myeloproliferative disorder

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.


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.


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.


COMMENT: Acute and chronic infections may be

associated with reactive thrombocytosis and

granulocytosis.

HISTORY

• Do you have any itching?

– Good choice.


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.


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.


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.


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.


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.


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!


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!


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



– 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.



– 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).



– 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.



– 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.


• 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.


• 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.


• 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


• Bone marrow aspirate

– Correct.

PATIENT RESULTS


• There is granulocytic

hyperplasia

(myeloid:erythroid

ratio=10:1; normal M:E

ratio is 3:1)


• The bone marrow is

markedly hypercellular

with an increase in

megakaryocytes.

Megakaryocytes are

hypolobulated and seen

in clusters


• 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


• Bone marrow cytogenetics

– Correct.

PATIENT RESULTS


• 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.


• Bone marrow fluorescence in situ

hybridization (FISH) analysis for the BCR-

ABL rearrangement

– Correct.

PATIENT RESULTS


• 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.


• 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.


• 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


• 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.


• 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


• The bone marrow findings confirm a diagnosis of which disease?





• Chronic Myelomonocytic Leukemia

• Reactive Granulocytosis/Thrombocytosis



– 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


• 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.


• 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.


• 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.


• What would be the treatment of choice for this patient?

• Observation

• Hydroxyurea

• Interferon alpha

• Allogeneic stem cell transplantation

• Imatinib mesylate (Gleevec)


• 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.


• 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.


• Interferon alpha

– Incorrect. Interferon alpha is no longer indicated

as the treatment of choice in patients with newly

diagnosed CML


• Allogeneic stem cell transplantation

– Incorrect. Allogeneic stem cell transplant would

not be the initial treatment of choice for this

patient.


• Imatinib mesylate (Gleevec)

– Correct! This is the treatment of choice for this

patient.

TEACHING POINTS

myeloproliferative disorder

Documents