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
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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.</div></div><div><h3>Results</h3><div>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 (<em>P</em> = 0.003), number of anti-HLA (<em>P</em> < 0.001), maximum MFI (MFI max) (<em>P</em> = 0.053), and the sum of MFI (MFI sum) (<em>P</em> < 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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":17761,"journal":{"name":"Kidney International Reports","volume":null,"pages":null},"PeriodicalIF":5.7000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Open-Label Phase 1/2 Study of Daratumumab-Based Desensitization Before Kidney Transplantation\",\"authors\":\"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\",\"doi\":\"10.1016/j.ekir.2024.08.020\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Introduction</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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 (<em>P</em> = 0.003), number of anti-HLA (<em>P</em> < 0.001), maximum MFI (MFI max) (<em>P</em> = 0.053), and the sum of MFI (MFI sum) (<em>P</em> < 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. 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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 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.
期刊介绍：
Kidney International Reports, an official journal of the International Society of Nephrology, is a peer-reviewed, open access journal devoted to the publication of leading research and developments related to kidney disease. With the primary aim of contributing to improved care of patients with kidney disease, the journal will publish original clinical and select translational articles and educational content related to the pathogenesis, evaluation and management of acute and chronic kidney disease, end stage renal disease (including transplantation), acid-base, fluid and electrolyte disturbances and hypertension. Of particular interest are submissions related to clinical trials, epidemiology, systematic reviews (including meta-analyses) and outcomes research. The journal will also provide a platform for wider dissemination of national and regional guidelines as well as consensus meeting reports.
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