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 (RBC) leads to chronic and/or paroxysmal intravascular hemolysis and a propensity for thrombosis. Patients may also have hypocellular or dysplastic bone marrow, and a subset have clinically significant aplastic anemia or myelodysplastic syndrome [1]. Therapy for PNH is evolving rapidly, spurred by the availability of biologic therapies that target the underlying complement-mediated hemolysis.
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".)
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately.
●(See "COVID-19: Considerations in patients with cancer".)
BASELINE EVALUATION
Clinical and laboratory studies — The diagnostic evaluation for PNH, including clinical and laboratory studies, flow cytometry to document hematopoietic clonality, and evaluation for associated aplastic anemia (AA) or myelodysplastic syndrome (MDS) is described separately. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Diagnosis and classification'.)
The following should be performed prior to initiating treatment for PNH:
●Clinical – The history and physical examination should elicit the nature and severity of findings related to hemolytic anemia (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 also be evaluated for findings of venous thrombosis, including atypical sites such as mesenteric or hepatic veins (eg, abdominal pain, increasing abdominal girth, ascites, esophageal or gastric varices, hepatosplenomegaly) or cerebral vein thrombosis (intractable headache, abnormal neurologic findings).
Comorbid conditions and performance status should be assessed (table 1).
●Laboratory studies:
•Complete blood count (CBC) with differential
•Reticulocyte count
•D-dimer
•Serum electrolytes, glucose, kidney function tests, and liver function tests, including lactate dehydrogenase (LDH), fractionated bilirubin, haptoglobin
•Iron studies – serum iron, total iron binding capacity, and ferritin
Previous laboratory results should be reviewed, as they may reflect prior levels and duration of hemolysis, size of the PNH clone, and the trajectory of the condition.
●Flow cytometry – The size (ie, percentage) of the PNH population is measured by flow cytometry of both granulocytes and red blood cells (RBC). The size of the PNH population will be underestimated if only RBCs are analyzed, due to dilution from recent RBC transfusions coupled with selective destruction of PNH RBCs by complement. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Flow cytometry/FLAER'.)
●Bone marrow aspirate and biopsy define cellularity, dysplasia, and other abnormalities associated with AA and/or MDS. Bone marrow examination should include microscopy, karyotype, fluorescence in situ hybridization (FISH) for MDS, quantitative CD34 cell count, and iron staining. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Bone marrow examination' and "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Bone marrow examination'.)
●Imaging
•Symptomatic for thrombosis – Diagnostic evaluation for individuals with findings suggestive of thrombosis, including suspected thrombosis of mesenteric, hepatic, and cerebral veins, is described separately. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity" and "Acute portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management" and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".)
•Asymptomatic – For asymptomatic patients, we do not perform imaging for venous thromboembolic disease, as there is no evidence to support a benefit of routine imaging for deep vein thrombosis in the absence of a clinical suspicion.
Evaluation for transplantation — For patients who have PNH with co-existing severe bone marrow failure (ie, significant leukopenia, thrombocytopenia, and/or dysplasia due to severe AA or MDS), we suggest referral to evaluate eligibility for allogeneic hematopoietic cell transplantation (HCT). (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)
PNH CLASSIFICATION — PNH is categorized based on the presence of symptoms (eg, anemia-related symptoms, thrombosis, pain, organ dysfunction) and findings from bone marrow examination. PNH is a dynamic condition and the category of PNH may evolve; as examples, patients who were originally classified as having subclinical PNH or PNH with bone marrow failure (BMF) may later evolve to hemolytic PNH.
Surrogate markers, such as level of serum lactate dehydrogenase (LDH) or leukocyte clone size differ between PNH categories, but they are not used for classification because they do not correlate precisely with the severity of symptoms and bone marrow findings.
Details of the clinical manifestations, diagnosis, and classification of PNH are presented separately. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Diagnostic criteria'.)
●Hemolytic (classical) PNH:
•Prominent symptoms related to hemolysis (eg, fatigue, dyspnea, transfusion-dependence, episodic hemoglobinuria, thrombosis, pain, and/or organ dysfunction)
•LDH typically >1.5x 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 hemolytic PNH' below.)
