PNH symptoms suddenly return for 50% of patients in treatment
Real-world study finds breakthrough hemolysis notably high with Empaveli
Despite therapy with complement inhibitors, half of individuals with paroxysmal nocturnal hemoglobinuria (PNH) develop breakthrough hemolysis, or BTH — when PNH symptoms suddenly return despite ongoing treatment — according to a real-world study.
The incidence and severity of BTH were found to be particularly high in patients treated with Empaveli (pegcetacoplan), an approved injection therapy for the rare acquired disease. Female patients and those with poorer treatment responses also had a greater likelihood of developing BTH, the data showed.
The researchers noted that “this is the first real-world analysis of BTH frequency among a large cohort of PNH patients treated with different complement inhibitors, outside the setting of clinical trials.” Suddenly recurring PNH symptoms “occurred with all [medications] and in approximately 50% of patients,” the team wrote.
“An important point,” the scientists noted, “is the practical management of BTH episodes since there is no standardization.”
Their study, “Characterization of Breakthrough Hemolysis in Patients With Paroxysmal Nocturnal Hemoglobinuria: An International Multicenter Experience,” was published in the American Journal of Hematology by researchers in Europe.
PNH is characterized by the abnormal activation of the complement system — a cascade of proteins that’s part of the immune system — that mistakenly targets the body’s red blood cells, leading to hemolysis, or red blood cell destruction.
Complement inhibitors like Soliris, Ultomiris used to ease PNH symptoms
While blood transfusions are commonly given to resupply red blood cells, the treatment landscape for PNH patients has improved markedly with the introduction of complement inhibitors. The first of these treatments to win widespread approval were Soliris (eculizumab) and Ultomiris (ravulizumab), which work to block complement activation by targeting a complement protein called C5. These are called terminal inhibitors.
Empaveli works by targeting C3, a different complement protein that acts upstream, or before, C5 in the complement cascade. It is known as a proximal inhibitor.
Even while on treatment, PNH patients may still experience BTH, which occurs when symptoms suddenly come back. BTH can range from mild elevations in markers of red blood cell destruction to severe anemia requiring transfusions and leading to increased thrombotic risk.
Despite the challenges associated with BTH — including a lack of standardized clinical management and diverse risks associated with different complement inhibitors — there currently are no established guidelines related to BTH severity.
To better understand the frequency and triggers of BTH episodes, as well as their clinical severity, a team led by researchers in Italy retrospectively analyzed real-world data from 198 PNH patients in Europe. All were treated with complement inhibitors across 10 centers — nine in Italy and one in the U.K. — over a span of 18 years, from 2007 to early 2025.
Soliris was the most common complement inhibitor, used in 88% of cases, followed by Ultomiris and other C5 inhibitors. Empaveli was used in 15% of patients, while other proximal inhibitors targeting other complement proteins were used in 14%. Study data showed that many patients received a sequence of different complement inhibitors over the follow-up period.
Treatment duration varied according to the agent used: Soliris was used for a median of 51 months, or more than four years, while Empavel was used for a median of 10 months. Each patient received a mean of two complement inhibitors.
PNH patients tracked over 18 years for episodes of symptom return
During the 18 years of follow-up, a total of 271 BTH episodes affecting 102 patients (51%) were registered. Among the patients, 18% experienced three or more episodes.
Of the 238 events for which trigger data were available, the majority (55%) were linked to infections. More than one-fifth (22%) had no identifiable cause, and 10% were associated with poor compliance with oral alternative pathway inhibitors. Other triggers were acute inflammatory conditions (4%), vaccinations (3%), and pregnancy (3%).
A total of 46% of patients with a BTH required blood transfusions. The second most common intervention was the use of preventive anticoagulants, which was administered in 16% of cases. Antibiotics were given in 11% of cases.
Adjustments to complement inhibitor schedules were made in 47 episodes, consisting of either administering an extra dose of the inhibitor or advancing the next scheduled dose. The use of complement inhibitors was never discontinued during BTH episodes, but four patients switched their therapy within one month of BTH. The other two patients switched within two weeks of treatment. The switch was either to Empaveli or other proximal inhibitors.
The overall incidence of BTH was 0.19 events per patient-year, with Empaveli having a significantly higher incidence (0.43) compared to Soliris (0.18) and other C5 inhibitors (0.18), as well as other proximal inhibitors (0.3).
Patients treated with Empaveli had the greatest drop in hemoglobin levels and the highest peak of lactate dehydrogenase (LDH), a marker of red blood cell destruction, which reached 7.35 times the upper limit of normal. As a result, transfusions were most often required for patients on Empaveli (82%), followed by Soliris (51%), other C5 inhibitors (51%), and other proximal inhibitors (40%).
A total of 56% of BTH events had a significant clinical impact with the development of blood clotting, need for blood transfusion, or a modification of the complement inhibitor schedule. The highest prevalence was seen in the Empaveli group (91%).
Regarding triggers, infections were the most common trigger across all treatment categories (32% to 49%).
Worse response rate seen in patients treated with Empaveli
The researchers assessed the recovery rate after one month, with the worst response rates seen in patients treated with Empaveli (44.5%), followed by other proximal inhibitors (36%), Soliris (28%), and other C5 inhibitors (11%).
A statistical analysis revealed that female patients were 2.75 times more likely to experience BTH events compared with male patients. More severe disease at diagnosis, as shown by elevated LDH levels, increased the risk by 1.14 times, and shorter time from diagnosis to treatment was a risk factor.
Treatment with Empaveli and other proximal inhibitors increased the risk by 4.85 times when compared with Soliris, and patients with poor responses to treatment were also 4.62 times more likely to develop BTH.
In this real-world study BTH events occurred in 50% of PNH patients, with higher incidence and severity in those treated with proximal inhibitors, particularly with [Empaveli].
The researchers also looked at the frequency of BTH events and found that a larger size of a specific type of blood cell associated with PNH, called monocyte, at the time of diagnosis was associated with three or more BTH episodes. They also found that male patients and those who had been pregnant were more likely to face severe BTH episodes.
Finally, lab tests revealed potential markers for a higher risk for clinical BTH events: a drop in hemoglobin levels of 2.85 grams per deciliter (g/dL) and an increase in LDH levels of 0.79 times the normal range were two important markers.
“In this real-world study BTH events occurred in 50% of PNH patients, with higher incidence and severity in those treated with proximal inhibitors, particularly with [Empaveli],” the researchers concluded.
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