Characteristics and Long-Term Efficacy of 25 Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Eculizumab or Ravulizumab in Taiwan

Background: Complement inhibitors are the standard of care for patients with paroxysmal nocturnal hemoglobinuria (PNH), a rare, disabling, and life-threatening blood disorder characterized by chronic intravascular hemolysis. Due to the rarity of PNH, the high cost of treatment, and resource limitations of eculizumab and ravulizumab in Asia-Pacific countries, clinical experience is very limited. Method: This retrospective, single-center observational study enrolled Taiwanese patients with PNH who received eculizumab or ravulizumab treatment between January 2009 and May 2024. Clinical features and laboratory data were collected from the time of PNH diagnosis to the end of treatment or until July 20, 2024. Results: Twenty-five patients were enrolled in the study, with a median age at PNH diagnosis of 38 years. Of these patients, 60% were male. Fifteen patients (60%) were diagnosed with classical PNH, and ten patients (40%) had PNH with concurrent bone marrow diseases, including eight patients (32%) with aplastic anemia and two patients (8%) with myelodysplastic syndrome at baseline. The most common PNH-associated symptom was dyspnea (64%). Nine patients (36%) experienced PNH-related complications, including four (16%) with renal failure and five (20%) with thrombotic events. Median PNH clones were 94.36% (range 62-99.42%) and 95% (range 71.05-99.71%) for monocytes and granulocytes, respectively. The median LDH level was 6.9 (range 1.67-14.74) times the upper limit of normal (ULN) at baseline. Before receiving eculizumab or ravulizumab, thirteen patients (52%) had previously received other therapies, including steroids in nine patients (36%), cyclosporine and/or anti-thymocyte globulin (ATG) in five (20%), danazol in five (20%), and crovalimab in one (4%) who had been enrolled in a trial. Twenty-one patients (84%) were treated with eculizumab, while four patients (16%) received ravulizumab. Despite high disease activity in the cohort before treatment initiation, overall survival was 92% with a median follow-up time of 109 months and LDH levels were stabilized in 84% of patients. After a median treatment duration of 78 months, treatment with eculizumab or ravulizumab led to a significant reduction in the median LDH ratio to the ULN from 6.9 (range 1.67-14.74) at baseline to 0.74 (range 0.53-6.57) at the time of the last dose (P<0.05). Clinically significant extravascular hemolysis occurred in 16% of patients and breakthrough hemolysis in 40%. Except for one patient who achieved remission of PNH and three patients who crossed over to clinical trials of iptacopan or pozelimab/cemdisiran, seven patients discontinued eculizumab. Five patients discontinued treatment because Taiwan's National Health Insurance disapproved the continued reimbursement of the drug. This decision was based on the patients requiring more than two units of blood transfusion within three months while on treatment, which violated the reimbursement criteria. Another patient discontinued the drug because of no response, and the remaining one died from fungemia. Eculizumab and ravulizumab were well-tolerated, and no cases of meningococcal disease were reported. Conclusion: Our experiences demonstrated the clinical characteristics and long-term efficacy and safety of eculizumab and ravulizumab in Taiwanese PNH patients with high disease burdens. However, a major reason for discontinuing treatment was the need for frequent transfusions, which did not meet the reimbursement criteria of Taiwan's National Health Insurance.