Caplacizumab use in immune-mediated thrombotic thrombocytopenic purpura: an international multicentre retrospective Cohort study (The Capla 1000+ project)

Paul Coppo^{1

2}, Michael Bubenheim³, Ygal Benhamou^{1

4

5}, Linus Völker^{6

7}, Paul Brinkkötter^{6

7}, Lucas Kühne^{6

7}, Paul Knöbl⁸, Maria Eva Mingot-Castellano⁹, Cristina Pascual-Izquierdo¹⁰, Javier de la Rubia¹¹, Julio Del Rio Garma¹², Shruti Chaturvedi¹³, Camila Masias¹⁴, Marshall Mazepa¹⁵, X Long Zheng¹⁶, György Sinkovits¹⁷, Marienn Réti¹⁸, Christopher J Patriquin¹⁹, Katerina Pavenski²⁰, Tiago Boechat²¹, João Farias²², Eduardo Flavio Oliveira Ribeiro²³, Michaela Larissa Lobo de Andrade²³, Agnès Veyradier^{2

24}, Bérangère Joly^{2

24}, Raïda Bouzid^{1

2}, Kazuya Sakai²⁵, Masanori Matsumoto²⁵, Pasquale Agosti^{26

27}, Ilaria Mancini²⁷, Flora Peyvandi^{26

27}, Eleni Gavriilaki²⁸, Matthew Stubbs²⁹, Amjad Hmaid²⁹, Spero Cataland³⁰, Bernhard Lämmle^{31

32}, Marie Scully²⁹

Affiliations

¹ Centre de Référence des Microangiopathies Thrombotiques, Service d'Hématologie, Assistance Publique-Hôpitaux de Paris (AP-HP) and Sorbonne Université, Paris, France.
² INSERM Unité Mixte de Recherche (UMRS) 1138, Centre de Recherche des Cordeliers, Paris, France.
³ Department of Clinical Research and Innovation, Centre Hospitalier Universitaire (CHU) de Rouen.
⁴ Département de Médecine Interne, CHU Charles Nicolle, Rouen, France.
⁵ Normandie University, UNIROUEN, INSERM U1096 EnVI, Rouen, France.
⁶ Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.
⁷ Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases, Cologne, Germany.
⁸ Division of Hematology and Hemostasis, Department of Medicine 1, Medical University of Vienna, Austria.
⁹ Servicio de Hematología, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Spain.
¹⁰ Servicio de Hematología, Hospital Universitario Gregorio Marañón, Instituto de Investigación Gregorio Marañón, Madrid, Spain.
¹¹ Servicio de Hematología, Hospital Universitario y Politécnico La Fe, Valencia & Universidad Católica de Valencia, Spain.
¹² Complexo Hospitalario Universitario de Santiago, Spain.
¹³ Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹⁴ Baptist Health South Florida, Miami, FL, USA.
¹⁵ Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
¹⁶ Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
¹⁷ Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary.
¹⁸ Department of Hematology and Stem Cell Transplantation, Central Hospital of Southern Pest - Institute of Hematology and Infectious Diseases, Budapest, Hungary.
¹⁹ Department of Hematology, University Health Network, Toronto, Canada.
²⁰ Department of Laboratory Medicine, St. Michael's Hospital, Toronto, Canada.
²¹ Department of Hematology - Hematology and Hemotherapy Institute of Rio de Janeiro (HEMORIO), Rio de Janeiro, RJ, Brazil.
²² Department of Hematology, Hospital Erasto Gaertner, Curitiba, Brazil.
²³ Santa Lucia Hospital, Brasilia, DF, Brazil.
²⁴ Hématologie Biologique, Hôpital Lariboisière, AP-HP, Paris, France.
²⁵ Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan.
²⁶ Università degli Studi di Milano, Department of Pathophysiology and Transplantation and Fondazione Luigi Villa, Milan, Italy.
²⁷ Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.
²⁸ BMT Unit - Department of Hematology, G. Papanicolaou Hospital, Thessaloniki, Greece.
²⁹ University College London Hospitals NHS Foundation Trust, London, UK.
³⁰ Department of Internal Medicine, Ohio State University, Columbus, OH, USA.
³¹ Center for Thrombosis and Hemostasis, University Medical Center of Johannes Gutenberg University, Mainz, Germany.
³² Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

PMID: 40235949
PMCID: PMC11997362
DOI: 10.1016/j.eclinm.2025.103168

Caplacizumab use in immune-mediated thrombotic thrombocytopenic purpura: an international multicentre retrospective Cohort study (The Capla 1000+ project)

Paul Coppo et al. EClinicalMedicine. 2025.

. 2025 Mar 30:82:103168.

doi: 10.1016/j.eclinm.2025.103168. eCollection 2025 Apr.

Authors

Affiliations

¹ Centre de Référence des Microangiopathies Thrombotiques, Service d'Hématologie, Assistance Publique-Hôpitaux de Paris (AP-HP) and Sorbonne Université, Paris, France.
² INSERM Unité Mixte de Recherche (UMRS) 1138, Centre de Recherche des Cordeliers, Paris, France.
³ Department of Clinical Research and Innovation, Centre Hospitalier Universitaire (CHU) de Rouen.
⁴ Département de Médecine Interne, CHU Charles Nicolle, Rouen, France.
⁵ Normandie University, UNIROUEN, INSERM U1096 EnVI, Rouen, France.
⁶ Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany.
⁷ Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases, Cologne, Germany.
⁸ Division of Hematology and Hemostasis, Department of Medicine 1, Medical University of Vienna, Austria.
⁹ Servicio de Hematología, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Spain.
¹⁰ Servicio de Hematología, Hospital Universitario Gregorio Marañón, Instituto de Investigación Gregorio Marañón, Madrid, Spain.
¹¹ Servicio de Hematología, Hospital Universitario y Politécnico La Fe, Valencia & Universidad Católica de Valencia, Spain.
¹² Complexo Hospitalario Universitario de Santiago, Spain.
¹³ Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹⁴ Baptist Health South Florida, Miami, FL, USA.
¹⁵ Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
¹⁶ Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
¹⁷ Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary.
¹⁸ Department of Hematology and Stem Cell Transplantation, Central Hospital of Southern Pest - Institute of Hematology and Infectious Diseases, Budapest, Hungary.
¹⁹ Department of Hematology, University Health Network, Toronto, Canada.
²⁰ Department of Laboratory Medicine, St. Michael's Hospital, Toronto, Canada.
²¹ Department of Hematology - Hematology and Hemotherapy Institute of Rio de Janeiro (HEMORIO), Rio de Janeiro, RJ, Brazil.
²² Department of Hematology, Hospital Erasto Gaertner, Curitiba, Brazil.
²³ Santa Lucia Hospital, Brasilia, DF, Brazil.
²⁴ Hématologie Biologique, Hôpital Lariboisière, AP-HP, Paris, France.
²⁵ Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan.
²⁶ Università degli Studi di Milano, Department of Pathophysiology and Transplantation and Fondazione Luigi Villa, Milan, Italy.
²⁷ Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.
²⁸ BMT Unit - Department of Hematology, G. Papanicolaou Hospital, Thessaloniki, Greece.
²⁹ University College London Hospitals NHS Foundation Trust, London, UK.
³⁰ Department of Internal Medicine, Ohio State University, Columbus, OH, USA.
³¹ Center for Thrombosis and Hemostasis, University Medical Center of Johannes Gutenberg University, Mainz, Germany.
³² Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

PMID: 40235949
PMCID: PMC11997362
DOI: 10.1016/j.eclinm.2025.103168

Abstract

Background: The anti-Von Willebrand Factor (VWF) nanobody caplacizumab is licensed for adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in association with therapeutic plasma exchange (TPE) and immunosuppression. However, whether caplacizumab reduces mortality, and its optimal timing of initiation, is not completely settled.

Methods: This international, multicenter retrospective cohort study recruited patients from 2018 until 2023 and data collection took place from January 1st to June 30th 2023 in the participating centers. One thousand and fifteen patients were treated with daily TPE, immunosuppression with corticosteroids ± rituximab, and caplacizumab (caplacizumab group), which was compared to historic controls treated with TPE and corticosteroids ± rituximab (control group, N = 510). Caplacizumab initiation was classified as early (within 3 days; 76% of cases) or delayed (≥4 days from first TPE).

Findings: Three-month survival rate in the caplacizumab group was 98.5%, compared with 94% in controls (P < 0.0001). Three-month mortality rate was 4.2-fold higher in controls than in caplacizumab-treated patients (95% CI: 2.22-7.7, P < 0.0001), regardless of rituximab use. In both groups, death was observed primarily in elderly patients, and age was the factor most associated with 3-month mortality. Patients receiving caplacizumab showed reduced refractoriness, exacerbations, and required fewer TPE sessions to achieve clinical response versus controls (P < 0.0001 all). Time to clinical response in the caplacizumab group was shorter than in controls, and even shorter in patients with early caplacizumab initiation (P < 0.0001 both). Caplacizumab-related adverse events were observed in 21% of patients, with major bleeding in 2.4%, which was more common in elderly patients.

Interpretation: The early association of Caplacizumab to TPE and immunosuppression significantly reduces unfavorable outcomes during iTTP, including death, and alleviates the burden of care at the potential expense of bleeding events. Advanced age, however, remains an adverse factor for survival. The limitations of our study include its retrospective and multicentric design and the use of a historical control cohort.

Funding: None.

Keywords: ADAMTS13; Caplacizumab; Prognosis; Rituximab; Thrombotic thrombocytopenic purpura.

PubMed Disclaimer

Conflict of interest statement

P. Coppo is member of the Clinical Advisory Board for Alexion, Sanofi-Genzyme and Takeda. L. Kühne received consulting fees from Alexion and research funding from Sanofi-Genzyme. L.A. Völker received research funding and consulting fees from Alexion, AstraZeneca, Bayer, GC Biopharm and Sanofi-Genzyme, GC Biopharm. P.T. Brinkkötter received speaker honoraria and consultant fees from AstraZeneca, Alexion, Bayer, Boehringer-Ingelheim, Novartis, Roche, Sanofi-Genzyme, Travere, Vifor CSL and participated in advisory boards for Alexion, Sanofi-Genzyme, Novartis, Travere, Takeda, Vifor CSL and Bayer. He declares research funding from the German Research Foundation BR-2955/8 and Sanofi-Genzyme. P. Knöbl is member of the Clinical Advisory Boards for Sanofi and Takeda. T. Boechat has participated to advisory boards for Sanofi-Genzyme. Y. Benhamou, B. Joly and A. Veyradier have participated to Advisory boards for Sanofi-Genzyme and Takeda. M.E. Mingot-Castellano is member of the Clinical Advisory Board for Alexion, Werfen, Sanofi-Genzyme and Takeda, and grants from the 3 companies. X. Long Zheng is a consultant for Alexion, Apollo, GC Biopharma, Sanofi-Genzyme, Stago, and Takeda. X.L.Z. is also the co-founder of Clotsolution; he also received educational grant funding to support 2024 ISTH congress satellite symposium for platelets and hemostasis, Bangkok, Thailand, and grants unrelated to the present study, from NHLBI (HL157975-01A1 and HL164016-01A1) and Answering T.T.P. Foundation. Marienn Reti received congress support by Sanofi-Genzyme (EHA, 2024) and participated to the iTTP European and International Region Medical Advisory Board (2023). C.J. Patriquin has receive consultancy honoraria from Alexion, BioCryst, Novartis, Roche, Sanofi-Genzyme, Sobi, and Takeda, and speaking honoraria from Alexion, Amgen, and Sobi. K. Pavenski provided unpaid consultancy to Sanofi-Genzyme and Takeda; served as site PI in industry trials of Sanofi-Genzyme, Takeda, Roche and SOBI. She received honoraria from France foundation for travel and presentations and honoraria from Octapharma for travel. K. Sakai received lecture fees from Sanofi-Genzyme. M. Matsumoto has provided consultancy services for Takeda, Alexion and Sanofi-Genzyme, and has received speaker fees for Takeda, Alexion, Asahikasei Pharma, and Sanofi-Genzyme and has received research funding from Alexion, Chugai Pharmaceutical, Asahikasei Pharma, and Sanofi-Genzyme. P. Agosti received honoraria for participating as a speaker at educational meetings organized by Sanofi-Genzyme. I. Mancini received honoraria for participating as a speaker at educational meetings organized by Werfen and Sanofi-Genzyme. F. Peyvandi received honoraria for participating in symposia and educational events for Takeda/Spark and in advisory boards for Biomarin, Roche, Sanofi-Genzyme, Sobi, and CSL Behring. S. Cataland is member of the Clinical Advisory Board for Sanofi-Genzyme and Takeda. M. Scully is member of the Clinical Advisory Board for Alexion, Sanofi-Genzyme and Takeda. B. Lämmle is chairman of data monitoring committees of studies investigating recombinant ADAMTS13 for the treatment of congenital and acquired TTP (Takeda), chairman of a steering committee analyzing global impact of congenital TTP (Takeda), and chairman of the data monitoring committee of Mayari study (investigating caplacizumab for the treatment of autoimmune TTP without plasma exchange (Sanofi-Genzyme)). The other authors do not have any conflict of interest to declare.

