MPDs can transform into each other
5. JAK2 mutation in PV and other MPDs
Transitions among MPNs?
- All -> acute leukemia
- CML and PV may -> idipathic myelofibrosis
What is JAK2 mutation relevant to MPDs?
- JAK2 is a nonreceptor tyrosine kinase that couples with the erythropoietin and thrombopoietin receptors to mediate intracellular signaling
- Mutations in JAK2 can result in persistent signaling in the absence of ligand binding
- Such signaling can result in uncontrolled cell proliferation
- In PV, ET and MF, a single mutation in JAK2 has been found in many (but not all) patients.
- When mutated, JAK2 is active in the absence of Epo or Tpo, driving cell proliferation (of RBCs or platelets) in the absence of external signals
What is shown here?
Polycythemia vera (Erythrocytosis)
What is Polycythemia?
Erythrocytosis
- Increased number of RBCs
- Normal blood composition ~ WBC: 50 platelets: 700 RBCs
What may cause polycythemia (elevated hematocrit)?
1. Decreased plasma volume (relative polycythemia, as in dehydration/plasma loss)
2. Increased RBC mass (absolute polycythemia)
Can’t tell which it is just from hematocrit
Normal hematocrit level?
43%
Classification of polycythemias how? Causes?
What is primary absolute polycythemia? Ex?
- Abnormality within erythroid progenitors
- Grow in the presence of little or no Erythropoietin (Epo)
- Includes P. vera
What is secondary absolute polycythemia? Ex?
Physiologically appropriate:
- Lung or heart disease, sleep apnea
- High altitude
- Hemoglobin abnormalities
Physiologically inappropriate:
- Tumors that make ectopic Epo (renal, cerebellar, uterine)
- Renal disease/renal transplant
- Certain drugs like anabolic steroids or synthetic Epo
- Cobalt or Nickel exposure (Co interferes with oxygen sensing)
*In most of these, there is a circulating factor mst (commonly epo) that drives erythropoiesis
What is the mechanism and pathophysiology behind congenital polycythemias?
- High oxygen affinity Hb mutants
- 2,3-BPG deficiency
- Congenital methemoglobinemias
- Primary familial and congnital polycythemia (Epo receptor mutations and others)
- Chuvash polycythemia (mutation in the hypoxia signaling pathway)
- Other (unknown cause)
Clinical presentation of polycythemia?
- Symptoms
- Signs
Symptoms:
- Headache
- Thrombosis (venous and arterial)
- Hypermetabolic symptoms (fevers, night sweats, weight loss)
- Pruritis (frequently when taking hot bath)
Signs:
- Plethora
- Splenomegaly
Lab results in polycythemia?
- CBC
- Red cell mass and plasma volume
- Arterial blood gas (pO2, carboxyhemoglobin)
- p50 (by co-oximetry or calculated from venous blood gas)
- Erythropoietin assay
- Assessment of erythroid progenitor response to erythropoietin
Lab diagnosis in polycythemia vera/
Serum Epo Levels
- Low in virtually all pts with PV
- Not specific Jak2 mutation analysis for V617F (95% positive)
- Revolutionized diagnosis (not yet treatment)
Bone marrow
- Hypercellular, absence of stainable iron
- Abnormal karyotype in about 30% (del20q, trisomy 8, or del9p)
Major and minor criteria for diagnosis of Polycythemia vera?
Major:
- Elevated RBC mass (>32 mg/kg females, > 36 mg/kg males)
- Normal O2 saturation
- Splenomegaly
Minor:
- Platelet > 400,000/uL
- WBC > 12,000/uL
- Leukocyte alkaline phosphatases > 100
- Serum vitamin B12 > 900 pg/mL
Diagnosis requires all major criteria OR first 2 major and any 2 minor!!
What is the role of JAK2 in diagnosis?
- The V617F mutation is present in ~95% of all patients with P. vera, most hematologists will now check for this in peripheral blood.
- The test has been integrated into diagnostic criteria for P. vera, but there are still a few JAK-2 negative patients
Treatment of P. vera?
