Chronic myeloid leukemia: the bone marrow is hypercellular and
presence of significant basophilia which means increased basophils
in the bone marrow and the blood, the number of blasts in the
chronic case is less than 5 % in the blood and bone marrow but if it
is more than 5% and less than 20% this is accelerated case of
chronic myeloid leukemia which has a worse prognosis because
at anytime there might be frank transformation into acute
leukemia.
Chronic cases can last from 1 to 5 years and then after that there
maybe accelerated phase and frank acute leaukemia which is very
bad. Usually myeloid anemia has mild to moderate elevation of
leukocytes, blasts less than 5%, hepatomegaly, splenomegaly are
common.
Chronic myeloid leukemia prognosis: accelerated transformation
case: the blasts from 10-19% this is the accelerated transformation
case, basophils are more than usual and large more than 20% and
persistent thrombocytopenia or thrombocytosis despite the
treatment, another sign of accelerated or transformation phase is
worsening of anemia, increasing splenic size despite the treatment.
All these signs are warning signs of accelerated/transformation
case. Cytogenetic evidence of clonal evolution.
Blastic crises: transformation of chronic case into frank acute
leukemia, when 20% or more of the cells in the bone marrow or
blood are blasts which is acute leukemia. So if there is more than
20% myeloblasts this is acute myeoloblastic crises which is acute
myeloid leukemia. If lymphoblasts this is lymphoblastic crises
which is acute lymphoblastic leukemia.
So acute leukemia can be either myeloblastic or lymphoblastic
leukemia, but 70% of cases are myeloblastic. Usually when there is
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frank blast crises there will be additional cytogenetic
abnormalities. We mentioned last lecture that there is Philadelphia
chromosome in the chronic case, but if there is additional
Philadelphia chromosome it is a bad sign or additional new
cytogenetic abnormalities.
Chronic myeloid leukemia is a good example of a malignant
disease and its treated by targeted therapy glibec (hematenip) *the
spelling is wrong I think* inhibits the tyrosine kinase activity of
BCRABM (know this), also there is hydroxy uria and alphainterferon. In young patients bone marrow transplantation is the
treatment especially during chronic phase. After the age 60-65
B.M transplantation is difficult. SO chronic myeloid leukemia in
the elderly the prognosis is very bad, so the younger the patient the
more response from B.M transplantation BUT it should be done in
the chronic phase BEFORE development of blastic crises
BEFORE development of transformation (accelerated) phase. In
other words in the 1st few years of the disease.
Chronic myeloid leukemia is the 1st malignancy associated with
chromosomal transformation and therapeutic agents have been
used (glibec).
The 2nd disorder in the chronic myeloid proliferative disease is
polycythemia vera it is a serious clonal disorder of urypotent
hematopoietic stem cells. So stem cells are the major target in this
chronic myeloid disorder. It is characterized by expansion of the
red cell mass but the other marrow elements can also be affected
but the major predominant change is the RBC mass, many many
RBCs are produced so the Hemoglobin will increase. There are
certain criteria for polycythemia vera, all 3 hematopoietic cell lines
are affected coz the problem is in the stem cells. The characteristic
findings are: Expanded red cell mass, splenomegaly, bone marrow
hyperplasia, and leukocytosis. The majority of marrow cells are
affected. Diagnostic criteria: Category A (major and more
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important) and category B and a combination of A and B. For
example: red cell mass in male is more than 36. Calculate total
RBC mass and the total weight and divide them. In female more
than 32. Arterial oxygen should be normal, suppose we have
hypoxia there will be 2ndry polycythemia not called polycythemia
vera which is a primary disorder with no obvious cause. So oxygen
should be normal; saturation more than 92%. Splenomegaly and
clonal genetic abnormalities EXCLUDING Philadelphia
chromosome, Endogenous erythroid colony formation in vitro. In
category B: thrombocytosis more than 400,000 leukocytosis more
than 12,000 B.M with anylosis, low serum erythropoietin level.
A1+A2+any other category A is enough for the diagnosis or any
two from category A is enough.
Clinical findings are usually related to expanded RBCs.
Increased blood viscosity and a possibility of thrombosis,
headache, heaviness, weakness, hypertension, pruritus(itch)
especially after a hot bath, facial rubor, vascular occlusive episode
which is very important and splenomegaly.
Laboratory findings: RBC count, leukocyte count, platelet count.
Normal or elevated leukocyte alkaline phosphatase score.
Remember that’s this is decreased in chronic myeloid leukemia.
B.M hyperplasia, low iron, expanded red cell mass (more than
36%in male and more than 32% in female), positive endogenous
erythroid colony in assay. Stem cells will form these colonies
without added erythropoietin, elevated uric acid and vitamin B12
and low erythropoietin levels. The function of erythropoietin is
stimulating the bone marrow to produce more RBCs. There are
some diseases that produce more erythropoietin in that case there is
2ndry polycythemia not polycythemia vera. Ex. Renal cell
carcinoma and angioblastoma in the cerebellum can produce a lot
of erythropoietin which will cause 2ndry polycythemia.
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Causes of polycythemia: polycythemia vera: no cause, or 2ndry
polycythemia: smoking, heart disease, abnormal hemoglobin,
hypoxia, arterial-venous malformation, renal lesions,
hepatocellular carcinoma, renal cell carcinoma, adrenal
tumor…..etc. so there are many tumors that can secrete
erythropoietin and cause 2ndry polycythemia.
Treatment: hydroxy uria, radio active phosphorus (harmful that
can induce 2nd malignant process so only used in the elderly),
phlebotomy (drainage of venous blood), leeches. In the late stage
of polycythemia vera there maybe fibrosis, red cell mass
normalizes then decreases, leuko-lymphoblastic picture,
splenomegaly.
