Correlation between efficacy, clonal dynamics evolution, and development of bone marrow failure in PNH/AA syndrome treated with complement inhibitors: A single-center cohort study

Abstract Objective: To investigate the correlation between therapeutic response patterns to complement inhibitors, clonal dynamics changes, and progression of bone marrow failure (BMF) in patients with PNH/AA (paroxysmal nocturnal hemoglobinuria/aplastic anemia). Methods: A retrospective analysis was conducted on 92 PNH/AA patients treated at our center from 2021 to 2025. All patients received complement inhibitor therapy (eculizumab, crovalimab, or iptacopan), with a median follow-up of 29 months. Parameters monitored included PNH clone size, next-generation sequencing (NGS), lactate dehydrogenase (LDH) levels, hematologic response, breakthrough hemolysis (BTH), and dynamic changes in hematopoietic function (reticulocytes, absolute neutrophil count, platelets). Outcomes related to bone marrow failure were assessed. Results: Treatment Response: 89.1% (82/92) of patients achieved hemolysis control, but only 64.1% (59/92) attained a complete hematologic response. BTH occurred in 17.4% (16/92). BMF Progression: 10.9% (10/92) showed signs of BMF progression. This correlated with residual hemolysis and discontinuation of immunosuppressive therapy (IST). The median PNH clone size was significantly lower in the progression group (76.2%) compared to the stable group (91.3%) (p=0.04). Clonal Dynamics: Patients with an expanding PNH clone had a 3.2-fold increased risk of BMF progression (95% CI 1.8–5.6). New somatic mutations were detected in 5 patients (20%), which showed a significant association with BMF (p=0.003). Conclusion: Complement inhibitors effectively control hemolysis in PNH/AA patients but provide limited improvement in BMF. Residual hemolysis, the emergence of new subclones, and an expanding PNH clone are associated with BMF progression. Timely combination therapy with immunosuppressive agents is warranted. Keywords: PNH, Bone Marrow Failure, Complement Inhibitors, Immunosuppressive Therapy