Response to Pegcetacoplan in Patients with PNH Assessed By Erythroid Clonal Size and Laboratory Markers

Introduction: Pegcetacoplan (PEG) is a proximal complement inhibitor used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH). By blocking the complement at C3 level, it inhibits intravascular hemolysis without inducing extravascular hemolysis due to C3 deposition, a typical side effect of C5 inhibitors (C5i). This mechanism of action explains its greater effectiveness in controlling anemia compared to terminal inhibitors. Response criteria to PEG can be assessed using laboratory markers of hemolysis as well as erythroid clonal size, which increases to achieve the same size as in leukocytes.

Aim: The aim of this study is to analyze the timing and degree of response to PEG treatment in PNH patients who have switched from C5i in the autonomous region of Madrid (Spain). Response is assessed using easily accessible laboratory markers such as hemoglobin (Hb-g//dL), absolute reticulocytes (Ret-x10e9/L), lactate dehydrogenase (LDH, ratio with upper limit of normal-ULN) and bilirubin (Br-mg/dL). We specifically focus on PNH-red cell clone size (RC-c) and its kinetics of increase, compared to PNH-granulocyte clone (Gr-c), using the RC-c/Gr-c ratio.

Results and discussion: Four patients (2 male/2 female) with ages between 24 and 61 years (median: 47) were diagnosed with PNH, two of them associated with aplastic anemia and myelodysplastic syndrome. Laboratory parameters and clonal size (median/range) at diagnosis were Hb:7.8/4.8-14.4; Ret 273/117-510; LDH: 9.00/1.08-14; Br: 1.5/1.2-2.3; Gr-c: 98.2%/16-99.7; RC-c: 49.1%/22.6-75.6; RC-c/Gr-c ratio: 0.5. All patients were treated with C5i for 48 months (3-82) and subsequently changed to PEG due to persistent DAT-positive anemia for C3d. Pre-PEG parameters were: Hb:9.6/9.1-10.5; Ret 301/268-333; LDH: 1.07/1.04-1.27; Br: 2.2/1.3-3.4; Gr-c: 97%/94-99.8; RC-c: 48.7%/29-68.5; RC-c/Gr-c ratio: 0.5. One month after switching, all laboratory parameters normalized, without anemia (Hb:12.8/12.6-14.4), reticulocytosis (Ret 64/47-98) or other signs of hemolysis (Br: 0.6/0.3-0.8), including LDH levels lower than ULN (0.75/0.70-0.80). Response to PEG was maintained in all patients at 3 months (Hb:12.8/12-13.5; Ret 123/87-150; LDH: 1.00/0.84-1.10; Br: 0.7/0.6-1.1) and in those two who achieved 12 months of follow-up (Hb:12/11.8-12; Ret 101/63-140; LDH: 1.01/1.00-1.03; BR: 0.7/0.7-0.8).

Regarding RC-c size, a significant increase was observed after one month of PEG treatment (RC-c: 99%/86.3-99.4), reaching a similar Gr-c size (RC-c/Gr-c ratio:1) or slightly lower at 3 months (RC-c: 94.8%/93.5-95.6; RC-c/Gr-c ratio:0.97), and at 6 months (RC-c: 96.1%/96-96.1; RC-c/Gr-c ratio: 0.98). Beyond 9 months of PEG treatment, RC-c size remained at a similar level in one patient (RC-c: 95.8%/Ratio: 0.96) but slightly decreased in the other one (RC-c: 77,7%/Ratio: 0.78) in the context of viral infection without clinical or analytical impact, with progressive recovery one month later (RC-c: 83%).

No acute clinical breakthrough hemolysis, or relevant side effects were communicated during PEG treatment.

Conclusions: After switching from iC5, PEG quickly increases Hb to normal values without evidence of signs of hemolysis as soon as one month after treatment. RC-c approaches Gr-c size from the first month onwards. The combination of laboratory markers and RC-c size allows correct monitoring of the response to PEG. Subtle reductions of RC-c could be detected after minor infections, serving as early predictive markers of a potentially relevant hemolysis.

Morado-Arias:Sobi: Honoraria; Novonordisk: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; sanofi: Membership on an entity's Board of Directors or advisory committees. Ballesteros:novartis: Honoraria, Speakers Bureau; astrazeneca: Honoraria, Speakers Bureau; sobi: Honoraria, Speakers Bureau; zambon: Honoraria, Speakers Bureau. Villegas:Agios: Consultancy.