Approach to myeloproliferative neoplasms: Clinical sciences

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Introduction0:00–0:43

Myeloproliferative neoplasms are a group of neoplastic conditions characterized by the proliferation of bone marrow cells from the myeloid lineage.
These include red blood cells and platelets, as well as granulocytes, which include neutrophils, eosinophils, basophils, and monocytes.
The expanded cell lines are morphologically normal, meaning there’s no dysplasia, which distinguishes these conditions from myelodysplastic ones.
The four classic myeloproliferative neoplasms include chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and primary myelofibrosis.

Unstable Patient0:43–1:54

Now, if your patient presents with a chief concern suggesting a myeloproliferative neoplasm, first, perform an ABCDE assessment to determine if they are unstable or stable.
If unstable, stabilize their airway, breathing, and circulation. Next, obtain IV access and put your patient on continuous vital sign monitoring, including blood pressure, heart rate, and pulse oximetry.
Finally, if needed, don’t forget to provide supplemental oxygen! Now, here’s a clinical pearl!
Patients with myeloproliferative neoplasms may present as unstable due to several different reasons. The first one is thrombosis.
In fact, some individuals have an increased risk of acquired hypercoagulability, which can result in life-threatening thrombotic events, such as myocardial infarction or pulmonary embolism!
Next, there’s hemorrhage, which can occur due to platelet dysfunction and result in intracranial or gastrointestinal bleeding.
Finally, some individuals can develop acute myeloid leukemia and present with tumor lysis syndrome or acute disseminated intravascular coagulation.

Stable Patient1:54–2:47

Alright, now that we’ve addressed unstable patients, let’s go back to the ABCDE assessment and discuss stable ones. If your patient is stable, perform a focused history and physical examination and order labs, including a complete blood count with differential and a peripheral smear.
Your patient will typically report a history of non-specific systemic symptoms like fatigue, night sweats, fever, and weight loss.
Next, they might report a history of thrombosis or bleeding, while their physical exam often reveals splenomegaly. Complete blood cell count will reveal cytosis, or in other words, erythrocytosis, thrombocytosis, leukocytosis, or a combination of these.
Additionally, the peripheral smear will reveal the elevation of one or more myeloid-lineage cells with no dysplasia! With these findings, you should consider reactive or secondary cytosis and assess your patient for potential causes!

Reactive/Secondary causes2:47–3:21

For example, infections are typically associated with leukocytosis, while anemia and acute inflammation are often characterized by thrombocytosis.
Finally, chronic hypoxia in patients with cardiopulmonary conditions can result in erythrocytosis. If you identify a secondary cause of cytosis, you are dealing with reactive or secondary cytosis and not a primary problem of the bone marrow.

Philadelphia chromosome3:21–3:58

On the other hand, if you identify no secondary causes, this is highly suggestive of myeloproliferative neoplasms. Next, check for the presence of the Philadelphia chromosome by ordering BCR-ABL1 genetic testing.
The Philadelphia chromosome occurs as a result of a translocation that involves the BCR gene in chromosome 22 and the ABL1 gene in chromosome 9, which results in the formation of the BCR-ABL1 gene.
This gene encodes the continuously active tyrosine kinase that stimulates unregulated myeloid cell division and proliferation.

Philadelphia-positive MPN - CML3:58–4:24

If the BCR-ABL1 testing is positive, this means that your patient has a Philadelphia chromosome, so you can diagnose the PH-positive myeloproliferative neoplasm, more specifically chronic myeloid leukemia.
Next, obtain a bone marrow biopsy, which will reveal hypercellularity with proliferation of granulocyte lineage, as well as blasts and, in some cases, fibrosis.
Finally, don’t forget to assess the phase of chronic myeloid leukemia by reviewing peripheral blood and bone marrow findings!

CML phases4:24–5:20

If the peripheral smear reveals less than 20% of basophils, and the bone marrow reveals less than 10% of blasts, diagnose the chronic phase of chronic myeloid leukemia.
Chronic phase CML is relatively indolent and easily controlled with oral medications, but keep in mind these patients might progress to a more advanced phase, so they need to be monitored.
Next, if the peripheral smear reveals at least 20% of basophils or bone marrow with 10-19% of blasts, diagnose the accelerated phase.
Finally, if peripheral smear or bone marrow shows 20% of blasts, diagnose the blast phase. The accelerated phase and the blast phase both represent advanced disease, a more aggressive process that resembles acute leukemia.
Now, let’s go back to BCR-ABL1 testing and take a look at BCR-ABL1-negative individuals. In this case, there’s no Philadelphia chromosome, so you can diagnose Philadelphia-negative myeloproliferative neoplasms.

Ph-negative PMNs5:20–5:50

Next, order additional genetic testing and check for JAK2, CALR, and MPL mutations, which can also result in uncontrolled myeloid cell division and proliferation.
Finally, don’t forget to obtain a bone marrow biopsy. Alright, first let’s take a look at polycythemia vera.