Phlebotomy to hematocrit:
- Men: under 45%
- Women: under 42%
Some may require treatment to lower other counts as well:
- Hydrea
- Interferon
- Anagrelide
Also low dose aspirin (to prevent thrombosis)- still controversial; depends on pt
What is the prognosis for P. vera?
- Average survival: 10-12 yrs
Outcomes:
- Conversion to “spent phase” (myelofibrosis)
- Conversion to acute leukemia (increased risk if alkylating agents used in treatment… not hydroxyurea, though)
- Thrombosis or bleeding (unpredictable)
What is shown here?
Essential thrombocytopenia (excess platelets)
What is the clinical presentation of essential thrombocytopenia?
- Greatest diagnostic difficulty of all myeloproliferative disorders
- Many patients are completely asymptomatic
- No cytogenetic abnormalities
- Only about 50% with JAK2 V617F
- Splenomegaly seen in fewer than 50%
- Morbidity: Thrombotic and/or bleeding problems
Essential Thrombocythemia PVSG Diagnostic Criteria?
- Platelet count > 600,000
- Marked megakaryocytic hyperplasia
- Abundant platelet clumps
- Normal red cell mass (adequate iron)
- No Philadelphia chromosome
- No significant myelofibrosis
What is shown here?
Bone marrow aspirate showing essential thrombocythemia
What is the DDx in thrombocytosis?
- Malignancy (esp Hodgkin’s dz, renal cancer)- MCC in hospitalized pts
- Infections
- Hemolytic anemia
- Collagen-vascular and other chronic inflammatory disorders
- Iron deficiency anemia and bleeding (may just be reactive to this; body wants to plug hole and keep us from bleeding out)
- Rebound thrombocytosis (e.g. after chemo)
- Other myeloproliferative disorders
Is Essential Thrombocyotpenia (ET) clonal or polyclonal?
- Some patients with clinical diagnosis of ET have polyclonal hematopoiesis as determined by X-chromosome inactivation patterns
- Patients with polyclonal hematopoiesis have lower risk of thrombotic complications
Who do we treat in Essential Thrombocytopenia?
Not everyone necessarily requires treatment
- Observation is controversial, but may be appropriate alternative in young females
Consider treatment for:
- Older age
- Higher platelet count (e.g. > 1 million)
- Previous thrombosis risk (smoker, CAD…)
Study results of Bergamo Study:
- Pts with any of the above 3 criteria had fewer thrombotic events when treated
Treatment methods in Essential Thrombocytopenia?
- 32P- NOT USED; increased risk of blast transformation
- Alkylating agents: NOT USED; increased risk of blast transformation
- Hydroxyurea: no obvious risk of blast transformation
- Interferon: may be useful in PREGNANCY
- Anagrelide- inhibition of post-mitotic megakaryocyte development (used occasionally; may be associated with increased bleeding and thrombosis compared to hydroxyurea)
What is shown here?
Idiopathic Myelofibrosis
Some features of idiopathic myelofibrosis?
- Marrow activity outside the bone marrow in areas not active in post-fetal life (myeloid metaplasia)
- Myeloid metaplasia is a primary feature of the disease, not due to crowding out of the marrow by the fibrosis.
- Increased fibrotic activity and reticulin
- Fibroblasts are not part of the “clone”
Clinical presentation of idiopathic myelofibrosis?
Symptoms:
- Hypermetabolic
- Gout
- Bleeding/thrombosis
- Anemia
- Splenomegaly
(- Cachexia)
Signs:
- Splenomegaly
- Hepatomegaly
Diagnosis of Idiopathic Myelofibrosis?
PBS:
- Tear drop red cells (squeezing out of fibrosis)
- Nucleated RBCs
- Immature granulocytes
Bone marrow exam:
- Frequent “dry” tap (hard to suck out against fibrosis)
- Biopsy: hypercellular/fibrosis
Jak2 V617F positive in about 50%
Increased number of circulating CD34+ cells in myelofibrosis pts
What is shown here?
