WBR0487

Author	[[PageAuthor::Yazan Daaboul, M.D. (Reviewed by Yazan Daaboul, M.D. and Alison Leibowitz [1])]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Pathophysiology
Sub Category	SubCategory::Oncology
Prompt	[[Prompt::A 36-year-old woman presents to the physician's office with complaints of chronic fatigue and decreased exercise tolerance. She explains that over the past 4 months, these symptoms have became increasingly intolerable. Upon physical examination, the physician notes a mild splenomegaly. The results from the ordered lab tests are illustrated below. The patient's diagnosis is then confirmed and chemotherapy is initiated. What is the mechanism of action of the drug most likely administered to this patient? Hb = 9.0 g/dL Hct = 27.2 % MCV = 82 fL Plt = 120 x 109/L WBCs = 56000 / mm3 %Neutrophils = 96 % %Lymphocytes = 2 % Vitamin B12 level: Elevated Leukocyte alkaline phosphatase: Low]]
Answer A	AnswerA::Microtubule stabilization
Answer A Explanation	AnswerAExp::Paclitaxel is a microtubule stabilizer that is not effective for the management of CML.
Answer B	AnswerB::Inhibition of DNA polymerase
Answer B Explanation	AnswerBExp::Cytarabine is a pyrmidine analog that inhibits DNA polymerase. It is not effective for the management of CML.
Answer C	AnswerC::Inhibition of dihydrofolate reductase
Answer C Explanation	AnswerCExp::Methotrexate is a folic acid analog that inhibits dihydrofolate reductase to decrease DNA and protein synthesis. It is not effective for the management of CML.
Answer D	AnswerD::Inhibition of topoisomerase I
Answer D Explanation	AnswerDExp::Irinotecan and topotecan inhibit topoisomerase I and prevent the unwinding and replication of DNA.
Answer E	AnswerE::Inhibition of protein kinase
Answer E Explanation	AnswerEExp::Tyrosine kinase inhibitors, such as imatinib, are effective for the management of CML.
Right Answer	RightAnswer::E
Explanation	[[Explanation::Chronic myelogenous/myeloid leukemia (CML) is a myeloproliferative disorder that accounts for approximately 20% of adult leukemias. It is characterized by the increased and unregulated growth of myeloid cells (neutrophils, eosinophils, and basophils) without significant impairment of their differentiating ability. CML is frequently associated with a chromosomal translocation, which is referred to as the Philadelphia chromosome, where a reciprocal translocation between chromosome 9 and 22 occurs (specifically designated as t(9,22)). The translocation results in the BCR-ABL gene fusion that encodes a constitutively active oncogenic tyrosine kinase. CML is initially an insidious chronic disease (CML-CP) that features the expansion of normal myeloid lineage cells before it progresses into the blastic phase (CML-BP). Tha majority of patients are diagnosed with CML either incidentally or with constitutional non-specific symptoms during the chronic phase. Lab findings in CML may be remarkable for mild normochromic normocytic anemia with mild thrombocytopenia/thrombocytosis. The WBC count is usually markedly elevated with absolute basophilia and eosinophilia often present. Serum vitamin B12 levels are usually increased due to elevated levels of transcobalamins, which are vitamin B12 binding proteins in plasma. Leukocyte alkaline phosphatase (LAP) is a protein that is expressed on neutrophil plasma membrane. Its presence suggests post-mitotic full cellular differentiation. Accumulation of LAP mRNA is mediated by granulocyte-colony-stimulating factor (G-CSF) and occurs among normal individuals. It is elevated in specific physiological and pathological states such as acute promyelocytic leukemia (APL), infections (leukemoid reaction), Fanconi anemia, and polycythemia vera (PV), and pregnancy. In contrast, a defect in the expression of LAP is consistent with either the stable phase of CML or paroxysmal nocturnal hemoglobinuria (PNH). The tyrosine kinase inhibitor imatinib is a potent, selective pharmacologic option for the management of CML. The introduction of tyrosine kinase inhibitors, such as imatinib, asatinib, nilotinib, and bosutinib, dramatically increased survival rates among patients with CML. Fluid retention is a classical adverse effect following imatinib administration. Other adverse effects are either hematological (anemia, thrombocytopenia, and neutropenia) or non-hematological (GI distress, skin toxicity, myalgia, and hypothyroidism) Educational Objective: CML, characterized by very low leukocyte alkaline phosphatase staining, is frequently treated with tyrosine kinase inhibitors, such as dastinib and imatinib. References: Kantarjian HM, Talpaz M. Chronic myelogenous leukemia. Hematol Oncol Clin N Am. 2004;18(3):XV-XVI. Rambaldi A, Masuhara K, Borleri GM, et al. Flow cytometry of leukocyte alkaline phosphatase in human hematopoietic cells. First Aid 2014 page]]
Approved	Approved::Yes
Keyword	WBRKeyword::CML, WBRKeyword::Chronic myelogenous leukemia, WBRKeyword::Chronic myeloid leukemia, WBRKeyword::Imatinib, WBRKeyword::Bcr-abl, WBRKeyword::Imatinib, WBRKeyword::Chemotherapy, WBRKeyword::Tyrosine kinase inhibitor
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