Paroxysmal Nocturnal Hemoglobinuria Treatment & Management

According to current understanding of paroxysmal nocturnal hemoglobinuria (PNH), the ideal treatment is to replace the defective hematopoietic stem cell with a normal equivalent by stem cell transplantation; however, this is not realistic for many patients, because hematopoietic stem cell transplantation (HSCT) requires a histocompatible donor and is associated with significant morbidity and mortality. ^[29] HSCT is reserved for severe cases of PNH with aplastic anemia or transformation to leukemia, both of which are life-threatening complications.

Two monoclonal antibodies (ie, eculizumab, ravulizumab) that target the C5 complement component were approved for treatment of PNH by the US Food and Drug Administration (FDA) in 2007 and 2018, respectively. A monoclonal antibody that inhibits C3, pegcetacoplan, was approved in 2021 for treatment of PNH. 

Indications for allogeneic HSCT include persistent hemolysis, persistent thrombosis, and associated marrow failure. A review by Cooper et al of HSCT in 55 patients with PNH reported minimal to no graft versus host disease in 2 patients who received eculizumab after HSCT; these authors suggest that this warrants further study. ^[30]

Treatment of bone marrow hypoplasia

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. ^[31]

Treatment of thromboembolism

Patients with PNH who develop acute thrombosis should immediately be started on eculizumab or ravulizumab, if they are not already taking it, as this reduces the risk of thrombosis extension or recurrence. ^[13] Otherwise, management of thrombotic complications follows standard principles, including using heparin emergently, then maintenance therapy with an oral anticoagulant, such as warfarin. Sometimes, heparin can exacerbate the thrombotic problem, possibly by activating complement. This can be prevented by using inhibitors of the cyclooxygenase system such as aspirin, ibuprofen, or sulfinpyrazone.

Primary prophylaxis of thromboembolism for patients with PNH has been advocated. Whether this approach is safe and effective in all patients with PNH remains controversial, however.

Corticosteroids

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.

Investigational agents

A variety of agents that inhibit complement are under development for treatment of PNH. Novel anti-C5 agents include monoclonal antibodies (eg, crovalimab ^[32] ) and an anti-C5 small interfering RNA. ^[33] Because clinically relevant C3-mediated extravascular hemolysis can occur in PNH, ^[34]  (the C5 inhibitors eculizumab and ravulizumab reduce intravascular hemolysis only), the anti-C3 small peptide compstatin and its derivatives are being investigated. 

Inhibitors of complement Factor D or B are also being studied. ^[33]  Yuan et al reported that two novel small-molecule inhibitors of Factor D, which is a component of the alternative complement pathway, show potential as oral agents for treating PNH. In the Ham test, using cells from PNH patients, the Factor D inhibitors significantly reduced complement-mediated hemolysis at concentrations as low as 0.01 μM. In an animal model, the compound ACH-4471 blocked alternative pathway activity. ^[35]

Three monoclonal antibodies that target complement have been approved for use in PNH. Eculizumab and ravulizumab are humanized monoclonal antibodies that target terminal complement protein C5. Both agents have been shown to decrease intravascular hemolysis, reduce the need for blood transfusions, and improve PNH-related symptoms such as fatigue. ^{[36, 37, 38, 39]}  Both are administered intravenously, but eculizumab is infused IV every 2 weeks and ravulizumab is infused every 8 weeks. Pegcetacoplan targets complement protein C3, and can control both intravascular and extravascular hemolysis.

Eculizumab 

Eculizumab (Soliris) alleviates the intravascular hemolysis associated with PNH and its sequelae, dramatically improving symptoms, improving quality of life, and eliminating complications of PNH. ^{[9, 40]}  Eculizumab does not alter the underlying defect of the disease, however; thus, treatment needs to continue lifelong or until spontaneous remission, which occurred only in a minority of patients (12 of 80 patients in one study ^[18] ) before the advent of eculizumab. 

