Eculizumab: Inhibiting C5 Earns a High Five in Prospective Pediatric, Multicenter, High-risk Transplant-associated Thrombotic Microangiopathy Study

Transplant-associated thrombotic microangiopathy (TA-TMA) is a complement-mediated endothelial injury syndrome that complicates 16 to 39% of hematopoietic stem cell transplants (HSCTs).^1-3  Prospective TA-TMA screening is essential for diagnosis and is recommended by the American Society for Transplantation and Cellular Therapy for all allogeneic and pediatric autologous HSCT recipients.⁴  The first consensus criteria for TA-TMA diagnosis were recently proposed in a collaboration of four international HSCT organizations (Table 1).⁴  High-risk TA-TMA (hrTA-TMA) survival prior to complement inhibition has historically been dismal at 16.7% one year post-transplant.²  The kidneys are commonly injured by TA-TMA; however, multiple studies have shown that multiorgan dysfunction syndrome (MODS) frequently occurs.^2,5,6  MODS contributes to TA-TMA mortality and may involve the cardiovascular system, gastrointestinal system, lungs, and central nervous system.^2,5,6  Eculizumab, a monoclonal antibody that binds to complement protein C5 and prevents generation of the tissue-injuring terminal complement complex C5b-9, has recently emerged as the leading frontline treatment for hrTA-TMA.^3,6,7  A prior single-institution study showed that eculizumab for hrTA-TMA improved one-year post-transplant survival to 66%.⁶ 

This new study by Sonata Jodele, MD, and colleagues — the first prospective multi-institutional study of eculizumab for the treatment of hrTA-TMA in children and young adults — was completed at three major transplant centers: Cincinnati Children’s Hospital Medical Center, Children’s Hospital Los Angeles, and Children’s Hospital of Philadelphia. All patients were prospectively screened for TA-TMA. Those who met four or more of seven Jodele criteria (Table 1) and had both high-risk features (elevated soluble terminal complement sC5b-9 and a random urine protein/creatinine ratio >1 mg/mg) were promptly treated with eculizumab. Eculizumab was dosed using loading, induction, and maintenance phases based on prior pharmacodynamic/pharmacokinetic studies.^8,9 

Twenty-one hrTA-TMA patients were treated with eculizumab, all of whom developed MODS (median of four organs involved). Survival at six months and one year after TA-TMA diagnosis was 71% and 62%, respectively, consistent with the prior eculizumab study and significantly improved from untreated historical controls.^2,6  Residual MODS was present in 26.7% of patients alive at six months after hrTA-TMA diagnosis.

Twelve patients received a calcineurin inhibitor (CNI) for graft versus host disease (GvHD) prophylaxis, with only three requiring CNI dose modification due to dialysis. The remaining patients continued their CNI through eculizumab therapy. Prior studies also support that CNIs can be continued through TA-TMA-directed therapy, which is particularly important given the poor outcomes in patients with TA-TMA and concurrent GvHD.^5,10 

All patients in the study developed MODS, with complications including acute kidney injury (100%), renal replacement therapy (29%), pulmonary hypertension (29%), pericardial effusion (62%), altered mental status (38%), and intestinal TA-TMA (43%). Improved survival attributable to TA-TMA therapies means more patients will survive MODS and be at risk for long-term morbidity from organ injury. For this reason, detailed functional assessments of commonly involved organs should be part of routine post-transplant monitoring for TA-TMA patients.

Some patients in this cohort developed MODS at the time of initial hrTA-TMA diagnosis, suggesting that less stringent high-risk criteria may facilitate earlier initiation of therapy and improved outcomes. A recent paper by Dr. Jodele and colleagues supports this conclusion, showing that untreated, moderate-risk TA-TMA patients had a 42% incidence of MODS and a one-year survival rate comparable to that of treated high-risk patients (71% vs. 66%).¹¹  This resulted in liberalization of the international consensus criteria for high-risk TA-TMA to require only one high-risk feature (Table 2).⁴ 

Finally, 13 out of 21 patients in this study required modifications to their eculizumab dosing due to inadequate drug levels and/or inadequate complement suppression. While previously proposed “standard dosing regimens” in TA-TMA are helpful as guidelines, they may be inadequate in many patients. Prior studies have shown the value of real-time drug level monitoring in TA-TMA patients, especially those with intestinal involvement and/or intestinal bleeding.^8,9  The availability of eculizumab drug level testing is increasing across academic and private laboratories and should therefore be pursued in TA-TMA patients treated with eculizumab.