INTRODUCTION: Immune thrombotic thrombocytopenic purpura (iTTP) is caused by an autoantibody mediated deficiency of ADAMTS13 and characterized by recurrent episodes of life-threatening thrombotic microangiopathy. Rituximab (anti-CD20 monoclonal antibody) reduces relapse rates in many cases. This multicenter observational aimed at comparing durability of rituximab response (measured as relapse free survival, RFS) in first versus subsequent episodes of iTTP based on the clinical observation that patients with multiply relapsing disease may have attenuated responses to rituximab. METHODS: We first evaluated clinical RFS (time from rituximab treatment to clinical relapse) in the United States Thrombotic Microangiopathy Consortium retrospective iTTP registry that includes data from 15 high volume academic centers. We performed a subsequent analysis from the well-phenotyped Johns Hopkins University (JHU) and University of Minnesota (UM) prospective iTTP cohorts, that additionally include serial assessments of ADAMTS13 activity in remission, to confirm our findings and to evaluate overall RFS [a composite of clinical relapse, ADAMTS13 relapse including ADAMTS13 relapse treated with preemptive rituximab) which is a clinically relevant endpoint in the era of ADAMTS13 monitoring and receiving preemptive rituximab. ADAMTS13 relapse was defined as ADAMTS13 <20% without thrombocytopenia or symptoms. In both analyses, we included only patients with > 1 year follow up after treatment with rituximab (either during iTTP episodes or preemptive) and excluded those who received immunosuppression other than rituximab or steroids. Patients who started maintenance rituximab (every 3 or 6 months) were censored at that point). We used Cox regression to examine factors associated with clinical RFS and overall RFS including first versus subsequent rituximab treatment episodes as a covariate, and Kaplan-Meier survival curves to visualize these relationships. RESULTS: In the USTMA registry, 310 unique patients had a total of 384 iTTP episodes treated with rituximab (310 first, 53 second, and 21 were 3rd to 5th courses of rituximab) between 2003-2019. Presenting in relapsed iTTP [HR 2.10 (95% CI 1.24 - 3.58)], Black race [HR 3.12 (95% CI 1.68-5.80)] and second or subsequent rituximab course [HR 2.80 (95% CI 1.53-5.10)] were associated with clinical relapse in a Cox regression model that also included age, sex, and exacerbations. Median RFS was higher after the first compared with subsequent (2nd-5th) rituximab courses (6.0 vs 2.1 years, P = 0.04). Since race was significantly associated with clinical RFS in the Cox regression model, we evaluated clinical RFS after first and subsequent rituximab courses separately for Black and White participants. Among White patients, clinical RFS after the second or subsequent rituximab courses was not significantly different compared to the first course [HR=1.86 (95% CI 0.22-15.80), P=0.57]. However, in Black patients, clinical RFS was shorter after the second and subsequent rituximab courses [HR=2.82 (95% CI 1.52-5.24), P=0.001]. The JHU and UM cohort included 97 patients with 266 episodes of rituximab treatment. Similar to the USTMA cohort, median clinical RFS was shortened with reach subsequent rituximab course. Median overall RFS (time to clinical or ADAMTS13 relapse) was also longest after the first rituximab course [2.8 (IQR 2.0-6.0) years] followed by the second course [2.0 (IQR 1.2-3.6) years], and third and subsequent episodes courses [1.0 (IQR 0.5-2.5) years] (P< 0.001). Overall RFS was shorter in White patients and the loss of response durability with later courses was most prominent in Black versus patients. For examples, median overall RFS from the first to the third or later courses reduced from 3.6 years to 1.5 years for White patients, and from 2.7 years and 0.9 years in Black patients (Figure 1). CONCLUSIONS: Despite's rituximab's known effect of prolonging RFS in iTTP, the time to clinical relapse or ADAMTS13 relapse (often a precursor of clinical relapse) shortens with multiple episodes/treatment courses with an earlier ‘wearing off’ effect in Black patients especially those being treated in relapse. Patients who have had ≥ 2 rituximab courses may need closer monitoring and and consideration of maintenance rituximab or other immunomodulators.