Myeloproliferative Disorder
Dr Farzane Ashrafi
Hematologist/ Medical Oncologist
PATIENT PRESENTATION
A 50-year-old man presents with a two-month
history of fatigue and early satiety. His
complete blood count shows the following:
HISTORY
• What are the hematologic abnormalities present
here?
• Granulocytosis
• Anemia
• Thrombocytosis
• Normal Differential
• Basophilia
HISTORY
• Granulocytosis
– Correct!
– COMMENT: This patient has leukocytosis (an
increase in the total white blood cell count) due to an
increased number of neutrophils
HISTORY
• Anemia
– Incorrect.
No. The hemoglobin and hematocrit are within the
normal range
HISTORY
• Thrombocytosis
– Correct!
– COMMENT: The elevated platelet count indicates
thrombocytosis
HISTORY
• Normal Differential
– Incorrect.
No. There is a “left shift” in the differential of the
white blood cell count. “Left shift” refers to the
presence of immature granulocytes in the
peripheral blood, including bands, metamyelocytes
and myelocytes.
HISTORY
• Basophilia
– Correct!
– COMMENT: Basophils are granulocytes with large purple cytoplasmic
granules. They mediate allergic and inflammatory reactions and are increased
in these situations as well as in certain chronic infections such as tuberculosis.
They are also increased in certain hematologic diseases, including the
myeloproliferative disorders. Basophilia is the term for the presence of
increased numbers of basophils in the peripheral blood.
HISTORY
• Summary of hematologic abnormalities in this patient:
– Leukocytosis (increased WBC count) due to granulocytosis
with a left shift
– Thrombocytosis (elevated platelet count)
– Basophilia (elevated basophils
HISTORY
• Which of the following questions would be
helpful in distinguishing a primary from a
reactive cause of neutrophilia or
thrombocytosis?
HISTORY
•
Have you lost weight recently without dieting?
•
Do you drink alcohol?
•
Have you had any fevers?
•
Do you have an ongoing infection?
•
Do you have any itching?
•
Have you had any episodes of pain in your fingers or toes?
•
Do you have any joint pains?
•
Do you have bleeding from any site (for example, heavy menstrual bleeding, bright red blood per
rectum, or black tarry stools)?
•
Have you ever had a heart attack, stroke, or blood clot (myocardial infarction, cerebrovascular
accident, deep vein thrombosis)?
•
Are you taking any medications?
HISTORY
• Have you lost weight recently without dieting?
– Good choice.
PATIENT’S RESPONSE: No.
– COMMENT: Constitutional symptoms such as fever, anorexia, weight
loss and night sweats may be seen in infections (particularly chronic
infections such as tuberculosis), malignancies, chronic inflammatory
diseases, and hypermetabolic states (thyrotoxicosis, hematologic
malignancies associated with rapid cell turnover), all of which may be
associated with granulocytosis and thrombocytosis.
HISTORY
• Do you drink alcohol?
– Good choice.
PATIENT’S RESPONSE: No.
COMMENT: Liver disease resulting in portal
hypertension is associated with splenomegaly. Alcohol
can suppress bone marrow production of platelets.
"Rebound thrombocytosis" can occur with cessation of
drinking.
HISTORY
• Have you had any fevers?
– Good choice.
PATIENT’S RESPONSE: No.
COMMENT: Constitutional symptoms such as fever, anorexia, weight
loss and night sweats may be seen in infections (particularly chronic
infections such as tuberculosis), malignancies, chronic inflammatory
diseases, and hypermetabolic states (thyrotoxicosis, hematologic
malignancies associated with rapid cell turnover), all of which may be
associated with granulocytosis and thrombocytosis.
HISTORY
• Do you have an ongoing infection?
– Good choice.
PATIENT’S RESPONSE: No.
COMMENT: Acute and chronic infections may be
associated with reactive thrombocytosis and
granulocytosis.
HISTORY
• Do you have any itching?
– Good choice.
PATIENT’S RESPONSE: No.
