The complement-mediated intravascular hemolysis of PNH can be inhibited by blocking formation of the terminal complement pathway generated MAC, the cytolytic component of the complement system (see Fig. 40–1). The MAC consists of complement components C5b, C6, C7, C8, and multiple molecules of C9. Eculizumab (Soliris) is a humanized monoclonal antibody that binds to complement C5, preventing its activation to C5b and thereby inhibiting MAC formation (see Fig. 40–1).49 In 2007, eculizumab was approved by both the FDA and the European Union Commission (now the European Medicines Agency) for treatment of the hemolysis of PNH. Treatment with eculizumab reduces transfusion requirements, ameliorates the anemia of PNH, and markedly improves quality of life by resolving the debilitating constitutional symptoms (fatigue, lethargy, asthenia) associated with chronic complement-mediated intravascular hemolysis.50 Following treatment, serum LDH concentration returns to normal, but mild to moderate anemia and reticulocytosis usually persist, likely the result of ongoing extravascular hemolysis mediated by opsonization of PNH erythrocytes by activated complement C3, as eculizumab does not block the activity of the APC C3 convertase (see Fig. 40–1).51,52 In some cases, extravascular hemolysis is sufficiently severe so as to require therapy.53
Thromboembolic events are the major cause of morbidity and mortality in PNH,28 and eculizumab appears to ameliorate the thrombophilia of PNH, although the studies that support that conclusion had suboptimal design.54
Eculizumab is given by intravenous infusion on a biweekly schedule following an initial loading period consisting of five weekly treatments. In general, the drug is well tolerated; however, patients with congenital deficiency of complement C5 have an increased risk of infection with Neisseria species. For this reason, patients treated with eculizumab (which blocks the function of C5; see Fig. 40–1) are at risk for meningococcal septicemia. All patients must be inoculated with a meningococcal vaccine 2 weeks before starting therapy, but the vaccine is not 100 percent protective. Whether prophylactic antibiotic therapy aimed at preventing meningococcal infection is justified for a patient receiving eculizumab remains to be determined. Despite the fact that the percentage of GPI-AP–deficient erythrocytes increases during treatment with eculizumab,55 there have been no reports of catastrophic hemolytic crises in the relatively few PNH patients who have discontinued treatment with eculizumab.54,56
Eculizumab is expensive (approximately $400,000/year in the United States), and it has no effect on either the underlying stem cell abnormality or the associated marrow failure. Consequently, treatment must continue indefinitely and leukopenia, thrombocytopenia, and reticulocytopenia, if present, persist.
OTHER TREATMENT FOR PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
Other than eculizumab, there is no specific treatment for PNH, and for patients who are not being treated with eculizumab, management is largely supportive (reviewed in Ref. 28). Although hemolysis is ameliorated in some patients by treatment with glucocorticoids or androgens, the use of steroids in the management of patients with PNH is controversial.28 The main value of glucocorticoids may be in attenuating acute hemolytic exacerbations. Under these circumstances, brief pulses of prednisone may reduce the severity and duration of the crisis. The value of glucocorticoids in treating chronic hemolysis is limited by toxicity, and the harm that can accrue from long-term use cannot be overemphasized. An every-other-day schedule may attenuate some of the adverse effects of chronic glucocorticoid use,57 but patients may note worsening of symptoms on the off day.
Androgen therapy, either alone or in combination with glucocorticoids, has been used successfully to treat the anemia of PNH.57,58 As with glucocorticoids, the mechanism by which androgenic steroids ameliorate the anemia of PNH is not fully understood, although the rapid onset of action is consistent with complement inhibition.58 Potential complications of androgen therapy include liver toxicity, prostatic hypertrophy, and virilizing effects. The toxicity profile is more favorable for attenuated synthetic androgens such as danazol, making long-term use of this drug a reasonable management option in responding patients. A starting dose of 400 mg twice a day is recommended, but a lower dose (100 to 400 mg/day) may be adequate to control chronic hemolysis.28
Patients with PNH frequently become iron deficient as a result of both hemoglobinuria and hemosiderinuria.57,58 Clinically important iron loss from hemosiderinuria can occur (Chap. 43), even in the absence of gross hemoglobinuria. Replacement is often associated with exacerbation of hemolysis, regardless of the route of administration.57,58 Compared with parenteral replacement, oral administration of iron may be accompanied by less-severe hemolytic exacerbations, but urinary iron loss may be so great that repletion may not be achieved.57 Concern for inducing a hemolytic exacerbation should not deter iron repletion.57 If a hemolytic exacerbation occurs in the setting of iron repletion, the episode can be controlled by treatment with glucocorticoids or androgens or by suppression of erythropoiesis by transfusion. There is no concern about iron-replacement therapy inducing a hemolytic exacerbation in patients being treated with eculizumab as hemolysis is inhibited by the drug.
