Version July 2025
INTRODUCTION —
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder in which hematopoietic stem cells and their cellular progeny have lost the ability to anchor certain proteins to the cell surface. Loss of the complement inhibitors, CD55 and CD59, on the surface of red blood cells leads to chronic and/or paroxysmal intravascular hemolysis and a propensity for thrombosis.
The development of biologic therapies that target the underlying complement-mediated hemolysis has dramatically improved the prognosis of PNH.
Patients with PNH may also have hypocellular or dysplastic bone marrow, and a subset of patients has clinically significant aplastic anemia or myelodysplastic syndromes/neoplasms.
This topic discusses the treatment and prognosis of PNH.
Clinical manifestations, diagnosis, and pathophysiology of PNH are presented separately. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria" and "Pathogenesis of paroxysmal nocturnal hemoglobinuria".)
BASELINE EVALUATION —
The diagnostic evaluation for patients who are suspected to have PNH is discussed separately. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Diagnosis and classification'.)
Clinical/laboratory studies — The following evaluation should be performed prior to initiating management of PNH:
●Clinical – The history and physical examination should elicit the nature and severity of hemolysis-associated findings (eg, fatigue, dyspnea, tachycardia, jaundice, dark or red urine), muscle or bone pain, and recurrent infections or excessive bleeding/bruising from cytopenias associated with bone marrow failure.
The patient should be evaluated for clinical findings of venous thrombosis. In addition to deep vein thrombosis or pulmonary embolism, thrombosis of atypical sites should be considered, such as mesenteric or hepatic veins (eg, abdominal pain, increasing abdominal girth, ascites, esophageal or gastric varices, hepatosplenomegaly) and cerebral vein thrombosis (eg, intractable headache, abnormal neurologic findings).
Comorbid conditions and performance status should be assessed (table 1).
●Laboratory studies
•Hematology
-Complete blood count (CBC) with differential
-Reticulocyte count
-D-dimer
•Chemistries
-Serum electrolytes, glucose, kidney function tests, and liver function tests, including lactate dehydrogenase, fractionated bilirubin, and haptoglobin
-Serum iron, total iron binding capacity, and ferritin
Previous laboratory results should be reviewed, as they may reflect the duration and degree of hemolysis, size of the PNH clone, and the trajectory of the condition.
Other testing
●Flow cytometry – The population of PNH-affected cells is measured by flow cytometry to assess the percentage of CD55-negative and CD59-negative cells. Both granulocytes and red blood cells (RBCs) should be analyzed, as the population of PNH cells will be underestimated if only RBCs are analyzed due to selective destruction of PNH RBCs by complement coupled with dilution from recent RBC transfusions. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Flow cytometry/FLAER'.)
●Bone marrow examination – Bone marrow aspirate and biopsy are important for defining cellularity, dysplasia, and other abnormalities associated with PNH and aplastic anemia (AA) and/or myelodysplastic neoplasms/syndromes (MDS).
Bone marrow examination should include microscopy, karyotype, fluorescence in situ hybridization (FISH; for MDS-related genetic abnormalities), quantitative CD34 cell count, and iron staining. (See "Acquired aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Bone marrow examination' and "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Bone marrow examination'.)
●Imaging – We do not routinely image patients who are not clinically suspected to have thromboembolic abnormalities.
In addition to an increased risk for deep vein thrombosis and pulmonary embolism, patients with PNH may have thromboses at atypical sites (eg, mesenteric, hepatic, cerebral veins), as described above. Diagnostic evaluation for thromboembolism is discussed separately. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity" and "Recent portal vein thrombosis in adults: Clinical features, diagnosis, and management" and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".)
Evaluation for transplantation — For individuals who have PNH with coexisting severe bone marrow failure (ie, severe AA or higher-risk MDS), we refer the patient to evaluate eligibility for allogeneic hematopoietic cell transplantation. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)
PNH CATEGORIES —
Classification of PNH is based on symptoms, severity of hemolysis, current/prior thrombosis, and degree of bone marrow failure (BMF).
Details of clinical manifestations, diagnosis, and classification of PNH are presented separately. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Diagnostic criteria'.)
PNH is a dynamic condition, and the category can evolve over time. As examples, patients who were originally classified as having subclinical PNH or hemolytic PNH may later evolve to PNH with BMF.
Although surrogate markers such as the serum level of serum lactate dehydrogenase (LDH) or the size of the leukocyte PNH clone differ between categories, they are not used as classification criteria because they do not correlate precisely with the severity of symptoms and bone marrow findings.
PNH is classified as follows:
●Hemolytic (classical) PNH
•Prominent symptoms related to hemolysis (eg, fatigue, dyspnea, transfusion dependence, episodic hemoglobinuria, thrombosis, pain, and/or organ dysfunction)
•LDH typically >1.5 x upper limit of normal (ULN)
•PNH granulocyte clone size typically >50 percent
•Normal white blood cell (WBC) count and platelet count or modest, asymptomatic leukopenia and/or thrombocytopenia
•Cellular bone marrow with erythroid hyperplasia and no significant dysplasia
Management of hemolytic PNH is discussed below. (See 'Symptomatic PNH' below.)
●PNH with thrombosis
•PNH clone, usually >30 percent PNH granulocytes and LDH >1.5 ULN
plus
•Current thrombosis or a history of thromboembolic events
Management of patients with PNH and thrombosis is discussed below. (See 'Acute thrombosis' below.)
●PNH with BMF
•Variable anemia-related symptoms, thrombosis, pain, or organ dysfunction
•Variable LDH level
•Variable granulocyte PNH clone size
•Prominent severe, symptomatic leukopenia and/or thrombocytopenia that meets criteria for severe aplastic anemia (AA) or higher-risk myelodysplastic syndromes/neoplasms (MDS)
Management of PNH with BMF is discussed below. (See 'PNH with severe bone marrow failure' below.)
●Subclinical PNH
•No substantial hemolysis-related symptoms, thrombosis, pain, organ dysfunction, and no need for transfusions
•LDH typically ≤1.5 x ULN
•PNH granulocytes typically ≤20 percent
•Normal WBC count and platelet count or modest, asymptomatic leukopenia/thrombocytopenia
•Normal or near-normal bone marrow cellularity and morphology
Management of subclinical PNH is discussed below. (See 'Subclinical PNH' below.)
OVERVIEW OF MANAGEMENT —
Initial management of PNH is guided by the nature and severity of symptoms, severity of hemolysis, current or prior thrombosis, and degree of bone marrow failure.
Management is stratified according to the category of PNH, as described above. (See 'PNH categories' above.)
All symptomatic patients with PNH can benefit from supportive care, as described below. (See 'Supportive care' below.)
Our approach to management of PNH is consistent with recommendations of expert panels from the American Society of Hematology [1], Belgium [2], and Canada [3].
SUBCLINICAL PNH —
For patients who have no substantial hemolysis-associated symptoms, thrombosis, pain, organ dysfunction, or bone marrow failure (BMF), we manage with watchful waiting to avoid the inconvenience, adverse effects, and expense of a complement inhibitor (algorithm 1).
Patients with subclinical PNH should receive supportive care if needed. (See 'Supportive care' below.)
Patients are monitored regularly for worsening hemolysis-associated findings and for progression of cytopenias that may herald worsening BMF, as discussed below. (See 'Monitoring in all patients' below.)
SYMPTOMATIC PNH —
PNH can be associated with symptomatic hemolytic anemia, pain, thrombosis, and/or organ dysfunction.
Management of PNH with severe bone marrow failure (BMF) is discussed below. (See 'PNH with severe bone marrow failure' below.)
