Abstract
Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder caused by uncontrolled terminal complement activation, leading to intravascular hemolysis (IVH), high risk of thrombosis, and life-threatening complications. Terminal complement inhibition with C5 inhibitors ravulizumab (Rav), the standard of care for PNH treatment, and eculizumab (Ecu) have provided effective control of terminal complement activity and IVH and decreased rates of thrombosis. However, some patients may experience clinically significant extravascular hemolysis (EVH) with C5 inhibition. The proximal C3 inhibitor pegcetacoplan (Peg) offers broad complement blockade, providing control of both IVH and EVH, and improves hemoglobin levels and transfusion dependence in patients with PNH. However, breakthrough hemolysis (BTH) with proximal C3 inhibitors can be clinically significant, potentially life-threatening, and more severe than with terminal C5 inhibitors (Notaro R, Luzzatto L. N Engl J Med. 2022;387(2):160-166). Clinically significant EVH is defined as hemoglobin (Hb) ≤9.5 g/dL with an absolute reticulocyte count of ≥120×109/L. For patients with PNH and clinically significant EVH, Rav and add-on therapy with the complement factor D inhibitor danicopan (Dan) provide effective control of both IVH and EVH and reduce thrombotic risk. For patients who experience inadequate PNH disease control on Peg, switching to Rav with Dan add-on therapy may be a clinically viable, effective treatment option. Here, we report a case of PNH with BTH on Peg treatment that was successfully managed by switching back to Rav with Dan add-on therapy.
Case Study:A Filipino woman aged 32 years presented with pancytopenia after a minor incident resulting in a large hematoma, with no history of thrombosis or anticoagulation, and was diagnosed with PNH. The patient was treated intermittently with antithymocyte globulin and/or cyclosporine for ~5 years while receiving red blood cell transfusions. Due to ongoing significant BTH and resulting transfusion requirements (Hb, 7.4-12.6 g/dL; lactate dehydrogenase [LDH], 1,616 U/L), the patient started Ecu 600 mg every 2 weeks. With continued significant BTH over ~6 years (Hb, 7.8-9.9 g/dL; LDH, 260-4,037 U/L), Ecu was escalated up to 1,200 mg weekly. After continued transfusion requirements from significant BTH over ~5 years following the final Ecu dose increase, the patient switched to Rav 3,000 mg every 8 weeks, with dose change to 3,000 mg every 4 weeks after ~1.5 years of treatment (result: Hb, 6.7-8.0 g/dL; LDH, 547-562 U/L). The patient was switched to Peg 1,080 mg 2×/week after continued significant BTH and resulting transfusion requirements even after Rav dose change (Hb, 6.9-7.9 g/dL; LDH, 493 U/L). While receiving Peg for ~3 years, the patient experienced 3 hospital admissions in 16 months for BTH (first admission: Hb, 5.2 g/dL; LDH 2,846 U/L; second admission: Hb, 5.1 g/dL; LDH, 1,283 U/L; third admission: Hb, 5.4 g/dL; LDH 3,325 U/L). The patient required red blood cell transfusions during all admissions and Ecu infusions for the last 2. Despite the BTH episodes, the patient has not experienced thrombosis. The patient was then switched back to Rav with Dan add-on therapy a few months after the last admission, when dual therapy was approved, resulting in resolved hemoglobinuria (Hb, 10.2-10.3 g/dL; LDH, 331 U/L). After ~4 months of treatment, the patient missed 20 days of Dan add-on therapy and 1 dose of Rav due to insurance changes (result: Hb, 11.8 g/dL; LDH, 351 U/L). The patient restarted Rav with 2 loading doses 2 weeks apart. The patient experienced 1 mild episode of BTH ~4 months after restarting Rav (Hb, 9.9 g/dL; LDH, 382 U/L), resolving rapidly with her scheduled dose of Rav. At 57 years of age, the patient has resolved hemoglobinuria and continues Rav with Dan add-on therapy (Hb, 12.1 g/dL).Conclusions: After switching from terminal complement C5 inhibitors Ecu/Rav to the proximal complement C3 inhibitor Peg to treat symptoms of PNH, the patient was hospitalized 3 times in 16 months for recurrent, significant BTH. The patient switched back to Rav with Dan add-on therapy, resulting in resolved hemoglobinuria; the BTH episode was less severe and resolved rapidly. This case study supports the switch back to Rav with Dan add-on therapy for patients with PNH experiencing severe BTH on proximal complement inhibitors, such as Peg.
