Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by 3 primary features: intravascular hemolysis, thrombophilia, and bone marrow failure.
These disease hallmarks are driven by the fact that red blood cells in PNH are deficient in both CD55 and CD59, making them vulnerable to complement-mediated lysis. This is because CD55 and CD59 are needed to physiologically modulate complement activation on the cell surface. In PNH, both complement regulators are also lacking on PNH granulocytes and platelets. Combined, they heighten the risk of dangerous episodes of hemolysis/thrombosis.
Scientists have distinguished 3 main subtypes of PNH. The first is classical PNH, in which glycosylphosphatidylinositol (GPI)-negative cell clones exceed 50%. Leukocyte and platelet count is usually normal, and there is typically no significant evidence of bone marrow failure.
In aplastic PNH, around 10% to 50% of GPI-negative cell clones are present. Typically, mild hemolysis with concurrent leukopenia and/or thrombocytopenia are present, and bone marrow failure is significant.
Read more about PNH etiology
The third subtype of PNH is “subclinical,” meaning that it bears some hallmarks of the disease but falls short of clinical significance. It is typically diagnosed in patients with myelodysplastic syndromes (MDS) or aplastic anemia. Patients tend to have between 1% and 10% GPI-negative cell clones and no evidence of hemolysis.
Thromboembolic events are among the most feared complications of PNH as they are the primary cause of death. Before the advent of modern therapeutics, prognosis was very poor, especially for patients with classical PNH.
Current Treatment Standards
“Treatment indications are driven by the two clinical presentations: hemolytic, without overt marrow failure, referred to as classic, hemolytic PNH; and with marrow failure, often described as aplastic anemia/PNH syndrome,” Risitano and de Latour wrote in the British Journal of Hematology.
Eculizumab remains the most important drug for the treatment of hemolytic PNH. It is a humanized monoclonal antibody targeting C5 of the complement cascade; essentially, it protects red blood cells from lysis. The evidence for the use of eculizumab in PNH is convincing: studies indicate that it raises 5-year survival from 65% to 96.5% and improves renal function in patients with chronic kidney disease.
Eculizumab is also remarkable in that 90% of patients respond to treatment; also, the same proportion of patients are weaned off red blood cell transfusions as those who continue to require them. One in 10 patients achieves complete remission, with hemoglobin levels fully normalized.
Read more about PNH treatment
Ravulizumab is another C5 inhibitor that is used to treat PNH. Like eculizumab, it helps control the disease and is associated with a positive prognosis and improved quality of life. It is similarly safe and well-tolerated. Its main advantage over eculizumab is that it is longer acting, requiring less frequent injections. Nonetheless, all patients who are on C5 inhibitor therapy should be vaccinated and receive penicillin prophylaxis, given that the greatest risk of terminal complement blockade is life-threatening neisserial infection.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only therapy capable of curing PNH by eliminating autologous PNH clones. However, not all patients have human leukocyte antigen-compatible donors. In addition, the risk of graft-versus-host-disease is ever present. As a result, morbidity and mortality rates are significant; a study assessing the survival of patients who received allo-HSCT revealed a transplant-related mortality of 42%.
Because intravascular hemolysis forces the body to ramp up its production of red blood cells, patients with PNH are typically administered factors necessary for their production, such as iron, folic acid, and vitamin B12 supplementation.
Experimental PNH Therapies
Eculizumab is administered intravenously every 2 weeks. This means that despite its successes, it incurs a high treatment burden on both patients and their carers. Hence, researchers are engineering alternatives that target the complement system but require less frequent administration.
Crovalimab was developed for diseases eligible for C5 inhibition; crucially, it can be self-administered subcutaneously. Studies indicate that subcutaneous crovalimab can result in thorough, sustained terminal complement pathway inhibition in PNH when injected on a monthly basis. This is potentially revolutionary as it significantly reduces the time and effort needed to achieve disease control.
However, the risk of breakthrough hemolysis remains a concern with proximal complement inhibitors like crovalimab. Evidence suggests that breakthrough episodes are more likely in complement-amplifying conditions (such as infections, pregnancy, and autoimmunity, among others) and subtherapeutic dosing.
Read more about experimental therapies for PNH
Scientists are also developing drugs that target the complement system in other ways. For example, danicopan treats PNH by targeting the complement factor D and is being investigated as an add-on therapy to C5 inhibitors such as eculizumab and ravulizumab. Studies have indicated that it can increase hemoglobin levels, alleviate PNH-associated fatigue, and contribute to transfusion avoidance.
Commenting on the treatment landscape of PNH, Risitano and de Latour wrote, “Very long‐term outcome is required, unmet clinical needs still remain, and room for improvements is vast.” It is imperative that we continue to deepen our understanding regarding the mechanisms underlying PNH and broaden our therapeutic objectives according to the latest developments in research. An objective appraisal of current studies suggests that an effective cure is still beyond reach, and PNH will likely remain a chronic disorder requiring continuous monitoring and the periodic administration of therapeutics in the near future.
Szlendak U, Budziszewska B, Spychalska J, Drozd-Sokołowska J, Patkowska E, Nowak J. Paroxysmal nocturnal hemoglobinuria: advances in the understanding of pathophysiology, diagnosis, and treatment. Pol Arch Intern Med. 2022;132(6):16271. doi:10.20452/pamw.16271
Risitano AM, Peffault de Latour R. How we(‘ll) treat paroxysmal nocturnal haemoglobinuria: diving into the future. Br J Haematol. 2022;196(2):288-303. doi:10.1111/bjh.17753