Evans, Michael

Abstract Background: Immune Thrombotic thrombocytopenic purpura (iTTP) is a relapsing disorder, resulting from depletion of ADAMTS13. With the goal of preventing clinical relapse there has been considerable interest in ADAMTS13 monitoring and preemptive treatment. Indeed, preemptive treatment with rituximab has shown significant promise and is now included in the 2020 International Society on Thrombosis and Haemostasis (ISTH) treatment guidelines. Evaluation of long-term outcomes of ADAMTS13 based preemptive treatment have generally relied on limited numbers of historical controls which did not incorporate matching for known risk factors for relapse such as race, number of prior episodes, and immunosuppression. Our study aims to leverage the data in the United States Thrombotic Microangiopathy (USTMA) iTTP registry to compare the clinical relapse-free survival (RFS) intervals between iTTP patients treated preemptively based on ADAMTS13 level and those treated only for clinical relapse base on clinical and laboratory manifestations of iTTP. Methods: We carried out a retrospective study utilizing the multi-center cohort of patients with iTTP from the USTMA Consortium (spanning 1985-2019 and containing 780 participant records). We selected for patients with relapsing disease treated either preemptively based on ADAMTS13 level or for clinical relapse. Each preemptively treated episode was matched to up to five clinically relapsed episodes using covariate balancing propensity score nearest-neighbor matching by age, gender, race, prior relapse status, acute treatment, treatment center, and calendar year, with exact matching required for treatment center and prior relapse status. Time from prior episode to relapse was compared between preemptively treated episodes and matched controls using a Cox proportional hazards model weighted by the matching weights, including subclasses as a cluster, and using cluster-robust standard errors. Results: We identified 1068 episodes of iTTP. Of these. Thirteen participants accounting for a total of seventeen preemptive treatment episodes were included in the data set however, we included only the thirteen first uses of preemptive treatment to avoid selection bias. These were matched with 59 episodes treated for clinical relapse. Over 70% of the included participants in both groups were identified as black/African American. Distribution of immunosuppressive medications used in clinically relapsed cases were not significantly different than those used in preemptive treatment, and corticosteroids were the most frequently used. Demographic and treatment data before and after matching are included in Table 1. There was no significant difference in RFS between the groups, hazard ratio 0.63 (95% confidence interval 0.26-1.54), p=0.31. Conclusion: To our knowledge this is the first study to use matching controls to obtain a causal estimate of the effect of ADAMTS13 monitoring based preemptive treatment on RFS in iTTP. In contrast to previous work, we did not observe a significant increase in RFS in the preemptively treated group. It is possible that the limited number of preemptively treated episodes herein did not provide sufficient power to detect a difference. However, given the significant effect size that has been proposed, based on prior work, we suspect other factors may have also influenced this finding. Previous analysis of the USTMA iTTP registry has shown a higher incidence of relapse in African American participants. While the precise reason for this finding is not yet clear, it is worth considering that there may also be differential response to preemptive treatment. Our study highlights the importance of continued efforts to determine the generalizability and efficacy of ADAMTS13 monitoring based preemptive treatment in iTTP. Figure 1 Figure 1. Disclosures Gangaraju: Alexion: Consultancy; Sanofi Genzyme: Consultancy. Masias: Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees. Parnes: Sigilon: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; I-mAb: Consultancy; Sunovion: Consultancy; Genentech/Hoffman LaRoche: Research Funding; UniQure: Membership on an entity's Board of Directors or advisory committees; Aspa: Consultancy. Mazepa: Answering TTP Foundation: Research Funding; Sanofi Aventis: Other. OffLabel Disclosure: Rituximab, an anti CD20 monoclonal antibody will be discussed in relation to treatment of thrombotic thrombocytopenic purpura.

