Can We Improve on Prednisone and Rituximab for Immune TTP? an Analysis of Alternatives to the Standard of Care from the Ustma TTP Retrospective Registry

Introduction:

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disorder caused by an autoantibody-mediated deficiency of ADAMTS13, for which the goal of treatment with immunosuppression is to induce long term remission. Currently, the standard of care (SOC), corticosteroids and rituximab (RTX), fails to induce long term remission in many patients. Therefore, we aimed to assess whether alternative regimens for treatment of iTTP episodes improved upon or were less efficacious in inducing relapse-free survival (RFS) compared to SOC, using data from the United States Thrombotic Microangiopathies (USTMA) Consortium iTTP Registry.

Methods:

The study cohort included participants with iTTP from the USTMA retrospective registry from 1990 to 2020. Methods of selecting confirmed iTTP participants from the registry as previously been described (Chaturvedi et al Blood 2022). Briefly, iTTP diagnosis was confirmed by the presence of ADAMTS13 deficiency, severe thrombocytopenia, and microangiopathic hemolytic anemia. Participants were followed for iTTP diagnosis or first contact after iTTP diagnosis until death or last contact. Treatment for all participants included daily plasma exchange until a normal platelet count was sustained for at least 2 consecutive days. We excluded participants who were followed for <90 days, received preemptive immunosuppressive therapy, or received therapies outside of the treatments of interest.

The primary outcome of interest was relapse-free survival (RFS). Relapse was defined as recurrence of iTTP after at least 30 days of remission and each relapse was treated as an independent event; recurrence within 30 days was considered an exacerbation or continuation of the prior episode. Treatment cohorts were defined as SOC (prednisone and rituximab 375mg/m² x 4 weekly doses), RTX-PLUS (375 mg/m2 x 4 weekly doses and additional immunosuppressants, e.g. vincristine), Non-RTX (corticosteroids plus non-rituximab immunosuppressants), and splenectomy.

Relapse-free survival following each treated episode was compared between treatment groups using mixed-effects Cox regression models with a frailty term for patient.

Results:

The USTMA Consortium iTTP Registry contains data from 790 unique participants from 15 institutions; 645 met inclusion criteria for this study, with 1049 episodes of iTTP. A total of 381 episodes in 326 participants were selected for inclusion in this analysis. We identified 277 episodes (241 patients) in the SOC treatment cohort, 53 episodes (34 patients) in the Non-RTX cohort, 36 episodes (36 patients) in the RTX-PLUS cohort, and 15 episodes (15 patients) in the splenectomy cohort. Non-RTX regimens included cyclosporine only (N=30), vincristine only (N=1), cyclosporine + prednisone (N=4) and vincristine + prednisone (N=18). RTX-PLUS regimens included RTX plus either cyclosporine (N=4), vincristine (N=6), cyclosporine + vincristine (N=1), vincristine + prednisone (N=24), or cyclosporine + prednisone (N=1). Patients who underwent splenectomy were categorized under the splenectomy category, regardless of any other concurrent therapies.

Compared to SOC, Non-RTX regimens and splenectomy were associated with reduced RFS (HR, 2.7; 95% CI, 1.6-4.5; p=0.002, and HR, 2.1; 95% CI, 0.9-4.7; p=0.08, respectively). However, RTX-PLUS regimens trended towards improved RFS (HR, 0.7; 95% CI 0.3-1.3; p=0.24). Additionally, given the previously reported racial disparity in iTTP outcomes in the SOC cohort (higher relapse risk in Black patients compared to White patients), we investigated whether a similar disparity existed between Blacks and Whites for the treatment regimens assessed in this analysis. Outcomes for Blacks trended towards inferiority compared with Whites but were not statistically significant, though the small cohorts limited this analysis.

Conclusions:

This analysis gives further evidence that rituximab-containing regimens likely induces longer remissions than other commonly used immunosuppressants and splenectomy. There were similar trends in the racial disparity for alternative regimens as is known in the SOC. Though limited by the small treatment cohort, a trend in improved RFS when other immunosuppressants are added to SOC suggests that clinical trials of adding other immunosuppressants to SOC are warranted.