Paroxysmal nocturnal hemoglobinuria in the era of complement inhibition
Authors: Antonio M Risitano
Journal: American Journal of Hematology (2016)

In this issue of American Journal of Hematology, Loschi et al. describe the impact of eculizumab as treatment of paroxysmal nocturnal hemoglobinuria (PNH) comparing patients receiving anti-complement treatment with a historical cohort. This is the largest comparison between eculizumab and previous supportive care, providing the strongest evidence of long-term beneficial effect of anti-complement therapy in PNH 1. Eculizumab (Soliris®, Alexion), is an anti-complement component 5 (C5) humanized monoclonal antibody (mAb) approved for the treatment of PNH in 2007. The efficacy of eculizumab has been demonstrated in two parallel clinical trials enrolling two different (even if overlapping) PNH patient populations. In the TRIUMPH study, which randomized eculizumab against placebo in transfusion-dependent PNH patients, eculizumab resulted in sustained control of intravascular hemolysis, with subsequent transfusion-independence in half of the patients 2. These results were confirmed in the SHEPHERD study, which included a broader population of PNH patients (patients with lower transfusion requirement and with moderate cytopenias were allowed entry) 3. A subsequent Extension study which included patients enrolled in the two previous studies (as well in the initial pilot trial) demonstrated that the inhibition of hemolysis can be sustained over time, and all hemolysis-related symptoms and clinical manifestation are controlled. In addition, complement blockade is associated with a substantial reduction of the thromboembolic risk, eventually suggesting that eculizumab may also impact on the leading cause of death in PNH 4. However, the impact of eculizumab on survival has not been specifically investigated. The most recent data on the natural history of PNH show a median survival of 22.5 years 5; thus, even the latest follow-up of these studies does not allow any conclusion about overall survival 6. The only report describing the long-term survival of PNH patients on eculizumab comes from the UK, where investigators showed 79 patients with PNH on eculizumab a 5-year survival of 95%, which was obviously better as compared with a small cohort of 30 patients who did not receive eculizumab 7. Here Loschi et al. took advantage of an established National PNH Registry to compare robust data on natural history with their National experience of eculizumab treatment, which may work as a surrogate in absence of prospective randomized trials (which could not be performed because of obvious ethical reasons). To allow a robust comparison between homogenous populations of PNH patients, the authors defined inclusion criteria, which are classic hemolytic PNH and thrombotic PNH. These criteria are not arbitrary, since they represent the well-established clinical indications to eculizumab treatment. Using these inclusion criteria the authors have selected 191 untreated patients within the French PNH Registry, and 123 patients among those who have received eculizumab in France between 2005 and 2014. The authors were able to demonstrate a statistically significant difference in overall survival, with 6-year survival of 92% for patients receiving eculizumab (which was overlapping to that showed by the UK group) compared to 68% of historical controls not receiving eculizumab. The survival advantage was retained even when only the most recent historical cohort (PNH diagnosed after 1985) was considered (6-year survival of 80%). The reason possibly accounting for this beneficial effect became obvious looking at the cumulative incidence of the most feared complications of PNH, which usually represent the most common cause of death. Indeed, the incidence of thrombosis was much lower in patients on eculizumab, with a 6-year cumulative incidence of 4% compared to 29% observed in untreated patients diagnosed after 1985. Notably, the only two patients who died because of thrombosis while on eculizumab had already extensive thrombosis at the time of treatment starting. These data confirm the previous finding from the registration studies, where the reduced incidence of thromboembolic events was based only on an intra-patient comparison which considered pre-treatment and post-treatment periods 5. Looking at other key events, there was no difference in clonal evolution (5% in both groups), whereas quite surprisingly the authors found a reduced incidence of aplastic anemia (AA) in patients on eculizumab (6-year cumulative incidence was 1%) as compared to that of historical untreated PNH patients (10%). The authors correctly state that these data need confirmation, and likely they may suffer from selection bias in the eculizumab cohort. However, since it has been suggested that complement activation may play a role in the differentiation of Th17 cells 8 and Th17 are involved in the pathophysiology of AA 9, a causal relationship between eculizumab and development of AA cannot be ruled out. Eculizumab has dramatically changed the treatment paradigm of PNH 3, 4, 6; indeed, two of the three major clinical manifestations of