Initial therapy — For initial treatment of symptomatic hemolytic PNH without severe BMF, we suggest a complement inhibitor rather than supportive care/transfusion therapy alone.
Compared with transfusion therapy, complement inhibitors provide better control of pain and thromboses, less need for transfusions, and avoidance of iron overload, but they increase the risk for serious and life-threatening infections. Studies that compared complement inhibitors with transfusion therapy or that compared various complement inhibitors are described below.
Convenience is an important factor in selecting a complement inhibitor because hemolytic PNH requires lifelong treatment. We favor ravulizumab based on its convenient dosing and long track record of efficacy and toxicity. Other complement inhibitors may be acceptable for selected patients, but all require more frequent administration than ravulizumab and/or they have shorter track records (algorithm 1). Costs vary, but all complement inhibitors are expensive.
●Acceptable agents – Acceptable agents for frontline therapy of symptomatic hemolytic PNH include:
•Complement C5 inhibitors (C5i) – We favor ravulizumab based on the convenient maintenance therapy schedule (ie, intravenous infusions every eight weeks) and its long track record.
The efficacy and toxicity of eculizumab are comparable to ravulizumab, but eculizumab requires intravenous infusions every two weeks for maintenance therapy. Crovalimab is a C5i that requires maintenance therapy with subcutaneous infusions every four weeks (after initial intravenous loading).
The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) approved ravulizumab and eculizumab for treatment of PNH. The FDA also approved ravulizumab for treatment of PNH in children ≥1 month. The FDA approved crovalimab for PNH in patients ≥13 years and ≥40 kg. These agents are available only through a restricted program under a risk evaluation and mitigation strategy (REMS) in the United States.
•Alternative pathway complement inhibitors – Iptacopan (factor B inhibitor) and pegcetacoplan (complement C3 inhibitor) are acceptable for frontline therapy in selected patients, but we avoid these agents in patients with a history of thrombosis (because of limited long-term follow-up for thrombosis protection), a history of nonadherence to a medication schedule (because of their short half-lives), and in individuals who may become pregnant. Iptacopan is an oral agent that is taken twice daily. Pegcetacoplan is infused subcutaneously twice weekly.
Iptacopan and pegcetacoplan are approved by the EMA and the FDA for treatment of hemolytic PNH. They are only available through a REMS program in the United States.
●Outcomes – Studies of complement inhibitors for symptomatic hemolytic PNH include:
•C5i versus supportive care alone – Eculizumab was superior to transfusion therapy/supportive care for hemolytic PNH in a phase 3 trial. While transfusion therapy can alleviate pain and anemia-related symptoms, it can cause transfusion-associated iron overload and alloimmunization, and it does not mitigate the risk for thrombosis (which is common, difficult to predict, and may recur or progress despite antithrombotic therapy [4-8]).
-Eculizumab achieved better outcomes than placebo in the TRIUMPH trial, which randomly assigned treatment to 87 patients with severe PNH [9,10]. Eculizumab more effectively achieved red blood cell (RBC) transfusion independence (TI; 49 versus 0 percent, respectively) and led to clinically meaningful improvement in quality of life (measured with two different assessment instruments). There was no difference in overall survival (OS) between treatment arms during the 26-week trial, and no deaths or serious adverse effects (AEs) were attributed to eculizumab; one thrombotic event was reported in the placebo group.
-Ravulizumab has not been directly compared with placebo in a phase 3 trial, but its safety and efficacy were comparable with eculizumab in other randomized trials [11,12], as discussed below. (See 'C5 inhibitors' below.)
•Ravulizumab versus eculizumab – Ravulizumab and eculizumab have comparable efficacy for symptom relief and thrombosis prevention and comparable AEs.
-In an open-label randomized trial, ravulizumab and eculizumab achieved similar outcomes and safety [11]. The trial randomly assigned 246 patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal (ULN) to receive ravulizumab or eculizumab for 183 days. The agents achieved similar rates of RBC TI, normalization of serum LDH, and improvement of fatigue (change from baseline in Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue score).
-In another phase 3 trial, among 195 clinically stable patients with PNH who were previously treated with eculizumab and then randomly assigned to continue eculizumab or switch to ravulizumab, the two agents achieved comparable results [12].
●Alternative pathway complement inhibitors – No randomized trials have directly compared iptacopan or pegcetacoplan with transfusion therapy alone or with a C5i for initial management of hemolytic PNH.
-A single-arm study (APPOINT-PNH) reported that treatment with iptacopan in 33 evaluable patients with hemolytic PNH (LDH >1.5 x ULN) who had not previously received a complement inhibitor was associated with reduced transfusion needs and improved hemoglobin (Hb) levels [13]. No patient required or received RBC transfusion in the 24-week period of study, and Hb rose a mean of 4.3 g/dL; 31 of 33 evaluable patients had Hb rise ≥2 g/dL from baseline without RBC transfusions. There were no episodes of breakthrough hemolysis, and the most common AEs were mild headaches. There were no episodes of meningococcal or pneumococcal infections. Breakthrough hemolysis increased to 5 percent after 48 weeks of iptacopan monotherapy, according to preliminary results presented in abstract form [14]. We await the results of the longer-term follow-up of initial therapy with iptacopan.
Treatment breakthrough — Treatment breakthrough is defined as a return of PNH symptoms (eg, fatigue, hemoglobinuria, abdominal pain, thrombosis) in association with a rise in LDH to ≥2 x ULN after prior reduction to <1.5 x ULN while receiving treatment with a C5i.
Types of breakthrough — The return of PNH-associated symptoms may be due to pharmacokinetic effects, pharmacodynamic breakthrough (ie, complement-amplifying conditions, such as infection, surgery, pregnancy), exacerbation of extravascular hemolysis (EVH), or progressive BMF.
●Pharmacokinetic effects – Pharmacokinetic breakthrough (eg, recurrence before the next dose) is less common with ravulizumab than eculizumab because of its longer half-life and weight-based dosing [15]. If hemolysis-related symptoms worsen before the next dose of eculizumab, the dosing interval can be shortened (eg, to 12 or 13 days), or the dose can be increased.
●Pharmacodynamic breakthrough – Pharmacodynamic breakthrough refers to events that can increase complement activation, such as infection, surgery, and pregnancy. As a result, PNH RBCs that are densely coated with C3b can cause C5 to adopt a C5b-like conformation that is not inhibited by eculizumab or ravulizumab [16]. Treating the underlying complement-amplifying condition is necessary to mitigate pharmacodynamic breakthrough. Notably, patients with PNH often experience pharmacodynamic breakthrough within days of receiving coronavirus disease 2019 (COVID-19) vaccination [17].
●Exacerbation of EVH – Virtually all patients with PNH who are treated with a C5i experience mild to moderate EVH that may be accompanied by continued anemia, elevated reticulocyte count, and a positive direct antiglobulin test (DAT; ie, Coombs test) for C3d. Up to one-fifth of patients may require periodic RBC transfusions [18-20]. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria", section on 'Extravascular hemolysis from reduced CD55'.)
●Worsening leukopenia and/or thrombocytopenia – If pancytopenia develops or worsens, the patient should have a repeat bone marrow examination to re-evaluate for BMF. (See 'Other testing' above.)
Management of breakthrough hemolysis — For patients with symptomatic residual anemia due to breakthrough EVH, we suggest adding danicopan (factor D inhibitor) to the C5i, rather than continuing the C5i alone or switching to monotherapy with an alternative pathway complement inhibitor (ie, iptacopan or pegcetacoplan).
