263. Myeloproliferative Disorders, CML Flashcards
What are the four myeloproliferative disorders and what 5 common features are shared?
- Essential Thrombocythemia (ET)
- Polycythemia Vera (PV)
- Primary Myelofibrosis (PMF)
- Chronic Myeloid Leukemia (CML)
- Stem Cell Diseases
- Thrombotic AND Hemorrhagic Complications
- Extramedullary Hematopoiesis
- Marrow Fibrosis
- Leukemic Transformation
What are the top 4 mutations seen in Myeloproliferative disorders?
- Philadelphia Chromosome t(9;22) BCR-ABL fusion - constitutively activates tyrosine kinase = promotes proliferation and prohibits apoptosis - seen in all CML
- JAK2 V617F: loss of negative regulation, JAK2 has ligand-independent over-activation (EPO-R, TPO-R, G-CSF-R) - seen in 60% ET and MF, 95% PV
- MPL mutations: ligand independent over-activation of JAK2 receptor
- CALR mutation: mutant in ER chaperone causes direct contact and activation of MPL (TPO) receptor, acts as rogue cytokine to activate TPO-R cells
- occurs mutually exclusively from JAK2 mutations (cannot have both)
ESSENTIAL THROMBOCYTHEMIA
- WHO criteria (4)
- Peripheral blood findings (3)
- Bone marrow biopsy (3)
WHO
- Persistent thrombocytosis (>450K)
- Bone marrow with proliferating megakaryocytes (increased, enlarged, mature megakaryocytes)
- Not meeting WHO criteria for another chronic myeloid neoplasm
- Demonstration of a clonal marker (JAK2, CALR, or MPL), or if no gene - no evidence of reactive thrombocytosis (no iron deficiency, post-surgery, splenectomy, infection, inflammation, cancer)
Blood
- Thrombocytosis (marked small to giant sized platelets)
- Minimal to no leukocytosis
- Mild anemia, usually normal Hb
Bone Marrow
- Normo to hypercellular
- Increase in MK’s: large to giant, abundant cytoplasm, HYPERLOBULATED nuclei
- Reticulin (fibrosis) and iron stains NORMAL (no scarring)
ESSENTIAL THROMBOCYTHEMIA
- sx/CP
- mutations
- prognosis
- tx
CP: microvascular disturbance - HA, TIA, dizziness, vision disturbance, erythromelalgia (burning red hot digits due to platelet hypersensitivity)
macrovascular disturbance - Stroke, ACS, DVT/PE, Abd Vein Thrombosis (older age, leukocytosis, JAK2 V617F, prior thrombosis all increase risk)
Mutations:
CALR - low thrombosis risk
JAK2 V617F and MPL - high thrombosis risk
Prognosis: low risk of overt myelofibrosis and AML, good survival
Tx:
- manage CV risk factors: ASA if microvascular disturbance, high CV risk, JAK2+
- cytoreduction (Hydroxyurea, or IFN) only if high risk or macrovascular disturbance/sx
POLYCYTHEMIA VERA
- WHO Criteria (3 +1)
- Bone marrow features (3)
WHO:
1. Hb > 16.5 in M; > 16.0 in F (high Hb)
2. BM biopsy with hypercellularity for age with prominent erythroid, granulocytic, and pleomorphic MK proliferation
3. JAK2 V617 (96%) or JAK2 exon 12 (2-3%) mutation
Minor - subnormal serum EPO level (suppressed)
Bone Marrow
- Hypercellularity of tri-lineage proliferation (particularly MKs)
- Absent Iron (exhausted stores)
- Occasional Fibrosis
POLYCYTHEMIA VERA
- clinical concerns (3 categories)
- complications
- tx
CP: 1. Microvascular Disturbance (HA, TIA, dizziness, visual disturbance, erythromelalgia)
- Macrovascular Disturbance (Stroke, ACS, DVT/PE, Abd Vein Thrombosis)
- Unique: Aquagenic Pruritus (increased Histamine levels), Gout (high uric acid), Bleeding (acquired von willebrand disease)
Complications: 15% pts over 10 years evolve to myelofibrosis (more fibrosis, splenomegaly, anemia), 1-2% pts have Acute Leukemic Transformation
Tx:
- ASA (manage CV risk factors) and Phlebotomy are FIRST LINE
- Cytoreduction (HU or IFN) only in high risk pts (>60 yo and/or prior thrombosis hx)
- JAK-i’s do work in short term! (long term data still being collected)
MYELOFIBROSIS
- WHO CRITERIA (3 + 5)
- mutations and prognosis
- worst prognosis mutation?
WHO
1. MK proliferation with ATYPIA (pleomorphism, smaller) and FIBROSIS (reticulin stain+)
2. Absence of ET, PV, CML, MDS, or other myeloid neoplasm
3. Clonal marker (JAK2 V617F, CALR, MPL)
Minor: Leukoerythroblastosis, increased LDH, Anemia, Leukocytosis, Palpable splenomegaly
Mutations
CALR+: best prognosis (17.7yrs)
JAK2 or MPL+: 9.1-9.2years
Triple Negative: worst prognosis (3.2 years)
Worse prognosis with high molecular risk genes
Worst: CALR-/ASXL1+
MYELOFIBROSIS
- CP
- tx
CP: most sx of MPN disorders: Fatigue, pruritis, night sweats, weight loss (cachexia), bone pain, abd pain, anemia, hepatomegaly, MASSIVE SPLENOMEGALY
tx: sx tx (palliation of splenomegaly, constitutional sx, anemia)
Splenomegaly: Splenic radiation
Anemia: Prednisone (may worsen leukocytosis)
JAK2-inhibitors (RUXOLITINIB): decrease splenomegaly, resolve inflammatory sx (may worsen cytopenias - bone marrow suppression)
CHRONIC MYELOID LEUKEMIA
- 3 stages and features of each stage
- genetics
- Chronic Phase: LEUKOCYTOSIS with left shift, Basophilia +/- Anemia, Thrombocytosis/Thrombocytopenia
- Accelerated Phase: splenomegaly, Basophilia, Thrombocytosis/penia, Increasing Blasts
- Blast Phase: like acute leukemia (AML or ALL or bi-phenotypic)
Gene: t(9;22) - BCR-ABL (detect and monitor with PCR)
Tx: Tyrosine Kinase Inhibitor (ImatINIB) - markedly effective and FUNCTIONALLY cure patient by turning off BCR-ABL (can recover - less sx, less cell response, Philly Ch goes away, no BCR-ABL PCR detection - within 1 year) - and can eventually discontinue drug!
