Hematologic response to eculizumab in paroxysmal nocturnal hemoglobinuria

Irrespective of a remarkable effect on complement-mediated intravascular hemolysis, the hematologic benefit of PNH patients on eculizumab is extremely heterogeneous: indeed, a significant proportion of patients continue to require some blood transfusions. Different factors may be responsible for this insufficient hematologic response to eculizumab.

• 1.
  

  Bone marrow failure is the most obvious reason; it is clearly identified by low/inadequate reticulocyte counts in patients who do not show any laboratory sign of hemolysis, and it may require additional specific treatments (ie, bone marrow transplantation or immunosuppression).

  
  
• 2.
  

  A second possible reason is residual intravascular hemolysis; it may appear as “pharmacokinetic breakthrough,” recurrently appearing in the few hours preceding the next dosing of eculizumab (10%–15% of patients, who may benefit from changes in dosages of administration interval of eculizumab), or as “pharmacodynamic breakthrough,” occurring in concomitance with boosted complement activation (typically at time of infections).

  
  
• 3.
  

  A third possible reason is the presence of an intrinsic resistance to eculizumab due to mutated C5; this possibility has been recently demonstrated in a Japanese cohort, but it seems to be restricted to a limited number of patients (and possibly to specific ethnicities).

  
  
• 4.
  

  The forth and most common cause of residual anemia during eculizumab treatment is C3-mediated extravascular hemolysis ; it is mechanistically related to the pharmacologic effect of eculizumab and pertains to all PNH patients on eculizumab, even if it becomes clinically relevant in about one-third.

Hemolytic uremic syndrome

After its introduction in the clinic, eculizumab was tested in other indications; for the purpose of this review, discussion is limited to hemolytic anemias. Indeed, eculizumab has also been approved for the treatment of HUS, another rare disease that is characterized by thrombotic microangiopathy (TMA), leading to mechanic intravascular hemolytic anemia, platelet consumption, and end-stage renal disease. HUS can be distinct in a sporadic (typical) HUS form, which is acquired and usually associated with infectious events (typically by Shiga-toxin-producing Escherichia coli , STEC), and an atypical form (aHUS), which is inherited. Indeed, aHUS is associated with inherited mutations of different complement genes, including complement factor H (CFH), complement factor I (CFI), complement factor B (CFB), membrane cofactor protein, thrombomodulin, C3 convertase, and C3, clearly pointing out the pathogenic role of complement in this condition. The efficacy of eculizumab in aHUS has been initially demonstrated in 2 distinct prospective trials enrolling aHUS patients who were either resistant to plasma exchange (PE) and/or plasma infusion (PI), or who required PE/PI. In the first trial, which enrolled patients with evidence of platelet consumption, the increase in platelet count was used as efficacy endpoint, as an indicator of ceased TMA. After the initial 26 weeks of treatment, all 17 patients showed some increase in platelet count, with normalization of hematologic values in 88% of patients (15 of 15 who continued to receive the treatment, median treatment duration, 64 weeks). TMA-free status was achieved in 88% of patients (15/17), and only 2 patients required further PE (1 after eculizumab discontinuation due to study withdrawal). More than half of the patients also exhibited a substantial improvement in renal function (as measured by creatinine and GFR), with 4 of 5 patients on dialysis who did not require further procedures. In the second trial, which included 20 aHUS patients on chronic PE/PI, the primary endpoint was TMA-free status (defined as no platelet decrease and no requirement of PE/PI or dialysis), and it was achieved in 16 of 20 (80%) patients (in the remaining 4 patients the primary endpoint failed only because of a mild decrease of platelet count). Similarly to the previous trial, most patients (80%) achieved full normalization of hematologic values (platelets and LDH); however, improvement in renal function took longer and was observed in one-third of patients. These results on renal function are consistent with the mechanism of action of eculizumab, which immediately blocks the pathogenic complement derangement (as demonstrated by hematologic values) but requires longer time to recover from end-organ damages. Based on these studies, eculizumab has been approved by European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for the treatment of aHUS, and it represents the recommended therapy for this condition irrespective of the demonstration of a causative mutation, provided that other possible diagnoses (eg, thrombotic thrombocytopenic purpura) have been excluded. Nevertheless, a possible role of eculizumab has been suggested even for the treatment of STEC-HUS and of other forms of HUS.

Antibody-mediated hemolytic anemias

It has been hypothesized that eculizumab may be effective even for the treatment of autoimmune hemolytic anemias; so far, objective evidence is scanty and mostly limited to cold agglutinin disease (CAD). CAD is due to autoantibodies of immunoglobulin M (IgM) type, which are specific for some erythrocyte antigens (usually I, more rarely i). This autoimmune disorder may be primary, appearing as a chronic or subacute hemolytic anemia, or even as acute events secondary to some infections (eg, Mycoplasma pneumoniae , mononucleosis ), usually with a self-limiting course. The peculiarity of these auto-antibodies is that they have a typical thermal range, which allows the binding to erythrocytes in the cooler peripheral circulation, and subsequent complement activation in the warmer central circulation (mainly through the classical pathway). This complement activation may lead to MAC assembly and subsequent intravascular hemolysis, but more frequently simply results in an additional opsonization by C3 fragments, which may boost erythrocyte clearance through the reticulo-endothelial system. Indeed, CAD is commonly characterized by extravascular rather than intravascular hemolysis. Eculizumab has proven to be effective in blocking intravascular hemolysis in some cases of CAD, eventually leading to therapeutic benefit. Given the heterogeneous disease presentation and the broad spectrum of effector mechanisms (which may play different roles according to the specificity and the thermal range of patient-specific autoantibodies), it is not surprising that large experiences supporting the use of eculizumab in this condition are lacking.

Complement activation may theoretically occur in all antibody-mediated anemias, and its actual role in disease pathophysiology may differ according to the specific conditions; for instance, MAC-mediated intravascular hemolysis is also typical of isoagglutinin-mediated hemolysis as well as of paroxysmal cold hemoglobinuria. In addition, the complement cascade may contribute even to anemia due to some warm (and mixed warm/cold) autoantibodies, through both MAC-mediated hemolysis and C3-mediated extravascular hemolysis. Indeed, eculizumab has been considered in some refractory, life-threatening, severe hemolytic anemia as off-label, compassionate use ; future studies are needed to better understand the possible role of eculizumab in these specific conditions.

Antibody-based C5 inhibitors

Coversin

Another novel candidate complement inhibitor is coversin (also known as OmCI), a small (16 kDa) protein of the lipocalin family isolated from the tick Ornithodoros moubata . Coversin binds to human C5 and prevents its cleavage by C5 convertases ; it also exerts a broader anti-inflammatory effect by binding to leukotriene B4. Preliminary in vitro data in PNH suggest possible inhibitory effects on intravascular hemolysis as well as some effect in preventing C3 opsonization (this latter effect is not entirely clear, because it is not expected for a compound acting downstream in the complement cascade at the level of C5). However, coversin has shown amenable pharmacokinetic and pharmacodynamic profiles in a phase I study in healthy volunteers following subcutaneous administration; a clinical translation plan for PNH patients is planned.

Next-generation targeted C5 inhibitors

The spectrum of C5 inhibitors also includes several novel classes of compounds exploiting new technologies for specific design of more specific targeted therapeutics.