Adding danicopan to a C5i for breakthrough EVH reduced long-term transfusion needs and lessened symptoms compared with adding a placebo [21]. While pegcetacoplan and iptacopan reduced transfusion needs compared with continuing the C5i in this setting [13,22], the combination of danicopan plus a C5i offers the most complete protection from complement-driven hemolysis [23].
Alternative pathway complement inhibitors act upstream of C5 and do not inhibit the classical complement pathway. While they can effectively control intravascular and EVH in a steady state, an infection, trauma, or surgery can cause massive intravascular hemolysis. Furthermore, these agents have short half-lives (hours to days), and treatment interruptions (eg, gastroenteritis, lost pills) or nonadherence can provoke hemolysis. These agents should be avoided in individuals who may become pregnant and in patients presenting with thrombosis because of limited long-term follow-up for thrombosis protection.
Comorbidities, availability, convenience, and patient preference should be considered if monotherapy with iptacopan or pegcetacoplan is chosen for managing breakthrough EVH. Many patients favor oral iptacopan rather than pegcetacoplan, which is administered by subcutaneous infusions. When switching to pegcetacoplan, the C5i should be continued for ≥3 weeks to enable the new agent to reach a steady state; an overlap in therapy is not needed when switching to iptacopan. Administration of these agents is discussed below. (See 'Alternative pathway complement inhibitors' below.)
●Addition of danicopan to a C5i
•Administration – Danicopan 150 mg is taken by mouth three times daily.
•Toxicity – As with all complement inhibitors, there is increased risk for infections with encapsulated bacteria. There are no available data regarding use in pregnant individuals to evaluate birth defects, miscarriage, or adverse maternal or fetal outcomes.
•Outcomes – Adding danicopan to a C5i for breakthrough EVH was more effective than adding a placebo in the phase 3 ALPHA trial conducted in 86 patients, and long-term follow-up demonstrated continued efficacy and safety [21]. Compared with placebo, danicopan achieved superior transfusion avoidance (79 versus 28 percent, respectively) and symptom relief (based on Functional Assessment of Chronic Illness Therapy-Fatigue scale scores), and improved hemoglobin in the initial 12-week phase of the trial. Participants who were initially assigned placebo switched to danicopan after 12 weeks, and they experienced improved hemoglobin by week 24 and outcomes comparable to those of patients initially treated with danicopan. Improvements with danicopan were maintained up to week 72, and no new safety signals emerged.
●Monotherapy with iptacopan or pegcetacoplan
•Iptacopan – Iptacopan achieved superior TI and clinically important improvement in quality of life compared with continuation of the C5i for patients with breakthrough hemolysis. Iptacopan should be avoided in patients with severe liver or kidney disease.
-In the phase 3 APPLY-PNH trial, patients with Hb <10 g/dL while taking a C5i were randomly assigned (8:5) to switch to iptacopan 200 mg twice daily or to continue the prior C5i [13]. During 24 weeks of the study, TI was reported in 59 of 62 patients taking iptacopan compared with 14 of 35 patients continuing their C5i. Iptacopan achieved a 6.6-point mean improvement in the FACIT-Fatigue score (on a scale of 0 to 52, with a 5-point improvement considered clinically important for patients with PNH [24]), while continued C5i therapy was associated with a 0.3-point mean improvement. Among 60 evaluable patients taking iptacopan, 42 achieved Hb ≥12 g/dL (mean 3.6 g/dL improvement from baseline) compared with none of 35 patients treated with anti-C5i (with no improvement from baseline); 51 patients taking iptacopan had ≥2 g/dL improvement in Hb compared with none treated with C5i. Two of 62 patients taking iptacopan experienced breakthrough hemolysis compared with 6 of 35 on the C5i. Iptacopan was also associated with improvements in reticulocyte count and serum bilirubin. Serious AEs occurred in 10 percent of patients on iptacopan and in 14 percent taking a C5i. There were no deaths from meningococcal or pneumococcal infections.
•Pegcetacoplan – Pegcetacoplan was superior to eculizumab for achieving TI and lessening fatigue in patients with persistent hemolytic anemia while taking eculizumab.
-In the phase 3 PEGASUS trial, patients with Hb <10.5 g/dL on eculizumab therapy were randomly assigned to pegcetacoplan versus continued eculizumab [22]. After a four-week run-in phase in which all patients received pegcetacoplan plus eculizumab, patients were randomly assigned to pegcetacoplan monotherapy (41 patients) or eculizumab (39 patients). At week 16, pegcetacoplan achieved more TI (85 versus 15 percent), nearly 4 g/dL increase in Hb, and greater improvement in fatigue compared with eculizumab. The most common AEs during treatment with pegcetacoplan and eculizumab were injection site reactions (37 versus 3 percent, respectively), diarrhea (22 versus 3 percent), breakthrough hemolysis (10 versus 23 percent), headache (7 versus 23 percent), and fatigue (5 versus 15 percent).
PNH WITH SEVERE BONE MARROW FAILURE —
PNH can be accompanied by bone marrow failure (BMF) due to severe aplastic anemia (sAA) or higher-risk myelodysplastic syndromes/neoplasms (MDS).
Criteria for severe bone marrow failure — Criteria for sAA and higher-risk MDS are:
●sAA – Bone marrow cellularity <25 percent plus ≥2 of the following:
•Absolute neutrophil count (ANC) <500/microL (<0.5 x 109/L)
•Platelet count <20,000/microL
•Reticulocyte count <60,000/microL
Further details of diagnosis and classification of AA are discussed separately. (See "Acquired aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnosis and grading'.)
●Higher-risk MDS – Risk stratification is based on prognostic score:
•Revised international prognostic scoring system (IPSS-R) (table 2) (calculator 1): ≥4.0 points
or
•Original IPSS (table 3) (calculator 2): ≥1.5 points
Further details of diagnosis and prognostic classification of MDS are discussed separately. (See "Myelodysplastic syndromes/neoplasms (MDS): Overview of diagnosis and management", section on 'Prognostic category'.)
Management of PNH with severe bone marrow failure — Management of PNH with severe BMF is guided by eligibility for allogeneic hematopoietic cell transplantation (HCT).
Transplant eligible — For PNH with severe BMF in patients who are transplant eligible, we suggest allogeneic HCT rather than a complement inhibitor (algorithm 1) based on improved long-term outcomes alone.
Complement inhibitors are not effective for treating severe BMF, but they can be given for managing hemolysis-associated findings while awaiting transplantation [25].
Outcomes with transplantation for patients with PNH come from observational studies and case reports. No randomized trials have directly compared allogeneic HCT versus complement inhibitors or observation. Long-term overall survival after allogeneic HCT for PNH has been reported from 50 to 70 percent with myeloablative conditioning (MAC), while reduced-intensity conditioning (RIC)/nonmyeloablative (NMA) conditioning may be associated with rates that approach 90 percent [26-30].
Transplant candidates must have no severe lung, heart, liver, or kidney disease; a suitable graft source; and adequate social support. Although age limits vary, many institutions restrict allogeneic HCT to patients ≤70 years of age. Details of eligibility for allogeneic HCT are presented separately. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)
Preferred conditioning regimens and graft sources for PNH-associated transplantation vary between institutions and have not been directly compared in randomized trials.
●Conditioning regimen – MAC is not required to eradicate the PNH clone [31]. RIC/NMA conditioning may yield comparable rates of engraftment as MAC, while reducing transplant-related morbidity and mortality.
●Donor source – Human leukocyte antigen (HLA)-matched siblings are preferred when available, but matched unrelated donors are used successfully for PNH. Results with haploidentical donors are also encouraging [32]. Additional discussion of the choice of donor choice is presented separately. (See "Donor selection for hematopoietic cell transplantation".)
