Myeloproliferative and Myelodysplastic Syndromes

Question 1

Polycythemia Vera (genetics + symptoms + labs)

Answer 1

• Proliferation of RBCs
• 95-97% have V617F mutation in exon 14 of JAK2 gene
• Symptoms - (related to inc red cell mass) ruddy complexion, splenomegaly, hepatomegaly, conjunctival plethora, engorged optic veins, HTN, cutaneous ulcers, arterial or venous thrombosis
• Labs - inc red cell mass/Hb/HCT, depressed Epo (Epo insensitive), platelets/WBCs may be elevated, elevated LDH and uric acid (from inc cell turnover)

Question 2

PV versus Secondary Polcythemia

Answer 2

• Secondary Polycythemia (Epo sensitive)
• Appropriate - obesity hypovent, lung disease, sleep apnea, high altitude, cyanotic heart disease
• OR Inappropriate - tumors that cause atopic Epo production or stimulate hematopoiesis directly and endocrine disorders and use of exogenous Epo

Question 3

PV Dx

Answer 3

• (need all major or no mutation and minor)
• Major -
  - Inc Hb or HCT
  - JAK2V617F or similar mutation
  - BM showing hypercellularity of all myelocytes
• Minor -
  - Below normal Epo

Question 4

PV Complications

Answer 4

Myelofibrosis, MDS/AML, hyperviscosity –> thrombosis / hemorrhage

Question 5

PV Tx

Answer 5

• Phlebotomy to get down to HCT < .45
• Chemical cytoreduction (hydroxyurea or interferon)
• ASA to prevent thrombosis

Question 6

Essential Thrombocytopenia (genetics + symptoms)

Answer 6

• Proliferation of megakaryocytes
• > 50% have JAK2 mutation
• Majority asymptomatic (normally find high platelet count or thrombotic event w/ few risk factors)
• Headache, visual disturbance, dizziness, syncope, burning eryhtromelagia (episodic blockage of vessels - then red and inflammed when unblocked), thrombosis (arterial > venous), GI bleed, epitaxis, splenomegaly

Question 7

What is the number 1 concern in ET?

Answer 7

Death due to thrombosis

Question 8

ET Dx

Answer 8

(need all major or no mutation and minor)

• Major -
  - Inc platelets
  - BM biopsy shows loose clusters of megakaryocytes w/ staghorn appearance of nuclei w/ inc # nuclei
  - JAK2 mutation
  - R/o CML/PV/PMF/myelodysplasia
• Minor - clonal platelet marker

Question 9

ET versus Secondary Thrombocytosis

Answer 9

• Acute w/ known drug, infection or blood loss OR known iron def, asplenia, chronic inflammatory disease, hemolytic anemia, cancer
• Important b/C ET has risk of thrombosis while secondary thrombocytosis does NOT

Question 10

ET Tx

Answer 10

If high risk of thrombosis use platelet lowering agent (destroys platelets - hydroxyura, interferon-alpha, busulfan) or anagrelide (blocks megakaryocyte proliferation) AND aspirin

Question 11

Primary Myelofibrosis (hallmark/ presentation)

Answer 11

• Hallmark = marrow fibrosis and myeloid metaplasia (AKA extramedullary hematopoiesis)
• Extramedullary hematopoiesis –> splenomegaly, hepatomegaly, LUQ pain, early satiety
• Bone marrow failure –> fatigue, dyspnea, bleeding, bruising

Question 12

Labs and Smear in PMF

Answer 12

• Labs - anemia, early leukocytosis/ thrombocytosis as extradmedullary takes over but later the extramedullary sites cannot keep up so leukopenia/thrombocytopenia, can transform to AML –> blasts and inc in leukocytosis again, inc uric and LDH from cell turnover
• Smear - Nucleated RBCs and tear drop cells

Question 13

PMF Dx

Answer 13

(need all 3 major and 2 minor)

• Major
  - Megakaryocyte proliferation and gathered in tight clusters w/ atypical cloud-like nuclei
  - R/o CML, PV, MDS
  - JAK2 mutation or other clonal marker OR no evidence that fibrosis is reactive
• Minor
  - Leukoerythroblastosis
  - Inc LDH
  - Anemia
  - Palpable spleen

Question 14

PMF Complications

Answer 14

Morbidity/mortality associated w/ hematopoietic failure, hypersplenism, adv age, evolution to AML

Question 15

PMF Tx

Answer 15

• Only cure is HSCT (may not be possible in this older population)
• Ruxolitinib -JAK1 and JAK2 inhibitor to dec spleen size and dec symptoms
  
  • Side effects - thrombocytopenia, anemia, fatigue, dyspnea, headache, dizziness, nausea
• Largely supportive care

Question 16

What are myelodysplastic syndromes?

Answer 16

• Clonal disorders characterized by ineffective hematopoiesis –> development of acute leukemias (often AML)
• Hallmark = peripheral blood cytopenia + hypercellular bone marrow w/ dysplastic changes
• Incidence inc w/ age (mean age = 68)

Question 17

WHO Classification of MDS (7)

Answer 17

• Uni-lineage dysplasia (rare unless anemia)
• Multi-lineage dysplasia
• W/ ringed sideroblasts (just erythrocytes and >15% of them in BM have sideroblasts)
• W/ excess blasts
• Isolated del(5q) (often have severe anemia w/ normal platelets or thrombocytosis - respond to Lenalidomide)
• Unclassifiable
• MDS -MPN (proliferative neoplasms) - poor prognosis and cytosis alone

Question 18

MDS Prognosis and Tx

Answer 18

• IPSS - prognostic score (tells 25% chance of AML in blank years)
  
  • % BM Blasts
  • Specific mutation on karyotype
  • # diff lineages involved in cytopenia
• Tx (dep on prognosis)
  
  • Low risk - growth factors/cytokines and transfusions as needed
  • Intermediate / high risk - more aggressive and specific therapy
    • Hypo-methylating agents (azacitidine and decitabine)
    • HSCT (few eligible b/c age and co-morbidities) and more intense chemo