Heme malignancy 2

Question 1

Define the following terms:

CML

Polycythemia vera

Essential thrombocytopenia

Primary myelofibrosis

Answer 1

CML: excessive proliferation of mature granulocytes

Polycythemia vera: excessive proliferation of mature red blood cells

Essential thrombocythemia: excess platelet proliferation

Primary myelofibrosis: excessive proliferation of bone marrow stroma

**these can all lead to secondary AML**

Question 2

Myelodysplastic syndromes are characterized by ___ in the bone marrow

Answer 2

Myelodysplastic syndromes are characterized by:

abnormal maturation/differentiation of one or more myeloid lineages in the bone marrow

**marrow is typically hypercellular*

Question 3

2 signs of dysplasia in myeloid lineage cells are:

Answer 3

Signs of dysplasia:

The presence of ring sideroblasts (recall that another disorder in which you can see these is sideroblastic anemia) + many multinucleated cells

Question 4

How does MDS present/how is MDS diagnosed?

Answer 4

Normally presents with non-specific symptoms like worsening fatigue, weakness, SOB, bleeding etc

(can also be incidental finding)

**requires bine marrow biopsy for diagnosis**

Question 5

3 factors that can affect a MDS risk are ___

Answer 5

Risk is based on:

% of bone marrow blasts (more blasts = higher risk)

Favorable/unfavorable karyotype: favorable = normal, -Y, del(5q), del(20q); unfavorable = @ least 3 abnormalities, involvement of chromosome 7 (why?)

More cytopenias (and lower blood cell counts) = higher risk

Question 6

The most common presenting symptom of MDS is ___

(fill in the blanks/how would you manage MDS for pts with lower risk disease/higher risk disease?

Answer 6

Most common presenting symptom of MDS = anemia

**see image below**

Question 7

A 73 yo woman with a history of hypertension presents to her primary care physician for slowly worsening fatigue over the last several months. Labs show a WBC of 1100/μL (normal, 4,500 - 11,000), hemoglobin 7.8 g/dL (normal 12.6-16), hematocrit 24% (normal, 37% - 50%), and platelets 32,000/μL (normal, 153,000-367,000).
Peripheral smear shows 2% blasts and numerous pseudo-Pelger-Huet neutrophils in the peripheral smear.

A bone marrow biopsy and aspirate shows a hypercellular marrow with 18% myeloid blasts, and karyotype is 44, XX, inv(3), -5, -7.

Her disease is best characterized as which of the following?

A.Chronic myeloid leukemia

B.Acute myeloid leukemia

C.Higher risk myelodysplastic syndrome

D.Lower risk myelodysplastic syndrome

E.Polycythemia vera

Answer 7

C. Higher risk myelodysplastic syndrome

(pt has multiple genetic abnormalities, hypercellular marrow, high % of blasts, dysplasia of hher neutrophils and pancytopenia

Question 8

A 56 yo man with no PMH presents with 3 weeks of abdominal fullness and pain. On physical examination, vitals signs are normal. His spleen is palpable 7 cm below the left costal margin.
CBC data shows the following:

WBC: 52,300/mcL (normal, 4,500 - 11,000)
Hemoglobin 14 /dL (normal 12.6-16)
Hematocrit of 42% (normal, 37% - 50%)
Platelets 530,000/mcL (normal, 153,000-367,000)

Which of the classifications is the disease likely to fall into?

A.Acute lymphoblastic leukemia

B.Myeloproliferative neoplasm

C.Low risk myelodysplastic syndrome

D.High risk myelodysplastic syndrome

E.Acute myeloid leukemia

Answer 8

Pt has splenomegaly, elevated WBC count, elevated platelet count

**Hb and crit are normal**

B: Myeloproliferative neoplasm

Question 9

Myeloproliferative neoplasms tend to be due to ___ and are characterized by increased number of ___

Answer 9

Myeloproliferative neoplasms tend to be due to activating mutations of tyrosine kinases and are characterized by increased number of mature blood cells

Question 10

In myeloproliferative disorders, the bone marrow may transform to a “spent” phase, which is ___

What is a common presenting symptom of myeloproliferative disorders? (hint: related to splenomegaly seen with this disorder)

Answer 10

Spent phase: when marrow becomes so proliferative, it basically becomes “tired” and starts to scar/undergo fibrosis

Splenomegaly common because spleen starts taking over hematopoiesis >> leads to abdominal symptoms

(Myeloproliferative disorders do have a risk of transforming to acute leukemia - likely secondary AML)

Question 11

Chronic myeloid leukemia results from a translocation mutation of chromosomes 9 + 22 leading to __ fusion protein (“always on” tyrosine kinase)

Answer 11

Chronic myeloid leukemia results from a translocation mutation of chromosomes 9 + 22 leading to Bcr-Abl fusion protein (“always on” tyrosine kinase)

Question 12

___ results from a mutation in the JAK2 kinase

Answer 12

Polycythemia vera results from a mutation in the JAK2 kinase

Question 13

Essential thrombocytopenia and primary myelofibrosis can both result from mutations in which 3 genes/proteins?