●Graft source – We favor bone marrow over peripheral blood stem cells, when possible, because of a lower incidence of graft-versus-host disease (GVHD). A cohort study of 211 patients reported that the incidence of GVHD was lower with bone marrow-derived stem cells compared with peripheral blood stem cells [33]. Additional discussion of the choice of graft source is presented separately. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells", section on 'Allogeneic HCT for nonmalignant disorders'.)
Not transplant eligible — For patients with PNH with BMF who are not eligible for allogeneic HCT or who have nonsevere BMF, we treat with immunosuppressive therapy like that used for severe aplastic anemia (algorithm 1), as discussed separately. (See "Treatment of aplastic anemia in adults", section on 'Triple IST (hATG, CsA, EPAG)'.)
For patients with PNH-associated symptoms in addition to BMF, we treat with immunosuppressive therapy plus management for hemolytic PNH, as described above. (See 'Symptomatic PNH' above.)
MONITORING —
All patients with PNH should be assessed at least annually. Patients who are receiving treatment require clinical evaluation and laboratory studies to assess the response to a complement inhibitor.
Response to complement inhibition — Our approach to assessing the response to complement inhibition follows.
●First four weeks – For the first four weeks of treatment with complement inhibition, patients should be monitored weekly with [34]:
•Complete blood count (CBC)
•Reticulocyte count
•Serum chemistries, including lactate dehydrogenase (LDH)
●Subsequent monitoring – The schedule for further monitoring is guided by the clinical and laboratory response. After hemolysis has stabilized, monitoring the CBC, reticulocyte count, and LDH can generally then be extended to every two months to coincide with the schedule of ravulizumab infusions.
If treatment with a complement inhibitor is discontinued, the patient should be monitored periodically for ≥16 weeks to detect evidence of increased hemolysis, which may be manifest as worsening fatigue, dyspnea, hemoglobinuria, thrombosis, abdominal pain, decreasing hemoglobin, increasing LDH, erectile dysfunction, or other vascular events.
LDH typically falls to <1.5 x the upper limit of normal within days to weeks, the hemoglobin response is variable, and the reticulocyte count can remain elevated indefinitely due to extravascular hemolysis. There is insufficient evidence to support routine monitoring of CH50 or other measures of complement activity.
Management of patients with breakthrough symptoms is described below. (See 'Treatment breakthrough' above.)
Monitoring in all patients — All patients, whether or not they are treated with a complement inhibitor, should be monitored at least annually using flow cytometry to assess the PNH clone size, as described separately. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Flow cytometry/FLAER'.)
SPECIAL SETTINGS
Thromboembolism — Historically, thromboembolic (TE) events occurred in up to 40 percent of patients with PNH. Before the development of complement inhibitors, thromboembolism was the leading cause of death in patients with PNH.
Acute thrombosis — Acute thromboses should be treated with anticoagulation and/or thrombolysis for life-threatening events, according to the site of thrombosis and severity of clinical findings [34,35]. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)".)
●Duration of anticoagulation – For patients whose PNH is well-controlled with a complement inhibitor (ie, lactate dehydrogenase [LDH] <1.5 x upper limit of normal [ULN]) who have no other thrombosis-predisposing factors, we generally anticoagulate for three to six months rather than continue anticoagulation indefinitely. Some clinicians continue anticoagulation indefinitely. No prospective trials have compared continuation versus discontinuation of anticoagulation in PNH, but discontinuing anticoagulation after three to six months reduces the risk of bleeding and complications of thrombocytopenia.
Adequacy of a limited duration of anticoagulation for patients with PNH and a history of a TE event was evaluated in a retrospective single-institution study [36]. Treatment of four patients with a complement inhibitor plus indefinite anticoagulation was associated with an 86 percent relative reduction (RR) of TE events after initiation of the C5 complement inhibitor (C5i; 38.7 TE events/100 patient-years prior to beginning the C5i versus 5.4 events/100 patient-years while receiving C5i therapy plus indefinite anticoagulation). By comparison, among 18 other patients, treatment with a C5i while off anticoagulation was associated with a 94 percent RR of TE events (25.9 TE events/100 patient-years prior to initiating the C5i versus 1.5 TE events/100 patient-years post-C5i therapy while off anticoagulants). Among the entire cohort, TE events prior to C5i therapy included intra-abdominal and cerebrovascular locations; by contrast, TE events while receiving a C5i involved more common locations (ie, deep vein thrombosis, pulmonary emboli), and most were provoked by major surgery or uterine compression. There were two significant gastrointestinal bleeding episodes among patients treated with anticoagulation alone (ie, prior to C5i therapy).
For patients with PNH who have additional risk factor(s) for TE events, the duration of anticoagulation should be individualized. Factors that predispose to thromboses are described separately. (See "Overview of the causes of venous thrombosis in adults".)
●New TE event while receiving adequate complement inhibition – For patients who experience an unprovoked TE event while receiving adequate C5i therapy (ie, LDH <1.5 x ULN), we generally anticoagulate indefinitely.
●Thrombosis with concurrent thrombocytopenia – For patients with severe thrombocytopenia (eg, platelet count <50,000/microL) who experience a TE event, it may be necessary to transfuse platelets to safely administer anticoagulants and/or thrombolytic therapy. (See "Anticoagulation in individuals with thrombocytopenia".)
Thromboprophylaxis — For patients with PNH without a current or prior TE event and without an exacerbating thrombophilic condition, we suggest not treating with prophylactic anticoagulation based on a lack of high-quality evidence that it effectively prevents thromboses.
Exceptions include:
●Hospitalization – Short-term prophylactic anticoagulation is appropriate for patients with PNH who are hospitalized with an acute medical illness or for a surgical procedure because PNH may exacerbate the known risks of venous thromboembolism. When possible, elective surgery should be scheduled soon after treatment with a C5i to reduce the risk of a TE event.
Selection of a prophylactic anticoagulation regimen is presented separately. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults" and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)
●Pregnancy – Management of PNH in pregnant patients is discussed below. (See 'Pregnancy' below.)
●Other thrombophilic conditions – For patients with PNH who have additional thrombophilic conditions, the duration of anticoagulation should be individualized.
Other factors that predispose to thromboses are described separately. (See "Overview of the causes of venous thrombosis in adults".)
Surgery — Surgery can precipitate hemolysis in patients with PNH due to increased inflammatory stimuli and/or metabolic abnormalities [31].
Patients who are currently treated with C5i should be scheduled for surgery close to their most recent infusion, if possible, to minimize pharmacokinetic breakthrough hemolysis. For asymptomatic patients with large PNH clones who are not on therapy, some experts initiate complement inhibition to lessen the thrombotic risk of planned surgery.
The use of routine thromboprophylaxis in surgical patients is discussed in detail separately. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)
Pregnancy — Females with PNH can have successful pregnancies, but it may be associated with increased maternal and fetal morbidity and mortality [37]. A pregnant patient with PNH should be managed by a hematologist and an obstetrician with expertise in high-risk pregnancy.
The following considerations must be addressed:
●Iron and folate supplementation – Pregnancy increases iron and folate requirements, which may already be high in patients with PNH. Prenatal folate and iron should be administered to all patients. (See "Nutrition in pregnancy: Dietary requirements and supplements".)
●Transfusions – Transfusions are administered as needed for symptomatic anemia and/or thrombocytopenia. Some pregnant patients with PNH had increased transfusion requirements in a case series [38].
