P781: evaluation of pegcetacoplan treatment success in paroxysmal nocturnal hemoglobinuria with and without bone marrow failure: a move towards individualized patient treatment

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and potentially life-threatening hematological disease characterized by chronic complement-mediated hemolysis with multiple clinical consequences all of which impair quality of life. PNH patients are highly variable, as is their hematologic response to standard treatment, and the association of underlying bone marrow failure (BMF) syndromes is likely to limit the ability to achieve normalization of hematologic parameters in all patients. Pegcetacoplan (PEG), the first proximal complement inhibitor approved by FDA/EMA for the treatment of adults with PNH, has demonstrated broad control of both intravascular and extravascular hemolysis through complement factor 3 inhibition in several clinical trials. Aims: This post-hoc analysis assessed hematologic and clinical response in PNH patients with BMF treated with PEG or eculizumab (ECU) and examined a new set of parameters to evaluate treatment success in these patients. Methods: The post-hoc analysis included adult patients with PNH from the PEGASUS (NCT03500549) study. PNH patients (Hb <10.5 g/dL despite prior stable ECU) were randomized 1:1 to PEG, or ECU, for 16 weeks. Hematologic and clinical responses were assessed in patients with or without active BMF (aBMF) defined by at least two of the following criteria: Hb <10 g/dL, platelet count <50×109/L, neutrophil count <1.5×109/L at baseline, and those with or without a history of aplastic anemia or myelodysplastic syndrome (AA/MDS): Hemoglobin (Hb) (males: ≥13.6 g/dL; females: ≥12.0 g/dL), Hb ≥12 g/dL, lactate dehydrogenase (LDH) (≤upper limit of normal [ULN]: 226 U/L), and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score (≥population norm: 43.6). Treatment success was subsequently evaluated against a new set of parameters: Hb (change from baseline [CFB] ≥2 g/dL); LDH (≤1.5x ULN: 339 U/L); FACIT-Fatigue (CFB ≥5 points). Results: In total, 80 patients (PEG, n=41; ECU, n=39) were evaluated from PEGASUS. Overall, a greater proportion of PEG-treated patients with BMF syndromes experienced improvement in hematologic parameters and fatigue when compared to ECU treatment (Table 1). In general, the number of patients with BMF syndromes reaching assessed levels of relevant hematologic parameters was comparably lower than non-BMF patients. With PEG treatment, 11% of AA/MDS and 20% of aBMF patients achieved gender specific Hb normalization, compared to 41% of non-AA/MDS and 36% of non-aBMF patients. Similarly, PEG led to Hb ≥12 g/dL being reached in 33% and 20% of AA/MDS and aBMF patients, respectively, compared to 41% of non-AA/MDS and 42% of non-aBMF patients. The proportion of AA/MDS and aBMF patients treated with PEG achieving a ≥2 g/dL increase in Hb was 56% and 40%, respectively. No ECU treated patients with or without AA/MDS or aBMF achieved any of the Hb response parameters assessed. The proportion of AA/MDS, and aBMF PEG-treated patients achieving LDH normalization was 78% and 60%, compared to 69% and 72% of non-AA/MDS and non-aBMF patients, respectively. PEG-treatment led to LDH levels ≤1.5x ULN in all AA/MDS, and 60% of aBMF patients, and 78% and 86% of non-AA/MDS and non-aBMF patients, respectively. Summary/Conclusion: Not all PNH patients may be able to achieve normalization of hematologic parameters due to various reasons such as underlying BMF. Nevertheless, patients with BMF syndromes showed benefit in hematologic and clinical outcomes in response to PEG treatment. Treatment success may best be evaluated against individually set treatment targets.Keywords: Aplastic anemia, Paroxysmal nocturnal hemoglobinuria (PNH), Complement, Bone marrow failure