Author: Stephanie Lakritz, Christopher Geiger, Brandon McMahon

Section editor: Christopher Geiger

Executive editor: Yilin Zhang

Objectives
1. Diagnose the four most common myeloproliferative disorders
2. Develop a framework and differential for erythrocytosis, leukocytosis, and thrombocytosis
3. Describe the basic principles of treating myeloproliferative disorders

Teaching Instructions
Plan to spend at least 30-60 minutes preparing for this talk by using the Interactive Board and
clicking through the graphics animations to become familiar with the flow and content of the
talk. All clickable elements are denoted by a rounded shaded rectangle and mouse cursor. There are
questions that serve as prompts to engage the audience.

Begin with reviewing the objectives for the session. We recommend progressing in order, though
this gives you the flexibility to deliver more focused teaching. The anticipated time it will take to
give the talk is ~30-45 minutes to teach.

Overview
Ask your learners “What is a MPN?” and click to reveal the answer. Hematologic malignancies are
differentiated into myeloid and lymphoid neoplasms. A subset of hematologic malignancies includes
myeloproliferative disorders which are diseases of the hematopoietic stem cell leading to the
overproduction of mature cells. This differs from a myelodysplastic syndrome where there is a
disease of the hematopoietic stem cell leading to abnormal maturation.

The flow chart reviews normal hematopoiesis. Click on “what are the most common MPNs” to
reveal the answer. Overproduction of thrombocytes (or platelets) leads to essential thrombocytosis
(ET). Overproduction of erythrocytes leads to polycythemia vera (PV) (this is, however, an
oversimplification as leukocytosis and thrombocytosis are commonly seen as well). Overproduction
of mature granulocytes leads to chronic myeloid leukemia (CML). And finally, when the bone
marrow is replaced by connective tissue, it can lead to primary myelofibrosis (PMF). These are the 4
most common MPNs. Each of the MPNs can transform into an aggressive form of bone marrow
failure or acute leukemia. ET, PV, PMF are often grouped together because they are associated with
3 common driver mutations.

Essential thrombocythemia
Click on “what is ET?” to reveal the answer. ET is a disorder in which there is an increase in clonal
production of platelets. It is associated with one of three driver mutations including JAK2, CALR, MPL.
However, 10-20% of cases have no mutation that can be identified.
 Signs/symptoms: Ask your learners what signs and symptoms are associated with ET and click on
“Sign/symptoms?” to reveal the answer. Clinically, ET may present with vasomotor symptoms,
TIAs, ocular migraines, or 1st trimester pregnancy loss. Arterial or venous thromboses may occur
but are less common. Some patients may be asymptomatic, and it is first discovered on a CBC. If
the patient is negative for all three driver mutations (triple negative), a bone marrow biopsy
may be necessary to confirm the diagnosis as thrombocytosis can be seen in others MPNs.
 Differential Diagnosis: The differential for thrombocytosis includes reactive versus primary
thrombocytosis. Challenge learners to come up with examples of reactive thrombocytosis
 before clicking to reveal the answer. Reactive causes include iron deficiency anemia (commonly
missed), in addition to infection/inflammation and post-splenectomy state. Primary causes
include all 4 MPNs discussed in this talk.
 Treatment: The goal of treatment for ET is to prevent thrombosis. The magnitude of
thrombocytosis does not increase the risk of thrombosis (or bleeding). Thrombocytosis alone
without a diagnosis of ET does NOT warrant aspirin therapy. The treatment for ET depends on if
the patient is low risk or high risk for thrombosis. If low risk, one can manage with active
surveillance and low dose aspirin. If high risk, the patient will likely need aspirin therapy or
anticoagulation depending on thrombosis history (venous vs arterial) and may need a
cytoreductive agent (like hydroxyurea or pegylated interferon) as well.

Polycythemia vera (PV)

