Lack of correlation of eculizumab therapy in paroxysmal nocturnal hemoglobinuria (PNH) patients with myeloproliferative disorders, myelodysplastic syndromes, acute leukemias or aplastic anemia with long-term treatment

Abstract

7092 Background: PNH is a rare disorder characterized by bone marrow dysfunction and expansion of stem cell clones with somatic mutations in the PIG-A gene. Mutations in PIG-A result in deficiency of GPI-anchored proteins on the surface of blood cells including the complement inhibitor CD59. Lack of CD59 from PNH RBCs results in chronic hemolysis and leads to fatigue, thrombosis, anemia and poor quality of life. Development of myeloproliferative disorders, MDS, acute leukemias and AA/pancytopenia has been reported in PNH. In a previous retrospective analysis, 6.8% of patients developed either myeloid or lymphoid disorders and 1% developed acute leukemias. AA/pancytopenia has been reported to develop in PNH patients at a rate of ∼2%/year. Eculizumab prevents terminal complement activation and restores the PNH RBC clone resulting in improvements in anemia, thrombosis, fatigue, and quality of life. Eculizumab has been evaluated in 195 PNH patients initially enrolled in 1 of 3 parent trials who continued to receive drug in an extension trial (>382 patient years of exposure). Methods: Cell counts for RBCs, WBCs, platelets and neutrophils and leukocyte PNH clone size were assessed at baseline and at 18 mos. The frequency of MDS, leukemia and AA/pancytopenia was calculated across all eculizumab trials. Results: RBC, WBC, platelet and neutrophil counts did not change during 18 mos of eculizumab. PNH leukocyte clone size did not increase with eculizumab (median 96.7% at baseline vs 96.7% at 18 mos) suggesting that inhibition of complement does not destroy or result in the proliferation of PNH leukocyte clones. Additionally, the development of MDS (1/195 patients, 0.5%) and CMML (1/195 patients, 0.5%) during the treatment period was not increased over that expected. The case of CMML was attributed to a previously diagnosed high grade myelodysplasia. Interestingly, no new AA/pancytopenia cases developed during eculizumab, while 7–8 cases would have been expected from the reported rate. Conclusions: Long-term terminal complement inhibition with eculizumab does not increase myeloproliferative disorders, MDS, acute leukemias or AA/pancytopenia in PNH patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Alexion Pharmaceuticals Alexion Pharmaceuticals Alexion Pharmaceuticals Alexion Pharmaceuticals Alexion Pharmaceuticals