Chronic Myeloproliferative Disorders Flashcards
what are chronic myeloproliferative disorders?
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
what are the four main types of chronic myeloproliferative disorders?
- chronic myeloid leukemia (CML)
- polycythemia vera (PV)
- essential thrombocythemia (ET)
- primary myelofibrosis (PMF)
what are acute leukemias?
Acute leukemias are composed of very immature malignant cells (blasts, basically),
generally have a poor prognosis (with a few exceptions)
what are chronic leukemias?
Chronic leukemias are composed of more mature malignant cells (not very many blasts, but maturing – or fully mature – cells)
generally have a good prognosis.
what are myeloid leukemias?
Myeloid leukemias are composed of non-lymphoid cells (neutrophils, eosinophils, basophils, monocytes, red blood cells, and/or platelets) and their precursors
what are lymphoid leukemias?
Lymphoid leukemias are composed of lymphocytes and their precursors
what type of leukemia are chronic myeloproliferative disorders?
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
what type of disorder are chronic myeloproliferative disorders?
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
what is panmyelosis?
proliferation of all major myeloid cell lines in the bone marrow
includes RBCs and precursors, granulocytes—especially neutrophils—and precursors, and platelets and precursors
why are there different chronic myeloproliferative disorders if there’s panmyelosis in all of them?
because in each disorder one cell line proliferates more than all the others
which cell line proliferates the most in CML?
neutrophils
RBC precursors and megakaryocytes are proliferating too, but not nearly as much as the neutrophils
which cell line proliferates the most in PV?
RBCs
which cell line proliferates the most in ET?
platelets
which cell line proliferates the most in PMF?
megakaryocytes
why do we say that chronic myeloproliferative disorders originate in the stem cell and not myeloid stem cell?
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
what is CML?
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)
what is PV?
polycythemia vera
has a ton of erythroid precursors in the bone marrow and a markedly increased RBC count in the peripheral blood
what is ET?
essential thrombocythemia
has a lot of megakaryocytes in the bone marrow and a massively increased platelet count in the peripheral blood
what is PMF?
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
what are dacryocytes?
teardrop-shaped red blood cells
seen in PMF blood smear
What unusual finding is seen in the blood of a patient with PMF?
dacryocytes
what causes chronic myeloproliferative disorders?
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
what is the mutation that causes CML?
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”
what mutation causes PV?
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
what is the mutation that causes ET and PMF?
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
a constitutively active kinase is the pathogenesis in almost all cases of myeloproliferative disorders. What kinase is “out of control” din polycythemia vera?
JAK2 kinase
what are two classical clinical features of chronic myeloproliferative disorders?
- insidious onset
2. splenomegaly
what is the clinical presentation of chronic myeloproliferative disorders?
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
what is the clinical course of chronic myeloproliferative disorders?
clinical course includes a chronic phase, an accelerated phase, and a terminal blast crisis, which carries a very poor prognosis
what symptoms do PV patients have?
- symptoms related to the hyperviscosity due to the massively increased RBC:
- headaches
- visual disturbances
- ruddy/plethoric appearance of the face - pruritus after shower = itch
- thrombotic events
what is the treatment for PV?
phlebotomy to reduce RBC count
what is the main clinical symptom of PMF?
a massively enlarged spleen (the largest of any of the chronic myeloproliferative disorders)
due to the extramedullary hematopoiesis present in this disease
what are the clinical symptoms of ET?
may present with both bleeding and thrombosis due to the massive platelet count and abnormal platelet/endothelium interactions
What is the overall prognosis of chronic myeloproliferative disorders?
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
what’s the progression of chronic myeloproliferative disorders?
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
how do you treat chronic myeloid leukemia?
untreated, it progresses at a relatively fast rate
however, treatment with tyrosine kinase inhibitors such as imatinib has drastically improved the prognosis of CML
Which chronic myeloproliferative disorder is associated with the t9;22 translocation, also known as the Philadelphia chromosome?
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
polycythemia Vera presents with an increased RBC mass. What is the classic potential complication of the increased Hb and Hct?
thrombosis
PV is associated with thrombotic events as the viscosity of the blood will increase as the RBC mass increases
which tyrosine kinase mutation is associated with polycythemia vera, primary myelofibrosis, and essential thrombocythemia?
JAK2 kinase
