Obinutuzumab in Rituximab Refractory or Intolerant Immune-Mediated Thrombotic Thrombocytopenic Purpura
Authors: Weisinger Julia , Fadlallah Jehane , Barbet Christelle , Provot Francois , Poullin Pascale , Neel Antoine , Marie Manon , Rieu Virginie , Kanouni Tarik , Moranne Olivier , Azoulay Elie , Joly Bérangère , Veyradier Agnès , Coppo Paul 
Published: December 2024

Background
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare disease characterized by a severe deficiency in the von Willebrand factor-cleaving protease ADAMTS13 (A Disintegrin And Metalloproteinase with ThromboSpondin-1 motifs, 13th member) caused by autoantibodies, leading to microangiopathic hemolytic anemia, severe thrombocytopenia and ischemic end-organ damage. The B-cell depleting monoclonal antibody rituximab is used widely in the acute phase of the disease, and preemptively in patients experiencing a severe ADAMTS13 deficiency during follow-up (i.e., ADAMTS13 relapse) to prevent clinical relapses. However, in patients with refractoriness or intolerance to rituximab, further treatment options remain unclear. Based on previous case studies and small series of patients, obinutuzumab, a novel anti-CD20 monoclonal antibody might be effective in this context.
Aims and methods
Our aim was to evaluate the efficacy and safety of obinutuzumab in iTTP patients with intolerance or refractoriness to rituximab. In this inception study, data on basic demographic characteristics, treatment response, ADAMTS13 relapse and clinical relapse, survival and relapse-free survival (RFS) for ADAMTS13 relapse and clinical relapse were assessed in obinutuzumab-treated iTTP patients included in the French National Thrombotic Microangiopathy cohort. Patients treated before 1st June 2024 were involved in the analysis. Statistical analyses were performed using IBM SPSS statistical software. Data were summarized as counts and percentages. Medians and range (lowest and highest values) were indicated.
Results
Sixty patients were treated with obinutuzumab, with a median age of 44 years. Patients received a median 3 (range, 1-10) previous treatment lines. All patients received rituximab previously. Obinutuzumab was administered due to refractoriness to rituximab in 52% (n=31), intolerance to rituximab in 42% (n=25) and other causes (combined refractoriness and intolerance and short B-cell depletion) in the remaining cases (n=4). Obinutuzumab was used in the preemptive setting in 82% (n=49) and in the acute phase in 18% (n=11). Patients received a median of 3 infusions (range, 1-11). The majority of patients (85%, n=51) reached an ADAMTS13 activity of at least 20% after treatment, 72% (n=43) reached a normal activity, while 15% (n=9) failed to improve ADAMTS13 activity. Median combined (i.e., ADAMTS13 and clinical) RFS was not reached; the mean RFS was 33 months. Peripheral blood B-cell counts were assessed in 34 patients after obinutuzumab treatment, all of them had complete B-cell depletion within 2 months following treatment initiation. No statistically significant risk factors for refractoriness were identified; however, patients with previous refractoriness to rituximab tended to have a higher risk of refractoriness (p=0.052). Obinutuzumab-associated adverse events were reported in 11 cases, most of them were infusion-related reactions and none of them were severe. After a median follow-up of 11 months (range, 1-44), 2 ADAMTS13 relapses and 1 clinical relapse occurred; two patient died: one patient had intracranial bleeding during a relapse of iTTP and another patient with a history of severe cardiac disease died in cardiac arrest.
Conclusions
In this largest cohort of obinutuzumab treated iTTP patients, we provide evidence that obinutuzumab is an effective treatment option in both patients with rituximab intolerance, or refractoriness, with an acceptable safety profile. Although there is no direct comparison available, our results provide evidence that obinutuzumab partly circumvents rituximab refractoriness in a heavily pretreated patient population.