Abstract

Introduction: Thrombotic thrombocytopenic purpura (TTP) is a distinct and lethal subtype of thrombotic microangiopathy (TMA) requiring treatment with therapeutic plasma exchange (TPE). However, a significant proportion of patients suffer relapses of TTP, and predictors of relapse remain unclear. Whether rituximab (RTX) affects relapse rates in TTP is uncertain. We employed a multi-institutional, registry-based approach to study the effect of RTX on relapse in autoimmune TTP and identify predictors of relapse.

Methods: Consecutive adult patients presenting with acute autoimmune TTP (thrombocytopenia (<150 x 109 platelets/L) and schistocytes associated with an ADAMTS13 activity level of ≤10%) at 5 academic medical centers between 2004 and 2017 were studied. We recorded demographic information, laboratory parameters, treatment, and outcomes, including complications of TPE, death, and relapse. Extended Cox proportional hazards regression was used to identify variables associated with hazard of relapse. Kaplan-Meier survival analysis was used to study the impact of RTX on risk of relapse.

Results: Within our combined dataset, we identified 124 patients with autoimmune TTP. Patients were treated with a median (IQR) of 14 (8-22) TPE treatments until clinical remission was achieved. Seventy-five percent of patients experienced at least one complication from TPE; most common were mild urticarial reactions, but more serious allergic reactions including anaphylaxis occurred in 19% of TPE courses, and one patient died as the result of line-associated bacteremia during TPE. Of the 109 patients with 90-day or more follow up data, 8 (7.3%) died following presentation with TTP; five of these 8 deaths occurred in patients who presented in a moribund state or did not received TPE within the first 24 hours of hospitalization. Thirty-four patients (27%) subsequently relapsed, with a median time to relapse of 1.75 years. RTX was given to 48% of patients. The median time to the first dose of RTX was 12 (7-23) days following presentation. We observed a 3.6% increase per year in the proportion of patients presenting for the first time with acute TTP who were treated with RTX. Kaplan Meier analysis performed on the entire cohort did not show an overall difference in relapse free survival between patients who received RTX and those who did not (Figure 1) but did suggest the presence of a short-term benefit from RTX. A sensitivity analysis using only patients who presented with a first episode of TTP yielded similar results. Extended Cox multivariate analysis showed that the following parameters were independently associated with increased risk of relapse: younger age (HR=2.94, 95% CI: 1.2-7.2, P=0.018), non-O blood group (HR=2.11, 95% CI: 1.03-4.3, P=0.041), and history of a prior episode of TTP (HR=3.05, 95% CI: 1.4-6.6, P=0.005). By contrast, RTX reduced the risk of relapse (HR=0.15, 95% CI 0.03-0.68) but this protective effect appeared to diminish over time. ADAMTS13 inhibitor titer at initial presentation did not predict relapse.

Conclusions: Although a significant number of patients experienced complications from treatment with TPE, death from TTP was infrequent and generally associated with delay in seeking medical care or initiating treatment. Use of RTX was associated with short-term protection from relapse but not long-term relapse free survival. Age, non-O blood group, and prior TTP were significantly associated with an increased risk of relapse. Further studies in independent datasets are required to validate the role of these risk factors in identifying patients who would benefit most from therapies directed at prevention of relapse in TTP.

Disclosures

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.