Progress in the treatment of PNH: decisions, decisions, decisions

Paroxysmal nocturnal hemoglobinuria is a complex disorder characterized by intravascular hemolysis, thrombophilia and a variable degree of deficient hematopoiesis. The intravascular hemolysis leads to anemia and to the sequestration of nitric oxide on the free hemoglobin that is released, resulting in smooth muscle contraction manifest as erectile dysfunction, esophageal achalasia, abdominal pain and pulmonary hypertension. In addition, patients complain of a feeling of asthenia and fatigue that is not related to the degree of anemia and that can be debilitating. Intravascular hemolysis also results in passage of hemoglobin through the kidneys, which results in renal dysfunction in a majority of patients and leads to death by renal failure in about 10% of patients.

Thrombosis occurs in 30% to 40% of patients and may involve deep veins of the extremities; abdominal veins including mesenteric, splenic, portal and hepatic veins; cerebral veins; and dermal veins. Once established, thrombosis usually persists or recurs. Particularly when affecting abdominal and cerebral veins, thrombosis carries a negative prognosis and is the leading cause of death.

Wendell F. Rosse

All of these manifestations of PNH appear to be due to the faulty regulation of complement activation on the surface of red cells and platelets. Because of a somatic mutation in a hematopoietic stem cell, the characteristically abnormal blood cells are lacking in all proteins tethered externally to the membrane by the glycosylphosphatidylinositol anchor. The lack of one of these, CD59, results in the production of several times the normal number of membrane attack complexes of complement C5b-9 and polymeric C9. Even minimal activation of complement results in membrane damage that results in hemolysis of red cells, activation of platelets and generation of thrombogenic vesicles.

Emerging therapies

Until recently, no specific therapy was available that counteracted these reactions or ameliorated the manifestations. Glucocorticoids in high doses appear to reduce hemolysis in some patients but are of controversial benefit.

Transfusion can correct the anemia but leaves the other manifestations untouched. Anticoagulation may be of use prophylactically, but is not very effective against established thromboses. Hematopoietic stem cell transplant essentially cures the disease but with considerable risk.

Recently, eculizumab (Soliris, Alexion Pharmaceuticals), a humanized monoclonal antibody inhibiting the activation of the fifth component of complement (C5), has been developed and appears to prevent the formation of the terminal C5b-9 complex of complement. After an initial trial in 11 patients appeared hopeful, it entered into a comparative randomized trial and an extended safety trial involving 194 patients. Several conclusions have emerged from these trials.

The drug rapidly and effectively stops intravascular hemolysis as measured by a marked reduction in plasma lactic acid dehydrogenase level. This results in an amelioration of anemia and a marked reduction in the rate of transfusion of these patients.

With the reduction in free hemoglobin, the manifestations of nitric oxide sequestration (erectile dysfunction, esophageal spasm, etc.) are reduced in incidence. Many patients reported a marked improvement in the sense of well-being and loss of asthenia, sometimes for the first time in years.

Less thrombosis

The incidence of thrombosis was markedly lower in patients taking the drug when compared with the incidence in an equal period of time before starting the drug. It is still too early to know whether established thromboses are successfully diminished in size and recurrence, but this appears likely.

The renal abnormalities appear to be ameliorated, particularly if the degree of dysfunction is not far advanced.

The treatment is expensive (about $380,000 per year per patient) and somewhat inconvenient (an IV every 12 to 14 days). Further, it does not help the manifestations of hematopoietic deficiency (granulocytopenia, thrombocytopenia, marrow hypoplasia) present in some patients with PNH. Nevertheless, it is a great step forward in the treatment of PNH.

Because PNH is a disease of variable severity and manifestations, the decision whether or not to embark on an eculizumab program will be one that needs to be made by the doctor and the patient. In some cases, the effects of the disease will be so severe that there will be little question that the treatment is needed. In others, the disease is so mild that neither may wish to undertake treatment. It is in the moderately affected that the decision will be difficult.

Making the decision

Several things should be obtained when making the decision. First, both patient and physician need to be informed about the consequences of the disease and the effect of eculizumab upon the disease. This requires an increased educational effort to both groups. Both need to realize that the disease is, although chronic, not benign; the mean survival in untreated patients is about 15 years. Although eculizumab has been used for too short a time to know if it affects this measure, the fact that it seems to reduce both thrombosis and renal dysfunction would suggest that it should reduce both morbidity and mortality.

Second, both patient and physician need to assess the effect of the disease on lifestyle. The amelioration of fatigue and asthenia, of erectile dysfunction, of esophageal spasm and of abdominal discomfort may be important enough to warrant undertaking the treatment.

Third, freedom from transfusions reduces the risk and inconvenience that they entail.

Fourth, both should realize that the problem of thrombosis is not well treated by any other measures; whether or not eculizumab can reverse this serious complication is not certain but is highly probable.

Even in those instances when long-term treatment is not undertaken, there may be instances in which the patient is in particular danger, including surgery and pregnancy. Thrombosis is a frequent complication of both, and eculizumab is probably the best prophylaxis against it. Perhaps regimens will be developed that will permit administration of the drug for limited periods of time.

The role of hematopoietic stem cell transplantation needs to be reassessed with the advent of eculizumab therapy. Those patients with a major element of bone marrow failure will not benefit from the drug alone; transplantation, if feasible, should be considered. For other patients, the availability of a suitable donor and the willingness to take the risks of transplantation will go into the decision as to what treatment is most suitable. If immunosuppression is used to improve hematopoiesis, eculizumab may well be a useful adjunct, as the abnormal clone persists in that case.

Careful and continued surveillance of patients, both those taking the drug and those not, will be helpful in making these decisions in the future. The cooperation of the hematologic community with the International PNH Registry (www.pnhsource.com/f/15) in this effort will be essential. The result will be markedly improved treatment of patients with this uncommon but exasperating and serious disease.

Wendell F. Rosse, MD, is Professor Emeritus at Duke University and Red Cells & Hemoglobinopathies Section Editor for HemOnc Today.