●Complement inhibition – Both ravulizumab and eculizumab are acceptable choices for treatment of symptomatic hemolytic PNH in pregnant patients. Although most studies report treatment of pregnant patients with eculizumab, we favor ravulizumab because there is less risk for pharmacokinetic breakthrough. Note that other agents (eg, pegcetacoplan, iptacopan, danicopan) have not been shown to be safe for pregnant patients.
For patients who become pregnant while taking a C5i, we continue therapy throughout the pregnancy and while breastfeeding. It may be necessary to increase the dose and/or frequency of treatment during the third trimester because of increases in the volume of distribution. We initiate therapy with a C5i for patients who are newly diagnosed with symptomatic hemolytic PNH while pregnant. (See 'Initial therapy' above.)
An industry-sponsored observational study reported outcomes in 61 females (75 pregnancies) who were taking eculizumab while pregnant; 88 percent were also anticoagulated [38]. There were no maternal deaths, two females had a postpartum TE event while taking eculizumab, and an additional 2 of 10 females who stopped eculizumab postpartum had a TE event. In 36 of 67 pregnancies that progressed to delivery, breakthrough hemolysis necessitated an increased dose of eculizumab or shortened the treatment interval. Live births were reported in 92 percent of the 75 pregnancies compared with 39 percent in the same cohort before eculizumab therapy; first trimester miscarriages were reported in 8 percent, and there were three stillbirths. Delivery before 37 weeks of gestation was reported in 29 percent; common reasons included pre-eclampsia, growth retardation, or planned cesarian delivery. There was no evidence of teratogenicity in this small cohort. Eculizumab was detected in 7 of 20 cord blood samples and in 0 of 10 of breast milk samples tested.
Treatment with a C5i during pregnancy is associated with improved maternal outcomes and no evidence of increased fetal risks [37-40] compared with outcomes prior to the availability of complement inhibitor therapy [38,41-43]. Prior to the availability of complement inhibitors, studies reported 8 to 20 percent maternal mortality, up to 45 percent spontaneous miscarriage, and premature delivery in more than one-half of females [38,41-43].
●TE risk reduction – Pregnancy increases the already-high TE risk in PNH. Treatment must be individualized, as there are few data to guide management:
•All pregnant patients – For all pregnant females with PNH, we treat with low molecular weight heparin (eg, 40 mg subcutaneously once or twice daily) during the last trimester and continue treatment for 8 to 12 weeks postpartum.
•Pregnancy while taking a C5i – For females who become pregnant while taking a complement inhibitor, we continue that treatment. For females who are newly diagnosed with symptomatic hemolytic PNH during pregnancy, we initiate treatment with a complement inhibitor.
Further details of management of thrombosis in pregnancy are provided separately. (See "Anticoagulation during pregnancy and postpartum: Agent selection and dosing".)
Oral contraceptives — Oral contraceptives increase TE risk in females with PNH. Nonhormonal forms of contraception are preferred for sexually active females with PNH, although there is little information to guide the choice.
As with all females, the potential benefits of oral contraceptives in preventing pregnancy must be weighed against the risks, including the risk of unplanned pregnancy, and compared with other contraceptive options. Females with well-controlled PNH (eg, LDH <1.5 x ULN) are probably at no higher risk of thrombosis than age-matched controls.
Options for nonhormonal contraception and lower-risk hormonal methods are discussed separately. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use".)
Children — PNH is rare in children, and there is little published evidence to guide therapy. We manage children similarly to adults, using complement inhibitor therapy for hemolysis-related symptoms or thrombosis, watchful waiting for asymptomatic patients, and allogeneic hematopoietic cell transplantation for PNH with coexistent severe aplastic anemia.
Treatment with ravulizumab for patients <40 kg is described in the US Food and Drug Administration (FDA) label [44]. We administer the same dose of eculizumab to children as to adults based on complete resolution of hemolysis in all seven children (11 to 17 years) in a 12-week pilot study [45].
COMPLEMENT INHIBITORS
Adverse effects — Treatment with any complement inhibitor can cause life-threatening infections with Neisseria meningitidis and other encapsulated organisms. Treatment with any complement inhibitor is contraindicated in patients with active meningococcal or other severe infections. Other toxicity of these agents is relatively modest. Vaccination against streptococcal pneumonia and Haemophilus influenza B is recommended for patients who receive alternative pathway inhibitors.
●Meningitis – Complement inhibitors increase the risk of infections or sepsis with N. meningitidis, which can rapidly become life-threatening or fatal. These agents are contraindicated in patients with unresolved neisserial infections, unless the risks of delaying treatment outweigh the risks of developing a meningococcal infection.
We administer meningococcal vaccine plus antibiotic prophylaxis because invasive meningococcal disease (including nontypeable strains that are not included in the vaccine) has occurred despite vaccination [34,46]. Even after vaccination, the risk of Neisseria infection is as high as 0.5 percent per year; this risk is 1000-fold greater than the general population [47,48]. (See "Treatment and prevention of meningococcal infection", section on 'Patients receiving C5 inhibitors'.)
●Neisseria vaccination – We administer meningococcal vaccine (both ACYW135 and serogroup B) immediately after the first dose of the complement inhibitor because of reports of thrombosis precipitated by vaccine-induced complement amplification [34,49]. Some experts instead favor vaccination two weeks before the first dose of a C5 inhibitor.
•Antibiotic prophylaxis – Antimicrobial prophylaxis for prevention of meningococcal infection in patients receiving complement inhibitors is discussed separately. (See "Treatment and prevention of meningococcal infection", section on 'Patients receiving C5 inhibitors'.)
•Treatment of meningococcal infection – Patients should seek immediate medical attention if they develop fever, nausea, vomiting, headache, myalgias, or other symptoms suggestive of meningitis, regardless of vaccination status [34]. (See "Clinical manifestations of meningococcal infection" and "Meningococcal vaccination in children and adults", section on 'Immunization of persons at increased risk'.)
No meningococcal infections were reported among >200 patients in clinical trials of ravulizumab and eculizumab [11,12]. Both ravulizumab and eculizumab have boxed warnings about an increased risk for meningococcal infections. Patients who will be treated with a C5 complement inhibitor (C5i) should receive both meningococcal vaccinations plus antibiotic therapy, as discussed below.
●Other adverse effects – Treatment with ravulizumab and eculizumab can cause generally mild noninfectious adverse effects (AEs), are expensive, and may be associated with extravascular hemolysis and breakthrough symptoms.
•Other toxicity – AEs reported in ≥10 percent of patients in clinical trials included headache, nasopharyngitis, back pain, and nausea [9,50]. Headache initially occurs in up to one-half of patients, possibly due to increased nitric oxide levels, but it rarely persists after the first several doses [31].
•Extravascular hemolysis with C5 inhibitors – Despite effective control of intravascular hemolysis by C5i agents, up to one-fifth of patients require periodic red blood cell (RBC) transfusions due to an increase in extravascular hemolysis [18-20]. C5i drugs do not prevent deposition on PNH red cells of C3 fragments, which foster extravascular hemolysis by serving as opsonins. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria", section on 'Extravascular hemolysis from reduced CD55'.)
Management of extravascular hemolysis is discussed below. (See 'Management of breakthrough hemolysis' above.)
•Cost – Cost is a major barrier to the use of complement inhibitors, which has been estimated to be approximately $500,000 United States dollars (€370,000) per year. Continuous treatment is generally required to maintain suppression of intravascular hemolysis and prevent thrombosis.
C5 inhibitors — The C5 inhibitors (C5is) inhibit complement activity by preventing C5 convertase from cleaving C5 into C5a and C5b. Ravulizumab, eculizumab, and crovalimab have similar efficacy and toxicity profiles.