COMMENT: Pruritus (itching) is a common finding in
polycythemia vera, which is associated with
granulocytosis and thrombocytosis. Pruritus may also
occur in patients with hematologic malignancies such
as Hodgkin's Disease and non-Hodgkin's lymphoma
HISTORY
• Have you had any episodes of pain in your fingers
or toes?
– Good choice.
PATIENT’S RESPONSE: No.
COMMENT: Erythromelalgia is a symptom of
ischemia secondary to small vessel digital thrombosis
seen in the myeloproliferative disorders polycythemia
vera and essential thrombocythemia
HISTORY
• Do you have any joint pains?
– Good choice.
PATIENT’S RESPONSE: No.
COMMENT: Collagen vascular diseases such as
systemic lupus erythematosus and rheumatoid
arthritis may be associated with reactive
granulocytosis, thrombocytosis and splenomegaly
HISTORY
• Do you have bleeding from any site (for example, heavy
menstrual bleeding, bright red blood per rectum, or black
tarry stools)?
– Good choice.
PATIENT’S RESPONSE: No.
COMMENT: Bleeding and iron deficiency may be associated
with reactive thrombocytosis. Qualitative platelet defects and
bleeding may be seen in the myeloproliferative disorders
HISTORY
• Have you ever had a heart attack, stroke, or blood clot
(myocardial infarction, cerebrovascular accident, deep
vein thrombosis)?
– Good choice.
PATIENT’S RESPONSE: No.
COMMENT: Thrombotic complications are increased in
patients with myeloproliferative disorders. Malignancies
may be associated with increased thrombotic risk
HISTORY
• Are you taking any medications?
– Good choice.
PATIENT’S RESPONSE: No.
COMMENT: Steroids, lithium and hematopoietic
growth factors (granulocyte-colony stimulating factor
and granulocyte-macrophage colony) can cause
granulocytosis. Vincristine (a chemotherapeutic agent)
and epinephrine can cause thrombocytosis.
HISTORY
• Summary of History
– The most important elements from the history are
the apparent absence of evidence of acute or
chronic infections or inflammatory conditions that
might lead to reactive granulocytosis and
thrombocytosis
PHYSICAL EXAM
• Physical examination reveals a well-developed man in no acute distress.
– [Note: cachexia (profound wasting) would suggest chronic illness
(inflammatory or infectious) or malignancy.]
• Afebrile
• Head, ears, eyes, nose, throat: anicteric (absence of jaundice)
• No lymphadenopathy
PHYSICAL EXAM
• Lungs are clear (no pulmonary signs of infection or malignancy)
• Heart: no murmurs
• Abdomen: no signs of ascites; liver edge is not palpable; spleen edge is
palpable 4 cm below the left costal margin
• Skin: no petechiae. No ecchymoses. No spider angiomata.
• Neurologic exam: normal
PHYSICAL EXAM
• Which of the following negative findings can help you
rule out reactive causes of neutrophilia and
thrombocytosis?
• Afebrile
• Absence of jaundice
• No Lymphadenopathy
• No cardiac murmurs
• Normal neurologic exam
PHYSICAL EXAM
• Afebrile
– Correct!
COMMENT: This is a pertinent negative because
infection is the main differential for neutrophilia.
Note, however, that fever can occasionally be
present in myeloproliferative disorders
PHYSICAL EXAM
• Absence of jaundice
– Correct!
COMMENT: Jaundice may be seen in patients with liver disease
(impaired hepatic metabolism of bilirubin or biliary tract
obstruction) or hemolytic anemias (increased release of bilirubin
from the hemoglobin of destroyed red cells). Patients with liver
disease have splenomegaly secondary to portal hypertension.
Patients with chronic hemolytic anemias have splenomegaly
secondary to "work hypertrophy."
PHYSICAL EXAM
• No Lymphadenopathy
– Correct!
COMMENT: Lymphadenopathy may be secondary
to infection, inflammation or malignancy, either
metastatic solid tumors or hematologic
malignancies such as non-Hodgkin's lymphoma
and Hodgkin's Disease
PHYSICAL EXAM
• No cardiac murmurs
• Correct!