Answer 13

Essential thrombocytopenia and primary myelofibrosis can both result from mutations in JAK2, MPL, CALR

Question 14

How does the mutated Bcr-Abl fusion protein give rise to CML?

Answer 14

The Bcr-Abl kinase increases the growth of more mature myeloid forms and inhibits dna repair, leading to more mutations

Recall from Zanki that the Bcr part is the kinase part, and the Abl part is the cell proliferation part

Question 15

Morphology of CML is typically characterized by elevated numbers of ___ and ___, increased numbers but *small size* of ___ and low/normal ___

Answer 15

Morphology of CML is typically characterized by elevated numbers of eosinophils and basophils, increased numbers but *small size* of megakaryocytes and low/normal rbcs

Question 16

What is the treatment for CML and how does this drug work?

Answer 16

Imatinib/Gleevac

Imatinib works by inhibiting the ATP domain (of the Bcr portion of the protein) of the Bcr-Abl protein, thereby inhibiting its kinase activity and the downstream pathways

Question 17

The least aggresive phase of CML is the ___ phase.

The ___ phase is characterized by worsening anemia/thrombocytopenia and increased bone marrow blasts up to 19% (or so)

The blast/crisis phase is characterized by ___

Answer 17

The least aggresive phase of CML is the chronic phase.

The accelerated phase is characterized by worsening anemia/thrombocytopenia and increased bone marrow blasts up to 19% (or so)

The blast/crisis phase is characterized by resemblence of acute leukemia + persitent Bcr-Abl, >20% blasts +/or solid focus of blasts outside bone marrow

**note that the last 2 phases are the most difficult to Rx so pts will likely need a stem cell transplant**

Question 18

Polycythemia vera is characterized by __ Hb and crit. Pts can also have __ granulocytes and platelets

The most common kinase mutation in PV is ___, and the other rare one is exon 12. Pts with 2 mutated JAK copies tend to have a __ WBC count and __ progression

Answer 18

Polycythemia vera is characterized by elevated Hb and crit. Pts can also have elevated granulocytes and platelets

The most common kinase mutation in PV is JAK2 (V617F), and the other rare one is exon 12. Pts with 2 mutated JAK copies tend to have a increased WBC count and faster progression

Question 19

The classical symptoms of polycythemia vera include ___ (which worsens after exposure to warm water), ___ (which can cause pain in the extremities), hepatosplenomegaly and facial plethora

Answer 19

The classical symptoms of polycythemia vera include aquaphoric pruritus (which worsens after exposure to warm water), erythromelalgia (which can cause pain in the extremities), hepatosplenomegaly and facial plethora

**

Aquaphoric pruritus – whole body itching that worsens following exposure to warm water

Erythromelalgia – warm, painful microscopic clots that commonly appear on the extremities (cause pain that can lead to trouble walking)

Question 20

The most common complication of PCV is __, thus death in PCV is commonly due to ___

Other complications of PCV include ___, ___ and progression to ___

Answer 20

The most common complication of PCV is thrombosis, thus death in PCV is commonly due to acute coronary syndromes

Other complications of PCV include post PCV marrow fibrosis, splenomegaly and progression to (secondary) AML

Question 21

___ is characterized by elevated platelet counts and can be caused by activating mutations in JAK2/MPL/CALR genes

Answer 21

Essential thrombocytosis is characterized by elevated platelet counts and can be caused by activating mutations in JAK2/MPL/CALR genes

**on differential: PCV (need abscence of polycythemia for it to be ET), PMF (need abscence of marrow fibrosis for it to be ET)**

Question 22

One complication/presenting symptom of essential thrombocytosis is ___

Answer 22

One complication/presenting symptom of essential thrombocytosis is EMH: extramedullary hematopoiesis, or organomegaly

Question 23

What disease may be characterized by a marked increase in atypically large megakaryocytes and platelets?

Answer 23

Essential thrombocytosis

Question 24

How are PCV and ET treated in pts under the age of 60 w/ no prior thrombosis history, or those over 60/with prior thrombosis history?

Answer 24

see below

**note that everyone is started on aspirin unless contraindicated**

Question 25

___ is replacement of the bone marrow w/ fibrosis without a preceding myeloproliferative disorder

Answer 25

Primary myelofibrosis is replacement of the bone marrow w/ fibrosis without a preceding myeloproliferative disorder

**pts can have massive hepatosplenomegaly (can cause early satiety, altered appetite, adominal discomfort), leukocytosis, anemia/thrombocytopenia**

Most mutations are in JAK, others are MPL and CALR

Question 26

Describe the morphology of PMF

Answer 26

Progressive fibrosis with crowding out of marrow elements - so you actually get premature cells being pushed out into the blood (extramedullay hematopoiesis); bone marrow may also ossify

Question 27

Which disease is characterized by the presence of the cell type below?

