Outcomes of Patients with Worsening Acquired Thrombotic Thrombocytopenic Purpura Despite Daily Therapeutic Plasma Exchange in the Phase 3 Hercules Trial

Introduction
Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening thrombotic microangiopathy. While daily therapeutic plasma exchange (TPE) is the mainstay of therapy, some patients are refractory to treatment and acute mortality remains 10%–20% despite treatment (Scully et al. Br J Haematol. 2012). In the Phase 3 HERCULES trial, 3 placebo-treated patients met the definition of refractoriness versus none in the caplacizumab group (Scully et al. N Engl J Med. 2019). There was a subgroup of patients with a complicated disease course despite daily TPE, without meeting the definition of refractoriness. Here, we describe outcomes of patients with suboptimal responses to TPE.

Methods
In this post hoc analysis of the HERCULES intent-to-treat population (caplacizumab, n=72; placebo, n=73), we identified patients with a suboptimal response to daily TPE, defined by decreasing platelet counts and increasing lactate dehydrogenase (LDH) after initial but nonsustained partial improvement of platelet count and LDH during daily TPE. Baseline disease characteristics (previous thrombotic thrombocytopenic purpura [TTP] episodes, platelet count, cardiac troponin I, LDH, serum creatinine, disease severity) and treatment outcomes (time to platelet count response, time to stop daily TPE, death, exacerbation) were descriptively summarized.

Results
No patients in the caplacizumab group and 8 (11%) patients in the placebo group demonstrated a suboptimal response to TPE. Baseline disease characteristics were variable (Table 1). Their median time to achieve platelet count response was 10.88 days and median time to stop daily TPE 13.5 days (ranges: see Table 1), compared with 2.88 and 7.00 days, respectively, in the overall HERCULES placebo group. One patient had worsening TTP that led to coma and death. Subsequent exacerbations were reported in 5/8 patients receiving placebo (63%).

Conclusions
These results show the unpredictability of suboptimal responses to TPE, which can be fatal, and which were not observed in the caplacizumab group. This highlights the importance of the fast and sustained protective response observed with caplacizumab treatment in patients with aTTP.