The efficacy and safety of eculizumab has been demonstrated in two multinational phase III trials and a multinational extension study. ^[2] Long-term analysis showed that PNH improvements can be maintained over 3 years  in patients on eculizumab, and erythropoietin can overcome anemia due to bone marrow failure. ^[39]  The 5-year survival of patients with PNH prior to eculizumab therapy in a cohort followed at Leeds Hospital in the United Kingdom was 66.8%. With eculizumab therapy, 5-year survival improved to 95.5%, which is not statistically different from age-matched controls in the general population. ^[41]  

Treatment breakthrough from complement control can occur in small minority (10%) of patients due to an inadequate dosing schedule. The eculizumab level 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 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.

Ravulizumab 

In both C5 inhibitor–naïve patients with PNH and those previously treated with eculizumab, ravulizumab (Ultomiris) has proved non-inferior to eculizumab across all efficacy endpoints. ^{[36, 37, 42]}  In addition, ravulizumab has a low incidence of breakthrough hemolysis compared with eculizumab. ^{[43, 44, 45]}  Because of this lower incidence, ravulizumab has been shown to be more cost-effective than eculizumab. Patient acceptance is also high, because of the less-frequent dosing. ^{[45, 46, 47]}  

Ravulizumab gained approval for children aged 1 month and older with PHN in June 2021. Effectiveness was evaluated in a 26-week study enrolling 13 pediatric patients aged 9-17 years with PNH. Five of the 13 patients were complement inhibitor-naïve and 8 patients had received eculizumab. After the 26-week study, 60% of patients who had not previously received complement inhibitors avoided a transfusion and all patients who had received prior eculizumab treatment avoided a transfusion. ^[48]  

In July 2022, the US Food and Drug Administration (FDA) approved a subcutaneous formulation of ravulizumab for the treatment of adult patients with PNH. The efficacy of the subcutaneous formulation was established in a phase III study comparing subcutaneous ravulizumab with intravenous ravulizumab in 136 patients with PNH who had previously been treated with eculizumab. For 71 days, 90 patients received subcutaneous ravulizumab and 46 received intravenous (IV) ravulizumab, thereafter, all patients received subcutaneous (SC) ravulizumab.  At day 71, the amount of ravulizumab in the blood of patients taking SC ravulizumab was no less than in patients taking IV ravulizumab. Serum free C5 concentrations were maintained below the target threshold (< 0.5 mcg/mL) in all patients throughout the one year of SC treatment. Adverse effects were comparable to IV ravulizumab. ^[49]

Pegcetacoplan

Pegcetacoplan (Empaveli) binds to complement protein C3 and its activation fragment C3b, thereby regulating C3 cleavage and generation of downstream effector of complement activation. It is administered as a SC infusion twice weekly.

The phase III PEGASUS trial included patients with PNH who were still anemic despite at least 3 months of eculizumab therapy. Pegcetacoplan proved superior to eculizumab with respect to the change in hemoglobin level from baseline to week 16, with an adjusted mean difference of 3.84 g/dL (P < 0.001). A total of 35 patients (85%) receiving pegcetacoplan no longer required transfusions, as compared with 6 patients (15%) receiving eculizumab. The most common adverse events were injection site reactions, diarrhea, breakthrough hemolysis, headache, and fatigue. ^[50]  The ongoing phase III PRINCE study is evaluating pegcetacoplan in treatment-naïve patients with PNH. 

Wong and colleagues conducted a matching-adjusted indirect comparison (MAIC) using patient data from the phase III PRINCE trial and aggregate data from the ALXN1210-PNH-301 trial. The results of the comparison found pegcetacoplan was associated with statistically significant improvements in most clinical endpoints compared with ravulizumab or eculizumab treatment. ^[51]

Infection prophylaxis

Consequences of complement inhibition include an increased risk of infections from Neisseria meningitides, as seen in inherited terminal complement deficiency. ^[9] Before the administration of eculizumab or ravulizumab, all patients should be vaccinated with a serogroup B meningococcal vaccine. ^[52] Alashkar et al suggest that serologic response testing after vaccination is warranted, because immunological response to vaccines varies, and that re-vaccination with a tetravalent conjugate vaccine every 3 years is essential, or should be based on response rates, in patients on eculizumab therapy. ^[53]

Despite vaccination, patients may develop meningococcal septicemia (not meningitis). Although this is rare, occurring at a rate of 0.5 cases per 100-patient years, prophylactic antibiotics are recommended to prevent this complication. One study used penicillin V, 500 mg twice daily orally, or erythromycin 500 mg twice daily for patients intolerant to penicillin. ^[54]

Effect on thromboembolic complications

Complement inhibitor treatment reduces the risk of clinical thromboembolism in patients with PNH (the leading cause of death in PNH) and is recommended for PNH patients with a history of prior thromboembolism. ^[55] The rate of thrombotic complications prior to eculizumab was 5.6 per 100 patient years; after eculizumab, it dropped to 0.8 per 100 patient years.

