Acute GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute myeloid leukaemia in remission: final results of quality of life and long-term outcome analysis of a phase 3 randomised study

Francesca Bonifazi, Carlos Solano, Christine Wolschke, Mariarosaria Sessa, Francesca Patriarca, Francesco Zallio, Arnon Nagler, Carmine Selleri, Antonio Maria Risitano, Giuseppe Messina, Wolfgang Bethge, Pilar Herrera, Anna Sureda, Angelo Michele Carella, Michele Cimminiello, Stefano Guidi, Jürgen Finke, Roberto Sorasio, Christelle Ferra, Jorge Sierra & 13 others Domenico Russo, Edoardo Benedetti, Giuseppe Milone, Fabio Benedetti, Marion Heinzelmann, Domenico Pastore, Manuel Jurado, Elisabetta Terruzzi, Franco Narni, Andreas Völp, Francis Ayuk, Tapani Ruutu, Nicolaus Kröger

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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 We report unpublished data on quality of life (QoL) from the original study and the results of a follow-up extension.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-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.

LanguageEnglish
Pagese89-e99
JournalThe Lancet Haematology
Volume6
Issue number2
DOIs
Publication statusPublished - Feb 1 2019

ASJC Scopus subject areas

  • Hematology

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Acute GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute myeloid leukaemia in remission : final results of quality of life and long-term outcome analysis of a phase 3 randomised study. / Bonifazi, Francesca; Solano, Carlos; Wolschke, Christine; Sessa, Mariarosaria; Patriarca, Francesca; Zallio, Francesco; Nagler, Arnon; Selleri, Carmine; Risitano, Antonio Maria; Messina, Giuseppe; Bethge, Wolfgang; Herrera, Pilar; Sureda, Anna; Carella, Angelo Michele; Cimminiello, Michele; Guidi, Stefano; Finke, Jürgen; Sorasio, Roberto; Ferra, Christelle; Sierra, Jorge; Russo, Domenico; Benedetti, Edoardo; Milone, Giuseppe; Benedetti, Fabio; Heinzelmann, Marion; Pastore, Domenico; Jurado, Manuel; Terruzzi, Elisabetta; Narni, Franco; Völp, Andreas; Ayuk, Francis; Ruutu, Tapani; Kröger, Nicolaus.

In: The Lancet Haematology, Vol. 6, No. 2, 01.02.2019, p. e89-e99.

Research output: Contribution to journalArticle

Bonifazi, F, Solano, C, Wolschke, C, Sessa, M, Patriarca, F, Zallio, F, Nagler, A, Selleri, C, Risitano, AM, Messina, G, Bethge, W, Herrera, P, Sureda, A, Carella, AM, Cimminiello, M, Guidi, S, Finke, J, Sorasio, R, Ferra, C, Sierra, J, Russo, D, Benedetti, E, Milone, G, Benedetti, F, Heinzelmann, M, Pastore, D, Jurado, M, Terruzzi, E, Narni, F, Völp, A, Ayuk, F, Ruutu, T & Kröger, N 2019, 'Acute GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute myeloid leukaemia in remission: final results of quality of life and long-term outcome analysis of a phase 3 randomised study', The Lancet Haematology, vol. 6, no. 2, pp. e89-e99. https://doi.org/10.1016/S2352-3026(18)30214-X
Bonifazi, Francesca ; Solano, Carlos ; Wolschke, Christine ; Sessa, Mariarosaria ; Patriarca, Francesca ; Zallio, Francesco ; Nagler, Arnon ; Selleri, Carmine ; Risitano, Antonio Maria ; Messina, Giuseppe ; Bethge, Wolfgang ; Herrera, Pilar ; Sureda, Anna ; Carella, Angelo Michele ; Cimminiello, Michele ; Guidi, Stefano ; Finke, Jürgen ; Sorasio, Roberto ; Ferra, Christelle ; Sierra, Jorge ; Russo, Domenico ; Benedetti, Edoardo ; Milone, Giuseppe ; Benedetti, Fabio ; Heinzelmann, Marion ; Pastore, Domenico ; Jurado, Manuel ; Terruzzi, Elisabetta ; Narni, Franco ; Völp, Andreas ; Ayuk, Francis ; Ruutu, Tapani ; Kröger, Nicolaus. / Acute GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute myeloid leukaemia in remission : final results of quality of life and long-term outcome analysis of a phase 3 randomised study. In: The Lancet Haematology. 2019 ; Vol. 6, No. 2. pp. e89-e99.
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title = "Acute GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute myeloid leukaemia in remission: final results of quality of life and long-term outcome analysis of a phase 3 randomised study",
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-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.",
author = "Francesca Bonifazi and Carlos Solano and Christine Wolschke and Mariarosaria Sessa and Francesca Patriarca and Francesco Zallio and Arnon Nagler and Carmine Selleri and Risitano, {Antonio Maria} and Giuseppe Messina and Wolfgang Bethge and Pilar Herrera and Anna Sureda and Carella, {Angelo Michele} and Michele Cimminiello and Stefano Guidi and J{\"u}rgen Finke and Roberto Sorasio and Christelle Ferra and Jorge Sierra and Domenico Russo and Edoardo Benedetti and Giuseppe Milone and Fabio Benedetti and Marion Heinzelmann and Domenico Pastore and Manuel Jurado and Elisabetta Terruzzi and Franco Narni and Andreas V{\"o}lp and Francis Ayuk and Tapani Ruutu and Nicolaus Kr{\"o}ger",
year = "2019",
month = "2",
day = "1",
doi = "10.1016/S2352-3026(18)30214-X",
language = "English",
volume = "6",
pages = "e89--e99",
journal = "The Lancet Haematology",
issn = "2352-3026",
publisher = "Elsevier Ltd",
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}

TY - JOUR

T1 - Acute GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute myeloid leukaemia in remission

T2 - The Lancet Haematology

AU - Bonifazi, Francesca

AU - Solano, Carlos

AU - Wolschke, Christine

AU - Sessa, Mariarosaria

AU - Patriarca, Francesca

AU - Zallio, Francesco

AU - Nagler, Arnon

AU - Selleri, Carmine

AU - Risitano, Antonio Maria

AU - Messina, Giuseppe

AU - Bethge, Wolfgang

AU - Herrera, Pilar

AU - Sureda, Anna

AU - Carella, Angelo Michele

AU - Cimminiello, Michele

AU - Guidi, Stefano

AU - Finke, Jürgen

AU - Sorasio, Roberto

AU - Ferra, Christelle

AU - Sierra, Jorge

AU - Russo, Domenico

AU - Benedetti, Edoardo

AU - Milone, Giuseppe

AU - Benedetti, Fabio

AU - Heinzelmann, Marion

AU - Pastore, Domenico

AU - Jurado, Manuel

AU - Terruzzi, Elisabetta

AU - Narni, Franco

AU - Völp, Andreas

AU - Ayuk, Francis

AU - Ruutu, Tapani

AU - Kröger, Nicolaus

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

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U2 - 10.1016/S2352-3026(18)30214-X

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