Answer 27

PMF

**teardrop-like RBCs aka dacrocytes**

Question 28

How is primary myelofibrosis treated?

Answer 28

The early phase Rx is the same as that of PCV and ET: cytoreduction w/ hydroxyurea or observation

Overt/fibrotic phase: give Ruxolitinib

**Ruxolitinib is a JAK inhibitor that is good at shrinking the spleen and reducing systemic symptoms**

Question 29

A 56 yo man with no PMH presents with 3 weeks of abdominal fullness and pain. On physical examination, vitals signs are normal. His spleen is palpable 7 cm below the left costal margin.
CBC data shows the following:
WBC: 52,300/mcL (normal, 4,500 - 11,000)
Hemoglobin 14 /dL (normal 12.6-16)
Hematocrit of 42% (normal, 37% - 50%)
Platelets 530,000/mcL (normal, 153,000-367,000)

Bone marrow biopsy shows a hypercellular marrow with small megakaryocytes but no fibrosis or increased blasts.

Which of the following is tests is likely to be positive?

A.FISH for t(9;22)

B.JAK2 mutation

C.CALR mutation

D.Deletion of chromosome 7

E.FISH for t(15;17)

Answer 29

A. (This is CML. Note that the hemoglobin is NORMAL which is why its not PCV. If the hemoglobin and crit where elevated, it could potentially be PCV)

**CML also has small megakaryocytes + no fibrosis**

Question 30

A 56 yo man with no PMH presents with 3 weeks of abdominal fullness and pain. On physical examination, vitals signs are normal. His spleen is palpable 7 cm below the left costal margin.
CBC data shows the following:
WBC: 52,300/mcL (normal, 4,500 - 11,000),
Hemoglobin 14 /dL (normal 12.6-16)
Hematocrit of 42% (normal, 37% - 50%)
Platelets 530,000/mcL (normal, 153,000-367,000).

Bone marrow biopsy shows a hypercellular marrow with small megakaryocytes but no fibrosis or increased blasts.

What is the most appropriate initial treatment?

A.Imatinib mesylate

B.Idarubicin and cytarabin

C.Interferon alpha and cytarabine

D.Hydroxyurea and aspirin

E.Ruxolitinib

Answer 30

A. Always imatinib or some next gen variation thereof

Question 31

Fill in the blanks in the chart

Answer 31

Question 32

___ is the most common cancer in children.

Answer 32

Acute lymphoblastic leukemia is the most common cancer in children. (majority are B-cell ALL)

Question 33

ALL is characterized by what morphology of B or T cells? How can you tell if the ALL is B or T cell derived?

Answer 33

B and T cell ALL are morphologically similar and distinguished from each other thru antigenic expression (recall the markers from the earlier lecture: B cell markers = Cd19, Cd34 + TdT; T cell markers = CD7/5/5 + CD34 + TdT)

**note that B-ALL usually has a leukemic presentation: lymphoblasts in marrow vs T-ALL which has a lymphmatous presentation (mediastinal mass +/- lymphadenopathy, splenomegaly)

Morphologically: both will have cells with huge nuclei and scant cytoplasm

Question 34

Detection of (enzyme) characterizes the ALL diagnosis

Answer 34

Detection of TdT characterizes the ALL diagnosis

Question 35

B cell ALL can result from various chromosomal changes, namely ___

Answer 35

Hyperdiploidy

Hypodiploidy

Balanced translocation: t(9;22)- Philadelphia chromosome – Bad Prognosis; t(12;21)- Better prognosis

Question 36

Most T cell ALL is associated with mutations in (protein)

Answer 36

Most T cell ALL is associated with mutations in NOTCH-1

Question 37

Treatment for ALL includes ___ + CNS prophylaxos (why?). Also add imatinib/dasatinib if pt is also t(9;22) +ve.

Answer 37

Rx for ALL includes multi-agent chemo + CNS prophylaxis +/- imatinib if Philadelphia chromosome +ve

All patients with ALL need to have CNS prophylaxis as this cancer has a higher propensity of spreading thru CSF.

Question 38

___: bi-specific antibody (antibody binds to both CD19 ad CD3). The antibody pulls anti-tumor T cells in close proximity to tumor cells, thereby redirecting tumor lysis back to the tumor cell

___ is one of those conjugated antibodies that has a chemotherapeutic agent attached to it that causes ds dna breaks and it binds CD22 on B cells

Answer 38

Blinatumomab: bi-specific antibody (antibody binds to both CD19 ad CD3). The antibody pulls anti-tumor T cells in close proximity to tumor cells, thereby redirecting tumor lysis back to the tumor cell

Inotuzumab ozogamicin is one of those conjugated antibodies that has a chemotherapeutic agent attached to it that causes ds dna breaks and it binds CD22 on B cells