PNH—hemolytic anemia and thrombosis—largely benefit from eculizumab. Except PNH patients with overt AA, who should receive either immunosuppression or hematopoietic stem cell transplantation (HSCT) (according to age and donor availability), all the remaining PNH patients with symptomatic hemolysis and/or thromboembolic disease must receive eculizumab. With their work, Loschi et al. clearly demonstrate that this approach results in a substantial improvement of life expectancy, as compared with standard supportive care 1. The data shown in this study also suggest a better outcome in comparison to HSCT (which remain the only curative therapy for PNH), at least for patients with thromboembolic disease, which unfortunately exhibited high transplant-related mortality in a previous large retrospective EBMT study 10. Even if this latter study demonstrated excellent survival for patients transplanted for hemolytic PNH (in absence of AA and thrombosis), these patient's low mortality risk associated with the transplant procedure seems unacceptable. Nevertheless, HSCT remains an option for selected patients (in addition to the ones with severe AA associated to PNH), because a few PNH patients may have unsatisfactory response to eculizumab, eventually requiring further treatments. Indeed, even in the eculizumab era there are some unmet clinical needs in classic hemolytic/thrombotic PNH. Intrinsic resistance to eculizumab has been shown only in a few patients (all but one of Japanese ethnicity) carrying a C5 polymorphism which impairs the binding of eculizumab 11. For these patients there is an urgent need to develop alternative complement inhibitors 12; for all remaining patients, pharmacological inhibition of the terminal complement with subsequent control of intravascular hemolysis is the usual finding. In about 10–15% of patients pharmacokinetic breakthrough may occur, eventually requiring higher eculizumab doses (or shorter administration interval); the assessment of residual complement activity by CH50 may be useful to identify these patients, as recently demonstrated by Peffault de Latour et al. 13. However, irrespective of sustained control of intravascular hemolysis, the hematological benefit during eculizumab treatment is largely heterogeneous, with about one-third of patients still requiring some red cell transfusions, and another third showing persistent moderate anemia. We and others have demonstrated that the leading cause for this suboptimal hematological response is extravascular hemolysis secondary to C3 opsonization of PNH erythrocytes 14. This biological phenomenon can be detected in almost all PNH patients on eculizumab and may eventually become clinically meaningful in about half of them, possibly representing an emerging clinical need in the eculizumab era. Indeed, different novel strategies of pharmacological complement inhibition are under development, mostly aiming to intercept the complement pathway upstream, at the level of its key molecule C3 12, 15, 16. Irrespective of the initial fear, therapeutic complement inhibition has been proven extremely safe, with negligible risk of severe infectious complications when anti-meningococcal prophylaxis and other standard measures (e.g., immediate broad spectrum antimicrobial agents in case of any symptom of infection) are correctly taken. No risk of autoimmune complication has emerged, and even the possibility of developing human anti-human antibodies eventually neutralizing eculizumab has been recently ruled out 17. While the clinical benefit of eculizumab was not questionable even from initial registration trials, this study for the first time demonstrates that the control of intravascular hemolysis has a remarkable impact on disease course (mostly on development of thromboembolic complications) and on long-term survival of PNH patients. Based on the available data, this evidence is limited to PNH patients fulfilling the indication to eculizumab treatment. Can we extrapolate that a similar survival benefit may be anticipated even in patients with less severe disease? Given that eculizumab improves survival by reducing the thromboembolic risk, which is present in all PNH patients 5, is it justifiable offering eculizumab to more (or even all) PNH patients? In other medical conditions carrying substantial thrombotic risk (or even general cardiovascular risk), prophylactic strategies are usually recommended provided that they are safe and effective; however, clinical cost-to-benefit may also be influenced by financial issues. Eculizumab is the only effective prophylaxis of thromboembolic events in PNH, and apparently it works much better in primary prophylaxis rather than in secondary prophylaxis or in the presence of ongoing thrombosis. Since no safety concern has been identified, the only limitation to a broader use relies on its high treatment cost. Thus, this study also highlights that a further step in PNH treatment would be extending the access to anti-complement therapy to all PNH patients; hopefully, in the near future the availability of additional complement inhibitors may reduce treatment cost, eventually facilitating a broader use of anti-complement treatment in PNH.