The Importance of Eculizumab in Paroxysmal Nocturnal Hemoglobinuria: A Cohort Study
Authors: Yenerel Mustafa Nuri , Erdem Simge , Mastanzade Metban , Nalcaci Meliha 
Published: October 2019

Abstract
Introduction
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, often progressively debilitating and life-threatening acquired disease characterized by chronic, complement-mediated intravascular hemolysis. PNH is characterized by the deficiency of the endogenous glycosyl phosphatidylinositol-anchored complement regulatory proteins CD55 and CD59 and other proteins on the surface of blood cells, which results in chronic uncontrolled activation of the complement system at the site of the PNH cells and intravascular hemolysis and thrombosis. PNH may present in the absence of an underlying bone marrow disorder (BMD), as a condition secondary to BMDs, such as aplastic anemia (AA) or myelodysplastic syndrome, or as sub-clinical PNH. In this cohort study we will report clinical findings, management options and eculizumab response of 38 PNH cases in our clinic.
Materials and Metod
We followed 38 PNH cases in this cohort study. We used flow cytometric PNH clone detection test since 1993 but HAM's test and sucrose lysis test were the only tests for the PNH diagnosis in older cases. We used eculizumab in 20 of our patients who had transfusion dependent chronic intravascular hemolysis and/or thrombosis. All of of the patients were vaccinated for Neisseria meningitides, Pneumococcus and Hemophilus influenza type B prior to 2 weeks of initiation of Eculizumab. Eculizumab was administered 600 mg/day for 4 weeks and dosage was elevated to 900 mg/day at week 5, then 900 mg/day every other week as maintenance therapy. The response to therapy was evaluated by LDH, blood cell counts and haptoglobin levels. Clinical and laboratory findings, management options and treatment effect on survival curves were evaluated.
Findings
Thirty-eight PNH patients who were followed in our clinic since 1985 were enrolled in this study. Twenty of 38 were female and the median age was 35 years (ranging from 18 - 62). The oldest one has been followed for 32 years. Chronic hemolytic anemia and at least one lineage of cytopenia were seen in each patient during diagnosis.
Fifteen patients were diagnosed as AA and were treated with immunosuppressive therapy before PNH diagnosis. Following AA diagnosis, PNH was diagnosed on average 35 months (three to 192 months) . One of the patients was diagnosed as MDS and followed-up for five years with this diagnosis. Twenty-two of the cases were de-novo PNH disease. Thrombotic complications were seen at the diagnosis in two patients. Unfortunately, we also have seen thrombotic complications in 10 more patients during follow-up period before eculizumab availability.
Five of our patients were lost on eight, 14, 60, 86 and 260 months after their diagnosis. We lost two of them with infection and two of them with thrombotic complications. Fifth patient that we lost at 260 months of her follow-up had complete response with eculizumab and was deceased following a fall from height. Two of our patients went to abroad for treatment. Six of them were lost to follow-up. We currently follow 25 of 38 patients. We still use eculizumab in 20 of our patients. We used eculizumab in median 8 months after PNH diagnosis (One to 360 months). In 15 patients, transfusion dependent chronic intravascular hemolysis was the main indication and for the remaining 5 patients thrombosis was the main indication. Quality of life parameters changed significantly in all of the patients and we didn't observe any new thrombotic episodes. We used eculizumab as an important treatment option for a median 63 months (eight to 98 months) and we didn't encounter any side effects other than mild headache and flu-like symptoms in 5 of the cases.
Discussion and conclusion
PNH is a life-threatening disease and four of the patients in our cohort died in median 37 months of their diagnosis. Although thrombosis was the main mortality and morbidity reason in our cohort, we didn't see any thrombotic episodes under eculizumab treatment. Even in induction period of the therapy, both clinical and laboratory findings improved significantly with Eculizumab. None of our patients needed transfusion on eculizumab treatment. The survival of our PNH patients on eculizumab is excellent and we didn't lose any of our patients since induction of eculizumab therapy.
In conclusion, eculizumab is the first disease-modifying, targeted therapy for PNH and its availability has radically changed the management of patients with this rare disease.

Disclosures
Yenerel: Alexion: Honoraria, Speakers Bureau.