This is the most common type of all the MPNs. Click on “what is PV” to reveal the answer. Although
a hallmark of PV is erythrocytosis, commonly leukocytosis and thrombocytosis are seen with PV as
well. Over 95% of patients have the JAK2 V617F mutation.
 Signs/ Symptoms: Challenge your learners to come up with symptoms of PV before clicking
to reveal the answer. Symptoms may include headaches, aquagenic pruritus, thrombosis,
hemorrhage (from acquired von Willebrand’s disease), TIAs or ocular migraines. It should be
suspected in males with Hgb >16.5, females with Hgb >16, a 25% rise in typical RBC mass, or
if patient develops arterial or venous thrombosis. Maintain a high level of suspicion for PV in
patients with a diagnosis of Budd-Chiari syndrome, portal vein thrombosis, splenic vein
thrombosis, or mesenteric vein thrombosis as these conditions can result in portal
hypertension which may mask the laboratory signs of PV.
 Physiology of erythrocytosis : To review other etiologies of erythrocytosis, it is important to
understand the normal response to hypoxemia. In the setting of low oxygen in the blood (1),
specialized cells in our kidneys (2) produce a hormone called erythropoietin (EPO) (3). This
hormone stimulates our bone marrow (4) to produce more red blood cells (5) and thus can
lead to an increase in the red blood cell mass.
 Differential Diagnosis: Causes of erythrocytosis can be separated into relative
erythrocytosis, secondary erythrocytosis and PV. Prompt learners to identify the primary
problem in each type of erythrocytosis, give examples and determine what the measured
EPO level would be. Click on each button until the mouse cursor disappears.
o Relative erythrocytosis is from hemoconcentration of the blood from dehydration
(diuretics, vomiting, diarrhea). The graphic shows why measured hematocrit/
hemoglobin concentration would be higher in a patient who is dehydrated. EPO level
in relative erythrocytosis is unchanged/normal.
o Secondary erythrocytosis may be due to hypoxemia (COPD/OSA, high altitude, RAS)
or elevated EPO levels (typically from EPO secreting tumor such as HCC, RCC, or
pheochromocytoma). EPO levels in secondary erythrocytosis are elevated.
o PV – in PV, the primary problem is at the level of the bone marrow. As a result, there
is a negative feedback mechanism which suppresses EPO production. It is important
to note that although EPO level is typically suppressed in PV, it may also be normal
in as many as 15% of patients. EPO level is not the most sensitive or specific test;
however, it may point you in the direction of the most likely diagnosis.
 Treatment: The basics of treatment for polycythemia vera are to prevent complications such as
thrombosis. Patients are risk stratified into high or low risk depending on age and history of
thrombosis. The mainstay of treatment includes phlebotomy and low dose aspirin. If high risk,
you could consider adding a cytoreductive agent (such as hydroxyurea or pegylated interferon).
Primary Myelofibrosis (PMF)
Ask learners what they recall about PMF before clicking on “What is PMF”. This myeloproliferative
disorder occurs when the bone marrow is replaced by connective tissue or fibrosis. It is associated with
one of three driver mutations including JAK2, CALR, or MPL and can develop from other MPNs (PV or
ET). When the bone marrow is replaced by fibrosis it can lead to extramedullary hematopoiesis.
 Signs and symptoms include hepatosplenomegaly, bone pain, anemia (from low red blood cells),
bleeding (from low platelets), infections (from low white blood cells).
 Ask learners what they would expect to see on a peripheral smear or a bone marrow biopsy in a
patient with myelofibrosis. Click on each of these to reveal the answer. Teardrop cells
(dacrocytes) and a “dry tap” are classic findings.
 Treatment: The only known curative treatment option for PMF is hematopoietic stem cell
transplant. This is reserved for patients with poor prognostic features who are good transplant
candidates. Online tools exist to help predict outcomes and prognosis after HSCT (Here is an
online example: http://www.mipss70score.it/).
o Overall, If the patient has a good prognosis, they may be monitored with active
surveillance and symptom control for cytopenias with transfusions. EPO stimulating
agents can be considered for patients with transfusion dependent anemia.
o If the patient is transplant ineligible with poor prognosis, you can consider Janus Kinase
inhibitors (such as ruxolitinib) or hydroxyurea.