Because the hemolysis is a consequence of a defect intrinsic to patient’s erythrocytes, the anemia of PNH responds to red cell transfusion. Concerns about inducing a hemolytic exacerbation as a consequence of infusion of small amounts of donor plasma that may be included in red cell preparations appear unwarranted.59 However, hemofiltration is recommended to prevent transfusion reaction arising from the interaction between donor leukocytes and recipient antibodies. Iatrogenic hemochromatosis from chronic transfusion may be delayed in patients with PNH as a result of iron loss from hemoglobinuria/hemosiderinuria,57 but iron overload remains a concern in patients who require chronic transfusion when the anemia is primarily a consequence of marrow failure rather than intravascular hemolysis.
Supplemental folate (1 mg/day) is recommended to compensate for increased use (Chap. 41) associated with heightened erythropoiesis that is a consequence of ongoing hemolysis.28
The role of splenectomy in the management of patients with PNH has not been investigated systematically. Reports of amelioration of hemolysis and improvement in cytopenias following splenectomy are anecdotal. Concerns about lack of proven efficacy and the potential for postoperative complications, particularly thrombosis, have led some to argue that splenectomy has no role in the management of PNH.28
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Prior to the availability of eculizumab, the primary indications for transplantation were marrow failure, recurrent, life-threatening thrombosis, and uncontrollable hemolysis (Table 40–4).28 The latter process can be eliminated by treatment with eculizumab and the thrombophilia of PNH may also respond to inhibition of intravascular hemolysis by eculizumab.54,60 Nonetheless, transplantation is the only curative therapy for PNH, and the availability of molecularly defined, matched, unrelated donors, less-toxic conditioning regimens, reduction in transplantation-related morbidity and mortality, and improvements in posttransplantation supportive care make this option a viable alternative to medical management. Studies (see “Course and Prognosis” below) indicate a normal survival for patients with PNH treated with eculizumab, making the decision of whether to recommend medical management or hematopoietic stem cell transplant particularly complex.60 An understanding of the unique pathobiology of PNH and the input of physicians experienced in transplantation and medical management of PNH are essential to develop an appropriate management plan for transplantation-eligible patients.61
Table 40–4.Hematopoietic Stem Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria ||Download (.pdf) Table 40–4. Hematopoietic Stem Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria
Indications for transplantation
• Marrow failure—approach to management depends primarily on the underlying marrow abnormality (e.g., aplastic anemia) but the treatment regimen must be sufficient to eradicate the paroxysmal nocturnal hemoglobinuria (PNH) clone
• Major complications of PNH
• Refractory, transfusion-dependent hemolytic anemia*
• Recurrent, life-threatening, thromboembolic complications†
Conditioning regimens and donors
• Ablative and reduced intensity conditioning regimens have been successful
• For transplantations involving syngeneic twins, an ablative regimen is recommended‡
• Matched unrelated donor transplantations have been successful but experience is limited
• There are no PNH-specific adverse events. Severe, acute graft-versus-host disease occurs in approximately 33% of patients and the incidence of chronic graft-versus-host disease is roughly 35%
• Overall survival for unselected PNH patients who undergo transplantation using an human leukocyte antigen (HLA)-matched sibling donor is in the range of 50–60%
For patients who are receiving transplantation for marrow failure, the focus of management is on the etiology of the marrow failure (see Table 40–4). For patients with aplastic anemia and a small PNH clone who undergo matched sibling donor allotransplantation, the conditioning regimen of antithymocyte globulin and cyclophosphamide coupled with graft-versus-host effects appear sufficient to eradicate the PNH clone.28 However, in the unusual situation in which the patient has a syngeneic twin, a more intense conditioning regimen is required, as graft-versus-PNH effect does not contribute to clonal eradication in this circumstance.62 In the event that a patient with low-risk MDS with a PNH clone requires allotransplantation, the conditioning regimen (marrow ablative or reduced intensity) in combination with graft-versus-tumor effects usually is sufficient to eradicate the PNH clone.
Transplantation for classic PNH is aimed at eradicating the PNH clone, and both marrow ablative63,64,65 and reduced-intensity66,67 conditioning regimens are effective, although experience with the latter is more limited. Successful outcomes have been reported using matched, unrelated donors, as well as matched, sibling donors.66,68 There are no PNH-specific adverse events associated with transplantation; severe, acute graft-versus-host disease (GVHD) occurs in more than one-third of the patients and the incidence of chronic GVHD is approximately 35 percent. Overall survival for unselected PNH patients who undergo transplantation using an human leukocyte antigen (HLA)-matched sibling donor is in the range of 50 to 60 percent.28
MANAGEMENT OF THE THROMBOPHILIA OF PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
Thromboembolic complications are the leading cause of morbidity and mortality in PNH.69 Prophylaxis against thromboembolic events in patients with PNH is an issue of active debate.69 Current estimates of risk are based on retrospective analysis,54,70,71,72,73 but risk appears to correlate with size of the PNH clone (based on flow cytometric determination of the percentage of GPI-AP–deficient PMNs), leading to the recommendation that patients with greater than 50 to 60 percent GPI-AP–deficient PMNs be offered prophylactic anticoagulation.70,71 Treatment with warfarin with a goal international normalized ratio (INR) of between 2.0 and 3.0 is recommended for patients with PNH who require chronic anticoagulation either for treatment of a thromboembolic event or for prophylaxis. There are no empiric data to guide the use of low-molecular-weight heparin or novel oral anticoagulants in these settings, but their use can be considered in patients with adequate renal function who fail warfarin or in patients have difficulty maintaining a consistent therapeutic INR.
