WBR0162

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 74-year-old woman with chronic lymphocytic leukemia (CLL) presents to her oncologist for worsening fever and weight loss over the past month. The oncologist initiates therapy with fludarabine, cyclophosphamide, and rituximab. Three weeks later, the patient experiences bloody urine with suprapubic tenderness. Which of the following drugs could have prevented this condition?]]
Answer A	AnswerA::Acrolein
Answer A Explanation	AnswerAExp::Acrolein is the urotoxic metabolite of cyclophosphamide that is responsible for hemorrhagic cystitis.
Answer B	AnswerB::Leucovorin
Answer B Explanation	AnswerBExp::Leucovorin is equivalent to activated folinic acid (reduced vitamin B9). It may be administered to “rescue” the effects of methotrexate.
Answer C	AnswerC::Mesna
Answer C Explanation	AnswerCExp::Mesna binds to a urotoxic metabolite of cyclophosphamide (acrolein) in the bladder and prevents hemorrhagic cystitis and risk of bladder cancer associated with cyclophosphamide.
Answer D	AnswerD::Methylene blue
Answer D Explanation	[[AnswerDExp::Methylene blue and vitamin C are the antidotes for methemoglobin, a hemoglobin with an oxidized form of iron (Fe3+). Methemoglobinemia may be congenital or acquired (usually due to drugs). Patients may present with bluish skin, headache, dyspnea, seizures, and death.]]
Answer E	AnswerE::N-acetyl cysteine
Answer E Explanation	AnswerEExp::N-acetyl cysteine may be administered in patients with acetaminophen overdose.
Right Answer	RightAnswer::C
Explanation	[[Explanation::The patient in this vignette has developed hemorrhagic cystitis following cyclophosphamide administration. Chronic lymphocytic leukemia (CLL) is an indolent, slowly evolving hematopoetic malignancy that primarily affects the elderly. Because CLL is a slowly-growing malignancy that may not be clinically detectable for prolonged periods of time, chemotherapy is generally withheld until the patient is symptomatic. CLL is generally a B-cell leukemia that demonstrates CD20+ and CD5+. CLL may feature autoimmune hemolytic anemia, peripheral blood lymphocytosis, and the presence of smudge cells on peripheral blood smears (damaged leukocytes during the preparation of the smear). CLL may be treated using antineoplastic agents, such as cyclophosphamide. Cyclophosphamide is an alkylating agent that covalently cross-links guanine nucleotides at the N-7 nitrogen. Cyclophosphamide administration is associated with hemorrhagic cystitis that may take a few weeks to develop following after cyclophosphamide is started. A small portion of the original drug is metabolized to acrolein. Acrolein is toxic to the bladder urothelium and can, at least partly, lead to hemorrhagic cystitis. The high concentrations of acrolein may be prevented through the use of aggressive hydration and/or mesna. Mesna binds acrolein in the bladder, barring it from exerting its toxic effects. Cyclophosphamide itself is a carcinogen and may cause acute myeloid leukemia (AML) or transitional cell carcinoma of the bladder. Educational Objective: Mesna may be administered along with cyclophosphamide to prevent hemorrhagic cystitis. References: Korkmaz A, Topal T, Oter S. Pathophysiological aspects of cyclophosphamide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation. Cell Biol Toxicol. 2007.23(5):303-12. First Aid 2014 page 407]]
Approved	Approved::Yes
Keyword	WBRKeyword::Cancer, WBRKeyword::Chemotherapy, WBRKeyword::CLL, WBRKeyword::Chronic lymphocytic leukemia, WBRKeyword::Leukemia, WBRKeyword::Hematopoetic, WBRKeyword::Antidote, WBRKeyword::Chemotherapeutic, WBRKeyword::Mesna, WBRKeyword::Cyclophosphamide, WBRKeyword::Hemorrhagic cystitis, WBRKeyword::Hemorrhagic, WBRKeyword::Cystitis
Linked Question	Linked::
Order in Linked Questions	LinkedOrder::