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