Low Rate of Clinically Evident Extravascular Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with a Complement C5 Inhibitor: Results from a Large, Multicenter, US Real-World Study

Abstract

Purpose

Most patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with a complement protein 5 (C5) inhibitor achieve full control of terminal complement activity and intravascular hemolysis. The minority remains anemic and transfusion dependent despite this control. Etiology for ongoing anemia is multifactorial and includes bone marrow failure, breakthrough hemolysis, extravascular hemolysis (EVH) and nutritional deficiencies.

Patients and Methods

To evaluate the potential etiologies of hemoglobin levels <10 g/dL despite receiving C5 inhibitor therapy, we performed a retrospective US chart review of adult patients with PNH and treated for at least 12 months with eculizumab (n=53), ravulizumab (n=32), or eculizumab followed by ravulizumab (n=15). Clinically evident EVH was defined as at least one transfusion, reticulocyte count ≥120×10⁹/L and hemoglobin level ≤9.5 g/dL. Safety data were not collected. Mean treatment duration was 26.5±17.2 months.

Results

Treatment with C5 inhibitors significantly improved hemoglobin, lactate dehydrogenase, and number of transfusions versus baseline. Among the patients with hemoglobin <10 g/dL during the last 6 months of treatment (n=38), one patient (eculizumab) had clinically evident EVH, and 10 patients had active concomitant bone marrow failure. Bone marrow failure was a major contributor to hemoglobin <10 g/dL and transfusion dependence; clinically evident EVH was uncommon.

Conclusion

A range of hematologic causes need to be considered when evaluating anemia in the presence of treatment with a C5 inhibitor.

Keywords:

• real-world
• anemia
• intravascular hemolysis
• bone marrow failure

Abbreviations

BTH, breakthrough hemolysis; C, complement protein; EVH, extravascular hemolysis; GPI, glycosylphosphatidylinositol; IVH, intravascular hemolysis; IQR, interquartile range; LDH, lactate dehydrogenase; PNH, paroxysmal nocturnal hemoglobinuria; ULN, upper limit of normal.

Data Sharing Statement

Alexion will consider requests for disclosure of clinical study participant-level data provided that participant privacy is assured through methods like data de-identification, pseudonymization, or anonymization (as required by applicable law), and if such disclosure was included in the relevant study informed consent form or similar documentation. Qualified academic investigators may request participant-level clinical data and supporting documents (statistical analysis plan and protocol) pertaining to Alexion-sponsored studies. Further details regarding data availability and instructions for requesting information are available in the Alexion Clinical Trials Disclosure and Transparency Policy at https://alexionclinicaltrials.com/Disclosure-and-Transparency-Policy. Link to Data Request Form (https://alexion.com/contact-alexion/medical-information).

Ethics Approval and Consent to Participate

The study was conducted in accordance with International Society for Pharmacoepidemiology Guidelines for Good Pharmacoepidemiology Practices and applicable regulatory requirements. A waiver from the WCG Institutional Review Board under Privacy Rule: 45 CFR 164.512 was received prior to the start of the study. Patient-protected health information was kept confidential at all times and in accordance with the Health Insurance Portability and Accountability Act of 1996; no data that could directly identify patients were extracted. As such, patient informed consent was not needed. Providers were compensated at fair market value for the time needed to complete data abstraction and quality control procedures.

Acknowledgments

We thank Talia Miller (employee of Cardinal Health) for her contribution to the study, Hélène Dassule, PhD (employee of Alexion, AstraZeneca Rare Disease), for her medical writing support, and Oxford PharmaGenesis for their help with manuscript copy editing and formatting.

Author Contributions

All authors made a significant contribution to the work reported, have substantially revised and critically reviewed the article; have agreed on the journal to which the article has been submitted, have reviewed and agreed all versions of the article before submission and publication, agree to be accountable and take responsibility for the contents of the article.

Disclosure

JS has received research support from Alexion, AstraZeneca Rare Disease, BMS, CTI, Novartis, Kartos Pharma and Stemline Therapeutics;  consulting fees from Novartis; has been a speaker for Incyte, Alexion, BMS and Sanofi. She also owns stocks from Abbvie, chairs the Data and Safety Monitoring Board (DSMB) for NS Pharma and is a member of the DSMB for Apellis. AG and JK are employees of Cardinal Health Inc. YP, IT, AH and JRS are employees and shareholders of Alexion, AstraZeneca Rare Disease. DA provides consulting to Alexion, AstraZeneca Rare Disease. The authors report no other conflicts of interest in this work.

Additional information

Funding

This study was sponsored by Alexion Pharmaceuticals, Inc., Boston, MA (now Alexion, AstraZeneca Rare Disease).