Polycythemia vera if left untreated the average survivor is 18
months (1.5-3 years), but with treatment the average is 10 years.
Complications like thrombosis can be serious. Hemorrhage,
peptic ulcer, mild fibrosis, acute leukemia (transformation and
overlapping of 1 disorder into another), essential thrombocythemia
which is the opposite of thrombocytopenia. Significant increase in
the platelet count. Essential means no obvious cause. Colonal stem
cell disorder (all stem cells). Normal platelet count is 150,000450,000 but here it can be more than 1,000,000. Hyperplasia of
megakaryocytes in the B.M, and many platelets in the blood.
Absence of chromosomal abnormalities, expanded red cell mass,
myelofibrosis, abscess of known causes of thrombocytosis. We
mentioned that Iron Deficiency Anemia can cause thrombocytosis,
if obvious cause we say reactive not essential thrombocythemia.
In the blood film we can see a huge number of platelets and giant
platelets. Thrombocytosis has causes: essential, myeloproliferative
disorders, hemorrhage, iron deficiency anemia, hemolysis,
inflammation, and malignancy after removal of the spleen….etc.
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Clinical manifestations of essential thrombocythemia maybe
asymptomatic, splenomegaly, hemorrhage, thrombotic attacks
(bleeding tendency or thrombosis), venous or arterial thrombosis,
recurrent GIT bleeding, nasal bleeding, pain in the calf and toes,
iron deficiency due to bleeding and acute leukemia (10% of
essential thrombocythemia patients will develop acute leukemia).
If we perform a B.M study we see huge numbers of large
megakaryocytes that can be abnormal in morphology and sheets of
them. These megakaryocytes are active and can produce huge
numbers of platelets so the count can be more than 1 million.
In laboratory diagnosis: platelet count (more than 600,000), so if
the platelets are more than 600,000 and with no obvious cause its
essential thrombocythemia and usually more than 1 million, mild
anemia, leukocytosis (less than 40,000), normal leukocyte alkaline
phosphatase, hypercellular marrow and megakaryocytic
hyperplasia.
Lastly about chronic myeloid proliferative disorder is idiopathic
(primary, essential) this all means no obvious cause. Idiopathic
myeloid fibrosis is an example of chronic myeloid proliferative
disorder characterized by fibrosis of bone marrow, splenomegaly
like chronic myeloid leukemia (spleen weight more than 1000 gm),
extra-medullary hematopoiesis because there is no hematopoiesis
in the B.M coz of fibrosis, difficulty to produce adequate
hematopoietic cells so extra-medullary hematopoiesis compensates
for this so there will be hepatomegaly, splenomegaly,
lymphadenopathy. Leukoeryrthroblastic reaction and tear drop
RBC's which is very characteristic of myelofibrosis.
Leukoeryrthroblastic reaction means nucleated RBC's in the blood
and relatively immature stages of myeloid cells (myelocyte,
promyelocyte, band form, metamyelocyte and nucleated RBC's)
this is not specific but it is characteristic and common in
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myelofibrosis. The bone marrow in these patients is a dry tap
which means its difficult to aspirate the marrow coz of fibrosis. So
we can say on of the causes of dry tap is idiopathic myelofibrosis
but there are other causes. So we can't aspirate in dry tap so we…
BIOPSY. Trephine biopsy where we take a piece of the bone
where we will se evidence of fibrosis.
It's usually asymptomatic in the early phase (the 1st 2 years).
Splenomegaly due to the vascular expansion and myeloid
metaplasia, anemia with progressive worsening, elevated
neutrophil count with high leukocyte alkaline phosphatase score,
leukoerythroblastic reaction then dry tap in the B.M.
We see teardrop RBC's and nucleated RBC's. We do reticuline
stain on the biopsy and we see a lot of reticuline fibers that aren't
seen normally. Also increase in collagen fibers.
Differential diagnosis means what are the other diseases that can
be confused with myelofibrosis: cirrhosis, fibrotic marrow,
leukoerythroblastosis due to many things like leukemia and
lymphoma, myelodysplastic syndrome and osteopetrosis.
Myelodysplastic syndrome: clonal disorder of hematopoietic stem
cells, there is ineffective hematopoiesis and the bone marrow is
hyper cellular and there is evidence of ancytopenia in the blood,
peripheral ancytopenia, a tendency to develop acute myeloid
leukemia and morphological abnormalities of peripheral blood and
bone marrow cells.
The morphology of the bone marrow of myelodyplastic
syndrome: ring sidroblast, megaloblastic erythroid precursor,
hypogranular myeloid cells, hyposegmentation, hypersegmentation
and abnormal megakaryocytes, fragmentation of the nuclei which
is a sign of diserythropoiesis. With iron stain we see abnormal
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arrangement of iron particles around the nuclei which is called
ringed sidroblasts.
Refractory anemias with ringed sidroblast have dysplasia
confined to the erythroid cells but anything else isn't only in the
RBC's coz it’s a stem cell disorder.
Management/ supportive treatment: growth factor, chemotherapy
but most importantly bone marrow transplantation which is
effective in selected cases of acute leukemia, many cases of
chronic myeloid leukemia and some cases of myelodysplastic
syndrome but usually in young patients.
Myelodysplastic syndrome prognosis: aggressive when there
excess of blast, refractory anemia with excess or when there
chronic myelo-monocytic leukemia and the average survivor time
is 6 months to 1 year but in other types it can be 6-10 years and
they usually die of cytopenic complications (hemorrhage,
infection…) not transformation
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