Massimo Federico1, María Dolores Caballero Barrigón2, Luigi Marcheselli3, Vittoria Tarantino4, Martina Manni4, Clementine Sarkozy5, Sara Alonso-Álvarez6, Marielle Wondergem7, Guillaume Cartron8, Armando Lopez-Guillermo9, Djamila Issa10, Franck Morschhauser11, Miguel Alcoceba2, Eva Kimby12, Chiara Rusconi13, Martine Chamuleau7, Harald Holte14, Sandra Lockmer12, Silvia Montoto15, Maria Gomes da Silva16, Igor Aurer17, Emanuele Zucca18, Ewa Paszkiewicz-Kozik19, Carla Minoia20, Tetiana Skrypets4, Yngvild Nuvin Blaker14, Gilles Salles5, Bertrand Coiffier5. 1. Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy; Division of Medical Oncology, Città di Lecce Hospital, GVM Care and Research, Lecce, Italy. Electronic address: massimo.federico@unimore.it. 2. Department of Hematology, Complejo Hospitalario Universitario, Instituto Biosanitario (IBSAL), Salamanca, Spain. 3. Fondazione Italiana Linfomi, Onlus, University of Modena and Reggio Emilia, Modena, Italy. 4. Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy. 5. Hospices Civils de Lyon, Universite Claude Bernard Lyon 1, Department of Haematology, Pierre Benite, France. 6. Department of Haematology, Hospital Universitario Central de Asturias, Asturias, Spain. 7. Department of Hematology, VU University Medical Center, Amsterdam, Netherlands. 8. Department of Haematology, CHU Montpellier, Montpellier, France. 9. Haematology Department, Hospital Clinic, Barcelona, Spain. 10. Department of Haematology, Jeroen Bosch Ziekenhuis, Den Bosch, Netherlands. 11. Department of Clinical Haematology, CHU Lille, Unite GRITA, Universite de Lille 2, Lille, France. 12. Department of Hematology, Karolinska University Hospital and Department of Medicine, Karolinska Institutet, Stockholm, Sweden. 13. Division of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy. 14. Department of Oncology, Radiumhospitalet, Oslo University Hospital, Oslo, Norway. 15. Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. 16. Instituto Português de Oncologia, Departamento de Hematologia, Lisbon, Portugal. 17. Division of Hematology, Department of Internal Medicine, University Hospital Center Zagreb and Medical School, University of Zagreb, Zagreb, Croatia. 18. Oncology Institute of Southern Switzerland (IOSI), Ospedale San Giovanni, Bellinzona, Switzerland. 19. Department of Lymphoid Malignancies, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland. 20. Haematology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy.
Abstract
BACKGROUND: Histological transformation of follicular lymphoma to aggressive lymphoma is a serious event with a substantial effect on patient outcome. The aim of the Aristotle study was to assess the effect of rituximab on the risk of histological transformation and its outcome. METHODS: 11 cooperative groups or institutions across Europe contributed data to this study. Eligible patients (≥18 years) had histologically confirmed follicular lymphoma grade 1, 2, or 3a, diagnosed between Jan 2, 1997, and Dec 20, 2013. Histological transformation was defined as a biopsy-proven aggressive lymphoma that occurred as a first event after first-line therapy. The primary endpoints were the cumulative hazard of histological transformation and survival after transformation. FINDINGS: Information was available for 10 001 patients with follicular lymphoma, 8116 of whom were eligible for analysis. 509 histological transformations were reported. After a median follow-up of 87 months (range 1-221; 2·5-97·5th percentile 5-160), the 10-year cumulative hazard of histological transformation was 7·7% (95% CI 6·9-8·5). The 10-year cumulative hazard of histological transformation was 5·2% (95% CI 4·5-6·2) in patients who received rituximab and 8·7% (7·2-10·6) in those who did not (hazard ratio [HR] 0·73, 95% CI 0·58-0·90; p=0·004). The 10-year cumulative hazard of histological transformation was 5·9% (95% CI 5·0-7·0) for patients who received induction rituximab only and 3·6% (95% CI 2·3-5·5) for those treated with induction and maintenance rituximab (HR 0·55, 95% CI 0·37-0·81; p=0·003). This finding was confirmed in a multivariate analysis (p=0·016). 287 deaths were recorded in 509 patients with histological transformation, resulting in a 10-year survival after transformation of 32% (95% CI 26-38). Survival after transformation did not differ between patients not exposed to rituximab and those who received rituximab in induction only (HR 0·94, 95% CI 0·69-1·28; p=0·70), and those who received rituximab in induction and maintenance (0·96, 0·58-1·61; p=0·88). INTERPRETATION: The risk of histological transformation as a first event can be significantly reduced by the use of rituximab. These findings support the need to inform patients using rituximab nowadays that the risk of transformation is lower than it was before the introduction of rituxumab. FUNDING: Associazione Angela Serra per la Ricerca sul Cancro, European Lymphoma Institute, European Hematology Association Lymphoma Group, Fondazione Italiana Linfomi, Spanish Group of Lymphoma and Bone Marrow Transplantation.
BACKGROUND: Histological transformation of follicular lymphoma to aggressive lymphoma is a serious event with a substantial effect on patient outcome. The aim of the Aristotle study was to assess the effect of rituximab on the risk of histological transformation and its outcome. METHODS: 11 cooperative groups or institutions across Europe contributed data to this study. Eligible patients (≥18 years) had histologically confirmed follicular lymphoma grade 1, 2, or 3a, diagnosed between Jan 2, 1997, and Dec 20, 2013. Histological transformation was defined as a biopsy-proven aggressive lymphoma that occurred as a first event after first-line therapy. The primary endpoints were the cumulative hazard of histological transformation and survival after transformation. FINDINGS: Information was available for 10 001 patients with follicular lymphoma, 8116 of whom were eligible for analysis. 509 histological transformations were reported. After a median follow-up of 87 months (range 1-221; 2·5-97·5th percentile 5-160), the 10-year cumulative hazard of histological transformation was 7·7% (95% CI 6·9-8·5). The 10-year cumulative hazard of histological transformation was 5·2% (95% CI 4·5-6·2) in patients who received rituximab and 8·7% (7·2-10·6) in those who did not (hazard ratio [HR] 0·73, 95% CI 0·58-0·90; p=0·004). The 10-year cumulative hazard of histological transformation was 5·9% (95% CI 5·0-7·0) for patients who received induction rituximab only and 3·6% (95% CI 2·3-5·5) for those treated with induction and maintenance rituximab (HR 0·55, 95% CI 0·37-0·81; p=0·003). This finding was confirmed in a multivariate analysis (p=0·016). 287 deaths were recorded in 509 patients with histological transformation, resulting in a 10-year survival after transformation of 32% (95% CI 26-38). Survival after transformation did not differ between patients not exposed to rituximab and those who received rituximab in induction only (HR 0·94, 95% CI 0·69-1·28; p=0·70), and those who received rituximab in induction and maintenance (0·96, 0·58-1·61; p=0·88). INTERPRETATION: The risk of histological transformation as a first event can be significantly reduced by the use of rituximab. These findings support the need to inform patients using rituximab nowadays that the risk of transformation is lower than it was before the introduction of rituxumab. FUNDING: Associazione Angela Serra per la Ricerca sul Cancro, European Lymphoma Institute, European Hematology Association Lymphoma Group, Fondazione Italiana Linfomi, Spanish Group of Lymphoma and Bone Marrow Transplantation.
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