eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Paroxysmal Nocturnal Hemoglobinuria: Treatment & Medication

Author: Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Coauthor(s): Ulrich Woermann, MD, Consulting Staff, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland
Contributor Information and Disclosures

Updated: Mar 27, 2009

Treatment

Medical Care

Based on current understanding of paroxysmal nocturnal hemoglobinuria (PNH), ideal treatment is to replace the defective hematopoietic stem cell with a normal equivalent by stem cell transplantation; however, this is not realistic, because stem cell transplantation requires a histocompatible donor and is associated with significant morbidity and mortality. This form of treatment is reserved for severe cases of PNH with aplastic anemia or those whose conditions transform to leukemia, both of which are life-threatening complications.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, debilitating, acquired disorder that most frequently presents in early adulthood and usually continuous throughout the life of the patient. PNH results in the death of approximately 50% of affected individuals due to thrombotic complications and, until recently, had no specific therapy.

In 2007, eculizumab, an anti-complement antibody targeting the CD5 complement component was approved by the US Federal Drug Administration (FDA). This form of therapy alleviates the hemolysis associated with paroxysmal nocturnal hemoglobinuria (PNH) and its sequelae, dramatically improving symptoms, improving quality of life, and eliminating complications of PNH⁸ ; however, treatment with eculizumab does not alter the underlying defect of the disease, indicating the need to continue life-long therapy or until spontaneous remission which occurred in a minority of patients (12 of 80 patients in a study¹¹ ) before the advent of eculizumab.

The treatment of paroxysmal nocturnal hemoglobinuria (PNH) is largely based on symptoms.

Treatment for anemia, depending on the major cause and severity, can be approached with the following guidelines:

• The anemia may have 3 components: intravascular hemolysis, inadequate erythropoiesis, and superimposed iron deficiency (massive iron loss through hemoglobinuria).
  • In view of increased rate of erythropoiesis, give 5 mg/d of folic acid orally.
  • Assess iron stores with the use of the transferrin saturation index (TSI): Give oral ferrous sulfate if the result is <20%. (Ferritin is an acute-phase reactant and can be misleading.)
  • Determine steady state hemoglobin levels after correction for iron deficiency.
  • Transfuse packed RBCs (white blood cells (WBCs) depleted by filter) when appropriate. Washing RBCs is no longer necessary, and irradiated blood products is recommended for future stem cell transplantation.
• Modulation of complement is controlled poorly by high doses of glucocorticoids. The usual adult dose of prednisone is 20-40 mg/d (0.3-0.6 mg/kg/d) given daily during hemolysis and changed to alternate days during remission. On this regimen, about 70% of adult patients experience improvement in hemoglobin levels, but long-term therapy is fraught with complications.
• The new anticomplement agent eculizumab is a humanized monoclonal antibody against terminal protein C5; it has been shown to be highly effective in reducing intravascular hemolysis.^18,19 Eleven transfusion-dependent patients with paroxysmal nocturnal hemoglobinuria (PNH) were given intravenous (IV) eculizumab at 900 mg over 30 minutes every 2 weeks. The mean LDH decreased along with transfusion requirements from 2.1 units per patient per month to 0.0 in addition to a global improvement of quality of life.¹⁹ Long-term analysis show that these improvements can be maintained over 3 years, and erythropoietin can overcome anemia due to bone marrow failure in patients on the drug.
• Consequences of complement inhibition are of concern for an increased risk of infections from Neisseria meningitides as seen in inherited terminal complement deficiency.⁸  Before the administration of eculizumab, all patients should be vaccinated with the tetravalent vaccine (meningococcal ACWY vaccine), if available, as this vaccine covers all except the B strain, for which there is no vaccine available. However, a small risk of 0.5 cases per 100-patient years of septicemia (no meningitis) of meningococcal infections in vaccinated patients can still occur.
• Treatment breakthrough from complement control can occur in small minority (10%) of patients due to an inadequate dosing schedule. Eculizumab must remain above 35 μg/mL, but trough levels at 2 weeks may fall below this level and cause recurrence of hemolysis. The recommended adjustment for patients whose eculizumab levels fall into this category is to increase the dose to 900 mg every 12 days or 1200 mg every 2 weeks. Withdrawal hemolysis can occur by stopping therapy for any reason, as accumulation of paroxysmal nocturnal hemoglobinuria (PNH) RBC increases over time by protecting type II and III PNH cells from destruction due to therapy, which can potentially trigger a massive hemolysis.
• Monitoring iron even if the patients no longer require transfusions is recommended, because hemosiderinuria no longer occurs with eculizumab, which is a protective mechanism in paroxysmal nocturnal hemoglobinuria (PNH) to excrete iron. Measuring serum ferritin is recommended and chelation therapy may be necessary in patients with high levels. The risk of meningococcal infection is always present, and although the current vaccinations are protective, it is important to maintain up-to-date vaccinations, which is required every few years according to manufacturers guidelines. Due to the rarity of paroxysmal nocturnal hemoglobinuria (PNH), the drug is categorized as an ultra-orphan drug and is quite expensive, thus choosing PNH patients who will benefit is important and may not apply to those with hypoplastic anemia or mild asymptomatic hemolysis.
• Replacement of nutritional iron, because of increased loss of iron from the hemolysis and the 200-fold increase in iron urinary excretion, is necessary to prevent development of iron deficiency. Iron replacement can stimulate reticulocytosis that can trigger hemolysis by releasing a new cohort of complement-sensitive cells. This process can be prevented by adding prednisone during replacement therapy.
• Stimulation of erythropoiesis using androgenic hormones has been successful in patients with a moderate decrease in RBC production. This has been replaced mainly by using recombinant erythropoietin therapy.
• Supportive care for severe anemia includes blood transfusion using leuko-depleted packed RBCs to prevent alloimmunization. Development of alloantibodies can be a problem with future transfusions because of activation of complement and delayed hemolysis of transfused blood.
• Management of thrombotic complications follows standard principles, including using heparin emergently, then maintenance therapy with the use of an oral anticoagulant, such as Coumadin. Sometimes, heparin can exacerbate the thrombotic problem, possibly by activating complement. This can be prevented using inhibitors of the cyclooxygenase system, such as aspirin, ibuprofen, and sulfinpyrazone. Primary prophylaxis with warfarin has been advocated, but it remains controversial as to whether this approach is safe and effective in all patients with paroxysmal nocturnal hemoglobinuria (PNH). It has been shown that eculizumab therapy, which is effective in decreasing hemolysis, can also decrease the risk for venous thrombosis. Continuation of anticoagulation in patients with PNH with a previous thrombosis while on eculizumab is recommended, as stopping therapy has not been studied.
• Bone marrow hypoplasia is a serious cause of morbidity and mortality. It is treated most effectively with bone marrow transplantation; however, if there is no suitable donor available, antithymocyte globulin (ATG) has been used in the treatment of aplastic anemia with considerable success.
• Risks of pregnancy in patients with paroxysmal nocturnal hemoglobinuria (PNH) are very significant. There is a very high risk of thrombotic complications for the expectant mother, as well a risk of developing hypoplastic anemia. Maternal mortality in these patients is approximately 20%, mostly from thrombosis and infections, and there is an increased risk of fetal loss. It is recommended that pregnant women with paroxysmal nocturnal hemoglobinuria (PNH) should be fully anticoagulated with low-molecular weight heparin (LMWH). Warfarin may be substituted after the first trimester. There are no data regarding the administration of eculizumab during pregnancy.

