Park, Yara

Abstract Introduction: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy due to reduced activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, 13). This disorder can be due to a congenital deficiency state or be acquired (immune TTP (iTTP)) due to an antibody which either inhibits or causes clearance of ADAMTS13. The aim of our study was to determine whether ADAMTS13 inhibitor titer at initial presentation could serve as a predictor of refractory disease and relapse in iTTP. We also measured clinical outcomes across different gender and racial subgroups. Methods: The United States Thrombotic Microangiopathy (USTMA) iTTP registry was used to extract patient information for two academic institutions in Eastern North Carolina. Descriptive statistics were used to analyze the data. The first iTTP episode recorded in the data base was used as the index episode. All patients included in the final analysis had an ADAMTS13 activity of <10%. An inhibitor level of 5 Bethesda units was arbitrarily chosen as the cutoff between low (<5) and high (>/5) inhibitor level. Response time was defined as the number of days of plasma exchange (PEX) required to achieve a platelet count of 150,000 for two consecutive days. Relapse was defined as occurrence of a new episode of iTTP 30 days after achievement of response. Refractory disease was defined as persistence of thrombocytopenia or absence of a sustained platelet count increment or platelet counts of < 50,000 despite 4-7 days of plasma exchanges and steroid treatment. Rituximab resistance was defined as lack of platelet recovery to more than 150,000 within 11 to 14 days of administration of the first dose of Rituximab. Results: A total of 161 patients with iTTP were identified. Ten patients had ADAMTS13 activity >10% and 15 patients did not have a reported inhibitor level. These subjects were not included in the final analysis. The cohort had 28% male (n =38/136) and 72% (n=98/136) female patients. There were more African American patients 73% (n=99/136) than Caucasians 24% (n=32/136). There were also 2 Hispanic, 1 Native American and 2 patients with unidentified race. Median ADAMTS3 inhibitor titer was 1.05 (Range 0-87). Forty three patients with ADAMTS13 activity <10 % had an inhibitor level of 0 (i.e undetectable).They were included in the low inhibitor group. Overall, 88% patients (n=120/136) had low inhibitor level and only 12% (n=16/136) had a high inhibitor. Thirteen percent females (n=13/98) and 8% (n=3/38) males had a high inhibitor level (p=0.387). Fourteen percent (n=14/99) African Americans and 6 % (n=2/32) Caucasians had a high inhibitor, p=0.23. In the low inhibitor group 30% (n=36/120) patients suffered at least one episode of relapse whereas 31% (n=5/16) had relapsed in the high inhibitor group. The median time to response was 6 days (range 1-76) in the low inhibitor group and 7 days (range 4-20) in the high inhibitor group (p=0.61). While looking at the various subgroups, median time to response for males was 6 days (range 4-21), females 6 days (range 1-76) , African Americans 6 days (range 3-29) , and Caucasians 6 days (range 1-76). The frequency of refractory disease was 31 % (n=5/16) in the high inhibitor group and 29% (n=34/119) in the low inhibitor group. At the time of enrollment in the registry, Rituximab was not a part of first line therapy. Only 26 out of 136 patients had received Rituximab. In the low inhibitor group 5 patients displayed Rituximab resistance whereas there were no patients in the high inhibitor group with Rituximab resistance. Conclusion: When evaluating patients presenting with iTTP in two centers in North Carolina, no correlation was found between a high inhibitor levels of >/ 5 Bethesda units and risk of relapse or refractory disease. A larger study is needed to evaluate this further. Disclosures No relevant conflicts of interest to declare.

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.

Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal hematologic disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and ischemic organ impairment. The incidence of iTTP is higher among African-Americans (AA), however, differences in presentation and outcomes have not been fully investigated. In a multi-center cohort of patients with iTTP from the United States Thrombotic Microangiopathy (USTMA) Consortium, we tested the hypothesis that AA race is an independent predictor of poor outcomes including iTTP related mortality and relapse. Methods: We queried data from the USTMA iTTP registry, which currently includes data from 785 individual patients from 15 institutions across the United States. Data from at least one iTTP episode are available for 734 patients. The cohort is 35.1% (N = 272) White, 58.7% (N = 455) African American, 0.4% (N=3) Asian, 1.8% (N=14) Hispanic, and 4.0 % (N=31) other/unknown race. We restricted our analyses to AA and White participants because of small numbers in the other groups. We compared presenting features and treatments using the chi-squared test and t-test for categorical and continuous variables, respectively. A relapse was defined as a recurrent iTTP episode occurring at least 30 days after last therapeutic plasma exchange. To evaluate relapse-free survival, we included only patients enrolled in the registry at their first TTP episode (144 White and 246 AA) since patients presenting with a relapse as their index episode are already confirmed to have relapsing iTTP. Kaplan Meier analysis was used to compare relapse-free survival in White and AA patients, and a Cox regression model was developed to evaluate the independent effect of race on relapse, adjusting for potential confounders including age, sex, and the use of rituximab. Results: Demographics and presenting features of 390 individuals (144 White and 246 AA) presenting with a first episode of iTTP are shown in Table 1. Presenting symptoms including fever, confusion, seizure, memory deficits, stupor, headache, stroke, chest pain, abdominal pain, fatigue, and dark urine were similar between Whites and AA except for petechiae, which were more frequently documented in Whites (28.8% vs 17.7%, p=0.011). Presenting laboratory studies were also comparable though AA had a higher rate of elevated serum troponin (50.6% vs 32.5%, p=0.003), lower hemoglobin level (8.27 ± 0.13 vs 8.81 ± 0.19, p=0.0176) and platelet count (20.3 ± 1.2 vs 26.2 ± 3.2, p=0.0432). In addition to therapeutic plasma exchange and corticosteroids, rituximab was administered to 23.7% of White patients and 22.7% of AA during their first iTTP episode (P=0.815). Median time to platelet count recovery (days of daily plasma exchange until normal platelet count for two consecutive days) was shorter in AA compared with White patients [5 (IQR 4, 10) vs. 8 (IQR 5, 14), log rank P = 0.004]. AA race remained a significant predictor of the shorter time to platelet count recovery [HR 1.44 (95% CI 1.12, 1.85), P=0.004] after adjusting for rituximab therapy [HR 0.60 (95% CI 0.0.46, 0.80), P<0.001], female sex [HR 0.95 (95% CI 0.73, 1.22), P=0.669], age [HR 0.99 (95% CI 0.99, 1.01), P=0.682], platelet count [HR 1.00 (95% CI 0.99, 1.04), P=0.820] and LDH at presentation [HR 1.00 (95% CI 1.00, 1.00), P=0.525]. Death during the first episode occurred in 8.9% of White patients and 5.5% of AA patients (P=0.206). Relapse-free survival after the first episode of iTTP was lower in AA than White patients (Figure 1). AA race was associated with the reduced relapse free survival [HR 1.79 (95% CI 1.08, 2.98), P=0.024] in a Cox regression model adjusted for age [HR 1.00 (95% CI 0.98, 1.01), P=0.683], sex [HR 0.96 (95% CI 0.60, 1.54), P=0.867], and rituximab therapy [HR 0.93 (95% CI 0.55, 1.59), P=0.806]. Conclusion: African Americans with iTTP have a higher relapse rate and shorter relapse free survival after the first episode of the disease compared with Caucasian patients, which is independent of age, sex and rituximab therapy. Contrary to our hypothesis, acute outcomes of iTTP (time to platelet count recovery and mortality) were not worse in AA patients. The factors contributing to the higher relapse rate in AA with iTTP need to be further investigated. Our findings suggest that AA patients may also benefit from closer follow up. Disclosures 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:Shire: Other: PI on clinical trial Sickle cell ; Imara: 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: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; 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. Zheng:Alexion: Speakers Bureau; Ablynx/Sanofi: Consultancy, Speakers Bureau; Clotsolution: Other: Co-Founder; Shire/Takeda: Research Funding. Cataland:Alexion: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy, Research Funding. Chaturvedi:Shire/Takeda: Research Funding; Sanofi: Consultancy; Alexion: Consultancy.