●Subclinical PNH:
•No substantial hemolysis-related symptoms, thrombosis, pain, organ dysfunction, and no need for transfusions
•LDH typically ≤1.5x 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.)
●PNH with bone marrow failure:
•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 meet criteria for severe aplastic anemia (sAA) or high-risk myelodysplastic syndromes (MDS)
Management of PNH with bone marrow failure is discussed below. (See 'PNH with bone marrow failure' below.)
MANAGEMENT — Management is guided by the PNH category which, in turn, is informed by the severity of hemolysis-associated symptoms and degree of bone marrow failure. Details of the diagnosis and classification of PNH are presented separately. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Diagnostic criteria'.)
Our approach to management of PNH (algorithm 1) is consistent with recommendations of expert panels from the American Society of Hematology [2], Belgium [3], and Canada [4].
Symptomatic hemolytic PNH — For patients with symptomatic hemolytic PNH (including those with thrombosis, organ dysfunction, or pain) who do not have severe bone marrow failure (BMF), we recommend treatment with a complement inhibitor, rather than supportive care alone (algorithm 1). Compared with supportive care alone, complement inhibitors offer a more favorable profile of toxicity and efficacy for hemolytic PNH.
C5 complement inhibitors (eg, ravulizumab, eculizumab) are generally well-tolerated and effectively control PNH-associated hemolysis, prevent thrombosis, and control pain, but treatment is continued indefinitely, is expensive, and these agents do not ameliorate PNH-associated bone marrow failure. Supportive care alone can alleviate pain and anemia-related symptoms, but it may be associated with transfusion-associated iron overload, alloimmunization, and thrombotic events; thromboses occur in up to 40 percent of patients given supportive care, it is difficult to predict who will be affected, and thromboses may recur or progress despite anti-thrombotic therapy [5-9].
The phase 3 TRIUMPH trial of 87 patients with symptomatic PNH reported that, compared with placebo, eculizumab was more effective for achieving transfusion-independence (49 versus 0 percent, respectively) and led to clinically meaningful improved QoL (using two different assessment instruments) [10,11]. There was no difference in overall survival (OS) between treatment groups during the 26-week trial and no deaths or serious adverse events were related to eculizumab; one thrombosis was reported in the placebo group.
Administration, adverse effects, monitoring, and outcomes with complement inhibitor therapy are described below. (See 'Complement inhibition' below.)
Management of symptomatic hemolytic PNH in the setting of severe bone marrow failure is discussed below. (See 'PNH with bone marrow failure' below.)
Subclinical PNH — For patients who have no substantial hemolysis-associated symptoms, thrombosis, pain, organ dysfunction, or BMF, we manage with watchful waiting. There is no need for supportive care in the asymptomatic patient with subclinical PNH and watchful waiting avoids the inconvenience, expense, and possible adverse effects of a complement inhibitor and the substantial toxicity and possible TRM of allogeneic HCT (algorithm 1).
Patients with subclinical PNH should be monitored regularly for worsening of hemolysis-associated findings and for progression of cytopenias that may herald worsening BMF, as discussed below. (See 'Monitoring of clone size' below.)
PNH with bone marrow failure — PNH is often accompanied by some degree of BMF; this is generally AA, but rarely it may reveal MDS. When BMF is severe, we categorize the disorder as PNH with BMF. Classification of the severity of AA and the prognostic category of MDS (table 2) (calculator 1) are detailed separately. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnostic criteria' and "Overview of the treatment of myelodysplastic syndromes", section on 'Prognostic category'.)
For patients with PNH who have severe BMF, management is guided by the severity of the associated AA or MDS (algorithm 1):
●Severe AA – Patients who meet criteria for severe AA (sAA) should undergo allogeneic HCT if they have a suitable donor and are medically-eligible. Patients who are not transplant candidates should be treated with immunosuppressive therapy (eg, anti-thymocyte globulin plus cyclosporine), as discussed separately. (See "Treatment of aplastic anemia in adults", section on 'Severe AA/very severe AA'.)
