Real-world data on breakthrough hemolysis in patients with paroxysmal nocturnal hemoglobinuria treated with proximal and terminal complement inhibitors.

Taha Bat et al
University of Texas Southwestern Medical Center, Dallas, TX, United States

Background
  • Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare clonal disorder caused by a somatic mutation in the PIG-A gene. The resulting CD55 and CD59 deficiency causes complement-mediated hemolysis.
  • Breakthrough hemolysis (BTH), defined by reemergent intravascular hemolysis and classic PNH symptoms despite complement inhibition, remains a key clinical challenge that leads to persistent anemia, transfusion dependence, and major adverse vascular events.
  • This study examined real-world U.S. data on BTH in PNH patients on any complement inhibitor (CI) to identify risk factors, etiologies, and management of BTH events.
Results
  • The authors included patients with PNH between the ages 18-70 and treated with CIs between 2007-2025 at William P. Clements Jr. University Hospital and Parkland Health Foundation. A BTH event was defined as an acute decline >2 g/dL in hemoglobin within a six-month period with a corresponding LDH > 1.5 ULN and a minimum of 4 weeks between BTH events. Of the 87 patients with PNH at our institution, 18 experienced a BTH event.
  • The overall cohort had 7 females and 11 males, 9 of whom had concurrent aplastic anemia and 7 with a prior history of thrombotic events. At time of diagnosis, the median PNH granulocyte clone size, hemoglobin (g/dL), and LDH (units/L) were 96%, 7.8, and 1000 for the overall cohort (n=18) and 93%, 8.6, and 1250 for a subset with >2 BTH events (n=7). All patients with haptoglobin ordered (n=15) had levels below the limit of detection.
  • The median duration on CIs was 93.9 months (overall) and 105.2 months (>2 events), with a median of 2 CIs taken in both cohorts. The median duration, in months, on each CI was: eculizumab (34.6), ravulizumab (65.5), pegcetacoplan (38.1), iptacopan (7.5), and danicopan (27.3). All patients began treatment on terminal CIs eculizumab (n=15) or ravulizumab (n=3), though 11 of the patients on eculizumab later switched to ravulizumab due to poor symptomatic control.
  • Two patients were treated with C5 inhibitor zilucoplan (off-label). Nine patients were later switched to proximal CI monotherapy with pegcetacoplan (n=5) or iptacopan (n=4). Four patients were treated with factor D inhibitor danicopan (n=3) or iptacopan (n=1) concurrently with ravulizumab.
  • A total of 49 BTH events were identified; while on eculizumab (26 events, 12 patients), ravulizumab (14 events, 7 patients), ravulizumab and danicopan (6 events, 3 patients), pegcetacoplan (1 event, 1 patient), zilucoplan (2 events, 2 patients), and no events while on iptacopan. At time of BTH, the median decrease in hemoglobin (g/dL) was 2.5 (overall BTH cohort, n=49), 2.5 (eculizumab BTH cohort, n=26), and 2.8 (ravulizumab BTH cohort, n=14).
  • The median increase in LDH (units/L) was 228.5 (overall BTH cohort), 402 (eculizumab cohort), and 180 (ravulizumab cohort). Ten of 49 BTH events were due to 1 or more missed CI doses while 25/49 events were due to a complement amplifying condition such as infection (n=17), cancer (n=3), or pregnancy (n=1).
  • All except 2 BTH events occurred on standard dosing. Fifteen of 20 ravulizumab BTH events were on 8-week dosing and 5/20 events on 4-week dosing. Similarly, 16/26 eculizumab BTH events were on 14-day dosing, 8/26 events on 12-day dosing, and 2/26 events on <12- day dosing. The median time, in days, since last CI dose was 14 for eculizumab and 47 for ravulizumab.
  • Regarding management, 24/49 BTH events required transfused pRBC (median 2 units), 22/49 were treated inpatient, and 15/49 utilized IV fluids. Three events (across 3 patients) had acute complications, with 1 death from metastatic breast cancer comorbidity. Intensive CI administration was used in 3 events: pegcetacoplan 1080mg x 3 doses (n=1) and eculizumab 900mg x 1 dose (n=2).
  • Following BTH, 8 had adjustments in therapy: eculizumab to pegcetacoplan (n=1), eculizumab to ravulizumab (n=3), addition of danicopan to ravulizumab (n=2), and eculizumab dose increase from 900mg to 1200 mg (n=2). The former 2 changes showed improved PNH control and no subsequent BTH events, while the latter 2 changes resulted in continued hemolysis.
Conclusion
  • Patients should be strongly encouraged to minimize missed doses and infection risk, as these contributed to 71.42% of BTH events. Twelve BTH events were incidentally detected during routine CI administration; more frequent lab draws may be beneficial for patients with chronic hemolysis.
  • More data is needed to understand the BTH rates of different CIs and guide clinicians in BTH management