BL - Myeloproliferative Disorders

Question 1

Chronic myelogenous leukemia (CML)

Answer 1

BCR-ABL1 gene fusion. Presents with persistent neutrophilic leukocytosis, increased basophils/platelets in blood, markedly hypercellular bone marrow with granulocytic hyperplasia

Question 2

Polycythemia vera (PV)

Answer 2

Activating mutation of JAK2 (V617F point mutation). Presents with increase in RBC mass (erythrocytosis). Also increased neutrophils/platelets in blood, trilineage hyperplasia in marrow. Marrow biopsy shows clusters of “bizarre” megakaryocytes.
Treated with serial phlebotomy, aspirin therapy (to help prevent clots). Sometimes chemotherapy, but this is believed to increase risk of transformation to MDS or AML

Question 3

Primary myelofibrosis (PMF)

Answer 3

JAK2 mutations. Characterized by granulocytic and megakaryocytic hyperplasia, no erythrocytosis. Hypercellular marrow. Increased platelets/neutrophils in blood. Large, bizarre megakaryocytes in marrow. Fibrotic stage characterized by leukoerythroblastosis of blood and hepatosplenomegaly secondary to extramedullary hematopoiesis.

Question 4

Essential thrombocythemia (ET)

Answer 4

JAK2 mutations. Characterized by persistent thrombocytosis. Lacks marrow granulocytic hyperplasia seen in PMF, and has larger atypical megakaryocytes. Splenomegaly not common.

Question 5

2 clinical scenarios of MDS

Answer 5

1) Primary/idiopathic: usually in persons over 50 years old, insidious onset. Median age of diagnosis: 70. 3-5 cases/100,000 people/year.
2) Secondary/therapy-related (t-MDS): occurs 2-8 years after use of alkylating agents or exposure to ionizing radiation. Usually contains whole or partial deletions of chromosomes 5 and/or 7.

Question 6

4 possible causes of secondary myelodysplasia (that might mimic MDS)

Answer 6

1) vitamin deficiency: B12, folate, etc.
2) toxin exposure: heavy metals
3) exposure to certain drugs
4) viral infections

Question 7

Low grade vs high grade MDS

Answer 7

Low grade MDS: myeloblasts <2% of blood cells. Better prognosis. Two types: RCUD (better prognosis) and RCMD (worse prognosis than RCUD).
High grade MDS: myeloblasts 5-19% of marrow cells and/or 3-19% of blood cells. “Dismal” prognosis. Two types: RAEB-1 (better prognosis) and RAEB-2 (worse prognosis).

Question 8

3 sites of thrombosis in PV

Answer 8

Mesenteric vein, portal vein, splenic vein

Question 9

2 main features characterizing MDS

Answer 9

1) ineffective hematopoiesis

2) increased risk of transformation to AML

Question 10

3 types of tests that could be performed to diagnose MDS

Answer 10

1) morphologic evidence of dysplasia (dyshematopoiesis: dyserythropoiesis, dysgranulopoiesis, dysmegakarypoiesis)
2) increased myeloblasts, but less than 20% of blood and marrow cells
3) presence of clonal cytogenetic abnormality (complex karyotype: whole or partial deletions of chromosome 5 and/or 7, isolated deletion 5q, trisomy 8)
Tests: marrow aspirate, karyotype/genetic sequencing

Question 11

MDS vs MPNs

Answer 11

MPNs – clonal hematopoietic neoplasm arising from single transformed HSC. Neoplastic clone replaces normal marrow cells in multiple lineages. Examples: CML, PV, PMF, ET.

Question 12

2 reasons for hepatosplenomegaly in MDS

Answer 12

1) extramedullary hematopoiesis

2) sequestration of excess blood cells

Question 13

3 possible negative end points for MPNs

Answer 13

1) excessive marrow fibrosis with resultant marrow failure
2) transformation to acute leukemia
3) development of myelodysplasia with ineffective hematopoiesis

Question 14

Why is there a need for a 2nd and 3rd generation of PTKIs?

Answer 14

Resistance developed to imatinib – mostly through mutations altering imatimib binding site of fusion protein

Question 15

Peripheral blood smear findings of patient with leukoerythroblastosis

Answer 15

Presence of immature granulocytes and immature red cells (nucleated RBC) in blood. Dacrocytes also seen.

Question 16

Basis for marrow fibrosis

Answer 16

Reticulin (type IV collagen) fibers become fibrotic in the marrow