Myeloproliferative Neoplasm I

Chapter 18

Myeloproliferative Neoplasm (MPN)

Classification

• Chronic myeloid leukemia (CML)

• Polycythemia vera (PV)

• Essential thrombocythemia (ET)

• Primary myelofibrosis (PMF)

• Chronic neutrophilic leukemia (CNL)

• Chronic Eosinophilic leukemia (CEL)

• Unclassifiable MPN

Chronic Myeloid Leukemia (CML)

• Strongly associates with t(9;22); BCR-ABL1 (Philadelphia chromosome) using FISH or PCR

• Non-inherited diseased that i s prevalent in older adult, and often asymptomatic

• splenomegaly & hepatomegaly, lymphadenopathy, and leukostasis (high blood viscosity)

• Leukocytosis with granulocytic hyperplasia, myelocyte bulge (high myelocyte), pseudo-Pelger-Huet, increased basophils & eosinophils, low LAP score (differentiate from leukemoid reaction)

• 3 Phases

  1. Chronic phase (CP)

  2. Accelerated phase (AP)

  3. Blastic phase (BC)

MPN Classifications

Chronic Phase (CP)

• ≤10% blast count

• Most common diagnosed stage

• High prognosis and responsive to tyrosine kinase inhibitors

Accelerated Phase (AP)

• 10% to 20% blast count

• Worsening symtoms

• Tyrosine kinase inhibitor resistant that limit the TKI effectiveness

Blastic Phase (BC)

• >20% blast count

• Multiple mutation to the BCR-ABL1 proteins

• Poor prognosis, and may progress to AML or ALL

CML Treatment

• Imatinib mesyslate (Gleevec) is the first TKI to prevent BCR-ABL1 fusion gene

• Five TKIs have now been approved: imatinib, dasatinib, nilotinib, bosutinib, ponatinib

• Patient in blastic have less than 30% response rate and have less than 5 year survival rate

• Patient with ALL and Philadelphia chromosome has similar treatment response as blastic phase

Atypical Chronic Myeloid Leukemia (aCML)

• Features both MPN and myelodysplastic syndrome

• Resembles CML in neutrophilic leukocytosis, granulocytic hyperplasia

• No basophilia, no dysplastic features in granulocytic line

• No Philadelphia chromosome, but positive CSF3R mutation

Chronic Neutrophilic Leukemia (CNL)

• Over 80% WBC are neutrophils, high matured cells (band & segmented), low immature cells (blast, metamyelo, myelo promyelo)

• No basophilia, eosinophilia, and monocytosis

• No Philadelphia chromosome, JAK2/CLR/MPL mutations

• Positive CSF3R mutation

Chronic Eosinophilic Leukemia

• Eosinophilia, less than 2% blasts

• No Philadelphia chromosome

• Positive trisomy 8

• Does not respond to TKI therapy

Polycythemia Vera (PV)

• Erythroid hyperplasia leads to high RBC and hemoglobin, thrombosis

• No Philadelphia chromosome

• Positive JAK2 mutation

• Major PV shows increase red cell mass, not just elevate Hb & Hct

• Splenomegaly, plethora (rosy/reddish complexion) from excessive amount of blood

• Associate with iron-deficiency anemia (mycrocytic-hypochromic) due to therapeutic phlebotomy (blood draw), increased RBC production and gastrointestinal blood loss due to platelet dysfunction

• High LAP compared to CML, blood assay for EPO-independent colonies helps confirm diagnosis

• Treatments include therapeutic phlebotomy, aspirin. Cytoreduction therapy (hydroxyurea) controls blood cell count.

Essential Thrombocytopenia (ET)

• High platelet count and anisocytosis (size variation), and megakaryocytes in marrow, no left-shift in granulocytes

• No Philadelphia chromosome

• Positive JAK2 (60%), CALR (30%), MPL(3%) mutation, or triple-negative (12%)

• Higher risk in women

• Platelet clumping that leads to false-low platelet count. Manual count is mandatory

• Need to differentiate from reactive thrombocytosis (presence of inflammatory markers)

• Treatments include plateletpheresis (removal of platelets from blood), cytoreduction (hydroxyurea), and interferon (IFN) targets mutated stem cells

Primary Myelofibrosis (PMF)

• Pancytopenia due to fibrosis, early stage (pre-PMF) may show an increase in all cell types

• No Philadelphia chromosome

• Positive JAK2/CALR/MPL mutation

• Categories as prefibrotic & overfibrotic PMF

• Morphology shows dacrocytes

Relative Erythrocytosis

RBC and hematocrit appear elevated due to plasma volume decrease. In reality, it’s not an increase in erythrocytes.

Absolute Erythrocytosis

• Primary absolute erythrocytosis: The BM marrow proliferates neoplastic RBC independently of EPO such as in the case of PV. EPO level decreases in attempt to suppress the excessive production

• Secondary absolute erythrocytosis: Increased EPO level that directly impacts RBC production

JAK-STAT Pathway

1. Cytokine binds to receptor and activate JAK proteins kinase

2. JAK phosphorylates tyrosine residues on the receptor

3. STAT is recruited to the site

4. JAK directly phosphorylates STAT protein

5. Activated STAT protein forms dimer

6. STAT dimer enters nucleus and bind to DNA prompting cell proliferation & differentiation