COMMENT: Cardiac murmurs may indicate
the presence of endocarditis, which may be
associated with neutrophilia, thrombocytosis
and splenomegaly.
PHYSICAL EXAM
• Normal neurologic exam
– No. This is not relevant for ruling out reactive
causes of neutrophilias and thrombocytosis
PHYSICAL EXAM
• How does the finding of a palpable spleen on physical
examination narrow the differential diagnosis in this
patient?
• It might not narrow the differential diagnosis, since a spleen
may normally be palpable.
• The presence of splenomegaly makes infection unlikely.
• Myeloproliferative disorders are often associated with
splenomegaly
PHYSICAL EXAM
• It might not narrow the differential diagnosis,
since a spleen may normally be palpable.
– Incorrect.
COMMENT: A normal spleen is not palpable,
except perhaps in a very thin individual. A
palpable spleen generally indicates splenomegaly.
PHYSICAL EXAM
• The presence of splenomegaly makes infection
unlikely.
– Incorrect.
COMMENT: Infections such as bacterial endocarditis,
infectious mononucleosis, tuberculosis, malaria and
parasitic infections may all cause splenomegaly.
PHYSICAL EXAM
• Myeloproliferative disorders are often associated
with splenomegaly.
– Correct!
COMMENT: All of the myeloproliferative disorders
may be associated with splenomegaly, which is
secondary to extramedullary hematopoiesis.
Mechanisms of splenomegaly
LABORATORY DATA
•
Which laboratory and diagnostic studies would be helpful in making a
diagnosis?
•
Creatinine
•
Calcium
•
CXR
•
Liver enzymes
•
Uric acid
•
Serial stool testing for occult blood (guaiac tests)
•
Iron studies
•
Evaluation of peripheral smear
LABORATORY DATA
• Creatinine
– Not relevant in this case
LABORATORY DATA
• Calcium
– Not relevant in this case.
LABORATORY DATA
• CXR
– Good choice!
PATIENT RESULT: Normal
COMMENT: Chronic infections such as
tuberculosis may lead to reactive granulocytosis
and thrombocytosis
LABORATORY DATA
• Liver enzymes
– Good choice!
PATIENT RESULT: Normal
COMMENT: Splenomegaly may occur in patients
with liver disease secondary to portal hypertension.
However, this is usually associated with cytopenias
secondary to hypersplenism, and not elevated blood
counts.
LABORATORY DATA
• Uric acid
– Good choice!
PATIENT RESULT: 9 mg/dL
COMMENT: An elevated uric acid level can result from gout, renal
failure or increased purine catabolism that occurs with highly
proliferative malignancies, including acute myelogenous leukemia and
the myeloproliferative disorders. It may also be seen during treatment
of these malignancies with chemotherapy, when the rapid destruction of
cells releases large amounts of uric acid into the blood, so called "tumor
lysis
LABORATORY DATA
• Serial stool testing for occult blood (guaiac tests)
– Good choice!
PATIENT RESULT: Negative for occult blood
COMMENT: Gastrointestinal bleeding may be
associated with reactive thrombocytosis. Peptic ulcer
disease has a 4-5 fold increased incidence in patients
with polycythemia vera
LABORATORY DATA
• Iron studies
– Good choice!
PATIENT RESULT: Normal
COMMENT: Iron deficiency and bleeding may be
associated with reactive thrombocytosis. Polycythemia
vera is often associated with iron deficiency secondary
to gastrointestinal blood loss and increased iron
utilization from the marked increase in erythropoiesis.
LABORATORY DATA
• Evaluation of peripheral smear
– Good choice!
PATIENT RESULT:
LABORATORY DATA
LABORATORY DATA
• The peripheral smear shows a
marked increase in
granulocytic cells with a left
shift (the presence of immature
granulocytes in the peripheral
blood including bands,
metamyelocytes and
myelocytes). There is an
increase in platelets.
DIFFERENTIAL DIAGNOSIS
• Given this patient’s clinical and laboratory findings, what is the
most likely diagnosis?
