Pb2057: the combination of anti-complement therapy and cyclosporine +/- eltrombopag in pnh is effective and safe: a real-life observational study.

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by chronic hemolysis, bone marrow failure and increased risk of thrombosis. PNH is frequently associated with aplastic anemia (AA). In PNH, it is not unusual to observe a hypo or aplastic bone marrow with heterogeneous cellularity and variable percentages of lymphocytes infiltration. In these patients, the anti C5 therapy alone leads to suboptimal responses. Aims: In the present study, we analyzed data of PNH patients with hypo or aplastic bone marrow treated with anti C5 therapy combined with cyclosporine (CSA). Methods: We collected clinical data of patients treated in 5 hematological centers in Piemonte and Valle d’Aosta, Italy. Patients were treated with anti C5 monoclonal antibody Eculizumab (ECU) or Ravulizumab (RAVU) associated with immunosuppressive therapy with CSA. Clinical responses were evaluated using previously described criteria (Risitano et al, BJH 2022) and indicated as no response (NR), minor response (mR), partial response (PR), major response (MR), good response (GR) and complete response (CR). Results: A total of 5 patients were enrolled. Median age was 44 (18-58), 4/5 were male. Four of them did not show any relevant comorbidity, one had an history of smoking and cholecystectomy. Just 1 patient had a diagnosis of classical PNH, while 4 patients were diagnosed with PNH with associated hypo/aplastic anemia (AA). Bone marrow cellularity was heterogeneous, varying from 10% to 80% in AA-PNH patients, while the only classical PNH patient showed a homogeneous 80%-90% bone marrow cellularity. No karyotype abnormalities were detected, while a lymphocyte excess (15%-30%) in bone marrow biopsy was described in 4 patients (in the other patient it was not available). Hemoglobin (Hb) levels at diagnosis were 7-7.5 g/dl in the 4 AA-PNH patients, while Hb was 3.5 g/dl in the PNH patient. PNH clone size was detectable in all patients: average clone was 32,5% (±19) on Neutrophils, 34% (±12,7) on Monocytes and 12,3% (±10,4) on Erythrocytes. Blood transfusions were reported in all patients (average 2.5 units per month) in the 2 months before the therapy beginning. In all patients, therapy was started for anemia and hemolysis. In 4/5 patients, anti C5 treatment was started 15 days after PNH/AA-PNH diagnosis: all 5 patients were treated with ECU; 2 of them switched to RAVU in 2022; one patient started CSA 3 months before anti C5 therapy; two patients started thrombopoietin agonist eltrombopag together with CSA. Hematological responses were recorded at different timepoints: at 3 months, 4 patients were in NR, 1 in MR; at 6 months 1 patient was in NR, 3 were in PR and 1 in CR; at 9 months 3 were in PR and 1 stayed in CR, at 12 months 1 in PR, 1 in mR, 2 in GR and 1 in CR; at 18 months, 3 were in GR, 1 in CR. Hematologic responses were achieved faster in the two patients treated also with eltrombopag (Figure 1). Median follow up was 24 months. One patient died after allogeneic bone marrow transplantation due to invasive aspergillosis 14 months from diagnosis. At the last follow up, all alive patients maintained their best response achieved. No severe adverse events were recorded; we observed only one case of grade 2 renal toxicity. Just one episode of breakthrough hemolysis was described for one patient after Covid19 infection. Summary/Conclusion: In our study, despite the small sample size and the short follow up, we confirm that the association between CSA +/- eltrombopag and anti-C5 treatment is effective and safe in patients affected by AA-PNH and classical PNH. Further prospective trials with a large number of patients are needed to validate these results and elucidate the role of combination treatment with CSA and eltrombopag therapy together with anti C5 agents.Keywords: Aplastic anemia, Complement, Paroxysmal nocturnal hemoglobinuria (PNH), Cyclosporin A