Optimizing PNH treatment with the complement inhibitor pegcetacoplan: A case report

Abstract Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, serious hematologic disorder characterized primarily by intravascular hemolysis due to excessive erythrocyte sensitivity to physiological complement C3 activation. Patients with PNH often report symptoms of anemia, fatigue, dark urine, shortness of breath, and difficulty swallowing. Untreated PNH can culminate in serious complications including major adverse vascular events, thrombotic events, and impaired kidney function. The current treatment landscape includes 6 approved complement cascade inhibitors: 3 C5 inhibitors (eculizumab, ravulizumab, crovalimab), 1 C3/C3b inhibitor (pegcetacoplan), 1 factor B inhibitor (iptacopan), and 1 factor D inhibitor used as add-on treatment (danicopan). With 4 of these treatments (pegcetacoplan, iptacopan, crovalimab, danicopan) having been approved in the last 5 years, hematologists are in the early days of tailoring PNH treatment and identifying the optimal way to switch between treatments. Here we present a case report of a pediatric patient with PNH who switched from pegcetacoplan to iptacopan only to return to pegcetacoplan in the search for the optimal treatment. Methods: Records and laboratory results from a single patient were compiled to summarize the patient's transitions between complement inhibitors for PNH treatment. Results: Our female patient was diagnosed with PNH in July 2020 at 15 years of age. At presentation, she had low hemoglobin (3.7 g/dL) and elevated lactate dehydrogenase (LDH) (1930 U/L). After receiving the meningococcal vaccine, she started treatment in August 2020 with eculizumab at 600 mg/week for 4 weeks, 900 mg at week 5, and continued at 900 mg every other week. After 8 weeks on eculizumab, treatment was changed to ravulizumab to improve the patient's quality of life with less frequent administrations (loading dose, 2400 mg; followed by 3000-mg after 2 weeks and every 8 weeks thereafter). Concomitant medications included apixaban, penicillin, and folic acid. In November 2020, her platelets count declined, and a bone marrow evaluation was diagnostic for moderate aplastic anemia (55-65% cellularity for age) and she was started on eltrombopag and cyclosporin. Despite ravulizumab and eltrombopag treatments, the patient developed significant anemia related to extravascular hemolysis (hemoglobin, 5.7 g/dL; LDH, 495 U/L; C5, 26.1 mg/dL [high]; complement hemolytic activity 50 [CH50], 7 U/mL [low]). The patient required red blood cell transfusion. In December 2020, the ongoing extravascular hemolysis and ongoing anemia prompted to start treatment with pegcetacoplan 1080 mg subcutaneously twice weekly with cyclosporin (200 mg twice daily). Through January 2022, the patient's laboratory results were stabilized with platelet counts of 60,000-90,000 platelets per microliter, hemoglobin levels of 10.8-12.4 g/dL, and LDH levels of 204-256 U/L (with subtle changes); apixaban was discontinued after pegcetacoplan controlled extravascular hemolysis. Between 2022 and April 2023, cyclosporin was gradually reduced to 25 mg twice daily. In May 2024, the patient transitioned to iptacopan 200 mg twice daily to avoid subcutaneous infusions (pre-switch levels of hemoglobin and LDH of 12.9 g/dL and 235 U/L, respectively). After receiving both pegcetacoplan and iptacopan for 1 week and rivaroxaban 10 mg once daily for 48 hours, pegcetacoplan treatment ended on May 16, 2024. Five days later, the patient had a hemoglobin level of 13.1 g/dL and LDH of 318 U/L. Despite good hemoglobin and LDH levels, the patient reported tiredness, brain fog, and low energy in July 2024. In August, symptoms of fatigue and appetite loss appeared and levels of hemoglobin (13.3 g/dL) and LDH (343 U/L) were largely unchanged. The decision was made to switch back to pegcetacoplan. The switch occurred in September 2024, with 1-week overlap of complement inhibitors. By October 2024, all of her symptoms had resolved (hemoglobin, 12.2 g/dL). Conclusions: For this patient with PNH, the anticomplement therapy switch from pegcetacoplan to iptacopan, made for convenience of administration, was accompanied by increased symptoms. The patient then switched back to pegcetacoplan, which managed these symptoms. As new treatments are introduced for PNH, real-world experience will be essential to guide individualized therapy sequencing and symptom management.