Approach
Treatment in paroxysmal nocturnal hemoglobinuria (PNH) is directed at the three major aspects of the disease: intravascular hemolysis, thrombophilia, and marrow hypofunction. These are variably present and treatment therefore depends on those aspects that are manifested at the time.
Hemolytic anemia
First-line therapy for PNH is complement C5, C3, or factor B inhibition.
Eculizumab and ravulizumab
These are monoclonal antibodies directed against the complement protein C5, which inhibits intravascular hemolysis in PNH. Eculizumab and ravulizumab improve anemia in most patients and abolish symptoms due to nitric oxide deprivation (esophageal spasm, abdominal pain, erectile dysfunction, pulmonary hypertension, some renal dysfunction). They also rapidly relieve the "fatigue" experienced by patients.[25][26]
Eculizumab is given as long as the patient has hemolysis (usually lifelong). One Cochrane review concluded that evidence (from a single 26-week randomized-controlled trial) indicates that eculizumab increases health‐related quality of life compared with placebo.[27] The trial did not report overall survival. Observational data suggest significant prolongation of survival in eculizumab-treated patients compared with historical controls (best supportive care).[28][29] Biosimilars of eculizumab are available in some countries.[30][31]
The eculizumab dosing regimen (administered once every 2 weeks) may pose a treatment burden and impact patient adherence. Additionally, around 25% of patients may experience breakthrough hemolysis, increasing the risk of thrombotic events and other potentially life-threatening complications related to intravascular hemolysis.
Ravulizumab, an alternative treatment option, achieves immediate, complete, and sustained inhibition of complement-mediated hemolysis with a longer dosing interval. It has a high affinity for binding C5, and inhibits C5a and C5b formation, effectively preventing immune activation and hemolysis.[32]
There is a low risk of meningococcal infection with both eculizumab and ravulizumab; all patients must be immunized at least 2 weeks before beginning this treatment, according to current immunization recommendations. Immunization should be updated as long as the patient is receiving therapy. Antibacterial prophylaxis may be given in situations where treatment must start within 2 weeks of vaccination.
Pegcetacoplan
Pegcetacoplan, a complement C3 inhibitor, is an option as a first-line agent or for patients who may not respond well to C5 complement blockade. Pegcetacoplan controls both intravascular and extravascular hemolysis.
In one phase 3 open label trial, pegcetacoplan demonstrated superiority over eculizumab in improving hemoglobin levels and clinical and hematologic outcomes in patients with PNH (with a hemoglobin level below 10.5 g/dL, despite receiving stable doses of eculizumab for at least three months before entering the study).[33] Improved hematologic outcomes attributable to pegcetacoplan persisted during 48 weeks of treatment.[34]
In an indirect comparison of individual patient data, pegcetacoplan was associated with significantly reduced lactate dehydrogenase (LDH) and increased hemoglobin from baseline, compared with eculizumab or ravulizumab, in complement inhibitor-naïve patients with PNH.[35]
Iptacopan
Iptacopan is an oral complement factor B inhibitor that acts upstream of the C5 terminal pathway, preventing intravascular and extravascular hemolysis in patients with PNH. Iptacopan can be used as a first-line agent, or for patients who do not respond well to C5 complement inhibitors due to clinically significant extravascular hemolysis. Iptacopan is the first oral treatment for the management of adults with PNH.
In one phase 3 trial, patients who had received eculizumab or ravulizumab in a stable regimen for at least six months were randomized to receive iptacopan monotherapy or to continue anti-C5 therapy.[36] An estimated 82.0% of patients with PNH treated with iptacopan experienced an increase in hemoglobin levels by 2 g/dL or more from baseline, compared with 2.0% of patients with PNH treated with eculizumab or ravulizumab.[36] An estimated 69.0% of patients treated with iptacopan reached a hemoglobin level of at least 12 g/dL without transfusion of red blood cells, compared with 2.0% of patients who received eculizumab or ravulizumab.[36]
A discrete single-group trial provided evidence for the use of iptacopan in patients who had not received complement-inhibitor therapy and had LDH levels that were more than 1.5 times the upper limit of the normal range.[36] However, the absence of a control group means that efficacy cannot be solely attributed to the intervention.
Single agent proximal complement inhibitors: safety
There is a risk of serious infections with pegcetacoplan and with iptacopan. All patients must be immunized against encapsulated bacteria (e.g., Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae) at least 2 weeks before beginning treatment, according to current immunization recommendations. Immunization should be updated as long as the patient is receiving therapy. Antibacterial prophylaxis may be given in situations where treatment must start within 2 weeks of vaccination.