Patients with PNH-associated AA that does not meet criteria for sAA should be managed according to the presence and severity of hemolysis-associated symptoms, as described above. (See 'Symptomatic hemolytic PNH' above and 'Subclinical PNH' above.)
●Higher-risk MDS – Patients with higher-risk MDS should be evaluated as candidates for allogeneic HCT or other MDS-directed treatment, as guided by the pathologic, cytogenetic, and molecular findings of the MDS; medical fitness; and individual preference. (See "Overview of the treatment of myelodysplastic syndromes".)
Patients with PNH associated with lower-risk MDS and those who are not candidates for transplantation should be managed according to the presence and severity of hemolysis-associated symptoms, as described above. (See 'Symptomatic hemolytic PNH' above and 'Subclinical PNH' above.)
COMPLEMENT INHIBITION — C5 complement inhibitors (eg, ravulizumab, eculizumab) are generally well-tolerated and effective for managing hemolytic PNH, including anemia-related symptoms, thrombosis, pain, and organ dysfunction. The primary goal of treatment with a complement inhibitor is alleviation of PNH-related symptoms (eg, fatigue, dyspnea), elimination of transfusion-dependence, prevention of thromboses, and relief of pain. Clinical responses are usually accompanied by a reduction in serum lactate dehydrogenase (LDH) to <1.5x upper limit of normal (ULN). While these agents virtually eliminate the risk of thrombosis, >50 percent of patients continue to have mild to moderate symptoms and up to 20 percent require occasional transfusions.
Importantly, complement inhibitors do not mitigate symptoms and complications of PNH-associated bone marrow failure (BMF), such as aplastic anemia (AA) or myelodysplastic syndrome (MDS); management of PNH in association with severe AA and higher-risk MDS is addressed below. (See 'Hematopoietic cell transplantation' below.)
Choice of agent — For patients in whom a C5 complement inhibitor is indicated, we suggest ravulizumab rather than eculizumab based on greater convenience, lower overall expense, and fewer episodes of pharmacokinetic breakthrough hemolysis, but otherwise comparable efficacy and toxicity [12].
The terminal half-life of ravulizumab is four times longer than that of eculizumab, which enables longer intervals between treatments (eg, eight weeks versus two weeks, respectively) and reduces annual cost. Both agents bind the same epitope on C5 and inhibit complement activity by preventing C5 convertase from cleaving C5 into C5a and C5b. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria".)
●Comparable efficacy – In an open-label study in 246 treatment-naïve patients with PNH, ravulizumab was non-inferior to eculizumab for achieving transfusion-independence and normalizing serum LDH [13]. Ravulizumab was also non-inferior to eculizumab among 195 clinically stable patients with PNH who were previously treated with eculizumab and were randomly assigned to continue eculizumab or switch to ravulizumab [14].
●Similar adverse effects – C5 complement inhibitors are contraindicated in patients with active meningococcal or other severe infections and both ravulizumab and eculizumab have boxed warnings about an increased risk for meningococcal infections. Patients who will be treated with a C5 complement inhibitor should receive both meningococcal vaccination plus antibiotic therapy, as discussed below. (See 'Meningitis and other adverse effects' below.)
The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have approved both ravulizumab and eculizumab for treatment of PNH; the US FDA also approved ravulizumab for treatment of PNH in children ≥1 month and adolescents. In the US, these agents are available only through a restricted program under a risk evaluation and mitigation strategy (REMS).
Ravulizumab — Ravulizumab is the preferred complement inhibitor based on its more convenient treatment schedule and similar efficacy and adverse effects, compared with eculizumab. (See 'Choice of agent' 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
Treatment with ravulizumab for patients <40 kg is described in Lexicomp. Ravulizumab was approved for children by the US FDA based on interim results from a phase 3 study that showed it was effective in achieving complete C5 complement inhibition through 26 weeks in children and adolescents up to 18 years of age. Treatment was not associated with any treatment-related severe adverse events, and no patients discontinued therapy during the primary evaluation period, nor did they have any breakthrough hemolysis.
Ravulizumab is generally continued indefinitely in responding patients. No discontinuation studies of ravulizumab have been reported.
