Francesca Bonifazi1, Carlos Solano2, Christine Wolschke3, Mariarosaria Sessa4, Francesca Patriarca5, Francesco Zallio6, Arnon Nagler7, Carmine Selleri8, Antonio Maria Risitano9, Giuseppe Messina10, Wolfgang Bethge11, Pilar Herrera12, Anna Sureda13, Angelo Michele Carella14, Michele Cimminiello15, Stefano Guidi16, Jürgen Finke17, Roberto Sorasio18, Christelle Ferra19, Jorge Sierra20, Domenico Russo21, Edoardo Benedetti22, Giuseppe Milone23, Fabio Benedetti24, Marion Heinzelmann3, Domenico Pastore25, Manuel Jurado26, Elisabetta Terruzzi27, Franco Narni28, Andreas Völp29, Francis Ayuk3, Tapani Ruutu30, Nicolaus Kröger3. 1. Department of Hematology, L and A Seràgnoli, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy. Electronic address: francesca.bonifazi@unibo.it. 2. Hospital Clinico Universitario-INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain. 3. University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 4. Department of Hematology, L and A Seràgnoli, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy. 5. Hematology, Medical Department (DAME), University of Udine, Udine, Italy. 6. Azienda Ospedaliera SS Antonio e Biagio e C Arrigo, Alessandria, Italy. 7. Chaim Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel. 8. Department of Hematology, Università di Salerno, Salerno, Italy. 9. Università Federico II di Napoli, Naples, Italy. 10. Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy. 11. University Hospital Tübingen, Tübingen, Germany. 12. Servicio de Hematología y Hemoterapia, Hospital Universitario Ramon y Cajal, Madrid, Spain. 13. Hospital Durán i Reinals, Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain. 14. Ospedale Casa Sollievo della Sofferenza IRCCCS, San Giovanni Rotondo, Italy. 15. Azienda Ospedaliera San Carlo, Potenza, Italy. 16. SODc Terapia Cellulare e Medicina Trasfusionale, TMO Azienda Ospedaliera Universitaria Careggi, Florence, Italy. 17. University Hospital Freiburg, Freiburg, Germany. 18. Ospedale Santa Croce, e Carle, Cuneo, Italy. 19. Hospital Universitari Germans Trias i Pujol, Institut Català d'Oncologia, Badalona, Spain. 20. Hematology Department and Stem Cell Transplantation Program, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain. 21. Unit of Blood Diseases and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, ASST-Spedali Civili Brescia, Brescia, Italy. 22. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 23. Programma di Trapianto Emopoietico Metropolitano, Azienda Policlinico-Vittorio Emanuele, Catania, Italy. 24. Policlinico G B Rossi, Verona, Italy. 25. Azienda Ospedaliera, Universitaria Ospedale, Bari, Italy. 26. Hospital Universitario Virgen de las Nieves, Granada, Spain. 27. Ospedale San Gerardo, Monza, Italy. 28. Policlinico di Modena, Modena, Italy. 29. Psy Consult, Hamburg, Germany. 30. Helsinki University Hospital, Helsinki, Finland.