Figures

**Fig. 1**
Flow chart of the study. iTTP, immune-mediated Thrombotic Thrombocytopenic Purpura. Date of caplacizumab initiation was missing for 50 patients.

**Fig. 2**
Cumulative probability of death after first therapeutic plasma exchange (TPE) up to 3 months in patients of the caplacizumab group (blue line) versus patients of the control group (green dashed line).

**Fig. 3**
Cumulative incidence of clinical response after first therapeutic plasma exchange (TPE) (A) in patients treated with caplacizumab (blue line) versus patients of the control group (green dashed line), and (B) in patients treated with caplacizumab early (i.e., within three days from first TPE; blue line) versus patients of the control group (green dashed line).

**Fig. 4**
Cumulative incidence of exacerbation after clinical response in patients of the caplacizumab group (blue line) versus patients of the control group (green dashed line).

See this image and copyright information in PMC

References

1. Kremer Hovinga J.A., Coppo P., Lämmle B., Moake J.L., Miyata T., Vanhoorelbeke K. Thrombotic thrombocytopenic purpura. Nat Rev Dis Primer. 2017;3 - PubMed
1. Rock G.A., Shumak K.H., Buskard N.A., et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med. 1991;325:393–397. - PubMed
1. Kremer Hovinga J.A., Vesely S.K., Terrell D.R., Lämmle B., George J.N. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood. 2010;115:1500–1511. - PubMed
1. George J.N. Corticosteroids and rituximab as adjunctive treatments for thrombotic thrombocytopenic purpura. Am J Hematol. 2012;87(Suppl 1):S88–S91. - PubMed
1. Scully M., McDonald V., Cavenagh J., et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood. 2011;118:1746–1753. - PubMed

Grants and funding

R00 HL172303/HL/NHLBI NIH HHS/United States

LinkOut - more resources

Full Text Sources
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Caplacizumab use in immune-mediated thrombotic thrombocytopenic purpura: an international multicentre retrospective Cohort study (The Capla 1000+ project)

Affiliations

Caplacizumab use in immune-mediated thrombotic thrombocytopenic purpura: an international multicentre retrospective Cohort study (The Capla 1000+ project)

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous