Table II.

Reasons for inadequate haematological response to anti‐C5 agents and possible actions.

Cause	Cause	Prevalence	Mechanism	Clinical impact	Action
Intravascular haemolysis	Inherited C5 variants	Ultra‐rare (<1%, usually in Japanese patients)	Intrinsic resistance due to impaired binding of eculizumab (and of ALXN1210)	Minimal (but very significant for the few patients for whom there is no available treatment)	Switch to other investigational agents (mostly alternative C5 inhibitors)
	Recurrent pharmacokinetic breakthrough	10–15% of patients	Inadequate plasma level of eculizumab	Significant	Decrease interval of dosing (10–12 days) or increase dose of eculizumab (1 200 mg), or consider novel investigational agents
	Sporadic pharmacodynamic breakthrough	May occur in any patients	Massive complement activation due to concomitant clinical events	Irrelevant	None (treat the underlying cause)
Extravascular haemolysis	C3‐mediated extra‐vascular haemolysis	25–50% of patients (even more considering subclinical events)	Persistent uncontrolled activation of proximal complement, leading to C3‐fragment opsonization of PNH red blood cells and subsequent removal by professional hepato‐splenic phagocytes	Very significant	Consider investigational proximal inhibitors of the complement
Bone marrow disorders	Bone marrow failure	10–35% (depending also on initial patient selection)	Inadequate production of red blood cells	Significant	Treat underlying aplastic anaemia with either immunosuppression or bone marrow transplantation
	Clonal evolution to myeloid malignancies	1–5%	Additional stochastic somatic mutations	Relevant	Treat the myeloid malignancy

PNH, paroxysmal nocturnal haemoglobinuria.