Open-Label Phase 1/2 Study of Daratumumab-Based Desensitization Before Kidney Transplantation
Introduction: The safety and benefit of the anti-CD38 monoclonal antibody daratumumab, which induces lysis of antibody-producing plasma cells in sensitized patients prior to kidney transplantation, remain to be determined. Methods: A 2-phase (1 and 2), monocentric open-label study was conducted to e...
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Elsevier
2024-11-01
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| Series: | Kidney International Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468024924019053 |
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| author | Caroline Pilon Nizar Joher Cédric Usureau Emmanuelle Boutin Anna Boueilh Jean-Luc Taupin Allan Thiolat José L. Cohen Vissal David Kheav Florence Canoui-Poitrine Maryvonnick Carmagnat Philippe Grimbert Marie Matignon |
| author_facet | Caroline Pilon Nizar Joher Cédric Usureau Emmanuelle Boutin Anna Boueilh Jean-Luc Taupin Allan Thiolat José L. Cohen Vissal David Kheav Florence Canoui-Poitrine Maryvonnick Carmagnat Philippe Grimbert Marie Matignon |
| author_sort | Caroline Pilon |
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| description | Introduction: The safety and benefit of the anti-CD38 monoclonal antibody daratumumab, which induces lysis of antibody-producing plasma cells in sensitized patients prior to kidney transplantation, remain to be determined. Methods: A 2-phase (1 and 2), monocentric open-label study was conducted to evaluate the month 6 (M6) safety and efficacy of daratumumab in kidney transplant candidates with calculated panel reactive antibody (cPRA) > 95%. In the first (safety) phase, we used 4-weekly escalating doses of daratumumab. Phase 2 tested desensitization with 8 weekly infusions of 16 mg/kg daratumumab. cPRA 10,000 was calculated considering only human leukocyte antigen (HLA) antibodies with mean fluorescence intensity (MFI) of > 10,000. Results: Nine patients were enrolled in phase 1 and 14 in phase 2. Safety analysis showed 4 serious non-treatment-emergent adverse events (non-TEAEs), 36 mild TEAEs, mostly infusion-related reactions, grade 1 and 2 (causing 2 temporary drug discontinuations), but no serious TEAEs. Significant reductions in anti-HLA antibodies were observed at month 3 (M3), with cPRA 10,000 (P = 0.003), number of anti-HLA (P < 0.001), maximum MFI (MFI max) (P = 0.053), and the sum of MFI (MFI sum) (P < 0.001), with complete return to baseline levels at month 12 (M12). At M6, 46.15% (19.22%–74.87%) and 76.92% (46.19%–94.96%) of patients showed sustained response (1% decrease in cPRA) for cPRA 2000 and 10,000, respectively. At month 1 (M1), immune cells (T-reg, CD8 + TEMRA, CD19 + CD138 + B cells, and NK cells) significantly decreased. At M3, other antibodies decreased significantly, but returned to baseline levels at M12, except for gamma globulins, without any infectious complications. Conclusion: The first use of daratumumab in desensitization demonstrated infusion-related adverse (AEs) events and rapid, albeit transient, reductions in anti-HLA antibodies, with less than 40% of durable responders, limiting its potential clinical use. |
| format | Article |
| id | doaj-art-eeca4a74c5794623a771fd56fe7dbc14 |
| institution | Kabale University |
| issn | 2468-0249 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Elsevier |
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| series | Kidney International Reports |
| spelling | doaj-art-eeca4a74c5794623a771fd56fe7dbc142025-08-20T03:47:09ZengElsevierKidney International Reports2468-02492024-11-019113250326410.1016/j.ekir.2024.08.020Open-Label Phase 1/2 Study of Daratumumab-Based Desensitization Before Kidney TransplantationCaroline Pilon0Nizar Joher1Cédric Usureau2Emmanuelle Boutin3Anna Boueilh4Jean-Luc Taupin5Allan Thiolat6José L. Cohen7Vissal David Kheav8Florence Canoui-Poitrine9Maryvonnick Carmagnat10Philippe Grimbert11Marie Matignon12Universite Paris Est Creteil, INSERM IMRB U955, Créteil, France; Assistance Publique-Hôpitaux de Paris, Groupe hospitalo-universitaire Chenevier Mondor, Centre d’Investigation Clinique Biotherapy, Fédération hospitalo-Universitaire, Innovative therapy for immune disorders, Créteil, FranceDepartment of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Paris, Groupe hospitalo-universitaire Chenevier Mondor, Fédération Hospitalo-Universitaire, Innovative therapy for immune disorders, Créteil, FranceLaboratoire d'Immunologie et Histocompatibilité, Hôpital Saint Louis, Paris, France; INSERM UMR976, Institut de Recherche Saint-Louis, Université de Paris-Cité, Paris, FranceUniversite Paris Est Creteil, INSERM IMRB U955, Créteil, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor-Albert Chenevier, Public Health Department and URC, Créteil, FranceDepartment of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Paris, Groupe hospitalo-universitaire Chenevier Mondor, Fédération Hospitalo-Universitaire, Innovative therapy for immune disorders, Créteil, FranceINSERM UMR976, Institut de Recherche