• Acute Myelogenous Leukemia
• Polycythemia Vera
• Essential Thrombocythemia
• Chronic Myelogenous Leukemia
• Reactive thrombocytosis and granulocytosis secondary to infection
• Reactive thrombocytosis and granulocytosis secondary to
malignancy
DIFFERENTIAL DIAGNOSIS
• Acute Myelogenous Leukemia
– Incorrect.
COMMENT: Although acute myelogenous leukemia
frequently presents with an elevated total WBC count, the
white blood cells are last forms. Mature white blood cells
such as bands and neutrophils (granulocytes) are
decreased. Patients usually have thrombocytopenia (a
decreased platelet count). Patients are typically acutely ill
with fever and signs of bleeding.
DIFFERENTIAL DIAGNOSIS
•
Polycythemia Vera
– Unlikely.
COMMENT: Polycythemia vera may be associated with the constitutional symptoms
described as well as with splenomegaly, granulocytosis, basophilia and thrombocytosis.
However, one of its defining features, an elevated hematocrit, is not present in this patient.
Sometimes, with profound iron deficiency, the hematocrit may not be elevated. Iron studies
would indicate iron deficiency (low serum iron, elevated total iron binding capacity) and the
MCV would be decreased. This patient has normal iron studies and a normal MCV. Mutations
in JAK2, a tyrosine kinase involved in the physiology of the bone marrow response to
erythropoietin and in cell proliferation, have recently been identified in more than 95% of
patients with polycythemia vera (but not in patients with secondary erythrocytosis).
DIFFERENTIAL DIAGNOSIS
• Essential Thrombocythemia
– Unlikely.
COMMENT: The prominent feature of essential thrombocythemia is
thrombocytosis. Granulocytosis and splenomegaly are seen in about
50% of patients, but there is not typically a marked left shift in the
granulocyte differential as seen in this patient. Basophils may be mildly
increased. Mutations in JAK2, a tyrosine kinase involved in the
physiology of the bone marrow response to erythropoietin and in cell
proliferation, have been identified in 30-50% of patients with essential
thrombocythemia.
DIFFERENTIAL DIAGNOSIS
• Chronic Myelogenous Leukemia
– Correct! This is the most likely diagnosis.
COMMENT: CML is characterized by granulocytosis with a left
shift, basophilia, thrombocytosis and splenomegaly. Increasingly
patients are being diagnosed while asymptomatic, on the basis of
an elevated WBC count detected on routine screening. However,
symptoms including fatigue and night sweats may be seen,
secondary to the increased metabolic state. Early satiety may
occur as a result of splenomegaly.
DIFFERENTIAL DIAGNOSIS
• Reactive thrombocytosis and granulocytosis
secondary to infection
– Unlikely.
COMMENT: The absence of fever, CXR
abnormalities (Tb), and cardiac murmur (endocarditis)
makes infection unlikely. Patients with reactive
thrombocytosis and granulocytosis secondary to
infection would likely be more ill appearing.
DIFFERENTIAL DIAGNOSIS
• Reactive thrombocytosis and granulocytosis
secondary to malignancy
– Unlikely.
COMMENT: The absence of weight loss, cachexia,
CXR abnormalities, gastrointestinal bleeding, and
lymphadenopathy makes a malignancy unlikely.
DIFFERENTIAL DIAGNOSIS
• What diagnostic tests would you perform to make a diagnosis?
• Bone marrow aspirate
• Bone marrow cytogenetics
• Bone marrow fluorescence in situ hybridization (FISH) analysis for
the BCR-ABL rearrangement
• Bone marrow quantitative polymerase chain reaction (qPCR)
analysis for bcr-abl gene
• Flow cytometry of peripheral blood
• JAK2 mutation analysis Red cell mass
DIFFERENTIAL DIAGNOSIS
• Bone marrow aspirate
– Correct.
