Chronic Myeloproliferative Disorders

Question 1

what are chronic myeloproliferative disorders?

Answer 1

a group of malignant diseases in which the bone marrow produces too many maturing myeloid cells, which end up spilling out into the blood

they are a type of leukemia! leukemias are malignancies of hematopoietic cells which begin in the bone marrow and spill into the blood

Question 2

what are the four main types of chronic myeloproliferative disorders?

Answer 2

1. chronic myeloid leukemia (CML)
2. polycythemia vera (PV)
3. essential thrombocythemia (ET)
4. primary myelofibrosis (PMF)

Question 3

what are acute leukemias?

Answer 3

Acute leukemias are composed of very immature malignant cells (blasts, basically),

generally have a poor prognosis (with a few exceptions)

Question 4

what are chronic leukemias?

Answer 4

Chronic leukemias are composed of more mature malignant cells (not very many blasts, but maturing – or fully mature – cells)

generally have a good prognosis.

Question 5

what are myeloid leukemias?

Answer 5

Myeloid leukemias are composed of non-lymphoid cells (neutrophils, eosinophils, basophils, monocytes, red blood cells, and/or platelets) and their precursors

Question 6

what are lymphoid leukemias?

Answer 6

Lymphoid leukemias are composed of lymphocytes and their precursors

Question 7

what type of leukemia are chronic myeloproliferative disorders?

Answer 7

chronic leukemia because they don’t have many blasts at all, but are composed of more mature cells

AND

myeloid leukemia because they arise from any non-lymphoid cell line

Question 8

what type of disorder are chronic myeloproliferative disorders?

Answer 8

stem cell disorders

they are caused by activating, growth-promoting genetic mutations in stem cells

this results in proliferation of ALL the cells that can arise from that stem cell = panmyelosis

Question 9

what is panmyelosis?

Answer 9

proliferation of all major myeloid cell lines in the bone marrow

includes RBCs and precursors, granulocytes—especially neutrophils—and precursors, and platelets and precursors

Question 10

why are there different chronic myeloproliferative disorders if there’s panmyelosis in all of them?

Answer 10

because in each disorder one cell line proliferates more than all the others

Question 11

which cell line proliferates the most in CML?

Answer 11

neutrophils

RBC precursors and megakaryocytes are proliferating too, but not nearly as much as the neutrophils

Question 12

which cell line proliferates the most in PV?

Answer 12

RBCs

Question 13

which cell line proliferates the most in ET?

Answer 13

platelets

Question 14

which cell line proliferates the most in PMF?

Answer 14

megakaryocytes

Question 15

why do we say that chronic myeloproliferative disorders originate in the stem cell and not myeloid stem cell?

Answer 15

it’s because sometimes the genetic mutation happens in a really undifferentiated stem cell that hasn’t even decided whether it is going to be myeloid or lymphoid

we know this is true because chronic myeloproliferative disorders occasionally turn into acute leukemias–and sometimes, those acute leukemias are lymphoblastic

Question 16

what is CML?

Answer 16

chronic myeloid leukemia

has a markedly increased number of neutrophils and precursors in the bone marrow

the blood, too, shows a neutrophilic leukocytosis (way more neutrophils than normal) with a left shift (immature precursors, like myelocytes, are also present)

Question 17

what is PV?

Answer 17

polycythemia vera

has a ton of erythroid precursors in the bone marrow and a markedly increased RBC count in the peripheral blood

Question 18

what is ET?

Answer 18

essential thrombocythemia

has a lot of megakaryocytes in the bone marrow and a massively increased platelet count in the peripheral blood

Question 19

what is PMF?

Answer 19

primary myelofibrosis

the problem in this disorder is that the marrow becomes fibrotic

there is a panmyelosis early on – but eventually, the marrow is filled with fibrous tissue, and the poor hematopoietic precursors try to find other homes, like the spleen

RBCs have a hard time squeezing through the fibrotic marrow and the huge spleen, and often we can see teardrop-shaped red blood cells (dacryocytes) in the blood

Question 20

what are dacryocytes?

Answer 20

teardrop-shaped red blood cells

seen in PMF blood smear

Question 21

What unusual finding is seen in the blood of a patient with PMF?

Answer 21

dacryocytes

Question 22

what causes chronic myeloproliferative disorders?