In an international multi-institutional cooperative study involving 195 PNH patients, the thromboembolic (TE) event rate per 100 patient-years with eculizumab treatment was 1.07, compared with 7.37 events (P< 0.001) prior to eculizumab treatment, a relative absolute reduction of 85%. With equalization of duration of exposure before and during treatment for each patient, TE events were reduced from 39 before eculizumab to 3 during eculizumab (P< 0.001). The TE event rate in antithrombotic-treated patients (n = 103) was reduced from 10.61 to 0.62 events/100 patient-years with eculizumab treatment (P< 0.001).

One study has documented elevated D-dimer levels in PNH patients with a history of thrombosis. D-dimer levels decreased immediately after initiation of eculizumab therapy. ^[56]

Continuation of anticoagulation in patients with PNH with a previous thrombosis while on eculizumab is recommended, as stopping therapy has not been studied. However, patients with no previous thrombosis have discontinued warfarin after starting eculizumab, with no thrombotic sequelae. ^{[54, 57]}

Kidney dysfunction

Chronic hemosiderosis and/or microvascular thrombosis from PNH causes kidney dysfunction or damage at an incidence of 65%, defined by stages of chronic kidney disease (CKD), in a large cohort of PNH patients. Eculizumab treatment was safe and well-tolerated in patients with Kidney dysfunction or damage and resulted in the likelihood of improvement as defined as categorical reduction in CKD stage (P< 0.001) compared with baseline and placebo (P = 0.04).

Improvement in kidney function was more commonly seen in those with less severe impairment. Improvements occurred quickly and were sustained for at least 18 months of treatment. Administration of eculizumab to patients with kidney dysfunction or damage was well tolerated and was usually associated with clinical improvement. ^[58]

Iron

Monitoring iron even if the patients no longer require transfusions is recommended, because hemosiderinuria—a protective mechanism in PNH to excrete iron—no longer occurs with eculizumab. Measuring serum ferritin is recommended and chelation therapy may be necessary in patients with high levels.

The anemia of PNH may have three 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) and give oral ferrous sulfate if the result is < 20%. (Ferritin levels should not be used for this purpose, as ferritin is an acute-phase reactant and levels can be misleading.)

Determine steady-state hemoglobin levels after correction for iron deficiency. When appropriate, transfuse packed red blood cells (RBCs) with leukocytes depleted by filter. Washing RBCs is no longer necessary, and use of irradiated blood products is recommended for future stem cell transplantation.

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.

Iron

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.

In severe cases with of paroxysmal nocturnal hemoglobinuria (PNH) with an aplastic phase, referral to a bone marrow transplantation center is indicated for possible allogeneic bone marrow transplantation. Umbilical cord stem cell transplantation from the patient's own cord blood, from a related donor, or from the registry for HLA–matched unrelated donors may be an option in pediatric patients.

Hematopoietic stem cell transplantation (HSCT) using allogeneic donors is the only curative therapy for PNH. With the advent of eculizumab, the indications for HSCT have changed. Clinical results from HSCT from various programs in a rare disease are limited to small numbers of patients. A retrospective analysis of the Italian BM transplantation group in 26 patients with a median age of 32 years (22-60 y, range) with 23 HLA-identical donors (22 siblings, one unrelated) shows a transplant-related mortality of 42%, 8% graft failure, and a 10-year survival (disease-free) of 57% for all patients. ^[59] The mortality rate remains high, so this form of therapy is reserved for those who are severely hypoplastic and refractory to other forms of therapy.

