WBR0163

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Pharmacology
Sub Category	SubCategory::Hematology, SubCategory::Oncology
Prompt	[[Prompt::A 45-year-old man presents to his primary care physician for fatigue and weight loss of 10 pounds over the past month. On physical examination, the spleen is palpable 7 cm below the costal margin, and several bruises are observed across the body. Laboratory testing is significant for an elevated white blood cell count and reduced platelet count. Bone marrow biopsy demonstrates hyperplastic granulocytes which are positive for a t(9;22) translocation. The patient is started on an inhibitor of the fusion gene produced by this translocation. The administered drug is most likely also effective to treat which of the following conditions?]]
Answer A	AnswerA::Breast cancer
Answer A Explanation	AnswerAExp::Breast cancer is not currently treated with tyrosine kinase inhibitors. HER2-positive breast cancers may be treated with trastuzamab.
Answer B	AnswerB::Gastrointestinal stromal tumor
Answer B Explanation	[[AnswerBExp::The pathogenesis of GIST tumors involves a gain-of-function mutation in the KIT proto-oncogene, which encodes a transmembrane receptor for stem cell factor that includes a tyrosine kinase component in its intracytoplasmic region. Similar to CML, imatinib has demonstrated efficacy in GIST, whereby it similarly inhibits the tyrosine kinase receptor KIT in a similar fashion to its inhibition of the tyrosine kinase receptor BCR-ABL fusion protein.]]
Answer C	AnswerC::Hepatocellular carcinoma
Answer C Explanation	AnswerCExp::HCC may be secondary to chronic viral hepatitis and/or cirrhosis. Hepatocellular carcinoma (HCC) is not treated with imatinib.
Answer D	AnswerD::Mantle cell lymphoma
Answer D Explanation	AnswerDExp::Mantle cell lymphoma is a rare non-Hodgkin’s lymphoma that affects elderly males. Imatinib is not used to treat Mantle cell lymphoma.
Answer E	AnswerE::Mucosa-associated lymphoid tissue (MALT) lymphoma
Answer E Explanation	[[AnswerEExp::MALT Lymphoma is associated with H. pylori infection and is not susceptible to imatinib therapy. For early and localized MALT lymphoma, treatment of underlying H. pylori infection by antibiotics is often sufficient to induce tumor regression.]]
Right Answer	RightAnswer::B
Explanation	[[Explanation::The patient in this vignette has chronic myelogenous leukemia, a disorder of the hematopoietic stem cells that is caused by the juxtaposition of the ABL gene (chromosome 9) and the BCR gene (chromosome 22), resulting in BCR-ABL fusion gene, known as the Philadelphia chromosome. This translocation causes a novel tyrosine kinase that can constitutively transmit cell growth signals in affected cells. Although the pathogenesis of the disease is well-described, the mechanism that causes the translocation is poorly delineated. The diagnosis of CML is often suspected by the presence of excessive granulocytosis with left shift and confirmed by the identification of the Philadelphia chromosome in peripheral blood and bone marrow cells. Imatinib is a targeted pharmacologic therapy that inhibits the BCR-ABL tyrosine kinase via competitive binding at the ATP-binding site. It has demonstrated significant efficacy for patients with CML. Gastrointestinal stromal tumor (GIST) is a rare non-epithelial neoplasm of the GI tract, the mesentary, or the omentum. The majority of GIST tumors are spindle cell tumors that may be either malignant or benign. Most stromal tumors stain positively for C-kit/CD117 (>90%), CD34, muscle-specific actin, smooth muscle actin, S-100, and desmin. Patients with GIST may be asymptomatic or have non-specific GI symptoms. GIST often appears as a friable unencapsulated mass that does not arise from the epithelium, but from the muscular layer. Characteristically, the pathogenesis of GIST tumors involves a gain-of-function mutation in the KIT proto-oncogene, which encodes a transmembrane receptor for stem cell factor that includes a tyrosine kinase component in its intracytoplasmic region. Similar to CML, imatinib has demonstrated efficacy in GIST, whereby it similarly inhibits the tyrosine kinase receptor KIT in a similar fashion to its inhibition of the tyrosine kinase BCR-ABL fusion protein in CML. Educational Objective: Imatinib, a tyrosine kinase inhibitor, is an effective pharmacologic therapy for both CML and GIST. References: Din OS, Woll PJ. Treatment of gastrointestinal stromal tumor: focus on imatinib mesylate. Ther Clin Risk Manag. 2008;4(1):149-62. First Aid 2014 page 406]]
Approved	Approved::Yes
Keyword	WBRKeyword::Cancer, WBRKeyword::Chemotherapy, WBRKeyword::Leukemia, WBRKeyword::Imatinib, WBRKeyword::CML, WBRKeyword::Chronic myelogenous leukemia, WBRKeyword::GIST, WBRKeyword::Gastrointestinal stromal tumor
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