Short summary

Patients with PNH have in complement inhibition treatment have recently switched to a longer acting agent - ravilizumab. This study describes RW results

Rationale

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal haematopoietic stem cell disorder caused by a somatic PIG-A gene mutation in haematopoietic stem cells. The mutation blocks the synthesis of GPI proteins that anchors cell surface proteins such as the CD55 and CD59.1 The CD59 inhibits the formation of the complement terminal membrane attack complex, and red blood cells deficient of CD59 are particular susceptible to complement attack and lysis.1 Due to the constant complement activation, patients suffer from intravascular haemolysis, anaemia, fatigue, thrombosis, abdominal pain, haemoglobinuria and reduced quality of life1-3.

In the pivotal TRIUMPH phase III trial treatment with the monoclonal C5 complement inhibiting antibody eculizumab was tested against placebo in 87 adult PNH patients who were transfusion dependent. 4 Patients were required to have received at least four transfusions during the 12 months prior to study enrolment and to have a platelet count of at least 100 × 109/l.4 The end-points were the proportion of patients who maintained haemoglobin concentration above the threshold for transfusion and the units of transfusion given in the two groups. The study showed that approximately half of patients treated with eculizumab became transfusion independent vs none in the placebo group and that the median number of red blood cell units transfused was 0 vs 10 in the two groups.4 Additionally LDH levels in patients treated with eculizumab reduced markedly however remained above the ULN in indicating that haemolysis is partially blocked.

The subsequent SHEPHERD phase III trial included 97 patients who had received at least one transfusion during the past two years and had platelet count above 30× 109/l and obtained similar results.5 Additionally the occurrence of thrombo-embolic events was registered both prior to and after eculizumab treatment and this outcome was markedly reduced from 7.4 / 100 person-years to 1.1 / 100 person-years.6

Since 2007 eculizumab has therefore been the approved treatment of symptomatic PNH and introduction of complement inhibiting treatment with eculizumab treatment in routine care has led to markedly improved quality of life, reduced transfusion and improved survival prognosis for patients.2,5,7-9.

In 2019 two clinical trials compared a novel C5 complement inhibiting antibody ravulizumab in PNH patients who were either complement naïve (301 study) or were switched from eculizumab treatment (302 study).10,11

In the 301 study patients naïve to complement inhibition were randomly assigned to standard dosing of eculizumab (loading dose followed by 900mg biweekly) or ravulizumab.11 In the 302 study patients with PNH on the standard eculizumab dosing of 900mg biweekly were randomly assigned to continue on this treatment or to switch to ravulizumab.10 Therefore both these pivotal trials compared standard dosing of eculizumab with ravulizumab. Both trials concluded that ravulizumab was non-inferior to eculizumab on the main outcomes that were transfusion avoidance, signs of intravascular haemolysis (LDH levels) and breakthrough haemolysis episodes.10,11 Results, however generally favoured ravulizumab treatment for the defined outcomes although the differences were not statistically significant.10,11

Breakthrough haemolysis was defined as one new or worsening symptom or sign of intravascular haemolysis (fatigue, haemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [haemoglobin<10 g/dL], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥ 2× the ULN after prior reduction of LDH to <1.5× the ULN on treatment. 10 With the standard dose and biweekly administration of eculizumab breakthrough haemolysis still occurs in more than 10% and increased dosing schedules with higher doses (often 1200mg) or shorter intervals may be neccessary.12-14 Only one case report describes the successful switching of high dose eculizumab - in this case 1800mg biweekly - to standard loading dose, maintenance dose, and dosing interval of ravulizumab.15 In this study, we aim at describing outcomes using real World data from patients with PNH who switch from eculizumab to ravulizumab treatment with a special emphasis on switching from high dose eculizumab.

Based on our own clinical experience and the published case report we hypothesize that standard dose of ravulizumab provide the same or a better clinical results as high dose eculizumab. Switching patients from high dose eculizumab to standard dose ravulizumab will be of major financial benefit for hospitals and at the same time improve quality of life for patients. 16

Description of the cohort

Patients with classical PNH, AA-PNH, or MDS-PNH who has been treated for at least 6 months with eculizumab and at least 3 months with ravulizumab (total at least 9 months of treatment) . Patients from Denmark and Finland are included

Data and biological material

Data from medical files on PNH type, treatment effect, blood test results etc