Page 1 of 18 Dr. RAJENDRAN’S INSTITUTE OF MEDICAL EDUCATION CHRONIC MYELOGENOUS LEUKEMIA (20 MCQs) 1) What is the cytogenetic abnormality seen in chronic myeloid leukemia (CML)? a. Philadelphia chromosome T [ Chronic myeloid leukemia is unregulated cell division (myeloproliferation) of a pluripotent stem cell with a specific cytogenetic abnormality called Philadelphia chromosome. The Philadelphia chromosome is the cytogenetic hallmark of CML. See figure below.] b. Deletion of BCR gene [ Philadelphia chromosome is created by translocation involving the BCR (breakpoint cluster region) gene on chromosome 9 and the ABL gene (named after the abelson murine leukemia virus) on chromosome 22. Thus, a BCR-ABL fusion gene results. BCR-ABL is an oncogene that causes CML. The ultimate effect of BCR-ABL oncogene is unregulated cell division (myeloproliferation) and inhibition of apoptosis. A decrease in apoptosis of myeloid cells causes the expansion of myeloid cells.] c. Deletion of ABL gene d. Absence of chromosome 22 www.medicinemcq.com Page 2 of 18 2) Pathognomonic of CML is a. t(9;22)translocation [ The Philadelphia chromosome is detected in 95% of patients with CML and in 5% of children and 15% to 30% of adults with acute lymphoblastic leukemia. Those who do not express Philadelphia chromosome have atypical CML and have a different prognosis and treatment.] b. BCR-ABL gene T [ Conclusive diagnosis of CML relies on cytogenetic and molecular testing to identify the t(9;22)translocation and/or the BCR-ABL hybrid gene, which is pathognomonic of this disease. All patients should have evidence of t(9;22)translocation and/or the BCR-ABL gene to make a diagnosis of CML.] c. Both d. Neither www.medicinemcq.com Page 3 of 18 3) Philadelphia chromosome is found in a. Chronic myeloid leukemia [ It is found in approximately 95% of patients with CML.] b. Children with acute lymphocytic leukemia [ It also is observed in 5% of children and in about 25% of adults with acute lymphocytic leukemia.] c. Adults with acute lymphocytic leukemia d. Acute myelocytic leukemia [ It also is seen in 2% of patients with newly diagnosed acute myelocytic leukemia.] e. All T 4) Which is the first phase of CML? a. Chronic phase T [ There are 3 phases of disease progression: chronic phase, accelerated phase, and blast phase. The first phase is the chronic phase. 85% are diagnosed in the chronic phase, which is asymptomatic in up to 25% of patients. Frequently, the diagnosis of CML is made incidentally after a routine complete blood cell count. Patients with CML- chronic phase have a competent immune system. Therefore, they may remain asymptomatic for prolonged periods.] b. Blast phase [ The chronic phase terminates in a second, more acute or abrupt course, called the blast phase.] c. Accelerated phase [Sometimes there is an intervening short-lived phase between the chronic and blast phases called the accelerated phase. Accelerated phase is characterized by a more gradual increase in blast cells in the peripheral blood, progressive anemia, thrombocytopenia, and increasing splenomegaly.] d. Acute phase www.medicinemcq.com Page 4 of 18 5) Chronic myelogenous leukemia - True statement a. Peak incidence at about 50 years of age [ CML is a disease of adults between the ages of 25 and 60 years. The peak incidence is in the fourth and sixth decades of life. The median age of onset of CML is 50 years. There is no sex preference. CML is very rare in children.] b. Philadelphia chromosome is present In more than 90% of cases c. Invariably transforms to blast crisis [ If CML is untreated, chronic phase inevitably transforms to an accelerated phase and then to blast crisis (resembling acute leukemia). In the chronic phase, the white blood cell count approximates 200,000/mL.] d. CML marrows are usually 100% cellular [ The normal bone marrow is about 50% cellular and 50% fat. In contrast, CML marrows are usually 100% cellular, with maturing granulocytic precursors. Megakaryocytes are also frequently increased. Erythroid progenitors are usually normal or decreased.] e. All T [ CML is best differentiated from other chronic myeloproliferative disorders by detection of the BCR-ABL fusion gene. Fluorescence in situ hybridization (FISH) or the reverse transcriptasepolymerase chain reaction (RT-PCR) can be used to detect the BCR-ABL fusion gene.] www.medicinemcq.com Page 5 of 18 6) What percentages of patients with CML transform to blast crisis? a. 25 b. 50 c. 75 d. 100 T [ If CML is untreated, chronic phase inevitably transforms to an accelerated phase and then to blast crisis (resembling acute leukemia). After about 3 years, approximately 50% enter an "accelerated phase." Within 6 to 12 months, the accelerated phase terminates in blast crisis (resembles acute leukemia). In the remaining 50%, blast crises occur abruptly without an intermediate accelerated phase. The transition from chronic phase to accelerated phase is usually subclinical. Laboratory monitoring is necessary for detection of disease progression. Most patients with blast crisis experience signs and symptoms. These include inability to control WBC counts with previously stable doses of medication, marked constitutional symptoms (fever, night sweats, anorexia, malaise, weight loss), splenic infarcts due to massive splenomegaly, bone pain, and increased risk of infections and bleeding.] 7) What is/are bone marrow finding(s) in CML? a. Increased cellularity [ The bone marrow is hypercellular and devoid of fat. Bone marrow cellularity is increased in almost all patients with CML. Myeloid and megakaryocytic lineages are mainly involved. The myeloid cells in the peripheral blood and bone marrow show all stages of differentiation, with predominance of myelocytes.] b. Normal blast percentage [ The marrow blast percentage is generally normal or slightly elevated. In chronic phase, the sum of myeloblasts and promyelocytes form less than 10% of the marrow cellularity. Blood or marrow blasts between 10 and 20% indicates disease acceleration.] www.medicinemcq.com Page 6 of 18 c. Basophilia [ Marrow or blood basophilia, eosinophilia, and monocytosis may be present. 20% blood or marrow basophils indicates disease acceleration.] d. Fibrosis [ Marrow fibrosis is rare at presentation. Significant fibrosis is develops later in about half of the patients . Marrow fibrosis is a secondary phenomenon due to cytokines, such as plateletderived growth factor, transforming growth factor β, and basic fibroblastic growth factor. These cytokines modulate angiogenesis. The bone marrow in CML shows the highest number of blood vessels and largest vascular area of all leukemias.] e. All T [ All are true.] 8) Sea-blue histiocytes are seen in a. AML b. CML T [ A characteristic finding in the bone marrow is the presence of scattered storage histiocytes with wrinkled, greenblue cytoplasm (sea-blue histiocytes). Increased deposition of reticulin fibers is typical, but marrow fibrosis is rare at presentation. See figure below.] c. Hodgkin lymphoma d. Non-Hodgkin lymphoma e. Histiocytosis www.medicinemcq.com Page 7 of 18 9) What is/are the findings on peripheral blood examination in CML? a. Leukocytosis [ Leukocytosis with a remarkable left shift is a common feature of chronic phase. Peripheral blood examination shows a 3 marked leukocytosis, often exceeding 100,000 cells per mm . The circulating cells are predominantly neutrophils, metamyelocytes, and myelocytes. Myelocytes predominate in the peripheral blood. Myeloblasts form less than 10%. The very high WBC count can cause signs and symptoms of hyperviscosity (retinal hemorrhage, priapism, cerebrovascular accidents, tinnitus, confusion, and stupor).] b. Eosinophilia basophilia are also common.] www.medicinemcq.com [ Peripheral blood eosinophilia and Page 8 of 18 c. Basophilia [ Basophilia increase histamine production, causing pruritus, diarrhea, and flushing. The basophil is associated mainly with allergic reactions and some delayed cutaneous hypersensitivity states. Basophils have high-affinity surface receptors for IgE (FcRI). IgE activate mast cells and basophils by binding to these cells. When an antigen (i.e., allergen) interacts with the IgE bound to basophils, there is release of mediators of immediate (anaphylaxis) hypersensitivity responses.] d. Thrombocytosis [ Up to 50% of patients have thrombocytosis early in the course of their disease. More than half of patients have platelet counts greater than 1 million/mL, but thrombotic phenomena are rare.] e. All T Laboratory findings in CML include leukocytosis, basophilia, and eosinophilia. Platelet count may be either high or low, and mild anemia is commonly observed. 