Effects of Eculizumab Therapy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Receiving Concurrent Immunosuppressive Therapy for Bone Marrow Insufficiency.

PNH is a progressively debilitating and life-threatening disease characterized by chronic complement-mediated hemolysis. PNH evolves from a somatic mutation of the PIG-A gene in hematopoietic stem cells that leads to the loss of the GPI-anchored complement inhibitor proteins CD55 and CD59 on the surface of blood cells. The loss of complement inhibitors leads to complement-mediated hemolysis that underlies the life-threatening thrombosis, chronic kidney disease, pulmonary hypertension, and organ damage, as well as significant morbidities including impaired quality of life and anemia in PNH. PNH cells can be found in up to 70% of patients with aplastic anemia (AA), a bone marrow failure (BMF) syndrome, suggesting a common immune-mediated pathophysiology for the initial evolution of both PNH and AA. However, each disease is associated with different morbidities and mortality that requires distinct treatments. The aplasia of AA may be effectively treated with immunosuppressive therapy (IST). The unregulated terminal complement activation and hemolysis associated with PNH can be effectively treated with eculizumab, a humanized anti-C5 monoclonal antibody that inhibits terminal complement activation. We conducted a post hoc review of the PNH clinical trial database (N=195) to evaluate the efficacy and safety of eculizumab in a population of patients (n=17) receiving concomitant IST. In the first group, 12 patients (11 with AA; 1 pancytopenic) were started on cyclosporine A (CSA) from 9.8 to 160 months before eculizumab treatment. Patients were treated with CSA and concomitant eculizumab for a median of 2.5 years (8 patients maintained IST throughout the entire clinical program; 4 patients stopped IST). The median PNH granulocyte clone size was 88%. At baseline, despite IST, there was on-going hemolysis as measured by elevated LDH (median, 1,150 U/L), patients were severely fatigued (median FACIT-fatigue 22.8) and had substantial transfusion use (median 10 U/year per patient). The addition of eculizumab therapy significantly reduced hemolysis (P=0.002, 0.003, and 0.002 vs baseline, at 3, 6 and 12 months, respectively) and significantly improved fatigue (P=0.033, 0.042, and 0.024 vs baseline at 3, 6 and 12 months, respectively) in patients concomitantly treated with IST. Fatigue improved with eculizumab treatment without significant hemoglobin change and prior to a reduction in transfusion requirements (P=0.036 and 0.019 vs baseline at 6 and 12 months, respectively). In the second group, 5 patients started on IST treatment while already undergoing treatment with eculizumab. Patient medical history included 2 patients with pre-existing AA, 1 with pre-existing thrombocytopenia and 2 with no recorded pre-existing cytopenia. The median granulocyte clone size was 92 %. At the individual principal investigator's discretion, IST was started 1 to 19 months after the start of eculizumab.IST regimens included CSA alone (1), CSA/Azathioprine (1), CSA/ALG (1), CSA/ATG (1), or CSA/alemtuzmab (1). At the time of the first dose of IST, absolute neutrophil count (ANC) ranged from 0.9 to 1.1×10⁹/L, platelet counts ranged from16 to 165 ×10⁹/L and reticulocyte counts ranged from 1.9 to 7.5. Three of the five (60%) patients demonstrated a partial response to IST treatment added to eculizumab (Patient 1: Hgb increased +3.4 g/dL; Patient 2: platelet count increased >2 fold, transfusion independent; Patient 3: ANC increased >2 fold, transfusion independent). In both patient groups, the overall and infection-related adverse event rates and serious event rates (calculated as # events / patient / month) were similar to the overall clinical trial population and did not increase over time. In summary, PNH may be associated with some degree of bone marrow failure (frequently from mild cytopenia to severe AA). We show that patients with BMF and PNH treated with IST alone can continue to experience hemolysis, contributing to patient morbidities due to PNH. Patients with hemolysis who are already on IST can be given eculizumab, reducing hemolysis and subsequent morbidities. While eculizumab is approved to treat PNH patients with hemolysis it is not expected to affect the aplastic bone marrow component. A proportion of the patients who develop worsening cytopenias on eculizumab will respond to IST. Finally, we demonstrate that eculizumab appears well tolerated in patients requiring IST for their marrow failure.