Evaluation of risk for development of myeloproliferative disorders, myelodysplastic syndromes, or acute leukemias with long-term eculizumab therapy in paroxysmal nocturnal hemoglobinuria (PNH) patients

Abstract

7087 Background: PNH is a rare bone marrow failure disorder defined by stem cell clones with somatic mutations in the PIG-A gene. These mutations result in peripheral blood cells deficient in GPI-anchored proteins including complement inhibitors CD55 and CD59. Chronic lysis of PNH RBCs leads to severe anemia, life-threatening thrombosis, debilitating fatigue, and impaired quality of life. Previous studies have indicated an increased frequency of myeloproliferative disorders, MDS, and acute leukemias in PNH. In a previous retrospective analysis of 1,760 PNH patients, 6.8% developed either myeloid or lymphoid disorders and 1% developed acute leukemias. Eculizumab (Soliris) is a humanized antibody that prevents terminal complement activation. Long-term eculizumab treatment has been evaluated in 195 PNH patients (>250 patient years of exposure) and shown to significantly restore the endogenous PNH RBC clone resulting in improved anemia, as well as significant improvements in thrombosis, fatigue, and quality of life. Methods: Leukocyte clone sizes were assessed at baseline and 26 weeks for patients receiving eculizumab in the Phase III clinical trials (TRIUMPH and SHEPHERD) using flow cytometry. The frequency of MDS and leukemia was calculated as a percentage of the eculizumab-treated patients across all eculizumab trials. Results: PNH leukocyte clone size did not increase with eculizumab treatment (median 96.1% at baseline vs 95.5% at week 26; P=0.80, signed rank test) suggesting that inhibition of terminal complement does not destroy or result in the proliferation of PNH leukocyte clones. Additionally, the frequency of new MDS (1/195 patients, 0.5%) and CMML (1/195 patients, 0.5%) during the treatment period was not increased over that expected. The single case of CMML occurred in a patient previously diagnosed with and was attributed to high grade myelodysplasia. Conclusions: To date, eculizumab treatment of PNH patients does not increase the risk for the development of myeloproliferative disorders, MDS or acute leukemias. Patients on eculizumab will continue to be followed in a Global PNH Safety Registry. No significant financial relationships to disclose.