Ravulizumab requires less frequent administration than the other C5is because its half-life is longer. Ravulizumab and eculizumab are given by periodic intravenous infusions, whereas crovalimab can be administered by subcutaneous injection (after an initial loading dose). (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria".)
AEs associated with C5i treatment are discussed above. (See 'Adverse effects' above.)
Ravulizumab — Ravulizumab is the preferred complement inhibitor based on its more convenient treatment schedule and similar efficacy and toxicity profile as other C5is. (See 'Initial therapy' above.)
●Administration – Ravulizumab dosing is weight-based, as follows:
•Loading dose administered on days 1 and 15:
-≥40 to <60 kg – 2400 mg intravenously (IV)
-≥60 to <100 kg – 2700 mg IV
-≥100 kg – 3000 mg IV
•Maintenance dosing is administered every eight weeks and continued indefinitely:
-≥40 to <60 kg – 3000 mg IV
-≥60 to <100 kg – 3300 mg IV
-≥100 kg – 3600 mg IV
Ravulizumab is continued indefinitely in responding patients; no discontinuation studies of ravulizumab have been reported.
Treatment with ravulizumab for patients <40 kg is described in the US Food and Drug Administration (FDA) label [44]. Ravulizumab was approved for children by the FDA based on interim results from a phase 3 study that showed it was effective in achieving complete complement inhibition through 26 weeks in children and adolescents ≤18 years. Ravulizumab was not associated with any treatment-related severe AEs, and no patients discontinued therapy during the primary evaluation period nor experienced breakthrough hemolysis.
●Toxicity – Ravulizumab is associated with an increased risk for N. meningitidis infection and other AEs. Prevention and management of AEs are described above. (See 'Adverse effects' above.)
●Monitoring – Monitoring the response to a C5i is described below. (See 'Response to complement inhibition' above.)
●Treatment breakthrough – For patients who experience a recurrence of hemolysis and related symptoms while receiving ravulizumab, management is discussed below. (See 'Management of breakthrough hemolysis' above.)
●Outcomes – Phase 3 trials that directly compared ravulizumab versus eculizumab are discussed above. (See 'Treatment breakthrough' above.)
Eculizumab — Eculizumab is administered as a fixed dose (ie, treatment is not based on weight or body surface area).
●Administration – The standard schedule for eculizumab in adults is 600 mg IV once per week for the first four weeks, followed by 900 mg IV one week later, followed by 900 mg IV once every two weeks thereafter. Eculizumab is generally continued indefinitely in responding patients.
●Toxicity – Eculizumab is associated with an increased risk for N. meningitidis infection and other AEs; prevention and management of AEs are described below. (See 'Adverse effects' above.)
●Monitoring – Monitoring the response to a C5i is described below. (See 'Response to complement inhibition' above.)
●Treatment breakthrough – For patients who experience a recurrence of hemolysis and related symptoms while receiving eculizumab, management is discussed above. (See 'Management of breakthrough hemolysis' above.)
●Outcomes – A phase 3 trial that directly compared eculizumab versus placebo (TRIUMPH) [9,10] and studies of eculizumab versus ravulizumab [11,12] are discussed above. (See 'Initial therapy' above.)
Other informative studies of eculizumab in PNH include:
•In the SHEPHERD study, treatment of 97 patients with eculizumab for one year was associated with reduced RBC transfusion requirements (from 8 units/person/year to 0 units/person/year), improved hemoglobin (from 9.3 to 10.2 g/dL), less hemolysis, and improved quality of life [50]. Two thromboses occurred (but only in patients with prior thrombotic events) and grade ≥3 headache, abdominal distention, and viral infection that were potentially related to therapy were reported in seven patients.
•An open-label extension study of 187 patients enrolled in TRIUMPH, SHEPHERD, and an earlier pilot study reported 98 percent three-year survival and reduced transfusion requirements; the four deaths were unrelated to therapy [51]. Fewer patients experienced thromboembolic (TE) events while receiving eculizumab (4 percent) compared with their prior management (32 percent), and renal function improved or stabilized in 93 percent; there was no evidence of cumulative toxicity. Therapy was discontinued in 10 percent (one-half due to an adverse event). Overall survival in patients treated with eculizumab was comparable to age- and sex-matched controls from the general population [51,52]. Other studies also reported that eculizumab is effective for preventing TE events in patients with PNH [36,51,53].
•A study of 345 Japanese patients with PNH reported that 3.2 percent did not improve with eculizumab; these patients were heterozygous for a single missense mutation in the gene that encodes C5, which prevents eculizumab binding and is present in 3.5 percent of the general Japanese population [54]. A polymorphism in the complement receptor 1 (CR1) gene, which regulates the binding of C3 to RBCs, has also been associated with the reduced efficacy of eculizumab [55].
Crovalimab — Crovalimab is a subcutaneously administered C5i.
●Administration – Crovalimab is given as an intravenous loading dose on day 1, followed by four weekly subcutaneous loading doses; subcutaneous maintenance dosing is then given every four weeks.
Crovalimab is administered according to actual body weight.
•≥40 kg to <100 kg
-Day 1: 1000 mg intravenous loading dose
-Days 2, 8, 15, 22: 340 mg subcutaneous loading doses
-Day 29 and every 4 weeks thereafter: 680 mg maintenance subcutaneous injections
•≥100 kg
-Day 1: 1500 mg intravenous loading dose
-Days 2, 8, 15, 22: 340 mg subcutaneous loading doses
-Day 29 and every 4 weeks thereafter: 1020 mg maintenance subcutaneous injections
Crovalimab is approved by the FDA for administration by a health care provider for the treatment of PNH in patients ≥13 years and body weight ≥40 kg. Crovalimab is approved by the European Medicines Agency (EMA) in patients ≥12 years with body weight ≥40 kg. In the United Kingdom, crovalimab can be self-administered after proper training.
●Toxicity – Crovalimab is associated with an increased risk for N. meningitidis infection and other AEs; prevention and management of AEs are described above. (See 'Adverse effects' above.)
●Monitoring – Monitoring the response to a C5i is described above. (See 'Response to complement inhibition' above.)
●Treatment breakthrough – For patients who experience a recurrence of hemolysis and related symptoms while receiving crovalimab, management is discussed above. (See 'Management of breakthrough hemolysis' above.)
●Outcomes – Crovalimab achieved comparable efficacy and had similar toxicity compared with eculizumab in a phase 3 trial in 204 patients with symptomatic, C51-naïve hemolytic PNH [56]. Patients were randomly assigned (2:1) to 24 weeks of every four weeks treatment using subcutaneous crovalimab versus eculizumab infusion. There was no difference in rates of transfusion avoidance, control of hemolysis, breakthrough hemolysis, or hemoglobin stabilization. Both agents were associated with a clinically meaningful improvement in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, and the safety profiles were similar, with no meningococcal infections with either agent.
Pozelimab — Pozelimab is a C5i that is administered parenterally.
●Administration – Pozelimab 30 mg/kg is given as an intravenous loading dose on day 1, followed by four weekly 10 mg/kg subcutaneous loading doses (beginning on day 8); 10 mg/kg subcutaneous maintenance dosing is then given every four weeks.
The maximum maintenance dose is 800 mg once weekly; doses >400 mg require two injections.
The maintenance dose can be increased to 12 mg/kg once weekly if there is inadequate clinical response after ≥3 weekly doses (ie, increased dosing can begin on week 4).
Pozelimab is approved by the US FDA for treatment of CD55-deficient protein-losing enteropathy (PLE; also called CHAPLE disease).