Polycythemia vera5:50–7:58

In this case, labs will reveal erythrocytosis, also known as polycythemia, with persistently elevated hemoglobin levels.
Moreover, biologically male individuals will have hemoglobin greater than 16.5 g/dL, while biologically female individuals will have values greater than 16 g/dL.
Your patient might also have thrombocytosis and leukocytosis. Finally, if the patient is positive for the JAK2 mutation, negative for CALR and MPL, and if the bone marrow biopsy reveals panmyelosis, meaning hypercellularity with hyperproliferation of RBC, WBC, and platelet precursors, diagnose polycythemia vera.
Now, here’s a clinical pearl! Individuals with polycythemia vera often report symptoms due to increased blood viscosity, such as headaches, dizziness, and visual changes.
Additionally, hyperviscosity and turbulent flow of RBCs can cause platelet dysfunction and occlusion of small blood vessels in hands and feet.
As a result, your patient might report episodes of burning pain and redness in their hands or feet, called erythromelalgia.
But, thrombosis can also affect big blood vessels, so patients could also present with deep vein thrombosis, myocardial infarction, and even portal vein thrombosis.
Finally, in polycythemia vera, there’s an increased number of circulating basophils that can lead to aquagenic pruritus, which refers to intense itching, especially after warm showers.
Now, not every erythrocytosis is due to polycythemia vera! One way to differentiate polycythemia vera from secondary erythrocytosis, like hypoxia, is by measuring the serum erythropoietin level.
Patients with polycythemia vera will have a suppressed serum erythropoietin. On the other hand, individuals with secondary erythrocytosis, like hypoxia, produce more erythropoietin to stimulate the bone marrow to pump out more erythrocytes.
Next up is essential thrombocythemia! In this case, labs will reveal persistent thrombocytosis, meaning more than 450,000 platelets per microliter, usually for more than two months.

Essential Thrombocythemia7:58–8:55

Additionally, genetic testing could be positive for the JAK2, CALR, or MPL mutation. Finally, if the bone marrow biopsy reveals no erythroid and granulocytic hyperplasia, with megakaryocytic hyperplasia characterized by hyperlobulated segmented nuclei, diagnose essential thrombocythemia, which is a diagnosis of exclusion.
Now, here’s a clinical pearl! In essential thrombocythemia, individuals typically present with manifestations associated with thrombosis, such as erythromelalgia, as well as ischemia of extremities, myocardial infarction, or pulmonary embolism.
Now, switching gears and moving on to primary myelofibrosis, which is characterized by bone marrow fibrosis! In primary myelofibrosis, abnormal megakaryocytes release growth factors that eventually result in fibrosis and bone marrow suppression, which results in ineffective erythropoiesis and subsequent anemia.

Primary Myelofibrosis8:55–10:47

Additionally, labs will reveal variable levels of WBCs and platelets, depending on the degree of bone marrow fibrosis. Usually they’re elevated in the early stages, but their number drops as the disease progresses.
Additionally, as bone marrow fibrosis progresses, extramedullary hematopoiesis kicks in, producing blood cells outside the bone marrow, typically in the liver and spleen.
As fibrosis occludes and narrows normal bone marrow sinusoids, and as the spleen pumps out erythrocytes through rigid splenic sinuses, both, the bone marrow and spleen deform erythrocytes.
On the peripheral smear, these can be seen as teardrop-shaped RBCs, which are also known as dacrocytes. You may also see a leukoerythroblastic blood smear, characterized by nucleated red blood cells and immature white blood cells.
Next, the genetic testing will reveal a JAK2, CALR, or MPL mutation. In addition, the bone marrow is often difficult to aspirate, yielding a "dry" tap that indicates there’s bone marrow fibrosis.
With these findings in combination with the proliferation of both megakaryocytes and granulocytes, diagnose primary myelofibrosis!
One last clinical pearl! Often, these patients are asymptomatic, but they could also develop thrombotic complications.
Additionally, due to extramedullary hematopoiesis, they will often present with hepatosplenomegaly on physical exam. Alright, as a quick recap… Myeloproliferative neoplasms are a group of neoplastic conditions characterized by the proliferation of bone marrow cells from the myeloid lineage.

Review10:47–11:49

If you rule out reactive and secondary causes of cytosis, you should diagnose myeloproliferative neoplasm and check for the presence of the Philadelphia chromosome.
If your patient has the Philadelphia chromosome, diagnose Ph-positive myeloproliferative neoplasm called chronic myeloid leukemia.
On the flip side, if there’s no Philadelphia chromosome, diagnose Ph-negative myeloproliferative neoplasms, and order additional genetic testing to check for JAK2, CALR, and MPL mutations, and don’t forget peripheral smears and bone marrow biopsy!
Using genetic testing and bone marrow findings you can differentiate polycythemia vera, essential thrombocythemia, and primary myelofibrosis.
Approach to myeloproliferative neoplasms: Video | Osmosis