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Paroxysmal nocturnal hemoglobinuria, eculizumab and hemolysis: the SHEPHERD trial
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Paroxysmal nocturnal hemoglobinuria is a rare disorder that has fascinated clinicians and scientists for more than a hundred years.
The clinical features of the classic disorder are unmistakable: acute intravascular hemolysis with hemoglobinuria appearing most noticeably in the morning, variable marrow suppression, thrombosis involving mostly the splanchnic vessel and spasms of the gastrointestinal tract causing dysphagia and abdominal pains.
Many variations from the classic presentation occur, and there is a close association with aplastic anemia. The median survival is 10 years, with thrombosis and marrow failure as the main causes of death. Many patients with PNH require regular blood transfusions and lifelong warfarin. Thrombosis is a particular hazard during pregnancy and in the puerperium.
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Gene mutation
The disease is due to a somatic mutation in the hemopoietic stem cell of the PIG-A gene on the X chromosome. PIG-A is the catalytic element in a large enzymatic complex, which initiates the first step in the synthesis of glycosylphosphatidyl inositol (GPI).
GPI forms the anchor that attaches many different proteins to the surface of many types of cells. It is synthesized by a complex chain of reactions at the endoplasmic reticulum. Proteins are attached to GPI in the Golgi apparatus by their specifically configured carboxy terminus, and the complex is transported to the cell surface.
Of fundamental importance in the pathogenesis of PNH is the deficiency of two surface proteins that protect red cells from lysis by activated complement. The major complement inactivator is the membrane inhibitor of reactive lysis (CD59), which prevents the lysis of red cells by the membrane attack complex initiated by the activation of C5. CD59 is absent or reduced on PNH red cells, and the hemolysis is caused by activated complement.
Eculizumab (Soliris, Alexion) is a humanized monoclonal antibody that binds specifically to C5 and prevents its activation cleavage. Earlier steps in the complement cascade, important in clearance of micro-organisms and immune complexes, are preserved. Patients with inherited deficiency of C5 or complement components later in the cascade have few problems apart from increased risk for infection from encapsulated organisms, particularly Neisseria meningitidis.
Clinical testing of eculizumab
Eculizumab was specifically designed for the treatment of hemolytic PNH. A preliminary, open-label, clinical study demonstrated that the complement inhibition by eculizumab prevented or reduced the hemolysis, and that hitherto transfusion-dependent patients became transfusion-free. Follow-up of these patients at one year showed the treatment was well tolerated, and the initial improvement was maintained.
A much larger, randomized, double blind, placebo-controlled trial (TRIUMPH) confirmed the benefit in transfusion-dependent patients. Eighty-seven patients were recruited and randomly assigned to either placebo (44 patients) or eculizumab (43) intravenously at 600 mg weekly for four weeks, followed one week later by a 900-mg dose and then 900 mg every other week through week 26. The primary endpoints were stabilization of hemoglobin levels and the number of units of packed red cells transfused. Biochemical indicators of intravascular hemolysis and the patients’ quality of life were also assessed.
The results were clear-cut, with 51% of the treated group becoming transfusion-free compared with none in the placebo arm and a dramatic reduction in the overall number of transfusions in patients who did not become transfusion-free. Secondary endpoints, including quality-of-life studies, also showed a marked benefit in patients who received eculizumab, even if the hemoglobin did not completely stabilize.
So far there have been few serious side effects reported specific to the treatment group. An increased risk for infection due to complement inhibition remains a concern, though no cases were reported in the trial. Patients are vaccinated against N. meningitidis infection before treatment. Antibodies to eculizumab arose in two patients without affecting complement inhibition (the Coombs’ test became positive), and thrombosis occurred in one patient in the placebo arm.
SHEPHERD
A second open-label, phase-3 study, SHEPHERD (Safety in Hemolytic PNH Patients Treated with Eculizumab), is designed to track the safety of eculizumab. The researchers recruited 97 patients with PNH. Preliminary analysis showed headache and nausea at the time of the drug administration were the most common adverse effects.
Venous thrombosis is the most common cause of death in PNH, at least in Western populations. The incidence is much lower in Japan and China, although PNH seems to be more common. Typically, hepatic veins are involved leading to Budd-Chiari syndrome.
The TRIUMPH trial did not directly address the effect of C5 inhibition on thrombosis. The mechanism of thrombosis in PNH is not fully understood, but it is likely to be related to complement activation directly or to the effects of hemolysis. Either way, it might be hoped that prevention of hemolysis by complement inhibition would prevent or reduce the incidence of life-threatening thrombosis.
Results look promising. At the American Society of Hematology 48th Annual Meeting and Exhibition last year, Hillmen and colleagues presented data on some 250 patient-years exposure to eculizumab. The risk for thrombosis was reduced by 87%. If these results are upheld in more formal and long-term studies, the outlook for patients with PNH will be greatly improved. Interestingly, the symptoms of spasm are also promptly abolished by eculizumab.
Bone marrow failure
The problem of bone marrow failure associated with PNH remains unresolved. PNH clones are identified in nearly all patients with aplastic anemia, though the size of the clone may be small and hemolysis unapparent. However, patients with hemolytic PNH may go on to develop bone marrow failure and about 10% die from this complication.
Remaining hemopoietic progenitor cells in the PNH marrow that do not have the loss of the GPI anchor are defective in proliferation and differentiation, similar to those in typical acquired aplastic anemia. The GPI– stem cells of PNH have growth advantages compared with these remaining GPI+ cells, but not with normal stem cells. It is not clear whether progressive marrow failure in PNH is caused by loss of PNH clones or expansion of the underlying stem cell deficiency. It will be interesting to follow the impact of eculizumab treatment on underlying bone marrow function.
The TRIUMPH trial was an admirably designed and executed phase-3 study. Inclusion criteria required platelet counts of >100,000 per mL. The platelet count reflects the underlying marrow failure, and it will be interesting and important to see how patients with lower counts respond.
Of course, long-term follow-up is essential, particularly on the incidence of infection and the occurrence of bone marrow failure or malignant transformation, properties of the underlying marrow disorder. The SHEPHERD study should shed light on these questions. Still, the results of the trials show the major effect scientific theory, technical achievement and careful clinical studies may sometimes have on lives of patients.
For more information:
- Edward Gordon-Smith, MD, emeritus professor of hematology at St. George’s Hospital Medical School in London, is an editorial board member of Hem/Onc Today’s International Affairs section.
- Hill A, Hillmen P, Richards SJ, et al. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood. 2005;106:2559-2565.
- Hill A, Rother RP, Hillmen P. Improvement in the symptoms of smooth muscle dystonia during eculizumab therapy in paroxysmal nocturnal hemoglobinuria. Haematologica. 2005;90(12 Suppl):ECR40.
- Hillmen P, Hall C, Marsh JC, et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2004;350:552-559.
- Hillmen P, Lewis SM, Bessler M, et al. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995;333:1253-1258.
- Hillmen P, Muus P, Dührsen V, et al. The terminal component inhibitor eculizumab reduces thrombosis in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2006;106: Abstract #123.
- Hillmen P, Young NS, Schubert J. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355:1233-1243.
- Socié G, Mary JY, de Gramont A, et al. Paroxysmal nocturnal haemoglobinuria; long term follow up and prognostic factors: French society of haematology. Lancet. 1996;348:573-577.