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What is the basis of myeloproliferative diseases?

chronically proliferating clones which DIFFERENTIATE AND PROLIFERATIVE to MATURE circulating blood cells. So, for some reason you have a proliferation of a certain lineage of cells out of the BM


Two major myeloid lineage myeloproliferative diseases?

1) CML- chronic myelogenous leukemia

2) CMML- chronic myelomonocytic leukemia


Some characteristics of CML:

-High WBC
-All stages of granulocyte maturation end up in blood


Some characteristics of CMML:

-High WBC, monocytes, and promonocytes
-Weird hybrids between monocytes and granulocytes


What are two types of rare myeloproliferative neoplasms which present with an elevated eosinophil count?

CEL and PDGFR-related neoplasms.

REMEMBER: the two types respond differently to different therapies.


What two myeloproliferative diseases often present with thrombosis?

1) polycythemia vera (form erythroid line)- elevated red cell count

2) Essential thrombocythemia or Primary myelofibrosis - elevated platelet count


What things would make you suspect sepsis vs. myeloproliferative disease ?

A high WBC with toxic granulation and no left shift

If the typical symptoms of pneumonia are present, it’s easy to tell that the patient is unlikely to have a myeloproliferative disease. But what if the clinical signs of infection are weak, or ambiguous?

A review of the peripheral smear can help. Toxic granulation and a “left shift” composed of progressively fewer cells representing the more immature precursors (bands > metamyelocytes > meylocytes) supports an infectious etiology.

i.e. bands=20, metamyelo=15, myelocytes=10


What things would make you suspect myeloproliferative disease vs sepsis?

A patient with the same total white count, no evidence of toxic granulation, and more myelocytes than metamyelocytes (a “myeloid bulge”) is more likely to have a myeloproliferative neoplasm.

i.e. bands=15, metamyelo= 10, myelocytes= 20


What does the bone marrow of CML patients look like?

-many myeloid precursors,
-little in the way of dysplasia
-no increase in blasts.


How is CML diagnosed?

-RT-PCR positive assay for the BCR-Abl1 fusion protein, and you can do that with peripheral blood.
-follow up with BM biopsy to gauge progression

Because CML is treatable, you need to have a low threshold of suspicion for sending the RT-PCR assay. You should send enough of them that you get more negative results than positives, because the cost to the patient of missing the diagnosis is high.


How is treatment efficacy in CML determined? What is the treatment?

Treatment is Imatinib.

whether the fusion transcript is detectable by RT-PCR (a “complete molecular response”, down to levels at which the abnormal transcript is present at less than 0.001% of the normal parent transcripts).


Molecular diagnostics are excellent, but you still need to get a bone marrow biopsy when you diagnose CML. Why?

Because CML patients can progress to an accelerated phase (via more mutations), with increased blasts in the marrow, and then to a “blast phase” that is essentially the same as an acute leukemia (usually myeloid, sometimes lymphoid). At diagnosis, and occasionally during treatment, you need to make sure they’re not progressing.

If you miss the diagnosis, or let the condition slip by for a year or two before making the diagnosis and checking the status of the bone marrow, you increase the risk that the patient will progress to an acute leukemia.


So, what is the overall workup order in suspected CML?

1) CBC and manual diff
2) Suspect CML
3) RT-PCR of peripheral blood sample for BCR-Abl1
4) Bone marrow biopsy


What is Polycythemia Vera?

myeloproliferative disease resulting in increased red cell counts


What is the pathogenic basis of Polycthemia vera?

Activating Jak2 mutations in >95% of cases mimics the presence of EPO in a clone of committed erythroid progenitors– detectable in peripheral blood leukocytes.

Some patients have mutations in the Epo receptor instead (Mpl)


Precise designation for the PV mutation?


Molecular testing for this mutation is standard of care in suspected P vera cases and, and finding the mutation is diagnostic of P vera.


Clinical presentation of PV?

-Elevated red cells
-Thrombosis/hypertension/stroke or MI.

Increased RBC’s can also be due to lung disease!


How do you differentiate between increased red cells in PV and lung disease?

If an increased red cell count occurs due to lung disease, it will be associated with increased serum EPO levels. In P vera, it will not.


Immunophenotype of PV?

No known features (no red cell markers)


Prognosis of PV? Progression?

-10+ yr survival is common (14yr survival average)
-can progress to myelofibrosis, MDS, acute leukemia


What is an important fact about the morphology of PV?

megakaryocytes as well as the erythroid precursors are increased in number in P vera (normally myeloid precursors outnumber the erythroid ones by better than 2:1).


What is the pathophysiology of PV?

Constitutively active mutants of the Type 1 hematopoietic growth factor receptor complex with is a JAX/STAT system


Note on JAX/STAT system

For example, if the cytokine/receptor complex EPO and EPO-R, the transcription pattern generates red cell precursors.

For TPO and its receptor (Mpl), the result is proliferating megakaryocyte precursors.

Why you need to know this: acquired mutations in the receptors, or in the Jak-2 kinase, are clinically relevant – paticularly when they result in constitutive activation of these signal transduction pathways. If that were to occur in a self-sustaining clone of CFUs, you ought to be able to predict the result: excess, unregulated production of red cells, or platelets, or both.


What is the major cause of Essential Thrombocythemia?

Jak2 V617F mutations in ~50% of cases– detectable in peripheral blood leukocytes;

Mutations in another gene (calreticulin) occur in ~25%.


What is the clinical presentation of ET?

increased platelet counts (thrombosis risk)


When else are platelet counts elevated?

Increased platelets can also be due to iron deficiency, infection, chronic inflammation.

Much more common in these situations than in ET.


What is a major difference in the morphologic of ET vs. P. vera?

The Megs in ET look very abnormal and large


Prognosis of ET? Progression?

Prognosis: > 10 yr survival is common;
-can progress to myelofibrosis, MDS, acute leukemia


What is Primary myelofibrosis caused by?

see mind map (neoplastic and non-neoplastic common)

Jak2 mutations in ~50% of cases- detectable in peripheral blood leukocytes


Why is PM hard to diagnose?

This condition can be hard to diagnose because the CBC findings are quite variable: anemia is common, as is thrombocytosis, but they can also show a leukocytosis OR a leukopenia.

Review of the peripheral smear is usually the critical diagnostic step because it will show leukoerythroblastic findings (as discussed in my first presentation on blood cells). That in turn will inspire you to biopsy the bone marrow (as it always should).