●Toxicity – Pozelimab is associated with an increased risk for N. meningitidis infection and other AEs; prevention and management of AEs are described above. (See 'Adverse effects' above.)
Pozelimab has been associated with alopecia.
●Outcomes – Preliminary results, published in abstract form, reported that treatment with pozelimab was associated with transfusion avoidance and control of intravascular hemolysis in 22 of 23 patients for 26 weeks and transfusion avoidance in 15 of 16 patients through week 78; there was no breakthrough hemolysis [57]. Treatment was generally well tolerated, including 8 percent treatment-related AEs; there were no deaths or discontinuations of pozelimab due to treatment.
Alternative pathway complement inhibitors — Alternative pathway complement inhibitors (pegcetacoplan, iptacopan, danicopan) inhibit the alternative complement pathway.
Alternative pathway inhibitors act upstream of the classic complement pathway, so factors that trigger the classic complement pathway (eg, infections, surgery, trauma) can produce massive intravascular hemolysis. Even brief treatment interruptions (eg, from gastroenteritis) or limited treatment adherence can provoke severe hemolysis. No randomized clinical trials have directly compared alternative pathway complement inhibitors versus placebo or versus a C5i for frontline management of symptomatic hemolytic PNH. (See 'Initial therapy' above.)
Pegcetacoplan — Pegcetacoplan is a pegylated peptide that targets the proximal complement protein, C3, and can inhibit both intravascular and extravascular hemolysis. By contrast, ravulizumab and eculizumab target C5, which affects only intravascular hemolysis, and treatment with a C5i is associated with breakthrough extravascular hemolysis in a subset of patients. (See 'Initial therapy' above.)
The use of pegcetacoplan for initial therapy of hemolytic PNH is discussed above. (See 'Initial therapy' above.)
The use of pegcetacoplan for symptomatic extravascular hemolysis with a C5i is discussed above. (See 'Management of breakthrough hemolysis' above.)
●Administration – Pegcetacoplan 1080 mg is administered subcutaneously twice weekly. It requires refrigerated storage.
Pegcetacoplan should not be administered to pregnant patients.
Pegcetacoplan is not a good choice for patients who have a history of medication nonadherence because of its short half-life.
There are two methods of administration [58]:
•Subcutaneous infusion using a commercially available pump.
•Single-use, disposable on-body injector – The on-body injector is for abdominal subcutaneous injection only. Tender, bruised, red, or hard skin should be avoided, as should tattoos, scars, and stretch marks. The site of each administration should be rotated. The patient and/or caregiver should be trained to prepare and administer the on-body injector prior to use.
Pegcetacoplan is approved for treatment of PNH in adults by the FDA and for adults who remain anemic after at least three months of stable C5i therapy by the EMA.
●Toxicity – Pegcetacoplan is associated with an increased risk for N. meningitidis infection and other AEs. Prevention and management of AEs are described above. All patients should be vaccinated against Streptococcus pneumoniae and Haemophilus influenza B. (See 'Adverse effects' above.)
●Outcomes – A phase 3 trial (PEGASUS) of iptacopan versus continued C5i therapy for breakthrough extravascular hemolysis [22] is discussed above. (See 'Management of breakthrough hemolysis' above.)
There are no randomized trials of pegcetacoplan versus placebo or trials that compared pegcetacoplan versus a C5i (ie, eculizumab or ravulizumab) for initial treatment of hemolytic PNH.
Iptacopan — Iptacopan is a first-in-class oral factor B (FB) inhibitor that can reduce extravascular hemolysis while maintaining control of intravascular hemolysis in patients treated with a C5i.
Use of iptacopan for initial therapy of hemolytic PNH is discussed above. (See 'Initial therapy' above.)
Use of iptacopan for symptomatic extravascular hemolysis with a C5i is discussed above. (See 'Management of breakthrough hemolysis' above.)
●Administration – Iptacopan 200 mg is taken orally twice daily without regard to food.
Iptacopan is not a good choice for patients who have a history of medication nonadherence because of its short half-life (approximately 20 hours [59]). Missed doses, especially in the setting of complement-amplifying conditions (eg, infections) or excessive consumption of alcohol, could lead to massive hemolysis and risk for thrombosis.
If a dose of iptacopan is missed, one dose should be taken as soon as possible (even if it is soon before the next scheduled dose), and then the regular dosing schedule should be resumed.
Iptacopan is approved by the FDA for treatment of adults with PNH and received orphan drug designation from the EMA.
●Toxicity – Iptacopan is associated with an increased risk for N. meningitidis infection and other AEs. Prevention and management of AEs are described above. All patients should be vaccinated against Streptococcus pneumoniae and Haemophilus influenza B. (See 'Adverse effects' above.)
Diarrhea and lipid abnormalities may occur with iptacopan.
●Outcomes – A phase 3 trial (APPLY-PNH) of iptacopan versus continued C5i therapy for breakthrough extravascular hemolysis [13] is discussed above. (See 'Management of breakthrough hemolysis' above.)
There are no randomized trials of iptacopan versus a C5i (ie, eculizumab or ravulizumab) for initial treatment of hemolytic PNH.
Danicopan — Danicopan is an oral inhibitor of complement factor D (FD; a component of the alternative complement pathway) that can control signs and symptoms of extravascular hemolysis as an add-on treatment in patients receiving a C5i [60,61]. Danicopan is not approved for PNH as monotherapy.
The use of danicopan as an add-on to a C5i for symptomatic extravascular hemolysis is discussed above. (See 'Management of breakthrough hemolysis' above.)
●Administration – Danicopan 150 mg is taken three times daily by mouth.
Danicopan is not a good choice for patients who have a history of medication nonadherence because of its short half-life.
Danicopan is approved by the FDA as add-on therapy to a C5i for treatment of extravascular hemolysis in adults with PNH. It was granted priority medicine status by the EMA.
●Toxicity – Danicopan is associated with an increased risk for N. meningitidis infection and other AEs. Prevention and management of AEs are described below. All patients should be vaccinated against Streptococcus pneumoniae and Haemophilus influenza B. (See 'Adverse effects' above.)
●Outcomes – Preliminary results of a phase 3 trial (published in abstract form) indicate that, for patients with clinically significant extravascular hemolysis while receiving ravulizumab or eculizumab, the addition of danicopan was superior to the addition of placebo for reducing transfusions and elevating hemoglobin, with little toxicity and continued control of intravascular hemolysis [62].
SUPPORTIVE CARE —
Supportive care refers to management of PNH-associated symptoms without complement inhibitor therapy or transplantation.
●Pain control – Chronic pain is a common symptom with PNH and may persist despite treatment with a complement inhibitor. (See "Approach to the management of chronic non-cancer pain in adults".)
●Anemia – Anemia in PNH is predominantly caused by hemolysis of red blood cells (RBCs), but bone marrow failure, folate or vitamin B12 deficiency, chronic iron loss in urine, and other causes may also contribute. Patients who have an inappropriately low reticulocyte index should be tested for deficiencies of iron, folate, and vitamin B12 and receive supplementation, as appropriate. If there is an inadequate response to supplementation, the patient should undergo a bone marrow examination to evaluate for aplastic anemia or myelodysplastic syndromes/neoplasms [63].
•Transfusions – Patients with severe anemia (eg, hemoglobin level <7 g/dL or symptoms such as dyspnea and extreme fatigue without another etiology) should receive transfusions with RBCs, as needed. No special modifications (eg, washed RBCs) are needed for patients with PNH. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion".)
•Folate supplementation – All patients with PNH and ongoing hemolysis should be treated with supplemental folic acid 1 to 2 mg daily because of increased demands created by accelerated erythropoiesis.
