Treatment Outcomes of Complement Protein C5 Inhibition in 509 Patients with Paroxysmal Nocturnal Hemoglobinuria in the United Kingdom

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare hematological disorder. Affected individuals experience chronic intravascular hemolysis and an increased tendency to thrombosis. Clinical symptoms can include hemoglobinuria, dysphagia, abdominal pain, breathlessness, erectile dysfunction, fatigue and lethargy. Inhibition of terminal complement by targeting the complement protein 5 (C5) is currently the standard care used to treat PNH in the UK. Eculizumab and ravulizumab, bind to C5, stopping its cleavage to C5a and C5b and thereby preventing terminal complement activation and its consequences.

Method: A retrospective analysis of case records of all patients with PNH treated with eculizumab or ravulizumab in the UK since May 2002 was performed. Clinical features at presentation and diagnosis, prior history of bone marrow failure (BMF) as well as outcomes whilst on C5 inhibition (C5i) were collected.

Results: 509 patients with PNH (237 male and 272 female) have been treated with eculizumab or ravulizumab between May 2002 and July 2022. Mean age at diagnosis was 43 years and 11 months. A history of BMF was documented in 246 patients (48.3%) of which 215 had aplastic anemia (42.2%) and 31 (6.1%) had myelodysplastic syndrome. One hundred and thirty five patients (26.5%) had experienced thrombosis prior to commencing C5 inhibition. There were 192 documented thromboses in these 135 patients with 73 (38.0%) being intra-abdominal and 57 (29.7%) being arterial (mainly myocardial infarction and stroke).

Symptoms experienced by patients at diagnosis include anemia: 358 (70.3%), fatigue: 316 (62.1%), hemoglobinuria: 225 (44.2%), breathlessness: 114 (22.4%), abdominal pain: 92 (18.0%), dysphagia: 36 (7.1%) and erectile dysfunction: 32 of the 237 male patients (13.5%).

The median time from developing symptoms to diagnosis of PNH was 5 months (interquartile range 0-18, available in 454 cases) with 86 (16.9%) patients being originally referred to a different specialty, mainly urology, for investigation. Sixty-four (12.6%) patients were misdiagnosed with an alternative condition before the correct diagnosis of PNH was made.

Four hundred and seventy-four, (93.1%) patients have been treated with eculizumab with 77 (16.2%) requiring higher doses than is recommended in the summary of product characteristics due to pharmacokinetic breakthrough hemolysis. In 2021 ravulizumab became available for use on the National Health Service and 237 patients treated with eculizumab have switched to ravulizumab. The majority of patients have had no adverse clinical issues but 3 patients have reverted back to eculizumab due to side effects. Thirty-five patients (6.9%) presented after 2021 and have been treated with ravulizumab alone.

The median PNH granulocyte clone size at initiation of C5i was 85.5% (interquartile range 67-95%, available in 494 cases).

Indications for complement inhibition: hemolytic disease: 325 patients (63.8%), thrombosis: 93 patients (18.3%), other complication due to PNH: 27 patients (5.3%), pregnancy: 26 patients (5.1%), pre-allogeneic bone marrow transplantation: 14 patients (2.8%), exceptional cases after discussion at a joint service meeting: 17 patients (3.3%), indication unknown: 7 patients (1.4%).

Mean hemoglobin levels 12 and 24 months after initiating C5i were 107.7g/l (in 421 patients) and 108.6g/l (in 374 patients) respectively. In the most recent 12 months on C5i 123 out of 446 (27.6%) patients needed transfusions with 94 of the 123 (76.4%) requiring 3 or more transfusions. There were 23 thrombotic events on C5i (4.5%).

Over the 20-year period, 91 patients have died equating to a 79.0% survival rate (Figure 1). Infection was implicated in the cause of death in 44 individuals (48.4%).

There have been 11 cases of Neisseria Meningitidis septicemia in 10 individuals over 3,130 years of treatment with C5i and 1 death from this, equating to a meningococcal infection rate of 1 event per 284 years and 6 months.

Clonal evolution to acute leukemia occurred in 7 cases (1.4%) and to myelodysplastic syndrome in 10 cases (2.0%).

Conclusions: We report 20 years of C5i experience from the UK, for patients with PNH.

Our experience of treatment with C5i confirms the continued long-term safety and efficacy of eculizumab and ravulizumab. Overall survival remains high on C5i and complications such as thromboses, meningococcal infection and clonal evolution are uncommon events.

Kelly:Medscape: Other: educational work sponsored by Apellis with unrestricted grant paid to Medscape; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: conference support; Biocryst: Membership on an entity's Board of Directors or advisory committees; Swedish Orphan Biovitrum AB: Membership on an entity's Board of Directors or advisory committees; Sobi: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Biologix: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Amgen: Consultancy. Arnold:Alexion Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; AstraZeneca Rare Disease: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau. Large:Alexion Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; AstraZeneca Rare Disease: Consultancy, Honoraria, Speakers Bureau. Barnfield:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Sobi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Pike:Apellis Pharmaceuticals: Research Funding. Griffin:BioCryst Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Other: Conference support; Sobi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Medscape: Other: educational work sponsored by Apellis with unrestricted grant paid to Medscape. Munir:Janssen, AstraZeneca, Alexion, Sobi, Novartis, Roche, Abbvie, Gilead: Honoraria; Janssen, AstraZeneca, Alexion, Abbvie, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Muus:Sobi: Other: travel support , Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Nagumantry:Alexion: Honoraria; Janssen: Honoraria. Trikha:Sobi: Consultancy. Kulasekararaj:Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Samsung: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Speakers Bureau; Akari: Consultancy, Honoraria, Speakers Bureau; Achillion: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau. Ghandi:AstraZeneca Rare Disease: Consultancy, Honoraria, Research Funding, Speakers Bureau; Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau.