First-Line Rituximab Efficacy and Safety in Patients with Acquired Idiopathic Thrombotic Thrombocytopenic Purpura Experiencing a Non Optimal Response to Therapeutical Plasma Exchange: Results of a Prospective Multicenter Phase 2 Study From the French Reference Center for the Management of Thrombotic Microangiopathies.

Acquired idiopathic thrombotic thrombocytopenic purpura (TTP) is a rare form of thrombotic microangiopathy (TMA) resulting from an autoantibody-mediated defect in the von Willebrand factor-cleaving protease ADAMTS13. Therapeutical monoclonal antibodies directed against B-lymphocytes (rituximab) provided interesting results on preliminary studies.

We assessed rituximab efficacy and safety in adult patients with acquired idiopathic TTP who experienced a non optimal response to daily TPE, as defined by a refractory disease at day 5 or a flare-up of the disease within the first 15 days of standard intensive TPE treatment.

We conducted a prospective multicenter open-label single arm phase 2 trial. Patients with a non optimal response received 4 rituximab infusions at days 1, 4, 8 and 15, along with daily TPE continuation (R+ group). Peripheral blood B-lymphocyte count was evaluated before each rituximab administration, and then at 3, 6, 9 and 12 months. Outcome from the first TPE session was compared to this of 57 historical patients (R- group) treated by TPE alone (36 cases) or associated with vincristine (21 cases) for the same indication. ADAMTS13 activity was assessed at 3, 6, 9 and 12 months in both groups.

Both groups had comparable features on admission. Twenty-two patients were included to receive rituximab. All received 4 rituximab infusions. One patient died in a context of refractory disease, whereas the 21 others achieved durable remission. The median time to durable platelet count recovery was 20 days (extremes: 14-33), which required a median plasma volume of 950 mL/kg (extremes: 310-1940). The median time from the first rituximab infusion to durable platelet count recovery was 10 days (extremes: 5-27). All patients recovered platelet count before day-35. No relapse was observed during the first year. However, 3 (14.3%) patients relapsed after a mean follow-up of 21.2±13.8 months. In R- group, 4 patients died beyond day-5. The mean time to platelet count recovery and the mean plasma volume required to achieve remission did not significantly differ between survivors in R+ and R- groups (p=0.28 and 0.67, respectively). However, 13 (21.6%) patients of R- group were still thrombocytopenic at day-35 (p=0.01). Rituximab allowed a profound and sustained peripheral blood B-cell depletion as early as day day-4 despite associated daily plasmapheresis. Peripheral blood B-cells were undetectable from day-8 to the 6th or 9th month, and recovered at 1 year. Consistently, ADAMTS13 activity was significantly higher at 3, 6 and 9 months in R+ patients (85% [0-150], 90% [42-150], and 89% [92-125], respectively) when compared to R- patients (49% [0-150], 54% [0-130] and 40% [0-90], respectively, p<0.01, <0.05 and <0.001, respectively), which correlated with significantly lower levels of serum anti-ADAMTS13 antibodies (16 [0-77], 8 [0-18] and 10 [0-25] U/L, respectively, in R+ group and 44 [7-100], 33 [12-100] and 34 [10-130] U/L, respectively, in R- group; p=0.003, 0.007 and 0.04, respectively). However, these differences vanished at 12 months. Neither patient experienced side effects related to rituximab during infusions. No patient developed hypogammaglobulinemia. No significant infectious complications occurred during follow-up.

In patients with acquired idiopathic TTP, rituximab allows to shorten treatment duration in slow responders and prevents 1-year relapses by allowing a higher increase in ADAMTS13 activity. However, rituximab does not prevent long term relapses. Whether rituximab should be introduced systematically on diagnosis or only in patients identified as being slow responders with standard treatment remains a matter of debate which should be accurately assessed through larger, randomized trials.

No relevant conflicts of interest to declare.