Eculizumab and Other Therapies for the Treatment of High-Risk Transplant-Associated Thrombotic Microangiopathy
Eculizumab (Soliris; Alexion), a C5 inhibitor preventing cleavage into C5a and C5b, is widely considered the first-line therapy for high-risk TA-TMA.
Introduction
Man in a hospital bed | Image credit: Gorodenkoff | stock.adobe.com
Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is a well-known complication of HSCT that is associated with high rates of mortality and morbidity.1 The pathophysiology of TA-TMA is complex but can best be characterized by several factors including endothelial cell activation, complement dysregulation, thrombocytopenia, and microvascular hemolytic anemia.2-4
Most cases of TA-TMA are clinically characterized by the TA-TMA triad: hypertension (>99% for age, sex, and height) generally requiring more than 2 antihypertensive agents, de novo thrombocytopenia refractory to platelet transfusions, and elevated lactate dehydrogenase (LDH). Some other findings include proteinuria, elevated D-dimers, and falling haptoglobin. Once TMA is suspected, individual patients can be further stratified based on their risk for poor prognosis, which can help guide treatment decisions.5,6 The diagnostic and risk stratification criteria can be found in Table 1.7
Eculizumab
Eculizumab (Soliris; Alexion), a C5 inhibitor preventing cleavage into C5a and C5b, is widely considered the first-line therapy for high-risk TA-TMA. In one prospective study evaluating the use of eculizumab therapy for high-risk TA-TMA, it significantly improved survival and recovery of organ function at 6 months post-treatment as compared with untreated historical controls.8 A primary prognostic marker is the evidence of circulating soluble terminal complement activation (elevated sC5b-9) at the time of TMA diagnosis. A large cohort study of pediatric patients with diagnosed TA-TMA shows that those with a higher sC5b-9 (defined as elevated sC5b-9 ≥244 ng/mL) at the initiation of therapy of eculizumab are less likely to respond and will subsequently require more doses.9 Individualized dosing may also be required for patients with significant bleeding to optimize outcomes.10
Another important point to note with eculizumab therapy is that all participants should be started on antimicrobial prophylaxis to cover N. meningitidis, because vaccination is known to be infective during the early transplantation phase. This should be continued until eculizumab clearance (serum drug concentration <11 µg/mL) and CH50 recovery to normal levels have been documented.8 For the same reason, patients and providers must be registered with the Soliris Risk Evaluation and Mitigation Strategies program before the patient can receive infusions of eculizumab.
Other Therapies
Therapeutic plasma exchange (TPE) has been used for TA-TMA, although it has since fallen out of favor due to low response rates of less than 50%, mortality rates remaining above 80%, and risks for significant complications.1,11,12 If TPE is used concurrently with eculizumab, supplemental doses of eculizumab should be administered per package labeling.13
Another agent that has shown promise as prophylaxis is defibrotide (Defitelio; Jazz Pharmaceuticals). Defibrotide is an antiplatelet agent that reduces endothelial cell activation and increases endothelial cell-mediated fibrinolysis. One small study of 25 individuals shows that, when used for pediatric patients undergoing HSCT who are at high risk for TA-TMA, defibrotide reduces the incidence of TA-TMA from 18% to 40% without prophylaxis to 4% with prophylaxis. Further research to validate this small study is warranted.14
Conclusions
Eculizumab is the recommended first-line treatment for high-risk TA-TMA as a complication of HSCT. This is supported by a recent prospective study in which eculizumab drastically improved survival over a historical cohort not receiving it.8
