Long-Term Safety of Sustained Eculizumab Treatment in Patients with Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, progressive and life-threatening hematopoietic stem cell disorder. It is characterized by uncontrolled activation of the complement system leading to chronic intravascular hemolysis. Chronic hemolysis is the underlying cause of the thromboembolism (TE), renal insufficiency and other end organ damage, and early mortality associated with PNH. It has been demonstrated that long-term eculizumab treatment has a favorable efficacy profile due to continuous suppression of the terminal complement system.

To analyze the long-term safety of patients on continuous eculizumab treatment.

Patients receiving continuous eculizumab treatment (mean duration: 30.3 months) who were enrolled in the eculizumab PNH clinical development trials and associated extension studies were assessed for the incidence of adverse events (AEs). The incidence of AEs, irrespective of relation to treatment, reported during the first 26 weeks of eculizumab treatment was compared with the last 26 weeks of treatment. In patients with treatment duration <52 weeks, the incidence of AEs reported during the first 26 weeks of treatment was compared with the incidence of AEs from 26 weeks + 1 day until the patient's last dose of eculizumab.

The analysis included 192/195 patients enrolled in the trials; 3 patients were excluded because of treatment duration <26 weeks. Significantly fewer patients reported an AE in the last 26 weeks (n=145) compared with the first 26 weeks (n=189) of treatment (P<0.001); this included the most commonly reported AEs such as headache (P<0.001), nasopharyngitis (P=0.029), back pain (P=0.031), nausea (P=0.029), and fatigue (P=0.029). Results by system organ class revealed significantly fewer patients experienced infections and infestations (P=0.005); infusion site reactions (P=0.018); gastrointestinal, musculoskeletal and connective tissue and nervous systems (all P<0.001); and skin and subcutaneous tissue (P=0.006), metabolism and nutrition (P=0.008), psychiatric (P=0.014), vascular (P=0.025), or respiratory thoracic and mediastinal (P=0.030) disorders. None of the individual AEs reported increased significantly over time. In addition, the probability of a patient experiencing an AE decreased significantly with time (P<0.001).

All patients are required to be vaccinated against Neisseria meningitidis because suppression of terminal complement activity by eculizumab increases the risk of meningococcal infections. Patients were vaccinated at least 2 weeks before the first dose of eculizumab and were educated on the early signs and symptoms of these infections. Two cases of meningococcal sepsis were reported with a time to onset of 353 and 416 days. Both patients developed a strain of meningococcal infection that was not covered by their vaccination. The infections were successfully treated: 1 patient received ceftriaxone and ciprofloxacin, and the other imipenem, rocephin, vancomycin, ceftriaxone and penicillin. Both infections resolved without sequelae: 1 patient remained in the extension study and continued to receive eculizumab; the second patient withdrew from the study. Five (5/195) patients discontinued from the study due to an AE, which included the development of myelodysplastic syndrome, meningococcal sepsis, worsening of PNH and 2 pregnancies. Over the course of the study, 4 patient deaths were reported; no deaths were considered related to eculizumab treatment.

PNH patients receiving long-term eculizumab treatment (up to 5.5 years) did not experience signs of cumulative toxicity. In fact, patients showed a significantly decreased incidence of AEs with continuous eculizumab treatment, suggesting a favorable risk-to-benefit ratio over the long term. The low discontinuation rate due to an AE suggests long-term treatment with eculizumab is well tolerated.

Off Label Use: The use of romiplostim in MDS was examined in this trial. Muus:Alexion Pharmaceuticals.: Sat on advisory board of Alexion Pharmaceuticals. Other. Roeth:Alexion: Honoraria, Research Funding. Elebute:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Risitano:Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding. Maciejewski:NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding. Urbano-Ispizua:Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees. de Castro:Alexion Pharmaceuticals, Inc: Speakers Bureau.