●Toxicity – Ravulizumab is associated with an increased risk for Neisseria meningitidis infection and other adverse effects; prevention and management are described below. (See 'Meningitis and other adverse effects' below.)
●Monitoring – For the first four weeks of treatment, weekly monitoring should include complete blood count (CBC), LDH, reticulocyte count, and serum chemistries [12,15]. The schedule for monitoring should then be guided by the clinical and laboratory response. After hemolysis has stabilized, the monitoring interval can then be extended to every two months (to coincide with maintenance treatments). LDH typically normalizes within days to weeks, the reticulocyte count can remain elevated indefinitely (due to extravascular hemolysis), and the hemoglobin (Hb) response is highly variable. There is insufficient evidence to support routine monitoring of CH50 or other measures of complement activity.
●Outcomes – Treatment of 123 patients with ravulizumab for six months was associated with transfusion-independence in 74 percent, stabilization of Hb in 68 percent, LDH normalization in 54 percent, improved quality of life (QoL; 7 point improvement in Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue score), and only occasional episodes of breakthrough hemolysis (4 percent) [13]. Headache was reported in one-quarter of patients and no meningococcal infections occurred in >200 patients treated with ravulizumab in two trials [13,14].
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 adverse effects; prevention and management of adverse effects are described below. (See 'Meningitis and other adverse effects' below.)
●Monitoring – Monitoring the response to eculizumab is done weekly for the first four weeks (including CBC, LDH, reticulocyte count, and serum chemistries) and can be extended to every one to two months in responding patients. Other aspects of monitoring are discussed above. (See 'Ravulizumab' above.)
●Outcomes – Evidence for the efficacy of eculizumab in PNH comes from a randomized trial and several observational studies.
In the TRIUMPH trial, which randomly assigned 87 patients with severe PNH to eculizumab versus placebo for 26 weeks, eculizumab more effectively reduced transfusion-dependence and improved QoL; there were no deaths or serious adverse events related to eculizumab [10,11]. (See 'Symptomatic hemolytic PNH' above.)
In the SHEPHERD study, treatment of 97 patients with eculizumab for one year was associated with reduced transfusion requirements (from 8 to 0 red blood cell [RBC] units/patient annually), improved Hb (from 9.3 to 10.2 g/dL), less hemolysis, and improved QoL [16]. Two thromboses occurred (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 of the patients from TRIUMPH, SHEPHERD, and an earlier pilot study reported 98 percent three-year survival and reduced transfusion requirements; the four deaths were unrelated to therapy [17]. Fewer patients experienced thromboembolic 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 (half due to an adverse event). Overall survival (OS) in patients treated with eculizumab was comparable to age- and sex-matched controls from the general population [17,18].
Analysis of patients from earlier studies calculated that, per 100 patient years, eculizumab reduced thromboembolic events 7-fold and reduced thromboembolic events in anticoagulated patients 11-fold [19]. 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 [20]. A polymorphism in the complement receptor 1 (CR1) gene, which regulates the binding of C3 to RBCs, was also associated with reduced efficacy of eculizumab [21].
Treatment with eculizumab to control hemolysis-associated symptoms is safe, efficacious, and does not adversely affect outcomes for patients who later undergo allogeneic HCT for PNH with BMF [22]. (See 'Hematopoietic cell transplantation' below.)
Newer complement inhibitors
●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. Pegcetacoplan (1080 mg) is administered twice weekly by subcutaneous infusion using a commercially available pump.
Pegcetacoplan was superior to eculizumab for reducing transfusion-dependence and lessening fatigue in patients with PNH who had Hb <10.5 g/dL despite prior eculizumab therapy [23]. 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, patients who received pegcetacoplan had a nearly 4 g/dL increase in Hb, more transfusion-independence (85 versus 15 percent, respectively), and improvement in fatigue score (FACIT-Fatigue score) compared with eculizumab. The most common adverse events during treatment with pegcetacoplan and eculizumab groups 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).
Pegcetacoplan is approved by the US FDA.
●Danicopan – Danicopan is an oral inhibitor of factor D (FD; a component of the alternative complement pathway) that can control both intravascular and extravascular hemolysis [24,25].
A phase 2 study added danicopan (100 to 200 mg three times daily for 24 weeks) for 11 patients who remained transfusion-dependent while receiving eculizumab [26]. Danicopan was associated with increased hemoglobin (to 10.3 g/dL at week 24, compared with 7.9 g/dL at baseline), nearly eliminated transfusions (one unit transfused in one patient, compared with mean 4.4 units per patient over a 24 week run-in period), and improved quality of life (11 point mean rise in FACIT score). The most common adverse effects were generally mild and included headache, cough, and nasopharyngitis.
Danicopan is not currently approved by the US FDA or EMA.
●Iptacopan – Iptacopan is an oral factor B (FB) inhibitor with a terminal half-life of approximately 20 hours. Iptacopan (200 mg twice daily by mouth) was given to 10 patients with persistent intravascular hemolysis despite treatment with eculizumab [27]. The drug was well-tolerated and was associated with increased Hb and improved biomarkers of intravascular hemolysis; 7 of the treated 10 patients were able to discontinue eculizumab and maintain their response on iptacopan monotherapy for ≥13 weeks. Phase 3 trials with iptacopan are planned.
Iptacopan is not currently approved by the US FDA or the EMA.
●Other agents in development – Other approaches to blocking complement activation including monoclonal antibodies to other complement proteins, peptide inhibitors, small molecule inhibitors, and decoy receptors are also in various stages of preclinical development [28-31].
Meningitis and other adverse effects — Both ravulizumab and eculizumab increase the risk of infections or sepsis with N. meningitidis, which can rapidly become life-threatening or fatal if not recognized and treated early. Both agents are contraindicated in patients with unresolved neisserial infection, 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 non-typeable strains that are not included in the vaccine) has occurred despite vaccination [12,32]. 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 [33,34]. (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 [12,35]. Some experts instead favor vaccination two weeks prior to the first dose of a C5 inhibitor.
●Antibiotic prophylaxis – In addition to vaccination, we administer:
•Ciprofloxacin 500 mg twice daily for 14 days to all patients.
•For patients <40 years, we then continue antibiotic prophylaxis (eg, penicillin V 500 mg twice daily) for the duration of complement inhibitor therapy.
•For patients who require emergency treatment with a complement inhibitor (eg, for a severe hemolytic crisis or acute onset thrombosis), prophylactic antibiotics should be given for at least two to three weeks (until vaccine-associated immunity is expected).
●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 [12]. (See "Clinical manifestations of meningococcal infection" and "Meningococcal vaccination in children and adults", section on 'Immunization of persons at increased risk'.)
●Other adverse effects:
•Extravascular hemolysis with C5 inhibitors – Despite effective control of intravascular hemolysis by C5 complement inhibitors, up to one-fifth of patients require periodic RBC transfusions due to an increase in extravascular hemolysis [28,36,37]. C5 inhibitors 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'.)
•Other adverse effects – Adverse events reported in ≥10 percent of patients in clinical trials included headache, nasopharyngitis, back pain and nausea [10,16]. Headache initially occurs in up to half of patients (possibly due to increased nitric oxide levels), but it rarely persists after the first several doses [15].
•Cost – Cost is a major barrier to the use of complement inhibitors, which has been estimated to be approximately $400,000 US dollars (€370,000) per year. Continuous treatment is generally required to maintain suppression of intravascular hemolysis and prevent thrombosis.
If a C5 complement inhibitor is discontinued, the patient should be periodically monitored for ≥16 weeks to detect evidence of increased hemolysis, which may be manifest as worsening fatigue, dyspnea, hemoglobinuria, thrombosis, abdominal pain, decreasing Hb, increasing LDH, erectile dysfunction, or other vascular events.
Other aspects of care, including monitoring of the size of the PNH population, are discussed below. (See 'Other aspects of care and monitoring' below.)
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 ≥2x ULN after prior reduction to <1.5x ULN) while on complement inhibitor therapy.
Breakthrough may be caused by inadequate drug levels (pharmacokinetic breakthrough) or because of complement-amplifying conditions, such as infection, surgery, or pregnancy (pharmacodynamic breakthrough). Extravascular hemolysis or progressive BMF may also contribute to increased symptoms.