•Routine iron supplementation is not needed – Supplemental iron should be administered only to patients who are documented to be iron deficient. Supplementation in patients who are iron-replete can contribute to iron overload because they may also have received substantial amounts of iron from transfusions. (See "Treatment of iron deficiency anemia in adults".)
•Growth factors – Evidence is lacking to support a role for erythropoietin, glucocorticoids, or androgenic hormones. Glucocorticoids may improve hemoglobin levels and reduce hemolysis in some patients, but the substantial long-term adverse effects outweigh their efficacy.
HEMATOPOIETIC CELL TRANSPLANTATION —
Allogeneic hematopoietic cell transplantation (HCT) is used to treat PNH with significant bone marrow failure due to severe aplastic anemia or higher-risk myelodysplastic syndromes/neoplasms. (See 'PNH with severe bone marrow failure' above.)
Candidates for allogeneic HCT must have no severe lung, heart, liver, or kidney disease; a suitable graft source; and adequate social support. Although age limits vary, many institutions restrict allogeneic HCT to patients ≤70 years of age. Details of eligibility for allogeneic HCT are presented separately. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)
Preferred conditioning regimens and graft sources for PNH-associated transplantation vary between institutions and have not been directly compared in randomized trials.
●Conditioning regimen – Myeloablative conditioning (MAC) is not required to eradicate the PNH clone [31]. Reduced-intensity conditioning (RIC)/nonmyeloablative (NMA) conditioning may yield comparable rates of engraftment as MAC, while reducing transplant-related morbidity and mortality.
●Donor source – Human leukocyte antigen-matched siblings are preferred when available, but matched unrelated donors are used successfully for PNH. Results with haploidentical donors are also encouraging [32]. Additional discussion of donor choice is presented separately. (See "Donor selection for hematopoietic cell transplantation".)
●Graft source – We favor bone marrow over peripheral blood stem cells, when possible, because of a lower incidence of graft-versus-host disease (GVHD). A cohort study of 211 patients reported that the incidence of GVHD was lower with bone marrow-derived stem cells compared with peripheral blood stem cells [33]. Additional discussion of the choice of graft source is presented separately. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells", section on 'Allogeneic HCT for nonmalignant disorders'.)
Outcomes with transplantation for patients with PNH come from observational studies and case reports. No randomized trials have directly compared allogeneic HCT versus complement inhibitors or observation for PNH, and no trials have directly compared various conditioning regimens or graft sources. Long-term overall survival after allogeneic HCT for PNH has been reported from 50 to 70 percent with MAC, while RIC/NMA conditioning may be associated with rates that approach 90 percent [26-30].
PROGNOSIS —
PNH is a chronic disease with significant morbidity and mortality. Since the availability of complement inhibitors, mortality appears to be similar to age-matched controls, but the impact will be better-defined with longer follow-up.
●A series of 79 consecutive patients treated with eculizumab over an eight-year period reported that overall survival (OS) was similar to age-matched controls [52].
●A series of 220 patients from the precomplement inhibitor era (1996) reported 14.6-year median OS, with estimates of 78, 65, and 48 percent at 5, 10, and 15 years after diagnosis, respectively [64]. Eight-year rates of pancytopenia, thrombosis, and myelodysplastic syndrome were 15, 28, and 5 percent, respectively. Adverse prognostic factors included thrombosis, evolution to pancytopenia, myelodysplastic syndrome, or acute leukemia, and age >55 years at disease onset.
●Another series from the precomplement inhibitor era (2004) reported that outcomes differed between American and Japanese patients [65]. The mean OS for the Japanese patients was 32 years compared with 19 years for the American population, although the Kaplan-Meier survival curves were not different for the two groups. Japanese patients were more likely to have aplastic anemia, while American patients were more likely to have thrombosis (38 versus 6 percent). Adverse prognostic factors included age >50 years, severe cytopenias at diagnosis, severe infection, thrombosis, and renal failure.
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation in pregnancy" and "Society guideline links: Bone marrow failure syndromes".)
SUMMARY AND RECOMMENDATIONS
●Description – Paroxysmal nocturnal hemoglobinuria (PNH) is a rare complement-mediated hemolytic anemia that may be associated with thrombosis, pain, and/or organ dysfunction due to loss of complement inhibitor proteins on hematopoietic cells. Some cases are associated with bone marrow failure (BMF).
●Baseline evaluation – Includes flow cytometry to estimate PNH clone size and bone marrow examination to evaluate for aplastic anemia (AA) or myelodysplastic syndromes/neoplasms (MDS). (See 'Baseline evaluation' above.)
●PNH categories – PNG categories are defined by the nature/severity of symptoms, hemolysis, thrombosis, and BMF, as discussed above. (See 'PNH categories' above.)
●Subclinical PNH – For patients with no substantial PNH-associated symptoms or BMF, we suggest watchful waiting rather than treatment with a complement inhibitor (algorithm 1) (Grade 2C). (See 'Subclinical PNH' above.)
●Symptomatic PNH without BMF
•Initial therapy – For initial treatment of PNH with symptomatic hemolysis or acute thrombosis but no severe BMF, we suggest ravulizumab rather than other C5 inhibitors (C5is) or alternative pathway complement inhibitors (iptacopan or pegcetacoplan). We suggest ravulizumab for patients presenting with thrombosis (algorithm 1) (Grade 2C). (See 'Initial therapy' above.)
Other C5is (eg, eculizumab, crovalimab) are acceptable options, while alternative pathway complement inhibitors are acceptable for selected patients.
•Breakthrough hemolysis – For patients with symptomatic extravascular hemolysis (EVH) while receiving a C5i, we suggest adding danicopan to the C5i rather than continued treatment with the C5i or switching to monotherapy with iptacopan or pegcetacoplan (Grade 2C). (See 'Management of breakthrough hemolysis' above.)
●PNH with severe BMF – PNH may be associated with BMF due to AA or MDS.
•Criteria – Criteria for severe BMF are presented above. (See 'Criteria for severe bone marrow failure' above.)
•Management – Management is guided by medical fitness. (See 'PNH with severe bone marrow failure' above.)
-Transplant eligible – For transplant-eligible patients with severe BMF, we suggest allogeneic HCT rather than supportive care and/or a complement inhibitor (algorithm 1) (Grade 2C). (See 'PNH with severe bone marrow failure' above.)
-Not transplant eligible – We manage as symptomatic PNH (algorithm 1). (See 'Not transplant eligible' above.)
●Special settings
•Thromboembolism
-Acute thromboembolic events – Anticoagulation and/or thrombolysis is guided by the site of thromboembolism and severity of clinical findings, as described above. (See 'Acute thrombosis' above.)
-Thromboprophylaxis – Prophylaxis for patients who are hospitalized, pregnant, or have other thrombophilic conditions is described. (See 'Thromboprophylaxis' above.)
•Surgery – Perioperative management of PNH is discussed above. (See 'Surgery' above.)
•Pregnancy (see 'Pregnancy' above)
-Treatment – For pregnant patients who meet criteria for complement inhibitor therapy, we suggest initiation or continued treatment with a C5i (Grade 2C).
Complement inhibitors other than C5is are not proven safe in pregnant patients.
-Thrombosis prophylaxis – For pregnant patients with PNH, we suggest anticoagulation using low molecular weight heparin during the last trimester and continuing treatment for 8 to 12 weeks postpartum (Grade 2C). (See 'Pregnancy' above.)
ACKNOWLEDGMENTS
The UpToDate editorial staff acknowledges the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.
The UpToDate editorial staff also acknowledges Wendell F Rosse, MD, who contributed to earlier versions of this topic review.
