Treatment of Eculizumab Refractory Paroxysmal Nocturnal Hemoglobinuria: A Systematic Review about Current Treatment Options and Future Direction

Background:
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, debilitating condition of the hemopoietic stem cells. The morbidity and mortality depend upon the severity of hemolysis, bone marrow failure, and thrombophilia. Death can occur from complications such as thrombosis or bleeding. Hematopoietic stem cell transplantation is the definitive treatment option for PNH, but this treatment option is typically reserved for refractory or life-threatening cases including PNH related bone marrow failure due to its high transplant related morbidity and mortality. Eculizumab is a monoclonal antibody used as the first line treatment in the management of PNH and revolutionized its treatment. However, some patients with PNH are refractory to eculizumab or develop relapse of symptoms while on treatment with eculizumab. Until recently, we had limited treatment options for eculizumab refractory PNH.
Objective:
The aim of this study was to conduct a systematic review of the available literature on the treatment options available for the management of eculizumab refractory PNH.
Methods:
Two authors independently searched two databases according to the PRISMA guidelines resulting in eight studies. Four studies were about ravulizumab, two were about pegcetacoplan, one was about danicopan, and one was about iptacopan. Each study highlighted the safety and efficacy of the individual drugs.
Results:
From our review, we found that improved hemolysis rates were detected in all four of the alternative drugs. Ravulizumab was shown to improve LDH levels, BTH rates, FACIT-F scores, transfusion avoidance rates, and stabilized hemoglobin rates. Pegcetacoplan was found to improve hemolysis control and other clinical hematological outcomes. The addition of danicopan to eculizumab resulted in an increase of mean hemoglobin, a decrease in the transfusion rate, and an increase in the mean FACIT-F score. Finally, the combination therapy of iptacopan and eculizumab showed a significant reduction of LDH from baseline, with a marked improvement in hemoglobin concentrations and other biomarkers from baseline.