Abstract
BACKGROUND: We previously showed that human anti-T-lymphocyte globulin (ATLG) plus ciclosporin and methotrexate given to patients with acute leukaemia in remission, having allogeneic haemopoietic stem-cell transplantation with peripheral blood stem cells from an HLA-identical sibling donor after myeloablative conditioning, significantly reduced 2-year chronic graft-versus-host disease (cGVHD) incidence and severity, without increasing disease relapse and infections, and improves cGVHD-free and relapse-free survival (cGRFS). The aim of an extended follow-up study was the assessment of long-term outcomes, which are, in this context, scarcely reported in the literature. We report unpublished data on quality of life (QoL) from the original study and the results of a follow-up extension. METHODS: In the original open-label study, patients with acute myeloid and lymphoblastic leukaemia in first or subsequent remission, having sibling HLA-identical allogeneic peripheral blood stem-cell transplantation, were randomly assigned (1:1) to receive ATLG plus standard GVHD prophylaxis with ciclosporin and short-term methotrexate (ATLG group) or standard GVHD prophylaxis without ATLG (non-ATLG group). Conditioning regimens were cyclophosphamide 120 mg/kg with either total body irradiation (12 Gy) or busulfan (12·8 mg/kg intravenously or 16 mg/kg orally), with or without etoposide (30-60 mg/kg). Randomisation was stratified according to centre and disease risk. The primary endpoint was cumulative incidence of cGVHD at 2 years. The primary and secondary endpoints, excluding QoL, have been published. QoL, assessed using European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-HDC29 questionnaires, was an unpublished secondary endpoint, which we now report here. A follow-up extension was then done, with the primary endpoint cumulative incidence of cGVHD. Enrolment has been completed for both studies. The original trial (number, NCT00678275) and follow-up extension (number, NCT03042676) are registered at ClinicalTrials.gov. FINDINGS:In the original study, from Dec 14, 2006, to Feb 2, 2012, 161 patients were enrolled and 155 were randomly assigned to either the ATLG group (n=83) or to the non-ATLG group (n=72). In the follow-up study, which started on Feb 7, 2017, and was completed on June 30, 2017, 61 patients were included in the ATLG group and 53 were included in the non-ATLG group. Global health status showed a more favourable time course in the ATLG group compared with the non-ATLG group (p=0·02; treatment by visit interaction). ATLG was descriptively superior to non-ATLG at 24 months for physical function (points estimate -14·8 [95% CI -26·4 to -3·1]; p=0·014) and social function (-19·1 [-38·0 to -0·2]; p=0·047), gastrointestinal side-effects (8·8 [2·5-15·1]; p=0·008) and effect on family (13·5 [1·2-25·8]; p=0·032). Extended follow-up (median 5·9 years [IQR 1·7-7·9]) confirmed a lower 5-year cGVHD incidence (30·0% [95% CI 21·4-41·9] vs 69·1% [59·1-80·1]; analysis for entire follow-up, p<0·001), no increase in relapses (35·4% [26·4-47·5] vs 22·5% [14·6-34·7]; p=0·09), improved cGRFS (34·3% [24·2-44·5] vs 13·9% [7·1-22·9]; p=0·005), and fewer patients still in immunosuppression (9·6% vs 28·3%; p=0·017) in the ATLG group compared with the non-ATLG group. 5-yearoverall survival, relapse-free survival, and non-relapse mortality did not differ significantly between groups. INTERPRETATION: The addition of ATLG to standard GVHD prophylaxis improves the probability of surviving without disease relapse and cGVHD after myeloablative peripheral blood stem-cell transplantation from an HLA-identical sibling donor for patients with acute leukaemia in remission. Further additional benefits are better QoL and shorter immunosuppressive treatment compared with standard GVHD prophylaxis without ATLG. Therefore, in this setting, ATLG plus standard GVHD prophylaxis should be preferred over the standard GVHD prophylaxis alone. FUNDING: Neovii Biotech.