“Teardrop” RBCs
What is shown here?
Marrow fibrosis in Idiopathic Myelofibrosis
- Extreme reticulin and collagen fibrosis of the bone marrow
What is the DDx for Idiopathic myelofibrosis?
Extramedullary hematopoiesis
- Severe hemolytic anemia
- Severe inflammatory rxns
Myelofibrosis
- Tumor invasion of the marrow
- Granulomatous disorders
- infections
- Radiation or Drugs
Treatment for Idiopathic Myelofibrosis?
Stimulators of erythropoiesis
- But run the risk of worsening the splenomegaly
Cytotoxic agents (hydroxyurea)
- Balance decrease in spleen size with decrease in counts
Splenectomy in selected patients
- Some believe this accelerates conversion to leukemia
Thalidomide or Revlimid Ruxolitinib
- Inhibitor of JAK1 and JAK2 Stem Cell Transplant
What is the course and prognosis of Idiopathic Myelofibrosis?
- Average survival: 4-5 years
Common causes of morbidity/mortality:
- Anemia/splenomegaly
- Acute leukemia
- Infections/bleeding/thrombosis
What is this?
PBS in Chronic Myelogenous Leukemia (CML)
- Marked leukocytosis due to increased numbers of myeloid cells in all stages of maturation.
- Basophils may also be present
Clinical presentation of CML?
Symptoms:
- Gout
- Splenomegaly
- Anemia
- Bleeding
- Bone pain
Signs:
- Splenomegaly
Diagnosis of CML?
- All stages of granulocyte maturation in peripheral blood
- Platelets may be elevated
- Bone marrow hypercellular with elevated M:E ratio
- Ph chromosome present
- Decreased LAP (leukocyte alkaline phosphatase) score
- Rule out other causes of leukocytosis
What is the Philadelphia chromosome?
Translocation t(9;22) (q34,q11) causing fusion gene product BCR-ABL on chrom 22 (Philadelphia chromosome)
ABL gene (Chrom 9q)
BCR gene (Chrom 22q)
- Similar to JAK2, the ABL protein is a nonreceptor tyrosine kinase that is involved with signaling in hematopoietic cells
- Like the JAK2 mutant in the other MPDs, the ABL protein in CML is constitutively active preventing apoptosis.
What is the course of events in CML?
- Average survival 3-4 yrs (until recently)
- Chemotherapy- Evolution of Ph0 clone
- Blast crisis
1. Acquisition of the stem cell 9:22 translocation
2. The disease comes to clinical notice.
At this point the Ph clone has a growth advantage and has suppressed hematopoiesis by normal stem cells still in the marrow. In times past, this was the point at which chemotherapy agents would be given to control the counts. This was purely palliative and not curative.
- Patients remained in this so called chronic phase for about 4 years on average.
- Eventually additional cytogenetic abnormalities would develop, sometimes a second Ph chromosome. Counts would be more difficult to control, symptoms would worsen.
- Eventually an acute leukemia would develop known as “blast crisis” This acute leukemia could be myeloid, lymphoid or undifferentiated. These blast crises were and are difficult to treat and are frequently fatal even today.
Treatment of CML?
- Stem cell or bone marrow transplant (seldom used in chronic hase CML except in children or pts who fail other therapies)
- Transplant still done in pts with more advanced disease (accelerated phase or blast crisis)
- Interferon seldom used (except in pregnancy)
- Bisulfan is almost never used nowadays
- Imatinib or gleevec has revolutionized treatment of CML!
Mechanism of action of Imatinib (Gleevec)?
Imatinib is the first in a series of tyrosine kinase inhibitors designed to treat CML
AGAIN (TEST!)
Common featurs of all MPNs?
- Acquired mutation in a hematopoietic stem cell
- Clonal hematopoiesis
- Proliferation of granulocytes, red cells and/or platelets
- Splenomegaly (variable)
- Bone marrow fibrosis (variable)
- Possibility of transforming to acute leukemia
