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Questions and Answers
Which mutation is known as the 'gatekeeper' mutation and displays resistance to all currently available TKIs except ponatinib and asciminib?
Which mutation is known as the 'gatekeeper' mutation and displays resistance to all currently available TKIs except ponatinib and asciminib?
What categorization does the WHO recommend for CML-AP?
What categorization does the WHO recommend for CML-AP?
Which gene mutations are most frequently associated with progression to CML-BP?
Which gene mutations are most frequently associated with progression to CML-BP?
What is the expected median survival of patients with CML-AP that evolved from CML-CP?
What is the expected median survival of patients with CML-AP that evolved from CML-CP?
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What treatment option may be less beneficial for patients with somatic variants like ASXL1 mutations?
What treatment option may be less beneficial for patients with somatic variants like ASXL1 mutations?
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What is the primary genetic abnormality associated with chronic myeloid leukemia (CML)?
What is the primary genetic abnormality associated with chronic myeloid leukemia (CML)?
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Which of the following best describes the role of the BCR::ABL1 oncoprotein in CML pathogenesis?
Which of the following best describes the role of the BCR::ABL1 oncoprotein in CML pathogenesis?
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What is the primary feature of the chronic phase (CP) of CML?
What is the primary feature of the chronic phase (CP) of CML?
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Which signaling pathway is NOT typically activated by the BCR::ABL1 oncoprotein?
Which signaling pathway is NOT typically activated by the BCR::ABL1 oncoprotein?
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What percentage of newly diagnosed leukemia cases in adults is accounted for by CML?
What percentage of newly diagnosed leukemia cases in adults is accounted for by CML?
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What is a common clinical finding in patients with chronic myeloid leukemia during diagnosis?
What is a common clinical finding in patients with chronic myeloid leukemia during diagnosis?
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Which treatment approach is emphasized for managing chronic myeloid leukemia?
Which treatment approach is emphasized for managing chronic myeloid leukemia?
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What is the most common symptom experienced by patients in the chronic phase of CML?
What is the most common symptom experienced by patients in the chronic phase of CML?
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Which symptom is most consistently observed in patients with Chronic Myeloid Leukemia (CML)?
Which symptom is most consistently observed in patients with Chronic Myeloid Leukemia (CML)?
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What is the median platelet count observed in about 50% of patients with Chronic Myeloid Leukemia?
What is the median platelet count observed in about 50% of patients with Chronic Myeloid Leukemia?
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What percentage of patients with Chronic Myeloid Leukemia might present with leukocytosis greater than 100 × 10^9/L on diagnosis?
What percentage of patients with Chronic Myeloid Leukemia might present with leukocytosis greater than 100 × 10^9/L on diagnosis?
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Which laboratory finding is associated with Chronic Myeloid Leukemia in terms of granulocyte presence?
Which laboratory finding is associated with Chronic Myeloid Leukemia in terms of granulocyte presence?
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Which of the following conditions is a complication of Chronic Myeloid Leukemia associated with thrombocytosis?
Which of the following conditions is a complication of Chronic Myeloid Leukemia associated with thrombocytosis?
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In Chronic Myeloid Leukemia, which phase is characterized by an acute leukemia presentation?
In Chronic Myeloid Leukemia, which phase is characterized by an acute leukemia presentation?
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An increase in absolute basophil count is common in which phase of Chronic Myeloid Leukemia?
An increase in absolute basophil count is common in which phase of Chronic Myeloid Leukemia?
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What percentage of lymphocytes are expected to be present in the blood of chronic-phase CML patients?
What percentage of lymphocytes are expected to be present in the blood of chronic-phase CML patients?
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What is the minimum percentage of myeloid blasts in blood or bone marrow to meet the criteria for the blastic phase?
What is the minimum percentage of myeloid blasts in blood or bone marrow to meet the criteria for the blastic phase?
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Which laboratory finding is characteristic of chronic myeloid leukemia (CML)?
Which laboratory finding is characteristic of chronic myeloid leukemia (CML)?
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What type of PCR is ideal for monitoring residual disease in CML?
What type of PCR is ideal for monitoring residual disease in CML?
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What hallmark chromosomal abnormality is associated with chronic myeloid leukemia?
What hallmark chromosomal abnormality is associated with chronic myeloid leukemia?
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Which finding is NOT typically associated with the bone marrow aspiration in CML?
Which finding is NOT typically associated with the bone marrow aspiration in CML?
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How is the BCR::ABL1 gene fusion assessed using FISH analysis?
How is the BCR::ABL1 gene fusion assessed using FISH analysis?
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Which finding would indicate the presence of sea-blue histiocytes in the bone marrow?
Which finding would indicate the presence of sea-blue histiocytes in the bone marrow?
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What is the typical appearance of megakaryocytes in patients with increased numbers in CML?
What is the typical appearance of megakaryocytes in patients with increased numbers in CML?
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What is the prevalence of additional chromosomal abnormalities (ACAs) in patients with Ph-positive cells?
What is the prevalence of additional chromosomal abnormalities (ACAs) in patients with Ph-positive cells?
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Which variant translocation has exhibited a similar response to therapy and prognosis as Ph-positive CML?
Which variant translocation has exhibited a similar response to therapy and prognosis as Ph-positive CML?
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What is the typical translocation seen in 90% of patients with chronic myeloid leukemia (CML)?