PATIENT RESULTS
DIFFERENTIAL DIAGNOSIS
• There is granulocytic
hyperplasia
(myeloid:erythroid
ratio=10:1; normal M:E
ratio is 3:1)
DIFFERENTIAL DIAGNOSIS
• The bone marrow is
markedly hypercellular
with an increase in
megakaryocytes.
Megakaryocytes are
hypolobulated and seen
in clusters
DIFFERENTIAL DIAGNOSIS
• The bone marrow aspirate findings are typical of
the myeloproliferative disorders (though do not
distinguish among them), and rule out the
diagnosis of acute myelogenous leukemia. The
presence of atypical megakaryocytes and
megakaryocyte clustering is not seen in reactive
granulocytosis or thrombocytosis
DIFFERENTIAL DIAGNOSIS
• Bone marrow cytogenetics
– Correct.
PATIENT RESULTS
DIFFERENTIAL DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
• COMMENT: The chromosome abnormality
shown here is a reciprocal translocation (red
arrows) between the long arms of
chromosomes 9 and 22, resulting in the
formation of the Philadelphia chromosome.
DIFFERENTIAL DIAGNOSIS
• Bone marrow fluorescence in situ
hybridization (FISH) analysis for the BCR-
ABL rearrangement
– Correct.
PATIENT RESULTS
DIFFERENTIAL DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
• Fluorescence In Situ Hybridization: Interphase (non-dividing) bone
marrow cells stained with fluorescein labeled probes for bcr and abl
genes.
– COMMENT: FISH analysis using labeled probes for abl (red) and bcr
(green) loci shows the presence of non fused genes in a normal cell and
a bcr-abl fused signal (yellow) in an abnormal cell. The translocation
between chromosomes 9 and 22 results in the fusion of the cellular
oncogene abl (from chromosome 9) with the breakpoint cluster region
gene bcr (on chromosome 22). This chimeric gene (bcr-abl) can be
identified by FISH analysis.
DIFFERENTIAL DIAGNOSIS
•
Bone marrow quantitative polymerase chain reaction (qPCR) analysis for bcr-abl
gene
– Correct!
Result: Positive (% bcr-abl/abl: 8.1)
COMMENT: The assay shows the presence of bcr-abl transcripts. The qPCR assay uses
specific primers to amplify a DNA fragment from bcr-abl mRNA transcripts. The result is
usually expressed as the ratio of bcr-abl transcripts to normal abl transcripts. It is a quantitative
assay that is extremely sensitive and can detect one Philadelphia chromosome positive cell in
105 to 106 normal cells. It is now routinely used to monitor response to tyrosine kinase inhibitor
therapy. The degree of “log reduction” in transcript number from diagnosis has prognostic
importance and correlates with progression-free survival. In addition, rising transcript levels
may signal the development of resistance to treatment and warrant change in therapy.
DIFFERENTIAL DIAGNOSIS
• Flow cytometry of peripheral blood
– Incorrect.
COMMENT: Phenotypic analysis of the peripheral
blood granulocytes will not help distinguish a
myeloproliferative disorder from a reactive
granulocytosis since the granulocytes in both
conditions are phenotypically normal
DIFFERENTIAL DIAGNOSIS
• JAK2 mutation analysis
– Incorrect.
COMMENT: A mutation of the JAK2 gene has been
identified in upwards of 95% of patients with
polycythemia vera, and in about 50% of patients with
essential thrombocythemia and primary myelofibrosis.
It has not been identified in patients with classic
chronic myelogenous leukemia.
DIFFERENTIAL DIAGNOSIS
• Red cell mass
– Incorrect.
COMMENT: In the absence of an elevated hematocrit, this
test would not be indicated. A red cell mass should be
performed in patients with erythrocytosis (abnormally high
Hgb and hematocrit) to determine if there is a true or
relative (elevated hematocrit secondary to a decreased
plasma volume) erythrocytosis
DIFFERENTIAL DIAGNOSIS
• The bone marrow findings confirm a diagnosis of which
disease?