10) Which is low in CML? a. Platelet counts [ Platelet counts are almost always elevated at diagnosis. White blood cell counts are also elevated. Phagocytic functions are usually normal.] b. Leukocyte alkaline phosphatase T [ Leukocyte alkaline phosphatase is low in CML cells. Phagocytic function remains essentially normal. Activity may increase with infection, clinical remission, or at the onset of blast crisis. In leukemoid reactions, leukocyte alkaline phosphatase level is normal or increased.] c. Serum vitamin B12 [ The increase in the size of the WBC pool is reflected by marked elevation of serum B12 levels and unsaturated B12binding capacity.] d. Histamine production [ Histamine production is increased in later stages, causing pruritus, diarrhea, and flushing. Increased histamine production is secondary to basophilia.] www.medicinemcq.com Page 9 of 18 11) CML is differentiated from leukemoid reactions by a. WBC counts [ Patients with untreated CML usually have leukocytosis ranging from 10,000 to 500,000/ml. Leukemoid reactions usually produce WBC counts lower than 50,000/ml.] b. Toxic granulocytic vacuolation [ Leukemoid reactions produce toxic granulocytic vacuolation.] c. Basophil count [ Basophilia is absent in leukemoid reactions.] d. Döhle bodies [ Döhle bodies are seen in the granulocytes in leukemoid reactions.] e. All T [ Leukocyte alkaline phosphatase level is low in CML cells. In leukemoid reactions, leukocyte alkaline phosphatase level is normal or increased.] 12) CML may present with a. Weakness [ Patients with CML-chronic phase have a competent immune system and may remain asymptomatic for prolonged periods. When symptoms appear, they consist typically of weakness, weight loss, and discomfort caused by splenomegaly.] b. Acute onset of left upper quadrant pain [ Sometimes the first symptom is a dragging sensation in the abdomen caused by the extreme splenomegaly. Acute onset of left upper quadrant pain may be due to splenic infarction.] c. Pleuritic chest pain [Splenic infarction may cause acute left upper quadrant abdominal pain and pleuritic chest pain. Splenic infarction is commonly clinically silent.] www.medicinemcq.com Page 10 of 18 d. Thrombosis [ Less common presenting features are infections, thrombosis, and bleeding. Thrombotic manifestations include vasoocclusive disease, cerebrovascular accidents, myocardial infarction, venous thrombosis, priapism, visual disturbances, and pulmonary insufficiency. ] e. Any of the above T [ The onset of CML is insidious. 85% are diagnosed in the chronic phase, which is asymptomatic in up to 25% of patients. Frequently, the diagnosis is made incidentally after a routine complete blood cell count is done. CML progresses only slowly. Even without treatment, the median survival is 3 years. Clinically, most patients with blast crisis experience signs and symptoms. These include inability to control WBC counts with previously stable doses of medication, marked constitutional symptoms (fever, night sweats, anorexia, malaise, weight loss), splenic infarcts due to massive splenomegaly, bone pain, and increased risk of infections and bleeding.] 