13 - Acute Leukemia and Myeloproliferative Neoplasms

What is the simple pathophysiology of acute leukemia and how does it lead to the general symptoms?

1. A hematopoietic stem cell or progenitors become mutated and this stops growth into more mature forms + starts dividing rapidly

2. These useless mutated cells fill up the bone marrow and crowd out healthy cells, and this leads to less functional cells: Anemia symptoms due to less RBCs, easy bruising and petechiae due to less platelets, and recurrent infections due to less functioning neutrophils

What kind of differentiation does the leukemic cell undergo?

Clonal proliferation, aka all the cells that are produced by it are the same, non-functioning cell

Acute leukemia(What happens and why)

• Hb and Hct

• RBC morphology

• NRCs

• WBCs

• Platelets

• Decreased because we’re making less RBCs due to the leukemic cells crowding everyone out

• Normochromic normocytic because once made, they’re normal

• Can be increased if there is a stress response to push out NRCs early or if the filter system is affected by the presence of leukemic cells

• Increased overall, even though all normal WBCs like neutrophils go down, the blasts count as WBCs on a measurement

• Decreased due to crowding out and resources being used up

Bone marrow study result in AL

Hypercellular

How many blasts/leukemic cells must there be to warrant diagnosis of AL?

• 20% or more

What does AML and ALL stand for, which one occurs in what age?

1. Acute myeloid leukemia: Adults

2. Acute lymphoid leukemia: Children

What are the 2 best ways to classify acute leukemia?

1. Immunophenotyping: Running a flow cytometry test to see what surface markers are present

2. Cytogenetics: Studying the chromosomes themselves for mutations

What is the difference between recurrent and no recurrent genetic abnormalities types of AML?

The recurrent group normally shows the same mutated genes, and so we can diagnose these patients with AML before their leukemic/blast cell count reaches 20%, because we know they’re prolly gna develop it anyway

Myeloid Sarcoma

• A mass of myeloid blasts forming a tumor in a tissue outside the bone marrow; enough to be a diagnosis of AML on it’s own

4 Ways to diagnose AL:

1. CBC with blasts/leukemic cells >=20%

2. BM study with blasts/leukemic cells >=20%

3. If blasts/leukemic cells are <20% but there are specific recurrent genetic abnormalities

4. Myeloid sarcoma

What is the main difference between AL and MPNs, and what does MPN stand for?

• MPN stands for myeloproliferative neoplasms, and the main difference is that in AL, the mutated stem/progenitor cell blocks differentiation but also drives proliferation of the useless blasts. Meanwhile, MPNs involve only excessive proliferation and the cells still mature normally.

MPNs happen due to activation of ___

Tyrosine kinase signaling pathways

Ph chromosome is found in which MPN most of the time?

• ABL1 gene on chromosome 9 attaches to BCR on chromosome 22

• Found in CML

What mutations typically are seen on PV, ET, and PMF?

• PV: JAK2 mutation

• ET and PMF: JAK2 but also CALR(calreticulin) and MPL(Myeloproliferative leukemia) mutations or can be “triple negative”

What age can we spot MPNs usually?

• Older ages except for CML which can pop up in middle aged people too

CML

• Simple cause

• Explain these symptoms:

  • Anemia

  • Hepatosplenomegaly

  • Visual disturbances

  • Weight loss

  • Bleeding tendency and hypercoagulation

• Ph chromosome causes affected myeloid progenitors to divide out of control

• Anemia: CML causes growth of the granulocytic pathway the most, crowding out RBCs, causing pallor, dyspnea, and tachycardia

• Hepatosplenomegaly: The growth can spread out to extramedullar areas like liver/spleen

• Visual disturbances: The increased WBCs cause hyperviscosity, leading to decreased blood flow to areas like the eye, causing visual disturbances

• Weight loss: The increased production of cells leads to an increase in metabolism which demands more energy

• Bleeding tendency/hypercoagulation: Platelets get increased, causing hypercoagulation but function is often impaired so we can bleed easier

Polycythemia Vera(PV)

• Simple cause

• Explain these symptoms:

  • Visual disturbance/headache/dizziness

  • Thrombosis

  • Erythromelaglia

  • Aquagenic pruritus

  • Plethora

  • Splenomegaly

  • Gout/uric acid

• JAK2 mutation makes JAK2 constitutively active, which leads to overproduction of RBCs

• Visual disturbance/headache/dizziness: Excess RBCs actually make the blood more viscous, making blood flow to organs like the eye and brain worse

• Thrombosis: Thicker blood and also high platelets from the mutation causes body to lead to inappropriate clotting

• Erythromelalgia: Excess RBCs and platelets disrupt flow of the small vessels in hands/feet → pain

• Aquagenic pruritus: Mast cells/basophils get boosted and release too high of histamine leading to itching

• Plethora: Too much blood → red face

• Splenomegaly: Extramedullary hematopoiesis

• Gout/uric acid: More cells → More turnover → More waste products

Essential thromobocythemia(ET)

• Simple cause

• Explain these symptoms

  • Thrombosis

  • Bleeding tendency

  • Erythromelalgia

  • Splenomegaly

  • BUT

• Either JAK2, CALR, MPL mutations lead to an excess bias to the megakaryocytic pathway

  • Thrombosis: Excess platelets → Clotting

  • Bleeding tendency: These platelets don’t plug properly

  • Erythromelalgia: Increase in platelets → small vessels disturbed

  • Splenomegaly: Usually more mild but due to extramedullary hematopoiesis

  • BUT can be asymptomatic

Primary Myelofibrosis(PMF)

• Simple cause:

• Explain these symptoms:

  • Pancytopenia:

  • Hepatosplenomegaly:

  • Weight loss/night sweats/fatigue:

• Simple cause: Same as ET, either JAK2, CALR, or MPL mutations or a triple negative that causes megakaryocytes to release too much growth factors

• Explain these symptoms:

  • Pancytopenia: Fibrosis destroys the marrow’s structure

  • Hepatosplenomegaly: The marrow can’t support production is extramedullary hematopoiesis is super high

  • Weight loss/night sweats/fatigue: Cytokines are chronically released

Which MPN has increased Hb and Hct?

• Polycythemia vera

What kind of RBCs can we often see in PMF?

• Dacroycytes due to RBCs trying to squeeze out of the bone marrow

What are secondary polycythemia, reactive thrombocytosis and reactive marrow fibrosis?

• These are conditions that could be similar to PV, ET, and PMF, but aren’t due to clonal expansion, so we have to rule them out

  • Secondary polycythemia is high RBCs due to either actual need like living in high altitudes, smoking, or a renal tumor that makes more EPO. In these conditions, EPO will be high.'

  • Reactive thrombocytosis: High TPO that happens naturally in inflammation states like infection, surgery/trauma. Usually platelets wont’ be as high as ET

  • Reactive marrow fibrosis: Usually from another kind of disease process, so we have to find out what’s causing the fibrosis

Pre-PMF vs overt PMF

• Basically it’s PMF at an earlier timeline where fibrosis isn’t as bad yet

What if PV, PMF, and CML cells get another mutation?

• If that mutation blocks differentiation, these cells get stuck in blast form and now becomes like AL

Chronic vs blast stage of CML

• Chronic is the initial stage, and blast phase is when the amount of blasts have reached 20% or more, basically to a point where it’s acting like AL now, and it’s very dangerous