Saint-Louis, Université de Paris-Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor-Albert Chenevier, Public Health Department and URC, Créteil, FranceUniversite Paris Est Creteil, INSERM IMRB U955, Créteil, FranceUniversite Paris Est Creteil, INSERM IMRB U955, Créteil, France; Assistance Publique-Hôpitaux de Paris, Groupe hospitalo-universitaire Chenevier Mondor, Centre d’Investigation Clinique Biotherapy, Fédération hospitalo-Universitaire, Innovative therapy for immune disorders, Créteil, FranceINSERM UMR976, Institut de Recherche Saint-Louis, Université de Paris-Cité, Paris, FranceUniversite Paris Est Creteil, INSERM IMRB U955, Créteil, France; Laboratoire d'Immunologie et Histocompatibilité, Hôpital Saint Louis, Paris, FranceINSERM UMR976, Institut de Recherche Saint-Louis, Université de Paris-Cité, Paris, FranceUniversite Paris Est Creteil, INSERM IMRB U955, Créteil, France; Assistance Publique-Hôpitaux de Paris, Groupe hospitalo-universitaire Chenevier Mondor, Centre d’Investigation Clinique Biotherapy, Fédération hospitalo-Universitaire, Innovative therapy for immune disorders, Créteil, France; Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Paris, Groupe hospitalo-universitaire Chenevier Mondor, Fédération Hospitalo-Universitaire, Innovative therapy for immune disorders, Créteil, FranceUniversite Paris Est Creteil, INSERM IMRB U955, Créteil, France; Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Paris, Groupe hospitalo-universitaire Chenevier Mondor, Fédération Hospitalo-Universitaire, Innovative therapy for immune disorders, Créteil, France; Correspondence: Marie Matignon, Service de néphrologie transplantation, Hôpital Henri Mondor, 94000 Créteil, France.Introduction: The safety and benefit of the anti-CD38 monoclonal antibody daratumumab, which induces lysis of antibody-producing plasma cells in sensitized patients prior to kidney transplantation, remain to be determined. Methods: A 2-phase (1 and 2), monocentric open-label study was conducted to evaluate the month 6 (M6) safety and efficacy of daratumumab in kidney transplant candidates with calculated panel reactive antibody (cPRA) > 95%. In the first (safety) phase, we used 4-weekly escalating doses of daratumumab. Phase 2 tested desensitization with 8 weekly infusions of 16 mg/kg daratumumab. cPRA 10,000 was calculated considering only human leukocyte antigen (HLA) antibodies with mean fluorescence intensity (MFI) of > 10,000. Results: Nine patients were enrolled in phase 1 and 14 in phase 2. Safety analysis showed 4 serious non-treatment-emergent adverse events (non-TEAEs), 36 mild TEAEs, mostly infusion-related reactions, grade 1 and 2 (causing 2 temporary drug discontinuations), but no serious TEAEs. Significant reductions in anti-HLA antibodies were observed at month 3 (M3), with cPRA 10,000 (P = 0.003), number of anti-HLA (P < 0.001), maximum MFI (MFI max) (P = 0.053), and the sum of MFI (MFI sum) (P < 0.001), with complete return to baseline levels at month 12 (M12). At M6, 46.15% (19.22%–74.87%) and 76.92% (46.19%–94.96%) of patients showed sustained response (1% decrease in cPRA) for cPRA 2000 and 10,000, respectively. At month 1 (M1), immune cells (T-reg, CD8 + TEMRA, CD19 + CD138 + B cells, and NK cells) significantly decreased. At M3, other antibodies decreased significantly, but returned to baseline levels at M12, except for gamma globulins, without any infectious complications. Conclusion: The first use of daratumumab in desensitization demonstrated infusion-related adverse (AEs) events and rapid, albeit transient, reductions in anti-HLA antibodies, with less than 40% of durable responders, limiting its potential clinical use.http://www.sciencedirect.com/science/article/pii/S2468024924019053lymphocytespharmacokineticstranslationaltransplantation |
| spellingShingle | Caroline Pilon Nizar Joher Cédric Usureau Emmanuelle Boutin Anna Boueilh Jean-Luc Taupin Allan Thiolat José L. Cohen Vissal David Kheav Florence Canoui-Poitrine Maryvonnick Carmagnat Philippe Grimbert Marie Matignon Open-Label Phase 1/2 Study of Daratumumab-Based Desensitization Before Kidney Transplantation Kidney International Reports lymphocytes pharmacokinetics translational transplantation |
| title | Open-Label Phase 1/2 Study of Daratumumab-Based Desensitization Before Kidney Transplantation |
| title_full | Open-Label Phase 1/2 Study of Daratumumab-Based Desensitization Before Kidney Transplantation |
| title_fullStr | Open-Label Phase 1/2 Study of Daratumumab-Based Desensitization Before Kidney Transplantation |
| title_full_unstemmed | Open-Label Phase 1/2 Study of Daratumumab-Based Desensitization Before Kidney Transplantation |
| title_short | Open-Label Phase 1/2 Study of Daratumumab-Based Desensitization Before Kidney Transplantation |
| title_sort | open label phase 1 2 study of daratumumab based desensitization before kidney transplantation |
| topic | lymphocytes pharmacokinetics translational transplantation |
| url | http://www.sciencedirect.com/science/article/pii/S2468024924019053 |
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