• Acute Myelogenous Leukemia
• Chronic Myelogenous Leukemia
• Essential Thrombocythemia
• Polycythemia Vera
• Chronic Myelomonocytic Leukemia
• Reactive Granulocytosis/Thrombocytosis
DIFFERENTIAL DIAGNOSIS
• Chronic Myelogenous Leukemia
– Correct. The bone marrow cytogenetic, FISH and
PCR results confirm the diagnosis of CML.
PROGNOSIS/CLINICAL COURSE
• What phase of disease is this patient
currently in?
• Chronic Phase
• Accelerated Phase
• Blast Phase
PROGNOSIS/CLINICAL COURSE
• Chronic Phase
– Correct!
COMMENT: Clinically, CML is characterized by a triphasic course. Patients
typically present in the first (chronic) phase and are often asymptomatic,
presenting with an elevated white blood cell count identified during a routine
health screening. When symptoms are present, they are related to the
hypermetabolic state associated with this disease, and include fatigue, malaise,
fever, night sweats and weight loss. More than half the patients have
splenomegaly and hepatomegaly at diagnosis. Leukocytosis is a hallmark of
CML, with granulocytes from all stages of maturation present in the peripheral
blood.
PROGNOSIS/CLINICAL COURSE
• Accelerated Phase
– Incorrect.
COMMENT: The accelerated phase of CML is associated with a more
aggressive clinical course than is present in this patient. The accelerated phase
of CML is characterized by fever, bone pain, increasing splenomegaly,
progressive anemia, thrombocytopenia and increasing numbers of blasts in the
blood and bone marrow. The development of additional chromosomal
abnormalities (a double Philadelphia chromosome, or other cytogenetic
abnormalities) and the failure of previously successful therapy to control blood
counts, splenomegaly and symptoms herald the onset of this transforming or
"accelerated" phase. Average survival at this stage is about 1 year.
PROGNOSIS/CLINICAL COURSE
• Blast Phase
– Incorrect.
COMMENT: The terminal or "blastic" phase of CML is
characterized by blood and bone marrow findings
indistinguishable from acute leukemia. The majority of
acute leukemias are myelogenous; however, in 25-30% of
cases, the leukemic cells are of lymphoid lineage. Survival
in the blastic phase is uniformly short with a median
duration of 4-6 months.
PROGNOSIS/CLINICAL COURSE
• What would be the treatment of choice for this
patient?
• Observation
• Hydroxyurea
• Interferon alpha
• Allogeneic stem cell transplantation
• Imatinib mesylate (Gleevec)
PROGNOSIS/CLINICAL COURSE
• Observation
– Incorrect.
COMMENT: Even though the patient is relatively
asymptomatic, without appropriate, effective therapy,
all patients with CML in chronic phase will progress to
the accelerated phase and then the blast
phase. Therapy initiated in the accelerated or blast
phase is almost always unsuccessful.
PROGNOSIS/CLINICAL COURSE
• Hydroxyurea
– Incorrect.
COMMENT: Hydroxyurea is a ribonucleotide reductase inhibitor that exerts its
antileukemic effect by inhibiting DNA synthesis. In patients who present with
markedly elevated WBC counts (>250,000/µL) and/or signs and symptoms
associated with a hypermetabolic state (hyperuricemia, fever, weight loss, night
sweats), initiation of hydroxyurea may be appropriate to reduce the WBC count
quickly and to control symptoms. However, in this patient with a moderate
increase in WBC count and minimal symptoms, hydroxyurea is not indicated.
The use of myelosuppressive agents such as hydroxyurea does not eliminate
the Philadelphia chromosome or delay the progression to the accelerated and
blast phases of the disease.
PROGNOSIS/CLINICAL COURSE
• Interferon alpha
– Incorrect. Interferon alpha is no longer indicated
as the treatment of choice in patients with newly
diagnosed CML
PROGNOSIS/CLINICAL COURSE
• Allogeneic stem cell transplantation
– Incorrect. Allogeneic stem cell transplant would
not be the initial treatment of choice for this
patient.
PROGNOSIS/CLINICAL COURSE
• Imatinib mesylate (Gleevec)
– Correct! This is the treatment of choice for this
patient.
TEACHING POINTS