What is the typical translocation seen in 90% of patients with chronic myeloid leukemia (CML)?
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Which of the following chromosomal abnormalities is linked to a poor prognosis when detected?
Which of the following chromosomal abnormalities is linked to a poor prognosis when detected?
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What is the range of patients who may present with CML morphologically without Ph-positivity in cytogenetic studies?
What is the range of patients who may present with CML morphologically without Ph-positivity in cytogenetic studies?
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Which oncoprotein is produced by the typical BCR::ABL1 e13a2 or e14a2 transcripts?
Which oncoprotein is produced by the typical BCR::ABL1 e13a2 or e14a2 transcripts?
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In the differential diagnosis of leukemoid reactions, what is a typical maximum white blood cell count?
In the differential diagnosis of leukemoid reactions, what is a typical maximum white blood cell count?
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What would be the potential consequence of not testing for BCR::ABL1 transcripts at diagnosis?
What would be the potential consequence of not testing for BCR::ABL1 transcripts at diagnosis?
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Study Notes
Definition and Pathogenesis
- Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm (MPN) caused by a genetic translocation in pluripotent hematopoietic stem cells (HSC).
- This translocation involves the Abelson murine leukemia (ABL1) gene on chromosome 9 and the breakpoint cluster region (BCR) gene on chromosome 22, leading to the formation of a BCR::ABL1 fusion gene.
- The BCR::ABL1 fusion gene encodes an oncoprotein that acts as a constitutively active tyrosine kinase, promoting CML cell growth and survival.
- The prevalence of CML is 2 cases per 100,000 individuals.
- CML accounts for approximately 15% of newly diagnosed leukemia cases in adults, with a slight male predominance.
Diagnosis and Differential Diagnosis
- CML diagnosis primarily relies on the presence of the Philadelphia (Ph) chromosome, a t(9;22)(q34;q11) translocation detected by cytogenetics, fluorescence in situ hybridization (FISH), or molecular studies (RT PCR).
- 90% of patients exhibit the typical t(9;22), while 5% have variant translocations involving chromosome 9 and a chromosome other than chromosome 22 or complex translocations involving multiple chromosomes.
- Patients with Ph-variants respond to therapy and have a prognosis similar to Ph-positive CML.
- 2% to 5% of patients present morphologically like CML but are Ph-negative by cytogenetic studies.
- The typical (BCR::ABL1) e13a2 or e14a2 transcripts produce the oncoproteins p210.
- A small percentage of patients may exhibit e1a2/a3 transcript (producing p190) or e13a3, e14a3, or e19a2 transcripts (producing p230).
Clinical Manifestations and Phases
- CML can be classified into two phases: chronic phase (CP) and blastic phase (BP).
- Approximately 50% of patients diagnosed with CML are asymptomatic.
- CML-CP is characterized by symptoms such as fatigue, weight loss, malaise, easy satiety, and left upper quadrant fullness or pain caused by splenomegaly and anemia.
- CML-BP presents as an acute leukemia, with worsening constitutional symptoms, bleeding, fever, and infections.
Laboratory Findings
-
Peripheral Blood Smear:
- Marked granulocytic leukocytosis with left shift, neutrophilia, myelocyte "bulge," basophilia, and absence of increased blasts.
- Granulocytes lack dysplastic features
-
CBC and Blood Film:
- Mild to moderate normochromic normocytic anemia with occasional nucleated red blood cells (NRBC). Reticulocyte count is normal or slightly increased.
- Platelet count is elevated in about 50% of patients.
- Persistent unexplained leukocytosis, typically greater than 25 × 109/L, with all stages of granulocytes present.
- Hypersegmented neutrophils are common.
- Absolute eosinophil count is almost always increased.
- Absolute basophil count increases in almost all cases.
-
Bone Marrow Aspiration:
- Hypercellular marrow due to increased myeloid activity.
- Increased myeloid-to-erythroid ratio (>10:1).
- Dominant granulopoiesis with broader zones of immature granulocytes.
- Reduced erythropoiesis.
- Megakaryocytes are normal or increased in number.
- Sea-blue histiocytes are present due to marked cell turnover.
-
Bone Marrow Biopsy:
- Packed marrow with increased numbers of granulocytic cells and megakaryocytes.
- Marked fibrosis and streaming of hemopoietic cells.
Treatment and Monitoring
- Treatment for CML has advanced significantly in recent years, primarily due to the development of tyrosine kinase inhibitors (TKIs).
- TKIs target the BCR::ABL1 fusion protein, effectively controlling the leukemia.
- TKI therapy effectively reduces mortality rates to 2–3% annually.
- Monitoring response to TKIs includes assessing the levels of BCR::ABL1 transcripts in the blood using quantitative PCR (qPCR).
- Resistance to TKIs can occur, often due to mutations in the BCR::ABL1 gene.
- Second-generation TKIs, such as ponatinib and asciminib, can overcome resistance to certain mutations, including the T315I mutation.
References
- References for the provided information have been omitted in this response.
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Description
This quiz covers the definition, pathogenesis, and diagnostic criteria for Chronic Myeloid Leukemia (CML). It explores the genetic factors involved in CML, such as the BCR::ABL1 fusion gene, and details on diagnosis methods like the Philadelphia chromosome. Test your knowledge on this important hematological condition.