There is a risk of unprecedented intravascular breakthrough hemolysis with single agent proximal complement inhibitors such as pegcetacoplan and iptacopan.[37] Breakthrough hemolysis, necessitating a switch back to eculizumab, has been reported with single agent proximal complement inhibitors such as pegcetacoplan.[33][34] Prospective clinical trials are needed to determine the optimal management of breakthrough hemolysis associated with proximal complement inhibitors.[38]
Pregnancy
There is a lack of adequate clinical research focused on the use of ravulizumab, pegcetacoplan, and iptacopan during pregnancy. As a result of this limited data, and the potential risks to the developing fetus, the general practice is to avoid these drugs during pregnancy, except in cases where the potential benefits to the mother far outweigh the risks to the unborn child.
Several reports describe successful outcomes for both mother and child with eculizumab.[39][40] An analysis of 79 pregnancies involving 61 women receiving eculizumab during pregnancy demonstrated improved outcomes for the mother and fetus. All children achieved age-appropriate milestones. A higher dose of eculizumab was needed in the second and third trimester.[41] Anticoagulation should be given during the pregnancy and continued for at least 3 months postpartum.[42]
Underlying aplastic anemia and/or kidney damage
Although endogenous erythropoietin (EPO) levels are usually high in PNH, supplemental injections of recombinant EPO have been found useful in some patients.[43][44] It has been used in conjunction with eculizumab in a patient with underlying aplastic anemia.[45] It is also useful in patients with kidney damage due to PNH.[46]
Although EPO is considered generally safe in pregnancy, there are no conclusive data on its use in PNH during pregnancy. The potential benefit must be weighed against the risk of thrombosis related to EPO use.
Iron deficiency anemia
Patients with PNH lose up to 20 times as much iron per day as healthy people and may require supplementation with oral or parenteral iron. It is important to note that iron repletion may be followed by a brief episode of hemoglobinuria.[47] Oral iron supplementation is an easy way to replace iron and is usually given in its elemental form. If patients cannot tolerate this or have such rapid iron loss that oral iron cannot keep up with the losses, iron can be given parenterally. Parenteral iron is generally safe, although severe cases of anaphylaxis have been reported. Treatment is continued so long as iron stores, monitored by serum ferritin, are adequate and not excessive, or hemolysis has been blocked by complement inhibitors.
Symptomatic anemia
Patients may require transfusion with red blood cells if hemoglobin falls to a level, usually to <8.5 g/dL, that is symptomatic (fatigue, shortness of breath, symptoms of heart failure). This is occasionally accompanied by a bout of hemoglobinuria due to destruction of the abnormal PNH cells. This can be prevented by removing white blood cells from the transfused unit through washing or appropriate filtering.[48] Iron overload is not a problem in PNH patients, as chronic losses in urine result in iron deficiency even in heavily transfused patients.
Thrombosis
Thrombolytic agents may be used in the acute stage of thrombosis, unless the platelet count is <50,000/microliter or the thrombosis is intracranial.[49] This should be followed by full anticoagulation with warfarin or heparin (preferably low-molecular-weight heparin [LMWH]). For cerebral thrombosis, antiedema therapy (usually dexamethasone or mannitol) and anticoagulation are used, but evidence is limited.
Patients with documented thrombosis should receive lifelong secondary prophylaxis although, for patients on complement C5 inhibitor treatment, there is no clear evidence for the benefit of lifelong anticoagulation. Eculizumab has been shown to markedly reduce the incidence of thrombosis in PNH.[50]
Most authors suggest a target international normalized ratio of 2.0 to 2.5. Prophylactic anticoagulation with warfarin or heparin derivatives has been used with variable success in untreated patients.[51]
Pregnancy
There are no data to support thrombolytic therapy in pregnant women with PNH. Generally, systemic thrombolysis is considered risky in pregnant women, even though scant reports have shown encouraging outcomes with manageable complications in cases of life-threatening thrombosis.[52]
The risk of thrombotic complications in pregnant women with PNH is high.[53] For this reason, anticoagulation with LMWH has been recommended. Patients should be started on an LMWH as soon as pregnancy is documented and continue treatment for at least 3 months postpartum.[42] Warfarin is contraindicated in pregnancy due to its teratogenic effect.[54]
Marrow hypofunction
Marrow hypofunction in PNH may be treated, as in aplastic anemia, with antithymocyte globulin and cyclosporine with eltrombopag.[55]
If these are ineffective, hematopoietic stem cell transplantation may be considered, particularly if a suitably matched related donor is available.[56][57][58] These measures become necessary if the platelet count and/or granulocyte count in particular becomes too low (e.g., absolute neutrophil count <500/microliter).
Stem cell transplantation provides a cure for marrow hypofunction in PNH. When it is successful, all manifestations of the disease are eliminated. However, it carries the usual risk of death and chronic morbidity associated with chronic graft-versus-host disease.
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