Introduction The United States Thrombotic Microangiopathy (USTMA) Consortium consists of high-volume US referral centers that are committed to collaborative research in TMAs. The USTMA Immune Thrombotic Thrombocytopenic Purpura (iTTP) registry has compiled retrospective data on demographics, treatments and outcomes in patients with iTTP to create the world's largest database of patients with this rare disease. While there is consensus on the use of therapeutic plasma exchange (TPE) for treatment of iTTP, there are no large randomized trials on which to base use of rituximab. The drug is frequently used for refractory or relapsed iTTP, but is currently being used more frequently for de novo (first episode) iTTP. We queried the USTMA iTTP registry to determine whether relapse free survival (RFS) is superior when rituximab is added to TPE and corticosteroids for treatment of iTTP. We hypothesized that the addition of rituximab would improve RFS at 5 years in both de novo and relapsing iTTP. Methods Following IRB approval at each institution, investigators independently reviewed individual patient records to confirm diagnostic criteria and entered demographic, treatment and outcomes data into the REDCap database housed at the University of North Carolina. The diagnosis of iTTP was defined as ADAMTS13 < 10% or ADAMTS13 < 20% with an inhibitor or antibody detected at any point or a clinical diagnosis of iTTP based on presenting characteristics, response to treatment and/or relapsing phenotype before ADAMTS13 testing became available (N=173). Relapse was defined as a recurrence of iTTP after at least 30 days of remission (recurrence within 30 days was considered an exacerbation, or continuation of the prior episode). To explore the effect of rituximab added to TPE and corticosteroids, we first assessed the treatment effect in de novo iTTP patients and then separately in relapse. We constructed Kaplan-Meier curves to compare RFS for patients treated with rituximab plus corticosteroids versus corticosteroids alone in both groups, and compared RFS at specific time points using the Klein method. To better understand whether other patient variables had an effect on RFS in both de novo episodes and relapses, ordinary (time-to-event) and mixed-effects (recurrent time-to-event) Cox proportional hazards models were used to examine the relationships of treatment, race/ethnicity, sex, age, treatment year, and presenting signs/symptoms with the outcome. Analyses were conducted using R version 3.5.2 (R Foundation for Statistical Computing, Vienna, Austria). Results As of July, 2019, the USTMA database contains 775 unique study patients with a confirmed diagnosis of iTTP with 1397 unique iTTP episodes. The treatment of patients' de novo iTTP episode was available for analysis in 375 patients, 188 of whom were treated with corticosteroids alone, 131 with corticosteroids plus rituximab, and 56 with other therapies. RFS was significantly higher in patients treated with corticosteroids and rituximab compared to those treated with corticosteroids alone at 1 year (0.93 vs. 0.78, p=0.0002) and 3 years (0.82 vs. 0.66, p=0.004) but not 5 years (0.60 vs. 0.56, p=0.39). In addition, the risk of relapse decreased with later treatment year for de novo iTTP (hazard ratio (HR) 0.95, 95% CI 0.92-0.99, p=0.03), consistent with rituximab use increasing over time, and was increased in African Americans compared with Caucasians (HR 1.83, 1.10-3.06, p=0.02). We then explored the treatment effect in all iTTP relapses (743 relapses in 426 patients). Here, a significant (p=0.0007) interaction between treatment and race was found. Among African Americans, we found no difference in RFS when rituximab was added (HR 1.15, 0.81-1.62, p=0.43). However, among Caucasians, RFS was significantly improved when rituximab was added (HR 0.15, 0.06-0.35, p<0.0001). Conclusions For de novo iTTP, adding rituximab to corticosteroids for immunosuppression likely delays but does not prevent relapse. Unlike in de novo disease, in patients with relapsed iTTP, we found a novel and significant interaction between race and treatment: while Caucasians had significantly improved RFS with the addition of rituximab, there was no effect on RFS in African Americans. Further investigation is warranted to determine the mechanisms of this difference in the response to rituximab in relapsed iTTP to improve outcomes in African Americans. Figure Disclosures Marshall: Sanofi: Membership on an entity's Board of Directors or advisory committees. Farland:Sanofi: Membership on an entity's Board of Directors or advisory committees. Metjian:Sanofi: Membership on an entity's Board of Directors or advisory committees. Raval:Bayer, Inc: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Liles:Imara: Other: PI on Clinical trial- Sickle cell ; Shire: Other: PI on clinical trial Sickle cell ; Novartis: Other: PI on clinical trial Sickle cell . Baumann Kreuziger:CSL Behring: Consultancy; Vaccine Injury Compensation Program: Consultancy. McCrae:Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Chaturvedi:Shire/Takeda: Research Funding; Sanofi: Consultancy; Alexion: Consultancy. Zheng:Clotsolution: Other: Co-Founder; Shire/Takeda: Research Funding; Ablynx/Sanofi: Consultancy, Speakers Bureau; Alexion: Speakers Bureau. Cataland:Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Off Label Disclosure: rituximab for immunosuppression in TTP.