Variable Eculizumab Clearance Requires Pharmacodynamic Monitoring to Optimize Therapy for Thrombotic Microangiopathy after Hematopoietic Stem Cell Transplantation

Abstract

Thrombotic microangiopathy (TMA) after hematopoietic stem cell transplant (HSCT) associated with terminal complement activation, as measured by elevated plasma terminal complement (sC5b-9) concentrations, has a very high mortality. The complement inhibitor eculizumab may be a therapeutic option for HSCT-associated TMA. We examined the pharmacokinetics and pharmacodynamics (PK/PD) of eculizumab in children and young adult HSCT recipients with TMA and activated complement to determine drug dosing requirements for future efficacy trials. We analyzed prospectively collected laboratory samples and clinical data from 18 HSCT recipients with high-risk TMA presenting with complement activation who were treated with eculizumab. We measured eculizumab serum concentrations, total hemolytic complement activity (CH50), and plasma sC5b-9 concentrations. Population PK/PD analyses correlated eculizumab concentrations with complement blockade and clinical response and determined inter-individual differences in PK parameters. We also compared transplant survival in patients treated with eculizumab (n=18) to patients with the same high-risk TMA features who did not receive any targeted therapy during a separate prospective observational study (n=11). In the PK analysis, we found significant inter-patient variability in eculizumab clearance, ranging from 16 to 237 mL/hr/70kg in the induction phase. The degree of complement activation measured by sC5b-9 concentrations at the start of therapy, in addition to actual body weight, were significant determinants of eculizumab clearance and disease response. Sixty one percent of treated patients had complete resolution of TMA and were able to safely discontinue eculizumab without disease recurrence. Overall survival was significantly higher in treated subjects compared to untreated patients (56% versus 9%, p=0.003). Complement blocking therapy is associated with improved survival in HSCT patients with high-risk TMA who historically have dismal outcomes, but eculizumab pharmacokinetics in HSCT recipients differ significantly from reports in other diseases like atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinurina. Our eculizumab dosing algorithm, including pre-treatment plasma sC5b-9 concentrations, patient’s actual body weight, and the first eculizumab dose (mg), accurately determined eculizumab concentration-time profiles for HSCT recipients with high-risk TMA. This algorithm may guide eculizumab treatment and ensure that future efficacy studies use the most clinically appropriate and cost-efficient dosing schedules.

The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy

“…Overall survival in this group was 56% at 1 year after TMA diagnosis, whereas these patients historically had very poor survival of 9% (P 5 .003), as we show in our recent prospective study. 27 The good response to complement blockade that we observed in patients with severe TMA supports our current hypothesis that complement system dysregulation plays an important role in TMA pathogenesis, and the complement system is a potential therapeutic target for this disease. Future studies will be needed to examine the response to complement blocking therapy in patients with different complement gene variants.…”

In vitro evidence of complement activation in transplantation-associated thrombotic microangiopathy

“…Recent data demonstrating remission of TA-TMA after use of the anti-C5 monoclonal antibody eculizumab suggest a central pathophysiologic role of the complement cascade. [8][9][10] The modified Ham test uses PIGA-null TF-1 cells, which lack expression of the complement regulatory proteins CD55 and CD59, rendering them increasingly vulnerable to complement-mediated cell death. 11 This test has been used in the research setting to distinguish microangiopathic diseases based on the degree of complement activation.…”

Változások az őssejt-transzplantációhoz társult thromboticus microangiopathia diagnosztikus kritériumrendszerében

“…Az eculizumabot elsőként 2014-ben Jodele és mtsai alkalmazták komplementgátló kezelésként őssejt-transzplantáción átesett gyermekekben [32]. Megfigyeléseik alapján TA-TMA esetén nagyobb eculizumabdózisokra van szükség a terápiás eculizumabszint eléréséhez, mint atípusos HUS esetén, és javasolt a szérumszint monitorozása a kellően hatékony kezelés eléréséhez [33].…”