Chronic myeloid leukemia

Ask your learners to come up with what they know about CML before clicking on “What is CML” to
reveal the answer. CML is a malignancy associated with an increase in mature granulocytes
(neutrophils, basophils, eosinophils). CML is associated with BCR-ABL fusion gene also known as the
Philadelphia Chromosome. This mutation leads to an increase in tyrosine kinase activity. Although
granulocytes in CML are morphologically normal, they are cytochemically abnormal and have a low
leukocyte alkaline phosphatase (LAP) score.
 Differential of leukocytosis: Typically, the work up for CML begins when leukocytosis is
discovered on a complete blood count. Challenge learners to come up with a differential for
leukocytosis including a leukemoid reaction (infections, stress, medications, tobacco use,
etc) vs malignant etiologies. A history that may be more suspicious for CML include
constitutional symptoms (weight loss, fever, fatigue), abdominal fullness. Labs that are
suspicious for CML include neutrophilia with a left shift, basophilia, or eosinophilia without a
clinical suspicion for a leukemoid reaction. Although the WBC can be high in CML
(>100,000), leukostasis is much rarer compared to similar WBC levels seen in acute
leukemia.
 Natural disease course of CML: That natural disease course of CML without treatment
includes a chronic phase, an accelerated phase, and a blast crisis (which can resemble acute
leukemia). However, with treatment, many patients can have normal life expectancies.
Most patients are diagnosed in the chronic phase (85% of patients) and can be
asymptomatic when diagnosed.
 Treatment: The treatment for CML is typically a tyrosine kinase inhibitor (TKI). Imatinib was
the first TKI approved for CML and revolutionized treatment for what was previously
thought of as a fatal disease. There are now multiple approved next generation TKIs. If
patients develop resistance to a TKI (seen on BCR/ABL1 testing), they may be switched to
another TKI. Allogeneic stem cell transplantation is now very rare and only considered if the
patient fails later lines of therapy. The blast phase of CML may require induction
chemotherapy (like acute leukemia) in addition to TKI. Patients can be monitored for
 BCR/ABL levels using the peripheral blood in order to track responses to treatment and
need for resistance mutation testing.
 Leukemias - Click on the "Leukemias" button in the left hand table of contents to learn more
about different types of leukemia. Click on each type of leukemia until the cursor disappears
to learn more about demographic, diagnosis, and complications. If the patient history and
labs are concerning for malignant etiologies, it will be important to further differentiate the
four main types of leukemias – AML, CML, ALL, CLL. The following table helps to show the
main findings on peripheral smear and bone marrow biopsy that you would expect to see in
the four broad categories of leukemias. It is important to highlight the classic smear findings
in addition to number of blasts in the bone marrow, demographics, and other unique
features. Of note, acute leukemias may develop leukostasis or hyperleukocytosis, which are
hematologic emergencies, but these complications are much less likely with CML and CLL
(which often can tolerate higher WBC levels).

AML CML ALL CLL

Peripheral smear Myeloblasts Eosinophilia/ Lymphoblasts Lymphocytosis
Auer rods basophilia Smudge cells
Median WBC 100k
Bone marrow >20% myeloblasts Granulocytic >20% Lymphocytic
hyperplasia lymphoblasts hyperplasia
Typically <20%
myeloblasts
Demographic Adults > children Median age 50
Unique features DIC (especially in T(9;22) BCR-ABL1  Can infiltrate  Can infiltrate
APML) fusion lymph nodes lymph nodes
 CNS infiltration  Richter
(needs LP prior transformation
to treatment) (high grade
lymphoma)
 Autoimmune
cytopenias

Take Home Points

1. There are four main types of myeloproliferative disorders: polycythemia vera, essential
thrombocythemia, chronic myeloid leukemia, and primary myelofibrosis
2. An erythropoietin level can be useful in distinguishing secondary polycythemia from
polycythemia vera
3. Treatment of myeloproliferative disorders typically depends on risk stratification (PCV/ET) and
prognosis (MF). CML treatment is highly effective.

References
1. Tefferi, A. & Pardanani, A. Myeloproliferative Neoplasms A Contemporary Review. JAMA Oncol.
2015; 1(1):97-105. Doi:10.1001/jamaoncol.2015.89
2. Spivak, JL. Myeloproliferative Neoplasms. NEJM. 2017; 3782168-81.
3. Heim, D., Ebnöther, M., & Favre, G. (2019). Chronische Myeloische Leukämie – Update 2020
[Chronic myeloid leukemia - update 2020]. Therapeutische Umschau. Revue
therapeutique, 76(9), 503–509. https://doi.org/10.1024/0040-5930/a001124
4. Levine, R. L., & Gilliland, D. G. (2008). Myeloproliferative disorders. Blood, 112(6), 2190–2198.
https://doi.org/10.1182/blood-2008-03-077966
5. Meier, B., & Burton, J. H. (2017). Myeloproliferative Disorders. Hematology/oncology clinics of
North America, 31(6), 1029–1044. https://doi.org/10.1016/j.hoc.2017.08.007
6. Tefferi, A., & Pardanani, A. (2019). Essential Thrombocythemia. The New England journal of
medicine, 381(22), 2135–2144. https://doi.org/10.1056/NEJMcp1816082
7. Vannucchi, A. M., Guglielmelli, P., & Tefferi, A. (2018). Polycythemia vera and essential
thrombocythemia: algorithmic approach. Current opinion in hematology, 25(2), 112–119.
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