Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal hemolytic anemia caused by somatic loss-of-function mutations of the gene phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) in hematopoietic stem cells.1,2 In the absence of PIGA, the glycolipid glycosylphosphatidylinositol (GPI) which attaches proteins to the cell surface cannot be synthesized.3 As a result, 2 complement regulatory proteins, CD55 and CD59, are not anchored to the cell surface of red blood cells (RBCs).3
The main feature of PNH is chronic intravascular hemolysis due to persistent activation of the alternative pathway of complement on RBCs.4 Patients with PNH may also have severe paroxysms from conditions which amplify the complement pathway, such as infection, pregnancy, inflammatory states, or surgery.3,4 PNH can present in both male and female patients at any age and is typically associated with intravascular hemolysis, anemia, thrombosis, jaundice, and dark urine.4
“Diagnosis [of PNH] is actually quite easy,” Robert A Brodsky, MD, Director, Division of Hematology and Professor of Medicine at Johns Hopkins University, told Hematology Advisor. “The most common diagnostic assay is one that we developed, and it’s called FLAER. It’s based on a bacterial toxin that is one of the flesh-eating bacteria. What this toxin does is it binds to the GPI-anchored proteins and it oligomerizes the cells. In PNH the GPI-anchored proteins are missing, so no binding or oligomerization can occur. In short, [in this flow cytometry assay] normal cells will fluoresce and PNH cells won’t.”
After a diagnosis is established, the most important treatment goal is to reduce the risk for thrombosis, which is the leading cause of mortality in PNH.3 Dr Brodsky explained that unlike other conditions, anticoagulation therapy only partially mitigates thrombotic risk among patients with PNH or other complement-mediated disorders.
“When most people think about immunity, they think about B- and T-cells but complement is first and without complement, you can’t train B- and T-cells. Because [PNH] is a hematopoietic disorder, RBCs missing these [anchored regulatory] proteins are always under immune surveillance. That’s why these patients hemolyze and why they clot.”
Prior to modern treatment options, the median survival for PNH was about 15 years and patients had a reduced quality of life, requiring frequent blood transfusions and experiencing symptoms of extreme fatigue, headaches, and smooth muscle dystonias causing abdominal pain.3
“The only cure for PNH is a bone marrow transplant, but we seldom do that anymore because [newer] drug therapies are so effective,” said Dr Brodsky.
In 2007, the C5 inhibitor eculizumab was approved by the United States Food and Drug Administration (FDA)5 and the European Medicines Agency (EMA)6 for the treatment of PNH. Approval of its derivative, ravulizumab, followed in 2017 and 2018, respectively.7,8
Inhibiting C5 prevents thrombosis, decreases the need for blood transfusions, and improves quality of life. Eculizumab is administered via intravenous infusion every 2 weeks and ravulizumab, every 8.3
“The approval of these drugs was a big game changer. About 80% of patients became transfusion independent and the risk of clotting was reduced to a similar rate as an age-matched control. That really changed the natural history of the disease. Ravulizumab is no more effective than eculizumab, but it is much more convenient. Patients prefer only having six infusions a year,” said Dr Brodsky.
Eculizumab and ravulizumab do not eliminate the need for transfusion in all patients, however, and up to a third still have symptomatic anemia and occasionally require transfusion.3 Pegcetacoplan is another drug that was approved in 20219,10 which may be an option for patients who are not responsive to C5 inhibitors.3 This drug targets the complement pathway farther upstream than C5 inhibitors and prevents C3 convertase through steric hinderance.11 This drug is administered by subcutaneous infusion 2 to 3 times weekly.
In addition, there are one factor B (iptacopan) and two factor D (danicopan and BCX9930) inhibitors which are oral drugs that target farther upstream in the complement pathway that are currently in phase two and three clinical trials.3 In their current formulation, these drugs need to be taken two or three times daily. Dr Brodsky cautioned that if these drugs are approved in their current state, he would only consider them for patients who would be the most vigilant and compliant. Due to their short half-lives, missing a dose because medication is not available or the patient is unable due to gastrointestinal illness, the patient would need to seek emergency medical care.
Although there are now effective treatment options available to patients with PNH, Dr Brodsky emphasizes that clinicians should take into consideration that these drugs are expensive, up to hundreds of thousands of dollars yearly.12 “These are super, super expensive drugs. [These newer drugs] may have more convenient delivery methods, but we have thousands of patient years of evidence for C5 inhibitors. We know that [patients using them] don’t clot and breakthrough is very rare.” At this point, it remains unclear whether the benefits of these newer therapies justify potential costs. “I think as we gain more experience, it might be reasonable to move [the newer drugs] to frontline therapy in select patients. I emphasize in May of 2022, ravulizumab is my first-line therapy. But that could change as we get more experienced with these newer complement inhibitors,” concluded Dr Brodsky.
- Parker, CJ. Update on the diagnosis and management of paroxysmal nocturnal hemoglobinuria. Hematol Am Soc Hematol Educ Program. 2016, 1, 208–216. doi:10.1182/asheducation-2016.1.208
- Hill A, DeZern AE, Kinoshita T, Brodsky RA. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers. 2017;3:17028. doi:10.1038/nrdp.2017.28
- Gerber GF, Brodsky RA. Pegcetacoplan for paroxysmal nocturnal hemoglobinuria. Blood. 2022;blood.2021014868. doi:10.1182/blood.2021014868
- Fattizzo B, Serpenti F, Giannotta JA, Barcellini W. Difficult cases of paroxysmal nocturnal hemoglobinuria: diagnosis and therapeutic novelties. J Clin Med. 2021;10(5):948. doi:10.3390/jcm10050948
- Dmytrijuk A, Robie-S K, Cohen MH, Rieves D, Weiss K, Pazdur R. FDA report: eculizumab (Soliris®) for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Oncologist. 2008;13(9):993-1000. doi:10.1634/theoncologist.2008-0086
- EU/3/03/166: Orphan designation for the treatment of paroxysmal nocturnal haemoglobinuria. News release. European Medicines Agency. Accessed May 4, 2022. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu303166
- FDA statement on ravulizumab approval for paroxysmal nocturnal hemoglobinuria. News release. Food and Drug Administration. December 26, 2018. Accessed May 4, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ravulizumab-cwvz-paroxysmal-nocturnal-hemoglobinuria.
- European Medicines Agency. Ultomiris. Accessed May 4, 2022. https://www.ema.europa.eu/en/medicines/human/EPAR/ultomiris
- FDA statement on pegcetacoplan approval for paroxysmal nocturnal hemoglobinuria. News release. Food and Drug Administration. May 18, 2018. Accessed May 4, 2022. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-new-treatment-adults-serious-rare-blood-disease.
- European Medicines Agency. Aspaveli. Accessed May 4, 2022. https://www.ema.europa.eu/en/medicines/human/EPAR/aspaveli
- Mastellos DC, Yancopoulou D, Kokkinos P, et al. Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention. Eur J Clin Invest. 2015;45(4):423-440. doi:10.1111/eci.12419
- Burke JP, Sahli B, Broderick K, Gleason PP. Paroxysmal nocturnal hemoglobinuria real-world effectiveness of C5 inhibitors and cost assessment. Presented at: Academy of Managed Care Pharmacy (AMCP) Nexus. October 18-21, 2021.