Although arterial thrombosis may be observed,54 thromboembolic events in patients with PNH usually involve the venous system. Acute thrombotic events require anticoagulation with heparin. Systemic thrombolytic therapy,74,75 or thrombolytic therapy delivered via canalization directly to the affected site,76 should be strongly considered in patients with acute onset of Budd-Chiari syndrome.
Thrombocytopenia often complicates PNH, and this issue should be addressed when formulating an anticoagulation management plan. Thrombocytopenia is a relative contraindication to anticoagulation, and transfusions should be given to maintain the platelet count in a safe range rather than withholding therapy.77 Patients with PNH who experience a thromboembolic event should be anticoagulated indefinitely. Recurrent, life-threatening thrombosis merits consideration of marrow transplantation, but such patients are at high-risk for transplantation-related adverse events (see Table 40–4).61
Eculizumab reduces the risk of thromboembolic complications.54 For patients being treated with eculizumab who have no prior history of thromboembolic complications, prophylactic anticoagulation may not be necessary.
PREGNANCY AND PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
Women with PNH can have serious morbidity and increased mortality during pregnancy.77,78 Because of concerns about fetal/maternal risks from exposure to potentially toxic therapy, anticoagulation and transfusion have been the mainstay of management. Eculizumab has been assigned to pregnancy category C (risk cannot be ruled out) by the FDA. There are no controlled studies of the use of eculizumab in human pregnancy; however, anecdotal reports and small series have identified no significant adverse effects when eculizumab is used during pregnancy, including early in gestation and, in one case, from the time of conception.51,79,80 Nonetheless, until more is known about the safety of eculizumab in pregnancy, it seems prudent to restricted use of the drug to the third trimester and then only for patients who are at high-risk for thrombosis and who have no acceptable therapeutic alternatives.
Moderate to severe thrombocytopenia may complicate the pregnancy, and clinically significant bleeding in this setting necessitates platelet transfusion. The incidence of clinically apparent venous thromboembolism during pregnancy in women with PNH is approximately 10 percent,77 and these events are associated with a high risk of mortality.77,78 Similar to nonpregnant patients with PNH, cerebral and hepatic veins are commonly involved sites of thrombosis. Thrombolytic therapy should be considered for those with Budd-Chiari syndrome.
The role of prophylactic anticoagulation for pregnant women with PNH has not been studied prospectively; however, because of the significant morbidity and mortality associated with thromboembolism in this setting, prophylaxis is recommended. Coumadin is contraindicated because of teratogenic potential in the first trimester and hemorrhagic risks later in gestation (Chap. 8). Anticoagulation with heparin should begin immediately once the pregnancy is documented. Low-molecular-weight heparin has a hypothetical advantage over unfractionated heparin because of a lower incidence of drug-induced thrombocytopenia and less osteopenia (Chap. 118). Careful monitoring of the platelet count is required because thrombocytopenia may worsen during the period of anticoagulation. Anticoagulation can be discontinued briefly around the time of delivery. However, it should be restarted as soon as is feasible and continued for at least 6 weeks into the postpartum period, as thrombosis during the puerperium is a major concern.77,78 Most deliveries can be accomplished vaginally, although premature delivery may be necessary. Despite the many concerns surrounding PNH and pregnancy, successful outcomes appear to be the rule rather than the exception72,77; however, management is complicated and should involve the combined efforts of a knowledgeable hematologist and an obstetrician experienced in dealing with high-risk pregnancies.27
PEDIATRIC PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
PNH can occur in the young (approximately 10 percent of patients are younger than age 21 years at the time of diagnosis).28 A retrospective analysis of 26 cases, underscored the many similarities between childhood and adult PNH.81 Signs and symptoms of hemolysis, marrow failure, and thrombosis dominate the clinical picture, although gross hemoglobinuria as a presenting symptom may be less common in young patients. A generally good response to immunosuppressive therapy was observed,81 but based on poor long-term survival, hematopoietic cell transplantation is the recommended treatment for childhood PNH. One study82 confirmed the common presentation of marrow failure in 11 children with PNH, and reported that five patients eventually underwent hematopoietic cell transplant (three matched unrelated donors and two matched family donors), of whom four were long-term survivors. In another study of 12 young patients over an 18-year period, 10 presented with evidence of marrow failure and only one with hemoglobinuria.40 There were six children with thrombosis and five with myelodysplastic features, indicating that the clinical presentation may be more similar to adult PNH than previously recognized. The safety and effectiveness of eculizumab in pediatric patients below the age of 18 years has not been established, however, there are anecdotal reports of its use in pediatric patients with PNH.83 Although eculizumab is not approved for PNH patients younger than age 18 years, approval will likely be sought once pharmacodynamic and pharmacokinetic characteristics of the drug are defined for the pediatric/adolescent population.84 The availability of eculizumab for pediatric PNH may be particularly advantageous as a bridge prior to implementation of more definitive therapy.