●Pharmacokinetic breakthrough – Pharmacokinetic breakthrough (eg, recurrence prior to the next dose) is less common with ravulizumab than eculizumab because of its longer half-life and weight-based dosing [38]. If hemolysis-related symptoms worsen prior to 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 – Under strong complement activation, PNH red cells densely coated with C3b can cause C5 to adopt a C5b-like conformation that is not inhibited by eculizumab or ravulizumab [39]. 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 [40].
●Exacerbation of extravascular hemolysis – Virtually all patients with PNH who are treated with a C5 inhibitor experience mild to moderate extravascular hemolysis 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 [28,36,37]. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria", section on 'Extravascular hemolysis from reduced CD55'.)
Danicopan is a Factor D inhibitor that reduces C3 production and can lessen extravascular hemolysis in patients treated with a C5i. (See 'Newer complement inhibitors' above.)
●Worsening leukopenia and/or thrombocytopenia – If pancytopenia develops or worsens, the patient should have a repeat bone marrow examination to re-evaluate for BMF.
THROMBOSIS — Thrombosis occurs in up to 40 percent of patients with PNH. The presence or prior history of a thrombus is an indication for treatment with a complement inhibitor, as discussed above. (See 'Symptomatic hemolytic PNH' above.)
●Evaluation and diagnosis – The baseline evaluation for a patient with PNH should consider the possibility of thrombosis, including mesenteric, hepatic, dermal, or cerebral veins; suspicion should be increased by an elevated D-dimer. (See 'Clinical and laboratory studies' above.)
Evaluation for particular sites of thrombosis is discussed separately. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity" and "Acute portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management" and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".)
●Treatment of deep vein thrombosis (DVT) – Acute thromboses should be treated with anticoagulation and/or thrombolysis for life-threatening thromboses, according to the site of the DVT and the severity of clinical findings [12,41].
For patients whose PNH is well-controlled on a complement inhibitor, it appears to be safe to discontinue anticoagulation after three to six months [42]. However, patients who developed a thrombosis while receiving a complement inhibitor should be anticoagulated indefinitely. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration" and "Mesenteric venous thrombosis in adults".)
For patients with a life-threatening thrombosis in the setting of severe thrombocytopenia (eg, platelet count <50,000/microL), it may be necessary to transfuse platelets to safely administer anticoagulants and/or thrombolytic therapy. (See "Budd-Chiari syndrome: Management" and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Anticoagulation in individuals with thrombocytopenia".)
●No prior DVT – For patients with PNH who have not had a prior thrombosis, we suggest not treating with prophylactic anticoagulation, based on a lack of high-quality evidence that this is effective and to avoid precipitating or exacerbating bleeding in patients with concomitant thrombocytopenia.
For patients with PNH who are hospitalized with an acute medical illness or for a surgical procedure, short-term prophylactic anticoagulation is appropriate because PNH may exacerbate the known risks of venous thromboembolism. Choice of anticoagulant, timing of administration, and duration of therapy are 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".)
●Secondary prophylaxis – Thrombosis in a patient with PNH is an indication for complement inhibition, which should be initiated as soon as possible, rather than delaying therapy until completion of anticoagulation. (See 'Symptomatic hemolytic PNH' above.)
HEMATOPOIETIC CELL TRANSPLANTATION — Because of the efficacy of complement inhibition for controlling hemolysis and thrombosis, allogeneic hematopoietic stem cell transplantation (HCT) is generally reserved for patients who have PNH with co-existent severe bone marrow failure (BMF). Complement inhibitors are safe and effective for managing hemolysis-associated findings while awaiting identification of a suitable transplant donor [22].
Indications — Indications for allogeneic HCT in PNH include:
●Severe aplastic anemia (sAA) – Allogeneic HCT is indicated in patients with PNH and sAA who have a suitable donor. A decision to proceed with transplantation should be made on a case-by-case basis with input from clinicians with expertise in managing PNH and transplantation.
