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2636 Caplacizumab Frontline Added to Therapeutic Plasma Exchange and Immunosuppression Prevents Unfavorable Outcomes in Immune-Mediated TTP: An International Real-World Study of the TTP-IWG (The Capla 500 Project)

Program: Oral and Poster Abstracts
Session: 331. Thrombotic Microangiopathies/Thrombocytopenias and COVID-19-related Thrombotic/Vascular Disorders: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Bleeding and Clotting, platelet disorders, Diseases, thrombocytopenias
Sunday, December 10, 2023, 6:00 PM-8:00 PM

PAUL Coppo1*, Michaël Bubenheim2*, Ygal Benhamou, MD3*, Linus A. Voelker4*, Paul T. Brinkkoetter, MD5*, Lucas Kühne, MD6*, Paul N. Knoebl, MD7*, Maria Eva Mingot8*, Maria Cristina Pascual Izquierdo, MD, PhD9*, Javier De La Rubia10,11*, Julio Del Rio Garma, MD12*, Shruti Chaturvedi, MBBS13, Camila Masias, MD, MPH14, Marshall Mazepa, MD15, X. Long Zheng, MD, PhD16, Gyorgy Sinkovits, MD, PhD17*, Marienn Reti, MD, PhD18*, Christopher J. Patriquin, MD, MSc, FRCPC19, Katerina Pavenski, MD20, Tiago Boechat, MD21*, Joao Farias22*, Eduardo Flavio Oliveira Ribeiro23*, Michaela Larissa Lobo de Andrade23*, Agnès Veyradier, MD, PhD24,25,26*, Bérangère Joly Sr., PharmD27,28*, Raïda Bouzid29,30*, Kazuya Sakai31*, Masanori Matsumoto32, Ilaria Mancini, PhD33*, Pasquale Agosti, MD, PhD34*, Flora Peyvandi, Prof35, Matthew James Stubbs, MBBS, MRCP, FRCPath36*, Amjad Hmaid37*, Sobia Sharif, Sharif38*, Tina Dutt39*, Spero Cataland, MD40, Bernhard Lammle, MD41 and Marie Scully, MD42

1APHP - Hôpital St Antoine, PARIS CEDEX 12, France
2Department of Clinical Research and Innovation, Rouen, France
3Rouen University Hospital, Rouen, France, FRA
4Department II of Internal Medicine, University Hospital Cologne, Cologne, Germany
5Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
6University Hospital Cologne, Cologne, Germany
7Division of Hematology and Hemostasis, Department of Medicine I, Medical University of Vienna, Vienna, Austria
8Instituto de Biomedicina de Sevilla, IBIS, Servicio de Hematología, Hospital Universitario Virgen del Rocio, Sevilla, Spain
9Servicio de Hematología, Hospital Universitario Gregorio Marañón, Instituto de Investigación Gregorio Marañón, Madrid, Madrid, ESP
10Hospital Universitario y Politécnico La Fe, Valencia, Spain
11University Hospital La Fe, Valencia, Spain
12Complexo Hospitalario Universitario de Ourense, Ourense, ESP
13Division of Hematology, Johns Hopkins School of Medicine, Baltimore, MD, BALTIMORE, MD
14Miami Cancer Institute, Miami, FL
15Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN
16Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS
17Eötvös Loránd Research Network (Office for Supported Research Groups), Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
18Department of Hematology and Stem Cell Transplantation, South-Pest Central Hospital, Budapest, Hungary
19University of Toronto, Toronto, ON, CAN
20St. Michael's Hospital, Toronto, ON, Canada
21Hemorio, Rio De Janeiro, BRA
22HC - UFPR, Curitiba, BRA
23Curitiba, Brazil; Department of Hematology, Santa Lucia Hospital - Brasilia, DF, Brazil, Brasilia, Brazil
24Hôpital Lariboisière, Service d'Hématologie Biologique, Paris, France
25Saint-Antoine Hospital, Centre National de Référence sur les Microangiopathies Thrombotiques (CNR-MAT), Paris, France
26Biological Haematology - CRMW, Lariboisiere University Hospital, Paris, France
27AP-HP, Paris, France
28Hôpital Lariboisière, Paris, France
29Centre de Référence des Microangiopathies Thrombotiques, AP-HP, Paris, France
30HôPital Saint Antoine, PARIS, FRA
31Department of Blood Transfusion Medicine, Nara Medical University, Nara, Japan
32Department of Hematology and Blood Transfusion Medicine, Nara Medical University Hospital, Kashihara, Japan
33Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milano, MI, ITA
34Università Degli Studi Di Milano, Department of Pathophysiology and Tran, Milan, ITA
35Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
36University College London Hospitals NHS Foundation Trust, London, UK, London, GBR
37University College London Hospitals NHS Foundation Trust, London, GBR
38University College London Hospitals NHS Foundation Trust, London, UK, London, ENG, GBR
39Liverpool University Hospitals NHS Foundation Trust, Liverpool, GBR
40Division of Hematology, Department of Medicine, Ohio State University Comprehensive Cancer Center, Columbus, OH
41Universitätsklinik Für Hämatologie Bern, Mainz, Germany
42University College London, London, ENG, United Kingdom

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) results from autoantibody-mediated severe deficiency of ADAMTS13, the Von Willebrand factor (VWF)-cleaving protease. In this context, ultra-large VWF multimers accumulate in the circulation, leading to increased platelet clumping, with subsequent severe thrombocytopenia, microangiopathic hemolytic anemia and multiorgan failure. The anti-VWF nanobody caplacizumab is licensed for adults with iTTP. Prospective controlled trials and national real-world studies have provided evidence that caplacizumab improved outcome of the acute phase of the disease. However, whether caplacizumab decreases mortality, and the optimal timing of caplacizumab initiation, remain to be determined. To address these questions, an international survey, the Capla 500+ project, has been conducted.

An academic call for observations involving experienced teams from 10 worldwide countries recruited 942 adult patients treated with a regimen of daily therapeutic plasma exchange (TPE), caplacizumab and immunosuppression with corticosteroids ± rituximab (caplacizumab group). Cases were compared to historic controls (control group) randomly selected from 2015 to 2018 by 4 teams in a 2:1 ratio (N=495), treated with TPE and immunosuppression. Primary outcome was 3-month survival post-first TPE. Key secondary outcomes were refractoriness and exacerbations, time to clinical response, number of TPE to achieve clinical response, time to ADAMTS13 activity recovery ≥20%, and caplacizumab-related adverse events.

Clinical presentation and severity were comparable between groups (Table). All patients received TPE in both caplacizumab and control groups, in association with corticosteroids (99% and 93%, respectively), and rituximab (92% and 71%, respectively) frontline or as salvage therapy. Caplacizumab was started within 3 days (715 patients), or delayed by≥4 days from first TPE (218 patients); for those with delayed initiation, caplacizumab was added for management of exacerbation or refractoriness (63 cases) or a slow improvement to TPE/immunosuppression (155 cases). The 3-month survival post-first TPE in the caplacizumab group was 98.6% vs 93.3% in the control group (p<0.0001). Failure to achieve clinical response was 5-times less likely in the caplacizumab group as compared to the control group (95% confidence interval, 0.1-0.37, p<0.0001). Deaths in the caplacizumab group occurred after a median of 4.5 days (interquartile range [IQR], 3-5), mostly due to uncontrolled iTTP. Patients receiving caplacizumab experienced less refractoriness and exacerbations, and required less TPE to achieve clinical remission than controls (p<0.0001 for all), regardless of the use of rituximab. Forty-six patients experienced an exacerbation following caplacizumab interruption while ADAMTS13 activity was still undetectable. Time to ADAMTS13 activity ≥20% was shorter in the caplacizumab group (p=0.01) (Table), where rituximab was more systematically used. In patients with delayed caplacizumab initiation, clinical response was obtained after a median of 4 days (IQR, 2-8) following caplacizumab introduction. This result was comparable to the time to clinical response obtained in patients who initiated caplacizumab within 3 days of the first TPE (median, 4 days [IQR, 3-6], p=0.8). In patients with early caplacizumab initiation, unfavorable outcomes were particularly infrequent (death, 1%; refractoriness, 1.1%; exacerbations, 5.3%), and time to clinical response in survivors was half the time compared to control group survivors (p<0.0001) (Figure). Caplacizumab-related adverse events occurred in 220 patients (23%). They consisted of major bleeding (N=19, 2.2%), including: digestive tract bleeding (N=8), intracranial hemorrhage, severe central venous catheter insertion bleeding, metrorrhagia (N=2 cases each). Clinically relevant non-major bleeding (N=34, 3.7%), non-clinically relevant non-major bleeding (N=114, 14%), and inflammatory reaction at the injection site (N=35, 4.5%) were also reported.

This unprecedented, international academic effort on such a rare disease provides convincing evidence that caplacizumab added to TPE and immunosuppression prevents unfavorable outcomes during the acute phase of iTTP, including mortality, and alleviates the burden of care at the potential expense of rare, major bleeding events.

Disclosures: Coppo: SANOFI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALEXION: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Benhamou: SANOFI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Voelker: Alexion: Honoraria; Sanofi-Genzyme: Honoraria; Bayer: Honoraria; AstraZeneca: Honoraria; GC Biopharma: Honoraria. Brinkkoetter: AstraZeneca: Honoraria; Bayer: Honoraria; Vifor CSL: Honoraria; Travere: Honoraria; Novartis: Honoraria; Alexion: Honoraria; Roche: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding. Kühne: Alexion: Honoraria. Knoebl: Technoclone: Honoraria; Alexion: Honoraria; Biotest: Honoraria; CSL Behring: Honoraria; Roche: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; NovoNordisc: Honoraria, Research Funding; Ablynx/SOBI: Honoraria, Research Funding. De La Rubia: Janssen: Honoraria, Speakers Bureau; Pfizer: Speakers Bureau; Sanofi: Speakers Bureau; Takeda: Research Funding; Menarini: Honoraria; GSK: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria; Oncopharm: Honoraria. Chaturvedi: Sanofi: Other: Advisory board participation; Sobi: Honoraria; Alexion: Consultancy, Other: Advisory board participation; Sanofi Genzyme: Consultancy; Takeda: Other: Advisory board participation. Masias: Sanofi: Consultancy; Takeda: Consultancy; Argenx: Consultancy; Rigel: Consultancy. Zheng: Apollo: Consultancy, Honoraria; GC Biopharma: Consultancy, Honoraria; Clotsolution: Other: Co-founder; Sanofi: Consultancy, Honoraria; Stago: Consultancy, Honoraria; TAKEDA: Consultancy, Honoraria. Patriquin: TAKEDA: Consultancy, Honoraria. Veyradier: TAKEDA: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SANOFI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sakai: Takeda: Research Funding. Matsumoto: Chugai Pharmaceutical: Research Funding; Alexion Pharma: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Asahikasei Pharma: Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau. Peyvandi: Biomarin: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Spark: Speakers Bureau; Takeda: Speakers Bureau. Dutt: SANOFI: Consultancy, Honoraria. Cataland: Takeda: Consultancy; Sanofi: Consultancy. Scully: Takeda: Honoraria, Research Funding, Speakers Bureau; Alexion: Research Funding; Octopharma: Speakers Bureau; Sanofi: Honoraria, Speakers Bureau.

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