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
Based on the flow cytometry
results, what do you think is the most appropriate drug to use in this
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
- de Latour RP, Mary JY, Salanoubat C, et al. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood. 2008 Oct 15;112:3099-3106.
- Hillmen P, Young NS,
Schubert J, et al. The
complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria.
N Engl J Med. 2006, Sep21;355:1233-43.
- Brodsky RA, Young NS, Antonioli
E, et al. Multicenter
phase 3 study of the complement inhibitor eculizumab for the treatment of
patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008 Feb
- Rosse WF. Paroxysmal
nocturnal hemoglobinuria as a molecular disease. Medicine (Baltimore)
- Hartmann RC, Jenkins DE
Jr. The “sugar water” test for paroxysmal nocturnal hemoglobinuria. N Engl
J Med 1965; 275:155-57.
- 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
- Coiffier B, Lepage E,
Briere J, et al. CHOP
chemotherapy plus rituximab compared with CHOP alone in elderly patients
with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-42.
- Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab
compared with chlorambucil as first-line therapy for chronic lymphocytic
leukemia. J Clin Oncol. 2007;25:5616-23.
- Rothenberg ME, Klion AD,
Roufosse FE, et al. Treatment
of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med. 2008;358:1215-28.
- Morschhauser F, Radford J, Van Hoof A, et al.
III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan
compared with no additional therapy after first remission in advanced
follicular lymphoma. J Clin Oncol. 2008;26:5156-64.
Case study submitted by
Vikas Dembla, MD, University of Mississippi Medical Center Cancer Institute,
back to top