https://orcid.org/0000-0001-6783-2301
In this issue of Blood Advances, Kulasekararaj et al1 have described the features defining clinically significant extravascular hemolysis (csEVH) in patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with an inhibitor of the fifth component of complement (C5), eculizumab or ravulizumab. This is a truly timely contribution as the treatment landscape for this rare disease continues to expand. It is of particular importance to optimize the outcome of patients in as many domains as possible, with the overall aim of achieving optimal patient well-being coming to the fore.
PNH was a potentially fatal disease prior to the availability of eculizumab and more recently ravulizumab, both potent inhibitors of C5. Historically, the natural history of the disease resulted in compromised survival of these young patients with the 10-year probability of survival being ∼50%.2 Eculizumab has improved the survival of patients to nearly that of an age- and sex-matched population.3 Although in patients with a coincident requirement for immunosuppressive therapy or experiencing clonal evolution, survival improvement, while significant, was not as good.4
Although intravascular hemolysis (IVH), which results from unopposed action of terminal complement on blood cells, results in the major morbidities of PNH, such as thromboembolic phenomena and renal impairment and consequently mortality, the effective inhibition of this process with C5-targeting agents has, along with impressive control of IVH, seen the emergence of hemolysis in the extravascular space. This manifests as recurrent or persistent anemia, with or without a transfusion requirement, with consequent impacts on quality of life, in particular, fatigue. This is quite different to breakthrough IVH, which usually results from pharmacokinetic or pharmacodynamic factors relating to the C5 inhibitor.5
The majority of patients treated with eculizumab or ravulizumab develop some evidence of extravascular hemolysis consequent to C3 deposition on surviving PNH red cells due to the lack of CD55 on the cell membranes. This renders them susceptible to destruction by the reticuloendothelial system after opsonization.6 A minority of such patients will develop csEVH, and this is the subject of this post hoc analysis in patients with PNH treated with C5 inhibitors in 2 randomized trials of ravulizumab. This subset of patients experiences fatigue of various severities and persistent or recurrence of anemia, which may result in red-cell transfusions. A definition was established of csEVH as a hemoglobin level <9.5 g/dL with a coincident reticulocytosis. The investigators determined that csEVH occurred in a little more than 20% to 25% of all patients in the studies, independent of which C5 inhibitor they received. Fatigue was described as mild in most patients and was stable and close to a normal population overall, based on formal tools for assessing fatigue and quality of life (FACIT-F scores and EORTC QLQ-C30).
The utility of newer therapies for the control of csEVH was out of scope for this study. These inhibitors of more proximal complement components when studied have generally shown an improvement in fatigue and quality of life in the experimental arms,7-9 so it can be quite difficult to truly estimate the degree of functional impairment that an eculizumab- or ravulizumab-treated patient actually is experiencing. Patients in the switching studies of proximal inhibitors were mainly those with persistent anemia, whose functional status was improved by new therapies, and the improvement in treatment-naive patients with these new complement inhibitors is now expected.
The development of a disease-specific, quality-of-life tool for patients with PNH10 will be a major step forward in assessing the true functional impact of current and future therapies for this disease, and it is pleasing that the International PNH Interest Group11 is involved in the development and assessment of such a prototype tool and will use the IPIG Registry for this purpose.
We have come a long way in the management of this disease, which, for the first 122 years12 after its recognition, had no effective treatment and now has a growing arsenal of highly effective medicines. Having made major advances in the control of major morbidity and mortality for these patients, it is time to increasingly focus on achieving normal lives for them.
Conflict-of-interest disclosure: The author declares no competing financial interests.