Answer 22

a genetic mutation that allows cells to grow and survive on their own, without any input from normal growth factors

the mutation may produce a constitutively active tyrosine kinase, or it may turn on another signaling pathway

whatever the mutation, the end result is that the stem cell proliferates independently, without any need for normal growth factors

there’s no problem with differentiation or maturation of the proliferating cells, so the result is a ton of maturing myeloid cells in the bone marrow, usually with one cell line proliferating more than the others

Question 23

what is the mutation that causes CML?

Answer 23

reciprocal translocation between chromosomes 9 and 22 – t(9;22)

this leads to a new fusion gene on chromosome 22 (called the “Philadelphia chromosome”) that encodes a tyrosine kinase that is always “on”

Question 24

what mutation causes PV?

Answer 24

there is a mutation in a protein called JAK2, which is part of a hematopoietic cell growth pathway

the mutation leads to constitutive signaling, meaning that the cell is always being told to grow and divide

the result is the proliferation of myeloid cells, especially RBCs in the case of PV

Question 25

what is the mutation that causes ET and PMF?

Answer 25

half the cases of ET and PMF also have a mutation in the JAK2 protein

the mutation leads to constitutive signaling, meaning that the cell is always being told to grow and divide

the result is the proliferation of myeloid cells, especially platelets in the case of ET

Question 26

a constitutively active kinase is the pathogenesis in almost all cases of myeloproliferative disorders. What kinase is “out of control” din polycythemia vera?

Answer 26

JAK2 kinase

Question 27

what are two classical clinical features of chronic myeloproliferative disorders?

Answer 27

1. insidious onset

2. splenomegaly

Question 28

what is the clinical presentation of chronic myeloproliferative disorders?

Answer 28

Most patients present with fatigue and a dragging sensation in the left upper quadrant due to the splenomegaly)

fatigue

weight loss

excessive sweating

abdominal fullness, secondary to splenomegaly

Question 29

what is the clinical course of chronic myeloproliferative disorders?

Answer 29

clinical course includes a chronic phase, an accelerated phase, and a terminal blast crisis, which carries a very poor prognosis

Question 30

what symptoms do PV patients have?

Answer 30

1. symptoms related to the hyperviscosity due to the massively increased RBC:
   - headaches
   - visual disturbances
   - ruddy/plethoric appearance of the face
2. pruritus after shower = itch
3. thrombotic events

Question 31

what is the treatment for PV?

Answer 31

phlebotomy to reduce RBC count

Question 32

what is the main clinical symptom of PMF?

Answer 32

a massively enlarged spleen (the largest of any of the chronic myeloproliferative disorders)

due to the extramedullary hematopoiesis present in this disease

Question 33

what are the clinical symptoms of ET?

Answer 33

may present with both bleeding and thrombosis due to the massive platelet count and abnormal platelet/endothelium interactions

Question 34

What is the overall prognosis of chronic myeloproliferative disorders?

Answer 34

Usually, they have a slow progression, with patients typically living a normal lifespan.

However, they do have the potential to transform into AML or ALL, both of which are associated with a worse prognosis

Question 35

what’s the progression of chronic myeloproliferative disorders?

Answer 35

tend to progress slowly

as the marrow is replaced by malignant cells, normal hematopoietic cells have less and less room to grow, and patients may suffer infections or bleeding episodes due to the low numbers of normal white cells and platelets

there’s also a risk of transformation into acute lymphoblastic leukemia or acute myeloid leukemia which are really hard to treat

Question 36

how do you treat chronic myeloid leukemia?

Answer 36

untreated, it progresses at a relatively fast rate

however, treatment with tyrosine kinase inhibitors such as imatinib has drastically improved the prognosis of CML

Question 37

Which chronic myeloproliferative disorder is associated with the t9;22 translocation, also known as the Philadelphia chromosome?

Answer 37

CML

CML results when the ABL proto-oncogene on chromosome 9 fuses to the break cluster region (BCR) on chromosome 22 (BCR-ABL fusion gene: t9;22)

this translocation results in unregulated tyrosine kinase activity

Question 38

polycythemia Vera presents with an increased RBC mass. What is the classic potential complication of the increased Hb and Hct?

Answer 38

thrombosis

PV is associated with thrombotic events as the viscosity of the blood will increase as the RBC mass increases

Question 39

which tyrosine kinase mutation is associated with polycythemia vera, primary myelofibrosis, and essential thrombocythemia?

Answer 39

JAK2 kinase