Consultations

In centers that do not have a bone marrow transplantation program, consultation and identification of possible donors should be undertaken early.

• Stem cell transplantation is a curative therapeutic option for paroxysmal nocturnal hemoglobinuria (PNH). However, the risks of therapy must be carefully weighed against factors related both to PNH and comorbid conditions. Furthermore, the heterogeneous presentation of the disease, its unpredictable course, and its association with bone marrow failure conditions confound the decision process regarding transplantation.
• An analysis by the International PNH Interest Group reviewed data from 67 patients from single centers and from 2 registry studies, with special emphasis in eliminating duplication in patient reporting.³
  • Among the 67 patients, 7 were transplanted from a twin syngeneic donor. Four of the 7 syngeneic transplants had no conditioning therapy, and these 4 either failed to engraft or relapsed post transplantation, indicating that a marrow ablative conditioning is necessary before syngeneic transplantation.
  • In 47 of 67 patients, a human leukocyte antigen (HLA)-identical sibling was used as the donor, 1 from a haploidentical family member and 12 from an unrelated donor (matched unrelated donor [MUD]).
  • In the only single-center study providing a Kaplan-Meier analysis, overall survival at 5 years was 58 +/- 13%. This is less favorable than the survival estimate of approximately 75% generated by combining the data from the other reports.
  • Investigation is currently underway regarding whether reduced intensity conditioning can improve the outcome.

Medication

The drugs used in treatment of paroxysmal nocturnal hemoglobinuria (PNH) include eculizumab to stop hemolysis, recombinant erythropoietin or androgens to stimulate erythropoiesis, anticoagulants to treat thrombotic complications, and stimulation of hematopoiesis in the aplastic phase by immunosuppressive agents.

Androgens

Androgens are used to stimulate erythropoiesis by increasing endogenous levels of erythropoietin and by enhancing the response of precursor cells to the growth factor.

Attenuated androgens, such as danazol, are recommended for use in women, as the attenuated androgen has fewer adverse virilizing and masculinizing effects.

Oxymetholone (Anadrol-50)

Anabolic and androgenic derivative of testosterone in an oral formulation.

Used to stimulate erythropoiesis by increasing endogenous levels of erythropoietin and by enhancing the response of precursor cells to the growth factor.

Stanozolol (Winstrol)

Anabolic and androgenic derivative of testosterone in an oral formulation.

Danazol (Danocrine)

Synthetic steroid analogue, derived from ethisterone, with strong antigonadotropic activity (inhibits LH and FSH) and weak androgenic action without adverse virilizing and masculinizing effects. Increases levels of C4 component of the complement. May push the resting hematopoietic stem cells into cycle, making them more responsive to differentiation by hematopoietic growth factors. May also stimulate endogenous secretion of erythropoietin.

May impair clearance of immunoglobulin-coated platelets and decreases autoantibody production.

Immunosuppressive Agents

Antithymocyte globulin is an antiserum to human T cells prepared from horses or rabbits.²⁰ The mechanism of action of polyclonal antilymphocyte preparations to suppress immune responses is not fully understood.

Antithymocyte globulin; rabbit (Atgam)

Purified preparation of pasteurized polyclonal IgG obtained from rabbits immunized against human thymocytes (T cells) for IV use. This preparation has replaced the Upjohn preparation Atgam (horse serum) and is considered an equivalent.

Complement Inhibitor

The C-5 inhibitor eculizumab has been designated as an orphan drug for the treatment paroxysmal nocturnal hemoglobinuria (PNH).

Eculizumab (Soliris)

Orphan drug indicated for treatment of paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. Blocks complement-mediated destruction of PNH red blood cells. Inhibits C-5 component of complement system, thereby preventing final stages of complement activation.

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