Iron overload and iron chelation therapy in PNH patients on complement inhibitors: A single centre experience.

Abstract

Abstract Introduction: In untreated classic PNH, patients may develop iron defiency due to intravascular hemolysis (IVH) related haemoglobinuria. This phenomena can be demonstrated by kidney MRi showing kidney haemosiderosis. In PNH patients treated with terminal complement inhibitors (iC5), intravascular hemolysis (IVH) is controlled, and so there is no kidney haemosiderosis or iron defiency due to haemoglobinuria. These patients also develop a variable degree of extravascular haemolysis (EVH), so their iron metabolism mimics extravascular chronic anemias, like hereditary spherocytosis. Both these situations reverse iron metabolism in PNH patients treated with iC5, ending in iron overload, specially in the liver. There is a lack of data about the effect of proximal complement inhibitors, which control both IVH and EVH, on iron overload. Materials and methods: Here we present our single centre experience, showing the data on 12 PNH patients with classic PNH, high hemolytic activity and under complement inhibitor therapy. We collected data on which complement inhibitor were the patients recieving, if they needed iron chelation therapy and which drug was used, serum ferritin, liver iron overload measured by MRi (LIC) and duration of chelation therapy. Our goal is to define our population's characteristics in relation to iron overload so as to serve as a platform for future studdies. Results: We currently treat 12 PNH patients, 5 of which recieve proximal complement inhibitors (iptacopan) and 7 recieve terminal complement inhibitors, including ravulizumab, eculizumab and crovalimab. To date, in 4 cases (33%) we needed to initiate iron chelation therapy, using defesarirox in all patients. Full data are show on table 1. As relevant data, median time from start of complement inhibition therapy to initiation of iron chelation therapy was 5 years. When needing to start iron chelation therapy, all patients were under iC5. Median duration of desferasirox therapy was 2 years, with a median LIC at baseline of 6.05mg/g, showing moderate liver iron overload. After 2 years of follow-up of chelation therapy, median LIC was 2.11mg/g, which correlates to a minimal liver iron overload. 3 of the 4 patients on iron chelation therapy have been able to discontinue treatment after switching from iC5 to proximal complement inhibition (iptacopan and 1 case pegcetacoplan), due to said treatment being able to control both IVH and EVH. None of the 3 patients discontinuing have suffered a rise in serum ferriting after stopping desferasirox. Conclusions: Iron overload in PNH patients is a long-term rising complication, due to EVH under iC5 treatment. In our series, a third of patients under iC5 treatment required iron chelation therapy, due to moderate liver iron overload, with a median duration of 2 years and adequate response measured by liver MRi. 3 out of 4 patients were able to discontinue iron chelation therapy after switching to proximal complement inhibition and controlling EVH. Follow up on these cases will allow us to confirm if controlling EVH can prevent or reverse iron overload in PNH patients, and if such iron overload should be a reason to switch to proximal complement inhibition.