Eculizumab Treatment Improves Survival in Patients with High-Risk Hematopoietic STEM CELL Transplant (HSCT)-Associated Thrombotic Microangiopathy (TMA)

Background: TMA with high-risk features at diagnosis, including terminal complement activation measured by elevated sC5b-9 and proteinuria, is associated with very high mortality as <20% of such untreated patients survive at 1 year after HSCT (Jodele et al, Blood 2014). In a therapeutic pilot study, we observed TMA resolution in 4 of 6 patients with high-risk TMA who achieved complement blockade using eculizumab, with dosing guided pharmacodynamically by measurement of total hemolytic complement activity (CH50) (Jodele et al, BBMT 2014).  We now present an expanded patient cohort treated with eculizumab.

Methods: 18 patients with high-risk TMA were treated using a dosing schedule adjusted to maintain a suppressed CH50 which correlated with a therapeutic eculizumab level of >99µg/mL.  Response was defined as resolution of hematologic TMA parameters, normalization of sC5b-9, and a 50% increase in the cystatin C-estimated glomerular filtration rate (CystC GFR).  Data were compared to historical controls from our prospective observational study with the same high-risk TMA features who did not receive eculizumab (n=11). In both cohorts, high-risk TMA was diagnosed prospectively using uniform clinical and laboratory criteria.

Results: 12 of 18 (67%) patients treated with eculizumab achieved resolution of TMA. Median number of eculizumab doses given for therapy were 16 (range 4-38).  All patients required frequent drug dosing 2-3 times per week for at least the first 2 weeks to achieve and maintain therapeutic eculizumab levels. Patients with sC5b-9 levels >488ng/mL at diagnosis (normal <244ng/mL) required 11-13 days of therapy to normalize sC5b-9 and to achieve terminal complement blockade before clinical response could be observed, while patients with sC5b-9 level ≤488 required 2-5 days to block complement.  All responders were able to discontinue therapy without TMA relapse with median follow up time of 37 weeks (range 8-128 weeks).   One responder died from GVHD three month after resolution of TMA. Six patients (33%) who did not respond to therapy died with active TMA after receiving median of 4 doses (range 2-24) of eculizumab.  We did not observe any infections or toxicities attributed to eculizumab. Overall survival was significantly better in the group treated with eculizumab as compared to untreated historical controls with high risk TMA (p=0.002, Figure).

Conclusions:   Terminal complement blockade by eculizumab improves  survival in patients with high risk TMA who otherwise have a very poor outcome.  Pharmacodynamic monitoring is needed to optimize drug dosing to achieve prompt complement blockade and clinical response.  Therapy can be safely discontinued after TMA is controlled.