13) What is the most common abnormal finding on physical examination in CML? a. Anemia b. Lymph node enlargement c. Splenomegaly T [ In most patients, the abnormal finding on physical examination at diagnosis is minimal to moderate splenomegaly.] d. Hepatomegaly [ Mild hepatomegaly is found occasionally.] e. Fever and weight loss [ Unexplained fever, significant weight loss, bone and joint pain, bleeding, thrombosis, and infections suggest transformation into accelerated or blastic phases.] www.medicinemcq.com Page 11 of 18 14) Splenomegaly in CML is due to a. Repeated infections b. Hematopoiesis T [ Splenomegaly is due to neoplastic hematopoiesis within the splenic red pulp.] c. Infarction [ Marked splenomegaly is often complicated by focal infarction. Splenic infarction may cause acute left upper quadrant abdominal pain and pleuritic chest pain. Splenic infarction is commonly clinically silent.] d. Polycythemia e. Increased WBC count www.medicinemcq.com Page 12 of 18 15) What is the most reliable clinical finding of blast crisis in CML? a. Blood or marrow blasts more than 30% T [ Blast crisis is defined as acute leukemia, with blood or marrow blasts more than 20% to 30% (or the presence of extramedullary blastic foci). Clinically the most reliable finding is the presence in the peripheral blood, bone marrow, or both of myeloblasts 30% of the differential distribution. The blast crises are divided into 3 general types, myeloid (50%), lymphoid (25%) and undifferentiated phenotype (25%). Clinically, most patients with blast crisis experience signs and symptoms. These include inability to control WBC counts with previously stable doses of medication, marked constitutional symptoms (fever, night sweats, anorexia, malaise, weight loss), splenic infarcts due to massive splenomegaly, bone pain, and increased risk of infections and bleeding.] b. Pelger-Huet anomaly [ Pelger-Huet anomaly is hyposegmented neutrophils. The majority of granulocytes are bilobed (See figures above and below). This is benign and may appear in blast crisis.] c. Increasing splenomegaly [ In the absence of frank blast crisis, other criteria include the development of fever of undetermined origin, increasing splenomegaly or lymphadenopathy, a rising WBC count, basophilia, an increasing degree of anemia and thrombocytopenia, and refractoriness to previously effective therapy.] d. Rising WBC count e. Blood or marrow basophils more than 20% [ If CML is untreated, chronic phase inevitably transforms to an accelerated phase and then to blast crisis (resembling acute leukemia). Different criteria have been used to define blast phase and accelerated phase. One commonly used classification defines accelerated phase as the presence of at least 1 of the following hematologic features: blood or marrow blasts between 10% and 20%, 30% or more blasts plus promyelocytes, 20% or more blood or marrow basophils, or platelet counts lower than 100,000/ul unrelated to therapy or increasing anemia not due to bleeding or chemotherapy.] www.medicinemcq.com Page 13 of 18 16) How does Hasford system differ from Sokal index? a. Age [ Hasford system and Sokal index are prognostic models used to identify risk groups in CML. Both consider age, spleen size, percentage of circulating blasts and platelet count. See table below.] b. Spleen size c. Percentage of circulating blasts d. Platelet count e. Cytogenetic clonal evolution T [ Clonal evolution is considered only by Sokal index. Hasford system ignores clonal evolution and instead consider percentage of eosinophils and basophils.] www.medicinemcq.com Page 14 of 18 HASFORD SYSTEM Age Spleen size Percentage of circulating blasts Platelet count Percentage of eosinophils and basophils THE SOKAL INDEX Age Spleen size Percentage of circulating blasts Platelet count Cytogenetic clonal evolution 17) What is the treatment of choice for CML? a. Imatinib [ The molecular abnormality in CML is the unregulated activity of the tyrosine kinase produced by the BCR-ABL fusion protein. Imatinib mesylate (Gleevec) inhibits tyrosine kinase of the Bcr-Abl chimeric fusion protein. Imatinib (Gleevec) acts by competitive inhibition at the adenosine triphosphate binding site of tyrosine kinase of the Bcr-Abl chimeric fusion protein. See the two figures below. Imatinib mesylate (Gleevec) induce complete hematologic remissions in more than 90% of patients. Imatinib mesylate (Gleevec) suppress but do not extinguish the CML clone. Following imatinib therapy, only 5 to 10% develop molecular remission. Therefore, it may not prevent progression to blast crisis. Most patients without molecular remission are at risk of relapse. Blast crisis following initial therapy with imatinib (Gleevec) carries a