RCT Entities:
BACKGROUND: We previously showed that human anti-T-lymphocyte globulin (ATLG) plus ciclosporin and methotrexate given to patients with acute leukaemia in remission, having allogeneic haemopoietic stem-cell transplantation with peripheral blood stem cells from an HLA-identical sibling donor after myeloablative conditioning, significantly reduced 2-year chronic graft-versus-host disease (cGVHD) incidence and severity, without increasing disease relapse and infections, and improves cGVHD-free and relapse-free survival (cGRFS). The aim of an extended follow-up study was the assessment of long-term outcomes, which are, in this context, scarcely reported in the literature. We report unpublished data on quality of life (QoL) from the original study and the results of a follow-up extension. METHODS: In the original open-label study, patients with acute myeloid and lymphoblastic leukaemia in first or subsequent remission, having sibling HLA-identical allogeneic peripheral blood stem-cell transplantation, were randomly assigned (1:1) to receive ATLG plus standard GVHD prophylaxis with ciclosporin and short-term methotrexate (ATLG group) or standard GVHD prophylaxis without ATLG (non-ATLG group). Conditioning regimens were cyclophosphamide 120 mg/kg with either total body irradiation (12 Gy) or busulfan (12·8 mg/kg intravenously or 16 mg/kg orally), with or without etoposide (30-60 mg/kg). Randomisation was stratified according to centre and disease risk. The primary endpoint was cumulative incidence of cGVHD at 2 years. The primary and secondary endpoints, excluding QoL, have been published. QoL, assessed using European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-HDC29 questionnaires, was an unpublished secondary endpoint, which we now report here. A follow-up extension was then done, with the primary endpoint cumulative incidence of cGVHD. Enrolment has been completed for both studies. The original trial (number, NCT00678275) and follow-up extension (number, NCT03042676) are registered at ClinicalTrials.gov. FINDINGS: In the original study, from Dec 14, 2006, to Feb 2, 2012, 161 patients were enrolled and 155 were randomly assigned to either the ATLG group (n=83) or to the non-ATLG group (n=72). In the follow-up study, which started on Feb 7, 2017, and was completed on June 30, 2017, 61 patients were included in the ATLG group and 53 were included in the non-ATLG group. Global health status showed a more favourable time course in the ATLG group compared with the non-ATLG group (p=0·02; treatment by visit interaction). ATLG was descriptively superior to non-ATLG at 24 months for physical function (points estimate -14·8 [95% CI -26·4 to -3·1]; p=0·014) and social function (-19·1 [-38·0 to -0·2]; p=0·047), gastrointestinal side-effects (8·8 [2·5-15·1]; p=0·008) and effect on family (13·5 [1·2-25·8]; p=0·032). Extended follow-up (median 5·9 years [IQR 1·7-7·9]) confirmed a lower 5-year cGVHD incidence (30·0% [95% CI 21·4-41·9] vs 69·1% [59·1-80·1]; analysis for entire follow-up, p<0·001), no increase in relapses (35·4% [26·4-47·5] vs 22·5% [14·6-34·7]; p=0·09), improved cGRFS (34·3% [24·2-44·5] vs 13·9% [7·1-22·9]; p=0·005), and fewer patients still in immunosuppression (9·6% vs 28·3%; p=0·017) in the ATLG group compared with the non-ATLG group. 5-year overall survival, relapse-free survival, and non-relapse mortality did not differ significantly between groups. INTERPRETATION: The addition of ATLG to standard GVHD prophylaxis improves the probability of surviving without disease relapse and cGVHD after myeloablative peripheral blood stem-cell transplantation from an HLA-identical sibling donor for patients with acute leukaemia in remission. Further additional benefits are better QoL and shorter immunosuppressive treatment compared with standard GVHD prophylaxis without ATLG. Therefore, in this setting, ATLG plus standard GVHD prophylaxis should be preferred over the standard GVHD prophylaxis alone. FUNDING: Neovii Biotech.
Authors: Rachel Cusatis; Joanna Balza; Zachary Uttke; Vishwajit Kode; Elizabeth Suelzer; Bronwen E Shaw; Kathryn E Flynn Journal: Qual Life Res Date: 2022-10-06 Impact factor: 3.440
Authors: Nina Orfali; Mei-Jie Zhang; Mariam Allbee-Johnson; Jaap Jan Boelens; Andrew S Artz; Claudio G Brunstein; Ian K McNiece; Filippo Milano; Muhammad Bilal Abid; Lynette Chee; Miguel A Diaz; Michael R Grunwald; Peiman Hematti; Jingmei Hsu; Hillard M Lazarus; Pashna N Munshi; Timothy Prestidge; Olle Ringden; David Rizzieri; Marcie L Riches; Sachiko Seo; Melhem Solh; Scott Solomon; David Szwajcer; Jean Yared; Koen van Besien; Mary Eapen Journal: Transplant Cell Ther Date: 2021-10-02