A prospective multi-institutional study of eculizumab to treat high-risk stem cell transplantation-associated TMA

Abstract

High-risk, complement mediated, untreated transplant-associated thrombotic microangiopathy (hrTMA) has dismal outcomes due to multi-organ dysfunction syndrome (MODS). The complement C5 blocker eculizumab shows promising results in hrTMA, but has not been prospectively studied in hematopoietic stem cell transplant (HCT) recipients. We performed the first multi-institutional prospective study in children and young adults to evaluate eculizumab as an early targeted intervention for hrTMA/MODS. We hypothesized that eculizumab would more than double survival in HCT recipients with hrTMA, compared to our prior study of prospectively screened, untreated hrTMAs serving as historical controls. HrTMA features (elevated terminal complement (sC5b-9) and proteinuria measured by random urine protein/creatinine ratio (≥1mg/mg)) were required for inclusion. The primary endpoint was survival at 6 six-months from hrTMA diagnosis. Secondary endpoints were cumulative incidence of MODS 6 months after hrTMA diagnosis and 1-year posttransplant survival. Eculizumab dosing included intensive loading, induction, and maintenance phases for up to 24 weeks of therapy. All 21 evaluated study subjects had MODS. Primary and secondary study endpoints were met by demonstrating survival of 71% (P < .0001) 6 months after hrTMA diagnosis and 62% 1 year after transplant. Of fifteen survivors, 11 (73%) fully recovered organ function and are well. Our study demonstrates significant improvement in survival and recovery of organ function in hrTMA using an intensified eculizumab dosing and real time biomarker monitoring. This study serves as a benchmark for planning future studies that should focus on preventative measures or targeted therapy to be initiated prior to organ injury. This trial was registered at www.clinicaltrials.gov as #NCT03518203.

Graphical abstract

Figure 1.

Study schema. Figure displays overall study schema. Survival at 6 months from hrTMA diagnosis and at 1 year after HCT. LDH, lactate dehydrogenase; UA, urinalysis.

Figure 2.

Survival probability for recipient of HCT with hrTMA. (A) Kaplan-Meier estimate of survival probability in recipients of HCT with hrTMA treated with the terminal complement blocker eculizumab (n = 21) starting at hrTMA diagnosis. Survival at 6 months after hrTMA diagnosis was 71% (solid line; 95% confidence interval [CI], 55-94 [dotted lines]). (B) Kaplan-Meier estimate of survival in recipients of HCT with hrTMA treated with the terminal complement blocker eculizumab (n = 21) and untreated controls with the same risk TA-TMA (n = 12) starting at hrTMA diagnosis. Survival 6 months after hrTMA diagnosis in participants treated with eculizumab was 71%, and 18% in untreated historical controls. A P value for the comparison between the historical and treated cohorts is not provided because the 2 cohorts were not accrued concurrently. (C) Kaplan-Meier estimate of survival probability in recipients with HCT with hrTMA treated with the terminal complement blocker eculizumab (n = 21) starting at stem cell infusion (day 0). Survival at 1 year after HCT was 61.9% (solid line; 95% CI, 45-87 [dotted lines]).