How we('ll) treat paroxysmal nocturnal haemoglobinuria: diving into the future

Abstract

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by complement-mediated intravascular haemolysis, severe thrombophilia and bone marrow failure. While for patients with bone marrow failure the treatment follows that of immune-mediated aplastic anaemia, that of classic, haemolytic PNH is based on anti-complement medication. The anti-C5 monoclonal antibody eculizumab has revolutionized treatment, resulting in control of intravascular haemolysis and thromboembolic risk, with improved long-term survival. Novel strategies of complement inhibition are emerging. New anti-C5 agents reproduce the safety and efficacy of eculizumab, with improved patient convenience. Proximal complement inhibitors have been developed to address C3-mediated extra-vascular haemolysis and seem to improve haematological response.

Keywords: extravascular haemolysis; intravascular haemolysis; paroxysmal nocturnal haemoglobinuria; proximal complement inhibitors; terminal complement inhibitors.

Fig 1

Treatment algorithm. A tentative treatment algorithm of PNH; based on disease presentation and response to available treatments. BMF, bone marrow failure; EVH, extra‐vascular haemolysis; FU, follow‐up; GPI‐AP, glycosylphosphatidylinositol‐anchored proteins; IST, immuno‐suppressive therapy; IVH, intravascular haemolysis; LDH, lactate dehydrogenase; MAA/SAA, moderate/severe aplastic anaemia; PNH, paroxysmal nocturnal haemoglobinuria; SCT, stem cell transplantation.

Fig 2

Biology of complement‐mediated haemolysis in PNH on terminal complement inhibitors. (A) Initial complement activation. C3:H₂O generated by spontaneous hydrolysis of C3 (the so‐called “C3 tick‐over”) continuously initiates the complement cascade through its alternative pathway in the fluid phase. Due to the lack of CD55, PNH erythrocytes are unable to regulate complement activation on their surface, and C3bBb C3 convertase can be generated from C3 tick‐over and factor B cleavage operated by factor D. These C3 convertases generate further C3b, eventually self‐transforming into the C3bBbC3b C5 convertases. These steps are not affected by C5 inhibitors, which act downstream, making free C5 not available for the C5 convertases. (B) C3‐mediated extra‐vascular haemolysis. Terminal complement inhibitors (i.e. anti‐C5 agents) prevent the cleavage of C5 into C5a and C5b, thereby disabling the formation of the MAC and inhibiting intravascular lysis of PNH erythrocytes. Nevertheless, early steps of complement activation and upstream C5 cleavage remain uncontrolled, leading to opsonization of PNH erythrocytes with C3 fragments. C3‐opsonized erythrocytes can be recognised by C3‐specific receptors, expressed on professional macrophages in the liver and in the spleen, eventually resulting in extra‐vascular haemolysis. (C) Residual intravascular haemolysis due to pharmaco‐kinetic breakthrough. In the case of inadequate plasma levels of eculizumab (or any other anti‐C5 agent), free C5 becomes once again available for the C5 convertases. This eventually enables the terminal pathway of the complement, leading to MAC‐mediated residual intravascular haemolysis. (D) Residual intravascular haemolysis due to pharmaco‐dynamic breakthrough. During massive complement activation, C3 convertases may generate an excess of active forms of C3 (C3b), leading to the generation of “C3b‐rich” C5 convertases, which have higher affinity for C5. Thus, these high‐affinity C5 convertases may better compete with eculizumab for free C5, possibly displacing C5 from its inhibitor. This eventually enables the terminal pathway of the complement, leading to MAC‐mediated residual intravascular haemolysis. MAC, membrane attack complex; PNH, paroxysmal nocturnal haemoglobinuria.

Fig 3

Biology of complement‐mediated haemolysis in PNH on proximal complement inhibitors. (A) Modulation of complement activation on PNH erythrocytes on C3 inhibitors. The C3 inhibitor pegcetacoplan binds C3 in its naive and activated forms, eventually preventing the generation of C3 convertases on the surface of PNH erythrocytes. If the inhibition is pharmacologically sustained, the complement cascade is disabled in its early phases, resulting in inhibition of the MAC‐mediated intravascular haemolysis, and in the prevention of C3 opsonization (and thus of extra‐vascular haemolysis). (B) Modulation of complement activation on PNH erythrocytes on factor D inhibitors. The factor D inhibitor danicopan binds factor D, eventually preventing the cleavage of factor B, which is needed to generate C3 convertases. If the inhibition is pharmacologically sustained, the complement cascade is disabled in its early phases, resulting in inhibition of the MAC‐mediated intravascular haemolysis, and in the prevention of C3 opsonization (and thus of extra‐vascular haemolysis). (C) Modulation of complement activation on PNH erythrocytes on anti‐factor B inhibitors. The factor B inhibitor iptacopan binds factor B, eventually preventing its cleavage needed to generate C3 convertases. If the inhibition is pharmacologically sustained, the complement cascade is disabled in its early phases, resulting in inhibition of the MAC‐mediated intravascular haemolysis, and in the prevention of C3 opsonization (and thus of extra‐vascular haemolysis). MAC, membrane attack complex; PNH, paroxysmal nocturnal haemoglobinuria.