Unit III

Question 1

Primary MDS

Answer 1

Median age 70, usually over 50

Question 2

Secondary MDs

Answer 2

usually therapy related. Occurs as part of spectrum of therapy related-AML. Usually diagnosed 2-8 years post DNA alkylating agents or ionization radiation treatments. Contains complex karyotype with whole or partial deletions of Chr 5 and/or chr7

Question 3

MDS diagnosis

Answer 3

1. Morphologic evidence of dysplasia (in erythrocytes, granulocytes, or megakaryocytes) in more than 10% of cells in one lineage in the marrow.
2. Increases myeloblasts (but less than 20%)
3. Presence of a clonal cytogenetic abnormality (complex karyotype w/whole or partial deletion of chr 5 and/or chr 7; isolated deletion of 5q; trisomy 8)

Question 4

Low grade MDS

Answer 4

Myeloblasts are NOT increased

Question 5

Refractory cytopenia with unilineage dysplasia (RCUD)

Answer 5

Dysplasia only in one lineage (likely RBC). Low grade. Relatively good prognosis. 15 year durvival, only 2% transform to AML by 5 years

Question 6

Refractory cytopenia with multilineage dysplasia (RCMD)

Answer 6

Low grade MDS with dysplasia in 2+ lineages. Worse prognosis that RCUD. Medial survival is 2.5 years. 10% transform to AML by 2 years

Question 7

High grade MDS

Answer 7

Myeloblasts are increases, but less than 20% (otherwise that’s AML)

Question 8

Refractory Anemia with excess blasts-1 (RAEB-1)

Answer 8

5-9% blasts in the marrow, and 2-4% in the blood. Relatively dismal prognosis, median survival of 16 months. 25% of cases transform to AML

Question 9

Refractory Anemia with Excess Blasts-2 (RAEB-2)

Answer 9

10-19% blasts in the marrow, and/or 5-19% in the blood. Dismal prognosis, median survival of 9 months, with 33% of cases transforming to AML

Question 10

MDS Treatment

Answer 10

Can treat with allogeneic stem cell transplant. Treat with supportive care and transfusion for cytopenia.

Question 11

Myeloproliferative Neoplasms (MPN)

Answer 11

Clonal hematopoetic neoplasm arising from a transformed hematopoietic stem cell. Neoplasti clone partially or entirely replaces normal marrow cells in multiple lineages. The neoplastic clone gives rise to increased normal of NORMAL cells in 1+ lineages (not dysplastic). Usually in middle-aged to elderly patients (rare in children).

Question 12

Common Themes for MPNs

Answer 12

1. Early disease characterized by increase in 1+ blood cell types (neutrophil, platelet, RBCs) –> increase in marrow cellularity.
2. Splenomegaly and/or hepatomegaly due to sequestration of extra blood cells and/or extramedullary hematopoiesis.
3. Insidious onset - usually noticed incidentally on CBC
4. Without treatment, progresses to: excessive marrow fibrosis with resultant BM failure; transforms to MDS or rarely AML (sometimes ALL)

Question 13

Chronic Myelogenous Leukemia (CML)

Answer 13

MPN that manifests primarily as persistent neutrophilic leukocytosis and is associated with BCR-ABL1 gene fusion.
Progresses from chronic to blast stage.
In chronic phase, blasts are not significantly increased in the marrow/blood. Prominent leukocytosis due to neutrophilia. While blasts in marrow arent increased, you will see granulocytic hypercellularity and small megakaryocytes with round/non-lobulated nuclei.
If left untreated, CML progresses to blast phase. Acute. You find 20+% of blasts in the marrow/blood. Myeloblasts are usually increased (70% of cases). Sometimes lymphoblasts are increased.

Question 14

Diagnosis of CML

Answer 14

diagnose with BCR-ABL1 gene fusion - gives 210 kD fusion protein. t(9;22) - philadelphia chromosome

Question 15

Treatment/prognosis of CML

Answer 15

Untreated CML has a median survival of 2-3 years. Imatinib (Gleevec) is PTKI. Blocks ATP binding site. 2nd generation dasatinib was developed because of drug resistance.

Question 16

Polycythemia Vera (PV)

Answer 16

MPN characterized by increase in RBC mass (erythrocytosis). Usually also see increase in neutrophils and platelets in blood, tri-lineage hyperplasia in the BM. BM biopsy shows clusters of large, weird megakaryocytes.
Essentially all cases of PV contain an activating mutation of JAK2 (V617F point mutation).
Most serious complication of PV are venous or arterial thrombosis, leading to complications like DVT, MI, and stroke.
Thrombotic events are the most common PV-related cause of death in PV patients (though they more often die of diseases unrelated to PV)

Question 17

PV progression

Answer 17

Usually diagnoses in a polycythemic phase with increase blood cell counts. Over time, PV may progress to a spent phase, aka post-PV myelofibrosis. Spent phase is characterized by excessive marrow fibrosis with corresponding fall in blood cell counts.
Initial presenting symptoms: headaches/dizziness, plethora, pruritus after bathing, parasthesias, splenomegaly and hepatomegaly

Question 18

PV Therapy

Answer 18

Serial phlebotomy, aspirin therapy (to prevent clots)

Question 19

Primary Myelofibrosis (PMF)

Answer 19

MPN characterized by granulocytic and megakaryocytic hyperplasia, but NO erythrocytosis.
JAK2 mutations are present in around 50% of PMF cases. Cases lacking JAK2 often have MPL or CALR mutations

Question 20

PMF Progression

Answer 20

PMF starts in a pre-fibrotic stage (hypercellular marrow with granulocytic and megakaryocytic hyperplasia, weird megkaryocytes, markedly increased platelets and neutrophils in the blood).
Eventually progresses to fibrotic stage (significant reticulin fibrosis of the marrow, leukoerythroblastosis (presence of immature granulocytes and immature RBCs) in the blood, tear drop cells (dacryocytes), falling blood cell counts, enlargement of organs (liver, spleen, lymph nodes) due to extramedullary hematopoiesis

Question 21

Essential Thrombocythemia

Answer 21

MPN characterized by persistent thrombocytosis. It lacks the marrow granulocytic hyperplasia seen in PMF and the atypical megakaryocytes in ET are even alrger than those in PMF.
JAK 2 mutation seen in 50% of cases, otherwise you see mutations in MPL or CALR. You see clusters of very large megakaryocytes in the marrow.
Around 50% of ET patients are diagnosed incidentally, usually asymptomatic.
Signs/symptoms: transient ischemic attacks, digital ischemia, arterial or venous thrombosis (less common than in PV)
Splenomegaly is NOT common