very bad prognosis. For this reason, allogeneic bone marrow transplantation is the favored treatment in younger patients.] www.medicinemcq.com Page 15 of 18 b. Stem cell transplant T [ Allogeneic stem cell transplant is the only curative therapy for CML. Stem cell transplant is the treatment of choice when feasible. Stem cell transplantation remains an important treatment option for patients with CML, particularly younger individuals with HLA-identical siblings. The transplant procedure has a high early-mortality rate. Risks of stem cell transplant are graft-vs-host disease, veno-occlusive disease, life-threatening infections, risk of secondary malignancy, and late relapse. It has been suggested that a trial of imatinib must be pursued in every patient before considering SCT. Consensus exists that imatinib therapy is the standard approach to the treatment of CML.] c. Interferons [ When allogeneic stem cell transplant is not feasible, IFN-a therapy used to be the treatment of choice before imatinib became available.] d. Homoharringtonine [ There may be synergism between homoharringtonine and imatinib. There may be synergism between arsenic trioxide and imatinib also.] e. Leukapheresis and splenectomy [ Intensive leukapheresis is done to control the very high blood counts in chronic-phase CML. It is useful only in emergencies when complications due to leukostasis (e.g., pulmonary failure or cerebrovascular accidents) are likely to develop. It may be useful in the treatment of pregnant women in whom it is important to avoid potentially teratogenic drugs. Splenectomy is done for symptomatic relief of painful splenomegaly unresponsive to chemotherapy or for significant anemia or thrombocytopenia associated with hypersplenism.] www.medicinemcq.com Page 16 of 18 www.medicinemcq.com Page 17 of 18 18) Imatinib - False statement a. Imatinib inhibits tyrosine kinase [ Imatinib is a potent and selective tyrosine kinase inhibitor.] b. Induces apoptosis in cells expressing Bcr/Abl [ Imatinib mesylate (Gleevec) inhibit Bcr/Abl kinase. It shows a high degree of specificity for Bcr/Abl. Imatinib induces apoptosis in cells expressing Bcr/Abl.] c. Cause molecular remission in 90% of patients with CML F [ False statement. Imatinib mesylate (Gleevec) induce complete hematologic remissions in more than 90% of patients. Only 5 to 10% develop molecular remission. Imatinib mesylate (Gleevec) suppress but do not extinguish the CML clone. Therefore, it may not prevent progression to blast crisis. Most patients without molecular remission are at risk of relapse.] d. Blast crisis following initial therapy with imatinib carries a very bad prognosis [ Blast crisis following initial therapy with imatinib (Gleevec) carries a very bad prognosis. For this reason, allogeneic bone marrow transplantation is the favored treatment in younger patients.] e. All 19) Tyrosine kinase inhibitor(s) a. Imatinib b. Nilotinib [ Nilotinib 25 times more potent than imatinib against Bcr-Abl.] c. Dasatinib [ Dasatinib is a dual-specific Src- and Abl-kinase inhibitor. It is 200 times more potent than imatinib against Bcr-Abl.] www.medicinemcq.com Page 18 of 18 d. All T [ Imatinib, nilotinib, and dasatinib are ATP-competitive inhibitors.] 20) What is the treatment of choice for accelerated phase? a. Imatinib T [ The treatment for all forms of blast crisis is generally ineffective. Imatinib is currently the current treatment of choice for accelerated phase for all patients in accelerated phase who have not received prior imatinib therapy. Imatinib as a single-agent will not result in significant long-term remissions in most patients. Only 50% of patients treated with imatinib achieve hematologic remission. Blast crisis following initial therapy with imatinib carries a dismal prognosis. Blast phase remains a generally incurable leukemia for which advances in therapy are desperately required.] b. Stem cell transplant [ Patients who achieve complete hematologic remission or whose disease returns to a second chronic phase should be considered for allogeneic stem cell transplant.] c. Homoharringtonine d. Interferon www.medicinemcq.com