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The following case study focuses on a young woman who went to her primary-care physician for evaluation of new tea-colored urine. Test your knowledge by reading the background information below and making the proper selection.

A 24-year-old Caucasian woman presented to her primary-care physician for evaluation of new tea-colored urine noticed intermittently over the past five days. Her last menstrual cycle was two weeks ago, and they have been occurring regularly. There is no history of renal stones, NSAID abuse, weight loss, night sweats, fever, melena, or hemoptysis. Her vital signs were unremarkable. On initial evaluation, CBC, urinalysis, and renal ultrasound were normal and urine pregnancy test was negative. A few days later, she developed jaundice with abdominal pain. Repeat testing at that time showed the following: WBC count 3600/mm³, hemoglobin 4 g/dL, platelet count 189,000/ mm³, MCV 75 fl, RDW 28, reticulocyte count 10.9 percent (N.V.= 0.5-2.3%), total serum bilirubin 7.5 mg/dL (N.V.= 0.10-1.2 mg/dL), indirect bilirubin 5.5 mg/dL (N.V.= 0.10-1.0 mg/dL), AST 213 U/L serum LDH 1500 U/L (nv= 259-613), serum haptoglobin <10 mg/dL.  The urinalysis showed hemoglobinuria. Direct Coomb test is negative. Liver ultrasound shows mild hepatomegaly and no signs of stones, biliary ductal dilatation, or hepatic mass. Flow cytometry of peripheral blood showed absent expression of CD 55 and CD 59 on 78 percent of red blood cells.

Based on the flow cytometry results, what do you think is the most appropriate drug to use in this condition?

1. Rituximab
2. Alemtuzumab
3. Eculizumab
4. Mepolizumab
5. Ibritumomab

Answer

3. Eculizumab

Explanation

This patient’s clinical presentation is classical for paroxysmal nocturnal hemoglobinuria (PNH). PNH is characterized by intravascular hemolysis and anemia. Other manifestations of PNH may include thrombocytopenia and granulocytopenia, which reflect abnormal hematopoiesis, or it may occur in conjunction with aplastic anemia. Another feature is venous thrombosis especially in the intra-abdominal veins.¹

Eculizumab was approved by the FDA in March 2007 for the reduction of hemolysis in patients with PNH. It is a humanized monoclonal antibody that binds to the C5 component of complement and inhibits terminal complement activation on the red-cell surface. Treatment may be lifelong, as eculizumab does not affect the underlying abnormal hematopoiesis. Meningococcal vaccination is indicated prior to beginning therapy due to risk of severe meningococcal infections. Phase III trials of eculizumab² have shown significant reduction in hemolysis, thrombosis, transfusion independence, and also improved quality of life.³

The underlying defect in PNH is increased susceptibility of RBCs to complement-mediated lysis. This is because of absence of CD 55 and 59, two of the major proteins on the red cell membrane, which block the complement activation on its surface. Deficiency of CD 55 and 59 in turn is due to loss of the glycosylphosphatidylinositol (GPI) anchor, which in turn is due to a defective gene (PIG-A) on the X chromosome.⁴ Thus, PNH is an acquired clonal disease.

In the past, the sucrose lysis test⁵ was used as a screening test and confirmed by the Ham test.⁶ However, flow cytometry has replaced these functional assays due to improved reliability, sensitivity, and specificity.

Rituximab is a monoclonal antibody directed against CD20 antigen on B-lymphocytes and mediates cell killing through an antibody-dependent cellular toxicity. It is used mainly in the treatment of follicular non-Hodgkin lymphoma (NHL) and diffuse large B-cell NHL,⁷ among many other uses.

Alemtuzumab binds to CD52, an antigen present on the surface of B and T lymphocytes. After binding to CD52⁺ cells, an antibody-dependent lysis of leukemic cells occurs. It is used in B-cell chronic lymphocytic leukemia.⁸

Mepolizumab is a humanized monoclonal antibody against IL-5 and has found activity in a variety of hypereosinophilic syndromes⁹ (including eosinophilic esophagitis) and patients with uncontrolled asthma who have persistent airway eosinophilia despite steroids use.

Ibritumomab (Zevalin) is used in the treatment of relapsed or refractory follicular B-cell NHL.¹⁰ It is a murine anti CD –20 monoclonal antibody. However, ibritumomab is combined with a chelator tiuxetan, which acts as a specific chelation site for Yttrium-90 (Y-90). Thus, ibritumomab acts as a delivery system to direct the radioactive isotope to the targeted cells.

References

1. de Latour RP, Mary JY, Salanoubat C, et al. . Blood. 2008 Oct 15;112:3099-3106.
2. Hillmen P, Young NS, Schubert J, et al. . N Engl J Med. 2006, Sep21;355:1233-43.
3. Brodsky RA, Young NS, Antonioli E, et al. . Blood. 2008 Feb 15;111:1840-47.
4. Rosse WF. . Medicine (Baltimore) 1997;76:63-93
5. Hartmann RC, Jenkins DE Jr. The “sugar water” test for paroxysmal nocturnal hemoglobinuria. N Engl J Med 1965; 275:155-57.
6. Ham TH, Dingle JH. Studies on destruction of red blood cells. Chronic hemolytic anemia with paroxysmal nocturnal hemoglobinuria: Certain immunological aspects of the hemolytic mechanism with special reference to serum complement. J Clin Invest 1939;18:657-72.
7. Coiffier B, Lepage E, Briere J, et al. . N Engl J Med. 2002;346:235-42.
8. Hillmen P, Skotnicki AB, Robak T, et al. . J Clin Oncol. 2007;25:5616-23.
9. Rothenberg ME, Klion AD, Roufosse FE, et al. . N Engl J Med. 2008;358:1215-28.
10. Morschhauser F, Radford J, Van Hoof A, et al. . J Clin Oncol. 2008;26:5156-64.

Case study submitted by Vikas Dembla, MD, University of Mississippi Medical Center Cancer Institute, Jackson, MS.