Paroxysmal Nocturnal Hemoglobinuria


Safety of Treatments for Paroxysmal Nocturnal Hemoglobinuria

patient care perspectives by Carlos M. de Castro III, MD

The availability of complement inhibitors has revolutionized the treatment of paroxysmal nocturnal hemoglobinuria (PNH), decreasing the risk of hemolysis and thrombosis and improving survival. However, these agents can also be associated with potential side effects, including an increased risk of infections, injection site reactions, and diarrhea, highlighting the importance of vaccines and the proactive management of side effects.

Expert Commentary
“I think that it is important to talk about safety with all the treatment options that are out there for PNH. We tell patients about the drugs and the possible side effects, and, based on these discussions, we decide which therapy to use.”
— Carlos M. de Castro III, MD

I think that it is important to talk about safety with all the treatment options that are out there for PNH. We tell patients about the drugs and the possible side effects, and, based on these discussions, we decide which therapy to use.


The route of administration makes a difference in side effects. Infusion reactions occur very rarely with intravenous drugs. Patients can develop an injection site reaction with subcutaneous drugs where the needles go into their bodies, and, in some patients, that can be bothersome. However, treatment discontinuation from either infusion reactions or injection reactions is rare. With pegcetacoplan, trials reported some mild diarrhea that was self-limited and did not tend to recur, with no drug discontinuation from that side effect.


The phase 3 trials of iptacopan looked at lipid profiles and saw increases in cholesterol and low-density lipoprotein (LDL) levels in a small minority of patients. Most cases were mild and were treated appropriately, depending on the lipid level. The long-term effect of this increase in lipids is not known. There is nothing tying complement to the lipid pathway, so these data made us all wonder what is happening and if it will lead to long-term effects, such as having more cardiovascular disease.


With all the complement inhibitors, we have to worry about the risk of infection with encapsulated organisms such as Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type b. Patients should be vaccinated against these encapsulated bacteria at least 2 weeks before starting therapy. However, if a patient has a serious blood clot and needs to go on the drug right away, you can treat them with antibiotics while they get vaccinated.


For the meningococcal vaccines, it is important to remember that the meningococcal conjugate (MenACWY) vaccine is boosted every 5 years, and the serogroup B meningococcal (MenB) vaccine is given in 2 doses at least 1 month apart. Even with vaccination, however, patients can get meningococcemia and meningitis, partially because other serogroups are not covered. So, every patient needs education about the signs and symptoms of meningococcal infections. They should also carry a card that they can give to the Emergency Department in such cases so that the doctors there who may have never seen a case of PNH know what is going on. Quick and appropriate management can help to prevent complications of meningococcal disease and possible breakthrough hemolysis secondary to complement activation from infection.


Centers for Disease Control and Prevention. Managing the risk of meningococcal disease among patients who receive complement inhibitor therapy. Updated February 7, 2022. Accessed March 27, 2024. https://www.cdc.gov/meningococcal/clinical/eculizumab.html


de Castro CM, Mulherin B, Patriquin CJ, et al. Efficacy and safety is maintained in adult patients with paroxysmal nocturnal hemoglobinuria receiving pegcetacoplan for up to 3 years [abstract 574]. Abstract presented at: 65th American Society of Hematology Annual Meeting and Exposition; December 9-12, 2023; San Diego, CA.


Kelly RJ, Höchsmann B, Szer J, et al. Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2015;373(11):1032-1039. doi:10.1056/NEJMoa1502950


Mbaeyi SA, Bozio CH, Duffy J, et al. Meningococcal vaccination: recommendations of the Advisory Committee on Immunization Practices, United States, 2020. MMWR Recomm Rep. 2020;69(9):1-41. doi:10.15585/mmwr.rr6909a1


Oliver M, Patriquin CJ. Paroxysmal nocturnal hemoglobinuria: current management, unmet needs, and recommendations. J Blood Med. 2023;14:613-628. doi:10.2147/JBM.S431493


Peffault de Latour R, Röth A, Kulasekararaj AG, et al. Oral iptacopan monotherapy in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2024;390(11):994-1008. doi:10.1056/NEJMoa2308695


Sharma V, Koprivnikar J, Drago K, Savage J, Bachelor A. Injection site reactions with long-term pegcetacoplan use in patients with paroxysmal nocturnal hemoglobinuria: a brief report. Adv Ther. 2023;40(11):5115-5129. doi:10.1007/s12325-023-02653-4

Carlos M. de Castro III, MD

Professor of Medicine
Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine
Member, Duke Cancer Institute
Duke University School of Medicine
Durham, NC