Session: 311. Disorders of Platelet Number or Function: Thrombotic Thrombocytopenic Purpura and Platelet Dysfunction
Hematology Disease Topics & Pathways:
Biological, Adult, Diseases, Bleeding and Clotting, Therapies, Immune Disorders, immunotherapy, Study Population, Clinically relevant, Thrombocytopenias, Thrombotic Disorders
Methods: Consecutive patients with aHUS enrolled in the Hopkins Complement Associated Disease Registry between January 2014 and December 2019 who initiated eculizumab therapy during an acute episode of aHUS were included in the study. Patients starting eculizumab in the setting of renal transplant were excluded from the analysis. Physician directed discontinuation and monitoring was done according to the protocol outlined in Figure 1. We also evaluated relapse rate and renal outcomes and examined clinical and genetic risk factors for relapse.
Results: Thirty-two consecutive patients who initiated eculizumab therapy for acute aHUS. Median age at initial diagnosis of aHUS was 44 (IQR 25, 53.5) years, 78.1% were female, and complement gene variants were present in 59.0% (13 of 22 patients with sequencing data available). Of these 32 patients, 25 (78%) discontinued eculizumab therapy after a median duration on therapy of 2.37 (IQR 1.06, 9.70) months. Six (18%) patients continued receiving it and 1 patient died during the first episode of aHUS. Of the 25 patients that discontinued eculizumab, 18 (72%) discontinued under physician direction (17 per protocol due to TMA remission including two with no renal recovery and end stage renal disease, and 1 due to non-response and a metabolic TMA thought more likely). Seven (28%) patients interrupted or discontinued therapy due to non-adherence.
Overall relapse rate after eculizumab discontinuation was 20.0% (5 of 25); however, the relapse rate was higher in the case of non-adherence versus a physician directed cessation protocol (42.8% versus 11.1%, P=0.074) (Figure 2). Of the five patients who relapsed, four were re-treated and achieved remission without a decline in renal function with eculizumab; one patient died due to recurrent TMA and hypertensive emergency in the setting of non-adherence. On univariate analysis, non-adherence with therapy [OR 8.25 (95% CI 1.02 – 66.19) P=0.047] was associated with relapse while underlying complement gene variant [OR 1.39 (95% CI 0.39-4.87), P=0.598] and presence/absence of a trigger for aHUS [OR 0.66 (95% CI 0.09-4.79), P=0.687] were not significantly associated with relapse. We examined relapse rates in patients with CFH or MCP variants (40%, 2 of 5), other variants (33.3%, 2 of 6), no variants (0%, 0 of 6), and sequencing not completed (11.1%, 1 of 9) (P=0.217). These analyses are limited by the small sample size and limited number of events (5 relapses), which precluded multivariable regression analysis.
Among patients that discontinued eculizumab, there was no significant decline in mean estimated glomerular filtration rate (eGFR) from the date of stopping eculizumab (47.09 + 28.28 ml/min/1.73 m2) until the most recent follow-up (56.95 + 28.02 ml/min/1.73 m2, one sided t-test P = 0.987). As seen in figure 3, improvement in eGFR (changed to a less severe eGFR category between stopping eculizumab and end of follow up) was seen in 9 of 25 patients (36%) and stable eGFR (no change in eGFR category) was seen in 15 of 25 patients (60%).
Conclusion: Eculizumab discontinuation with close monitoring is safe in the majority of patients with aHUS (with native kidneys), with low rates of TMA recurrence and nearly complete salvage with eculizumab retreatment in the event of a recurrence. CFH and MCP variants may be associated with higher risk of relapse, which needs to be evaluated in larger, multicenter studies.
Disclosures: Moliterno: Pharmessentia: Consultancy; MPNRF: Research Funding. Chaturvedi: Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Advisory board participation; Argenx: Other: Advisory board participation.
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