Efficacy and Safety of Iptacopan in Paroxysmal Nocturnal Hemoglobinuria (PNH): A Multidimensional Analysis of 35 Patients Objective Paroxysmal nocturnal hemoglobinuria (PNH) is a rare complement-mediated hemolytic disorder with variable clinical outcomes, especially in patients with concurrent bone marrow failure (BMF) or suboptimal responses to prior therapies. Iptacopan, an oral complement factor B inhibitor, has shown promise in controlled trials, but real-world data on its performance across PNH subtypes and age groups remain sparse. We aimed to evaluate its multidimensional efficacy and safety in 35 Chinese PNH patients, with a focus on subtype-specific responses to inform clinical practice.

Methods We prospectively enrolled 35 consecutive PNH patients treated with iptacopan between January 2024 and July 2024. The cohort included 11 cases of classical PNH (31.4%) and 24 cases of PNH combined with BMF (myelodysplastic syndrome, aplastic anemia [AA], or severe AA; 68.6%). The median age was 42 years (range 23–76 years), with a male predominance (24/35, 68.6%). At baseline, patients showed severe anemia (median hemoglobin [Hb] 67 g/L, range 28–121 g/L), marked hemolysis (median lactate dehydrogenase [LDH] 2150 IU/L, range 251–5799 IU/L), and high clone burden (median erythrocyte CD59⁻ proportion 43.66%). All received iptacopan (200 mg twice daily), with 12 patients also taking cyclosporine and 8 receiving testosterone undecanoate. Over 4 months of follow-up, we monitored changes in hematological parameters, hemolysis markers (LDH, total bilirubin), fatigue scores (FACIT-F), clone size, and transfusion independence (TI). Safety was assessed via adverse events (AEs) and treatment tolerance.

Results Hematological and hemolytic control: Hb improved rapidly from a baseline median of 67 g/L to 88 g/L at 1 month (+31.3%, p<0.001) and 110 g/L at 2 months (+64.2%, p<0.001); 54.3% (19/35) achieved TI by month 2, up from 11.4% at baseline (p<0.001). LDH dropped by 87.5% (from 2150 IU/L to 268 IU/L, p<0.001), with 80.0% (28/35) reaching LDH ≤1.5×ULN by month 2, indicating effective hemolysis suppression.

Subgroup variations: Classical PNH patients had better responses, with median Hb reaching 125 g/L at 2 months (+86.6%), compared to 98 g/L (+46.3%) in PNH-AA patients (p=0.023). Younger patients (<40 years) showed faster Hb improvement (25.3 g/L/month) than those over 60 (12.1 g/L/month, p=0.027), reflecting differences in bone marrow reserve.

Symptom relief and clone reduction: Fatigue scores (FACIT-F) improved from a median of 21 to 42 (+100.0%, p<0.001). Among 11 patients with frequent hemoglobinuria, 8 (72.7%) achieved resolution, strongly correlating with LDH reduction (r=0.72, p<0.001). Erythrocyte CD59⁻ clones decreased by 58.1% (from 43.66% to 18.3%, p<0.001), a larger reduction than seen in granulocyte clones (37.9%, p=0.031), consistent with reduced erythrocyte destruction.

Safety profile: Mild rash occurred in 6 patients (17.1%), all on concurrent prednisone; symptoms resolved after stopping prednisone, with no recurrence on iptacopan monotherapy. No severe infections, thrombotic events, or nephrotoxicity were observed.

Conclusion Iptacopan effectively improves anemia, controls hemolysis, and enhances quality of life in real-world PNH patients. Responses are particularly robust in classical PNH and younger patients, while those with BMF may benefit from early combination therapy. Its favorable safety profile supports long-term use, offering valuable insights for individualized PNH management, particularly in Asian populations.

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2025
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