Patrice Chevallier1, Thomas Eugene2, Nelly Robillard3, Françoise Isnard4, Franck Nicolini5, Martine Escoffre-Barbe6, Françoise Huguet7, Mathilde Hunault8, Antoine Marcais9, Joelle Gaschet10, Michel Cherel11, Thierry Guillaume12, Jacques Delaunay12, Pierre Peterlin12, Marion Eveillard3, Xavier Thomas5, Norbert Ifrah8, Simona Lapusan4, Caroline Bodet-Milin13, Jacques Barbet14, Alain Faivre-Chauvet13, Ludovic Ferrer15, Marie C Bene3, Claire Le Houerou12, David M Goldenberg16, William A Wegener16, Françoise Kraeber-Bodéré17. 1. Hematology Department, Centre Hospitalo-Universitaire, Hotel-Dieu, Nantes, France. Electronic address: patrice.chevallier@chu-nantes.fr. 2. Nuclear Medicine Department, Centre Hospitalo-Universitaire, Nantes, France. 3. Hematology and Biology Department, Centre Hospitalo-Universitaire, Nantes, France. 4. Hematology Department, University Hospital, St Antoine, APHP, Paris, France. 5. Hematology Department, Centre Hospitalo-Universitaire, Lyon, France. 6. Hematology Department, Centre Hospitalo-Universitaire, Rennes, France. 7. Hematology Department, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France. 8. Hematology Department, Centre Hospitalo-Universitaire, Angers, France. 9. Hematology Department, Hopital Necker, Assistance-Publique Hôpitaux de Paris, Paris, France. 10. Centre de Recherche en Cancérologie Nantes Angers, Inserm U 892, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6299, France; Sciences de la vie et Santé, University of Nantes, Nantes, France. 11. Centre de Recherche en Cancérologie Nantes Angers, Inserm U 892, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6299, France; Sciences de la vie et Santé, University of Nantes, Nantes, France; Nuclear Medicine Department, Institut de Cancérologie de l'Ouest-Gauducheau, saint-Herblain, France; GIP ARRONAX, Saint-Herblain, France. 12. Hematology Department, Centre Hospitalo-Universitaire, Hotel-Dieu, Nantes, France. 13. Nuclear Medicine Department, Centre Hospitalo-Universitaire, Nantes, France; Centre de Recherche en Cancérologie Nantes Angers, Inserm U 892, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6299, France; Sciences de la vie et Santé, University of Nantes, Nantes, France. 14. Centre de Recherche en Cancérologie Nantes Angers, Inserm U 892, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6299, France; Sciences de la vie et Santé, University of Nantes, Nantes, France; GIP ARRONAX, Saint-Herblain, France. 15. Centre de Recherche en Cancérologie Nantes Angers, Inserm U 892, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6299, France; Medical Physics Department, Institut de Cancérologie de l'Ouest-Gauducheau, saint-Herblain, France. 16. Immunomedics, Morris Plains, NJ, USA. 17. Nuclear Medicine Department, Centre Hospitalo-Universitaire, Nantes, France; Centre de Recherche en Cancérologie Nantes Angers, Inserm U 892, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6299, France; Sciences de la vie et Santé, University of Nantes, Nantes, France; Nuclear Medicine Department, Institut de Cancérologie de l'Ouest-Gauducheau, saint-Herblain, France.
Abstract
BACKGROUND: Prognosis of patients with relapsed or refractory acute lymphoblastic leukaemia is poor and new treatments are needed. We aimed to assess the feasibility, tolerability, dosimetry, and efficacy of yttrium-90-labelled anti-CD22 epratuzumab tetraxetan ((90)Y-DOTA-epratuzumab) radioimmunotherapy in refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia in a standard 3 + 3 phase 1 study. METHODS: Adults (≥18 years) with relapsed or refractory B-cell acute lymphoblastic leukaemia (with CD22 expression on at least 70% of blast cells) were enrolled at six centres in France. Patients received one cycle of (90)Y-DOTA-epratuzumab on days 1 and 8 (give or take 2 days) successively at one of four dose levels: 2·5 mCi/m(2) (92·5 MBq/m(2); level 1), 5·0 mCi/m(2) (185 MBq/m(2); level 2), 7·5 mCi/m(2) (277·5 MBq/m(2); level 3), and 10·0 mCi/m(2) (370 MBq/m(2); level 4). The primary objective was to identify the maximum tolerated dose of (90)Y-DOTA-epratuzumab. We assessed safety during infusions and regularly after radioimmunotherapy over a 6-month period. Analyses included only patients who received radioimmunotherapy. The trial is closed to inclusion and is registered at ClinicalTrials.gov, NCT01354457. FINDINGS: Between Aug 25, 2011, and June 11, 2014, 17 patients (median age 62 years; range 27-77) were treated (five at level 1, three at level 2, three at level 3, and six at level 4). Radioimmunotherapy infusion was overall well tolerated. One dose-limiting toxic effect (aplasia lasting 8 weeks) occurred at level 4, but the maximum tolerated dose was not reached. The most common grade 3-4 adverse events were pancytopenia (one patient at level 2, one at level 3, and six at level 4) and infections (three at level 1, one at level 2, and five at level 4). INTERPRETATION: (90)Y-DOTA-epratuzumab radioimmunotherapy is well tolerated. We recommend the dose of 2 × 10·0 mCi/m(2) 1 week apart per cycle for phase 2 studies. FUNDING: Immunomedics and Direction de la Recherche Clinique of Nantes.
BACKGROUND: Prognosis of patients with relapsed or refractory acute lymphoblastic leukaemia is poor and new treatments are needed. We aimed to assess the feasibility, tolerability, dosimetry, and efficacy of yttrium-90-labelled anti-CD22epratuzumab tetraxetan ((90)Y-DOTA-epratuzumab) radioimmunotherapy in refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia in a standard 3 + 3 phase 1 study. METHODS: Adults (≥18 years) with relapsed or refractory B-cell acute lymphoblastic leukaemia (with CD22 expression on at least 70% of blast cells) were enrolled at six centres in France. Patients received one cycle of (90)Y-DOTA-epratuzumab on days 1 and 8 (give or take 2 days) successively at one of four dose levels: 2·5 mCi/m(2) (92·5 MBq/m(2); level 1), 5·0 mCi/m(2) (185 MBq/m(2); level 2), 7·5 mCi/m(2) (277·5 MBq/m(2); level 3), and 10·0 mCi/m(2) (370 MBq/m(2); level 4). The primary objective was to identify the maximum tolerated dose of (90)Y-DOTA-epratuzumab. We assessed safety during infusions and regularly after radioimmunotherapy over a 6-month period. Analyses included only patients who received radioimmunotherapy. The trial is closed to inclusion and is registered at ClinicalTrials.gov, NCT01354457. FINDINGS: Between Aug 25, 2011, and June 11, 2014, 17 patients (median age 62 years; range 27-77) were treated (five at level 1, three at level 2, three at level 3, and six at level 4). Radioimmunotherapy infusion was overall well tolerated. One dose-limiting toxic effect (aplasia lasting 8 weeks) occurred at level 4, but the maximum tolerated dose was not reached. The most common grade 3-4 adverse events were pancytopenia (one patient at level 2, one at level 3, and six at level 4) and infections (three at level 1, one at level 2, and five at level 4). INTERPRETATION: (90)Y-DOTA-epratuzumab radioimmunotherapy is well tolerated. We recommend the dose of 2 × 10·0 mCi/m(2) 1 week apart per cycle for phase 2 studies. FUNDING: Immunomedics and Direction de la Recherche Clinique of Nantes.
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