C5 inhibition in PNH: still effective and safe

In this issue of Blood, Kelly et al¹ demonstrate the strength of national or regional centralized management of rare disorders as well as the value of consistent and complete collection of data. The 509 patients studied were diagnosed with paroxysmal nocturnal hemoglobinuria (PNH) and had been treated with C5 inhibitor therapy over a 20-year period. The authors also demonstrate the long-term effectiveness of controlling intravascular hemolysis and its downstream effects as well as excellent overall survival, particularly in patients without bone marrow failure requiring treatment or in those whose condition had evolved into a malignant disease. These are not surprising new findings but very valuable information for treating physicians.

The introduction of eculizumab,² the first approved therapy for PNH, was transformational for hematologists familiar with outcomes of patients with this ultrarare disease when the only previous treatments available were supportive care or allogeneic stem-cell transplantation.³ Despite it being a “benign” disorder, patients were known to have poor outcomes with significant premature mortality, major life-impairing morbidities, and negative outcomes of pregnancy in mother and child.⁴ The role of intervention with this first-in-class monoclonal antibody targeting C5 was established in the largest placebo-controlled study to date of an ultrarare disease.⁵ The understanding of its effectiveness and limitations was subsequently enhanced by several observational studies from the International PNH Registry⁶ as well as national and center-specific reports. Ravulizumab, a second-generation C5 inhibitor with more favorable pharmacokinetic properties than eculizumab, has resulted in improved patient convenience, maintained effectiveness, and has a similar safety profile.⁷ 

In earlier work, Kelly and colleagues presented the definitive statement of survival outcomes for patients treated with PNH.⁸ Many of those patients had started treatment in clinical trials in which patients with significant bone marrow failure were ineligible to participate. Thus, the conclusion was that the survival rate in a broad group of PNH patients treated with eculizumab was nearly identical to that of an age- and sex-matched normal population. The authors show how that conclusion was somewhat optimistic and did not account for patients with comorbidities that could independently influence survival. Nevertheless, those patients with relatively “pure” PNH with intravascular hemolysis as the predominant clinical feature did do very well with C5 inhibition and demonstrated a nearly normal overall survival over a 20-year period. The study further emphasizes the importance of managing the comorbidities some of these patients suffer on their own merits---for example, treatment with C5 inhibitors cannot be expected to affect the hematologic consequences of aplastic anemia or myelodysplasia. The causes of death in the 91 patients who died highlights the importance of addressing infections prophylactically or promptly and aggressively in this population. Half of the infective deaths occurred in patients who had proceeded to allogeneic transplantation or were receiving immunosuppression for aplastic anemia.

In an era in which multiple new therapies are becoming available (many of them proximal complement inhibitors), the issue of incidence of normalization of hemoglobin concentration after eculizumab or ravulizumab therapy is important. Kelly et al clearly show that complete normalization only occurred in about 20% of patients. The clinical significance of this with regard to switching therapies to those with alternative mechanisms of action was not addressed with the data set.

The study mentions but does not define the outcomes of those patients with hemolytic PNH in the United Kingdom who were not treated, either because they did not meet nationally agreed-upon treatment criteria or due to patient refusal. It does, however, define how real-world experience may add value to earlier reports of new treatments during and after clinical trials, especially when the data collected are consistent and centralized.

Conflict-of-interest disclosure: J.S. has served on an advisory committee, as a consultant, on the speaker’s bureau, and has received travel assistance for Alexion Pharmaceuticals and Sobi Pharmaceuticals; served on an advisory committee and as a consultant for Novartis; and served as a consultant for ADARx, Kira Pharmaceuticals, and Samsung Bioepis.