The International Bone Marrow Transplant Registry (IBMTR) reported a 2-year survival probability of 56% in 48 recipients of HLA-identical sibling transplants between 1978 and 1995. ^[60] Data using nonmyeloablative conditioning and haploidentical donors was similar to the identical donors, indicating some form of graft-versus-PNH effects. Now that an effective, nontransplant therapy is available, the use of allogeneic HSCT to treat PNH has decreased.

Before the introduction of eculizumab, PNH patients with severe symptoms from classic PNH and patients with AA/PNH with peripheral cytopenias meeting criteria for severe aplastic anemia were considered good candidates for allogeneic bone marrow transplantation, especially if a matched sibling donor was available.

With eculizumab for PNH, the indications for allogeneic HSCT in this setting have changed. First, HSCT should not be offered as initial therapy for most patients with classic PNH, given the high transplant-related mortality, especially when using unrelated or mismatched donors. Exceptions are PNH patients in countries where eculizumab is not available. HSCT is also a reasonable option for patients who do not have a good response to eculizumab therapy. Second, aplastic anemia/PNH patients continue to be reasonable candidates for HSCT if they have life-threatening cytopenias. ^[29]

An analysis by the International PNH Interest Group reviewed data from 67 patients from single centers and from teo registry studies, with special emphasis in eliminating duplication in patient reporting. ^[22] Results included the following:

• Of the seven patients transplanted from a twin syngeneic donor, the four who had no conditioning therapy either failed to engraft or relapsed after 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 in progress regarding whether reduced-intensity conditioning can improve the outcome.

A retrospective study of 21 PNH patients who underwent HSCT after previous treatment with eculizumab found that HSCT was associated with almost 30% mortality, mainly due to infections and acute graft-versus-host disease (GvHD). Syngeneic HSCT transplants were well tolerated. The authors suggested that these results may call into question the role of HSCT for patients with classic PNH who continue to require transfusions despite eculizumab, in absence of a syngeneic donor. ^[61]

Pregnancy in patients with PNH poses very significant risks. 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 risk of fetal loss is increased. Consequently, full anticoagulation with low-molecular weight heparin (LMWH) is recommended for pregnant women with PNH. Warfarin may be substituted after the first trimester.

The use of eculizumab in pregnancy has proved beneficial. ^[62] In a review of 75 pregnancies in 61 women with PNH, Kelly and colleagues reported a high rate of fetal survival and a low rate of maternal complications. No maternal deaths occurred. There were three fetal deaths (4%) and six first-trimester miscarriages (8%). During pregnancy, patients demonstrated increased requirement of red blood cell transfusions, and approximately half required an increase in the eculizumab dosage. Ten hemorrhagic events occurred, and two postpartum thrombotic events. Eculizumab was detected in some infants' cord blood, but not in breast milk. ^[63]

 No information is available regarding the presence of eculizumab in human milk, the effects on the breastfed infant, or the effects on milk production. No information is available on the use of ravulizumab during breastfeeding, but the manufacturer recommends against breastfeeding during ravulizumab therapy and for 8 months after the final dose. ^[64]

Primary care physicians should be aware of the thrombotic complications of paroxysmal nocturnal hemoglobinuria (PNH) and how to diagnose them when they occur.

Kidney complications

Chronic hemolysis and renal iron deposition, which is a particular risk in PNH when complement inhibition therapy is delayed or not available, may result in acute tubular injury or acute kidney injury (AKI). Consultation with a nephrologist may be indicated to help manage these cases. Continuous renal replacement therapy (CRRT) is one of the best options for the treatment of PNH-associated AKI. Dialysis techniques may include immunoadsorption, dedicated hemodialysis filters that use convective techniques, backfiltration, or coupled plasma filtration adsorption (CPFA). ^[65]

In many patients with paroxysmal nocturnal hemoglobinuria (PNH), the abnormal clone may eventually disappear. This usually takes at least 5 years, and often as long as 15-20 years. Reactivation of PNH in these patients has been observed with acute infections. Patients with chronic anemia alone, without thrombotic complications, can live relatively normal lives for many years.

Outpatient RBC transfusion often is necessary to keep a patient with chronic anemia and paroxysmal nocturnal hemoglobinuria (PNH) able to function and live a normal life.