For patients with PNH and sAA who are not medically-fit for transplantation or do not have a suitable donor, we treat with immunosuppressive therapy (eg, anti-thymocyte globulin and cyclosporine), as described separately. (See "Treatment of aplastic anemia in adults", section on 'Less-fit or frail'.)
●Myelodysplastic syndromes (MDS) – Some patients with PNH and co-existent high-risk MDS are treated with allogeneic HCT. A decision to proceed with transplantation should be made on a case-by-case basis with input from clinicians with expertise in managing PNH, MDS, and transplantation. (See "Treatment of high or very high risk myelodysplastic syndromes".)
Candidates for allogeneic HCT must have no severe lung, heart, liver, or kidney disease; a suitable graft source; and adequate social supports. 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 "Determining eligibility for allogeneic hematopoietic cell transplantation".)
Conditioning regimen and stem cell product — 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 [15]. Reduced intensity conditioning (RIC)/nonmyeloablative (NMA) conditioning may yield comparable rates of engraftment as MAC, while reducing transplant-related morbidity and mortality.
●Graft 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 [43].
●Bone marrow versus peripheral blood stem cells – 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 [44].
Outcomes — Outcomes with transplantation 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 (OS) 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 [45-49].
OTHER ASPECTS OF CARE AND MONITORING
Adjunctive treatment of anemia — Anemia in PNH is predominantly caused by hemolysis of red blood cells (RBC), but bone marrow failure (BMF), 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 be evaluated for aplastic anemia (AA) or a myelodysplastic syndrome (MDS) with a bone marrow examination [50].
●Transfusions – Patients with severe anemia (eg, hemoglobin level <7 g/dL or symptoms such as dyspnea, 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 is some patients, but the substantial long-term adverse effects outweigh their efficacy.
Monitoring of clone size — The size of the PNH clone should be monitored at least annually for all patients with PNH. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Flow cytometry/FLAER'.)
SPECIAL POPULATIONS
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 transplant (HCT) for PNH with co-existent severe aplastic anemia. (See 'Management' above.)
We administer the same dose of complement inhibitors 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 [51]. (See 'Complement inhibition' above.)
Pregnancy — Women with PNH can have successful pregnancies, but it may be associated with increased maternal and fetal morbidity and mortality [52]. 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 [53].
●Complement inhibition – Both ravulizumab and eculizumab are acceptable choices for treatment of symptomatic hemolytic PNH in pregnant patients. Although most studies report treatment with eculizumab, we favor ravulizumab because there is less risk for pharmacokinetic breakthrough.
For patients who become pregnant while taking a C5 complement inhibitor, 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 complement inhibitor for patients who are newly diagnosed with symptomatic hemolytic PNH while pregnant. (See 'Eculizumab' above.)
An industry-sponsored observational study reported outcomes in 61 women (75 pregnancies) who were taking eculizumab while pregnant; 88 percent were also anticoagulated [53]. There were no maternal deaths, two women had a postpartum thromboembolic event while taking eculizumab, and an additional 2 of 10 women who stopped eculizumab postpartum had a thromboembolic event. In 36 of 67 pregnancies that progressed to delivery, breakthrough hemolysis necessitated an increased dose of eculizumab or shortened 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 3 stillbirths. Delivery before 37 weeks of gestation was reported in 29 percent; common reasons included preeclampsia, 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 C5 inhibitor during pregnancy is associated with improved maternal outcomes and no evidence of increased fetal risks [52-55], compared with outcomes prior to availability of complement inhibitor therapy [53,56-58]. Prior to availability of complement inhibitors, studies reported 8 to 20 percent maternal mortality, up to 45 percent spontaneous miscarriage, and premature delivery in more than half of women [53,56-58].
●Thromboembolic risk reduction – Pregnancy increases the already-high thromboembolic risk in PNH. Treatment must be individualized, as there are few data to guide management:
•For all pregnant women 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.
•For women who become pregnant while taking a complement inhibitor, we continue that treatment. For women 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 "Use of anticoagulants during pregnancy and postpartum".)
Oral contraceptives — Oral contraceptives (OCs) increase thromboembolic risk in women with PNH. Non-hormonal forms of contraception are preferred for sexually-active women with PNH, although there is little information to guide the choice.
