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139 Obinutuzumab in Rituximab Refractory or Intolerant Immune-Mediated Thrombotic Thrombocytopenic Purpura

Program: Oral and Poster Abstracts
Type: Oral
Session: 331. Thrombotic Microangiopathies/Thrombocytopenias: Clinical and Epidemiological: A Brave New World: Novel Tools, Targets and Treatments in TTP
Hematology Disease Topics & Pathways:
Treatment Considerations, Biological therapies, Monoclonal Antibody Therapy
Saturday, December 7, 2024: 12:00 PM

Julia Weisinger1*, Jehane Fadlallah2*, Christelle Barbet3*, Francois Provot4*, Pascale Poullin5*, Antoine Neel6*, Manon Marie7*, Virginie Rieu8*, Tarik Kanouni9*, Olivier Moranne10*, Elie Azoulay11*, Bérangère Joly12*, Agnès Veyradier12* and Paul Coppo, MD1*

1Centre de Référence des Microangiopathies Thrombotiques, Service d'hématologie, Hôpital Saint Antoine, Assistance Publique-Hôpitaux de Paris and Sorbonne Université, Paris, France
2Service d'Immunopathologie Clinique, Saint Louis hospital, AP-HP, Paris, France
3Service de Néphrologie-Immunologie Clinique, CHRU de Tours, Tours, France
4Service de Néphrologie, Hôpital Albert Calmette, Lille, France
5Service d'Hémaphérèse, Hôpital de La Conception, CHU de Marseille, Marseille, France
6Service de Médecine Interne, CHU de Nantes, Nantes, France
7Service de Médecine Interne, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
8Service de Médecine Interne, CHU de Clermont-Ferrand, Clermont-Ferrand, France
9Hopital Saint-Eloi, CHU de Montpellier, Montpellier, France
10CHU De Nimes, Nimes, France
11Médecine Intensive Réanimation, Hôpital Saint Louis, AP-HP, Paris, France
12Service d'Hématologie biologique, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris Nord, Université Paris Cité, Paris, France

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.

Disclosures: Coppo: Takeda: Honoraria, Other: Member of CAB, speakers fees; Sanofi: Honoraria, Other: Member of CAB, speakers fees; Alexion: Honoraria, Other: Member of CAB, speakers fees.

OffLabel Disclosure: Obinutuzumab and rituximab are used off label in immune-mediated thrombotic thrombocytopenic purpura.

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