As with all women, the potential benefits of OCs in preventing pregnancy must be weighed against the risks, including the risk of unplanned pregnancy, and compared with other contraceptive options. Women with well-controlled PNH (eg, LDH <1.5x upper limit of normal) are probably at no higher risk of thrombosis than age-matched controls. Options for non-hormonal contraception and lower-risk hormonal methods are discussed separately. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use".)
Surgery — Surgery can precipitate hemolysis in patients with PNH due to increased inflammatory stimuli and/or metabolic abnormalities [15].
Patients who are currently treated with C5 complement inhibitor 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 C5 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".)
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 [18].
●A series of 220 patients from the pre-complement 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 [59]. 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 pre-complement inhibitor era (2004) reported that outcomes differed between American and Japanese patients [60]. 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, and 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
●Paroxysmal nocturnal hemoglobinuria (PNH) is a rare complement-mediated hemolytic anemia associated with thrombosis, pain, and organ dysfunction caused by loss of complement inhibitor proteins on hematopoietic cells. PNH is often associated with aplastic anemia (AA) and, rarely, with myelodysplastic syndrome (MDS).
●Baseline evaluation – Pretreatment evaluation should include flow cytometry (to estimate PNH clone size) and bone marrow examination (to evaluate for AA or MDS). (See 'Baseline evaluation' above.)
●Management – Treatment is guided by the type and severity of manifestations and complications of PNH (algorithm 1).
•Symptomatic hemolytic PNH without bone marrow failure (BMF) – For patients with symptomatic hemolytic PNH (eg, thrombosis, organ dysfunction, pain) without severe BMF, we recommend a C5 complement inhibitor (C5i), rather than supportive care alone (Grade 1B). (See 'Symptomatic hemolytic PNH' above.)
•Subclinical PNH – For patients with no substantial PNH-associated symptoms or BMF, we suggest watchful waiting rather than treatment with a C5i or allogeneic hematopoietic cell transplantation (HCT) (Grade 2C). (See 'Subclinical PNH' above.)
•PNH with severe BMF – For patients with PNH and severe aplastic anemia (sAA) or high-risk MDS, management is guided by treatment for sAA or MDS. (See 'PNH with bone marrow failure' above.)
For less severe AA or lower-risk MDS, management is guided by PNH-associated symptoms. (See 'Symptomatic hemolytic PNH' above and 'Subclinical PNH' above.)
●Complement inhibitor therapy – C5i treatment can relieve PNH-related symptoms, eliminate transfusion-dependence, prevent thrombosis, and relieve pain, but does not mitigate AA/MDS. (See 'Complement inhibition' above.)
•Choice of agent – For a C5i, we suggest ravulizumab rather than eculizumab (Grade 2C), based on comparable efficacy and toxicity, but greater convenience, lower overall expense, and fewer episodes of pharmacokinetic breakthrough hemolysis. (See 'Choice of agent' above.)
•High risk of meningitis with C5i therapy – All patients who are treated with a C5i should be vaccinated and receive oral antibiotic prophylaxis, as described above. (See 'Meningitis and other adverse effects' above.)
•Breakthrough hemolysis – Pegcetacoplan or a clinical trial with a newer complement inhibitor should be offered to patients who remain transfusion-dependent or continue to have symptomatic extravascular hemolysis. (See 'Treatment breakthrough' above.)
●Thrombosis – Thrombosis or history of thrombosis is an indication for C5i therapy. (See 'Symptomatic hemolytic PNH' above.)
Management and prophylaxis of thrombosis are discussed above. (See 'Thrombosis' above.)
●Transplantation – Indications for allogeneic HCT in PNH include (see 'Hematopoietic cell transplantation' above):
•Severe aplastic anemia
•Myelodysplastic syndromes
●Pregnancy – A pregnant patient with PNH should be managed by a hematologist and an obstetrician specializing in high-risk pregnancy. For pregnant women with PNH who otherwise meet criteria for anticomplement therapy, we suggest continuing or initiating treatment with a C5i to decrease maternal morbidity/mortality and improve fetal outcomes (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.
