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Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial.
Lancet Oncol. 2009 Sep; 10(9):855-64.LO

Abstract

BACKGROUND

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic haematopoietic cell transplantation from unrelated donors. Anti-T-cell globulins (ATGs) might lower the incidence of GVHD. We did a prospective, randomised, multicentre, open-label, phase 3 trial to compare standard GVHD prophylaxis with ciclosporin and methotrexate with or without anti-Jurkat ATG-Fresenius (ATG-F).

METHODS

Between May 26, 2003, and Feb 8, 2007, 202 patients with haematological malignancies were centrally randomly assigned using computer-generated centre-stratified block randomisation between treatment groups receiving ciclosporin and methotrexate with or without additional ATG-F. One patient in the ATG-F group did not undergo transplantation, thus 201 patients who underwent transplantation with peripheral blood (n=164; 82%) or bone marrow (n=37; 18%) grafts from unrelated donors after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATG-F n=103, control n=98). The primary endpoint was severe acute GVHD (aGVHD) grade III-IV or death within 100 days of transplantation. The trial is registered with the numbers DRKS00000002 and NCT00655343.

FINDINGS

The number of patients in the ATG-F group who had severe aGVHD grade III-IV or who died within 100 days of transplantation was 12 and 10 (21.4%, 95% CI 13.4-29.3), respectively, compared with 24 and nine (33.7%, 24.3-43.0) patients, respectively, in the control group (adjusted odds ratio 0.59, 95% CI 0.30-1.17; p=0.13). The cumulative incidence of aGVHD grade III-IV was 11.7% (95% CI 6.8-19.8) in the ATG-F group versus 24.5% (17.3-34.7) in the control group (adjusted hazard ratio [HR] 0.50, 95% CI 0.25-1.01; p=0.054), and cumulative incidence of aGVHD grade II-IV was 33.0% (n=34; 95% CI 25.1-43.5) in the ATG-F group versus 51.0% (n=50; 95% CI 42.0-61.9) in the control group (adjusted HR 0.56, 0.36-0.87; p=0.011). The 2-year cumulative incidence of extensive chronic GVHD was 12.2% (n=11; 95% CI 7.0-21.3) versus 42.6% (n=34; 95% CI 33.0-55.0; adjusted HR 0.22, 0.11-0.43; p<0.0001). There were no differences between treatment groups with regard to relapse, non-relapse mortality, overall survival, and mortality from infectious causes.

INTERPRETATION

The addition of ATG-F to GVHD prophylaxis with ciclosporin and methotrexate resulted in decreased incidence of acute and chronic GVHD without an increase in relapse or non-relapse mortality, and without compromising overall survival. The use of ATG-F is safe for patients who are going to receive a haematopoietic cell transplantation from matched unrelated donors.

FUNDING

Fresenius Biotech GmbH.

Authors+Show Affiliations

Department of Hematology and Oncology, Universitätsklinikum Freiburg, Germany. juergen.finke@uniklinik-freiburg.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19695955

Citation

Finke, Jürgen, et al. "Standard Graft-versus-host Disease Prophylaxis With or Without anti-T-cell Globulin in Haematopoietic Cell Transplantation From Matched Unrelated Donors: a Randomised, Open-label, Multicentre Phase 3 Trial." The Lancet. Oncology, vol. 10, no. 9, 2009, pp. 855-64.
Finke J, Bethge WA, Schmoor C, et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10(9):855-64.
Finke, J., Bethge, W. A., Schmoor, C., Ottinger, H. D., Stelljes, M., Zander, A. R., Volin, L., Ruutu, T., Heim, D. A., Schwerdtfeger, R., Kolbe, K., Mayer, J., Maertens, J. A., Linkesch, W., Holler, E., Koza, V., Bornhäuser, M., Einsele, H., Kolb, H. J., ... Socié, G. (2009). Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. The Lancet. Oncology, 10(9), 855-64. https://doi.org/10.1016/S1470-2045(09)70225-6
Finke J, et al. Standard Graft-versus-host Disease Prophylaxis With or Without anti-T-cell Globulin in Haematopoietic Cell Transplantation From Matched Unrelated Donors: a Randomised, Open-label, Multicentre Phase 3 Trial. Lancet Oncol. 2009;10(9):855-64. PubMed PMID: 19695955.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. AU - Finke,Jürgen, AU - Bethge,Wolfgang A, AU - Schmoor,Claudia, AU - Ottinger,Hellmut D, AU - Stelljes,Matthias, AU - Zander,Axel R, AU - Volin,Liisa, AU - Ruutu,Tapani, AU - Heim,Dominik A, AU - Schwerdtfeger,Rainer, AU - Kolbe,Karin, AU - Mayer,Jiri, AU - Maertens,Johan A, AU - Linkesch,Werner, AU - Holler,Ernst, AU - Koza,Vladimir, AU - Bornhäuser,Martin, AU - Einsele,Hermann, AU - Kolb,Hans-Jochem, AU - Bertz,Hartmut, AU - Egger,Matthias, AU - Grishina,Olga, AU - Socié,Gérard, AU - ,, Y1 - 2009/08/18/ PY - 2009/8/22/entrez PY - 2009/8/22/pubmed PY - 2009/9/16/medline SP - 855 EP - 64 JF - The Lancet. Oncology JO - Lancet Oncol VL - 10 IS - 9 N2 - BACKGROUND: Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic haematopoietic cell transplantation from unrelated donors. Anti-T-cell globulins (ATGs) might lower the incidence of GVHD. We did a prospective, randomised, multicentre, open-label, phase 3 trial to compare standard GVHD prophylaxis with ciclosporin and methotrexate with or without anti-Jurkat ATG-Fresenius (ATG-F). METHODS: Between May 26, 2003, and Feb 8, 2007, 202 patients with haematological malignancies were centrally randomly assigned using computer-generated centre-stratified block randomisation between treatment groups receiving ciclosporin and methotrexate with or without additional ATG-F. One patient in the ATG-F group did not undergo transplantation, thus 201 patients who underwent transplantation with peripheral blood (n=164; 82%) or bone marrow (n=37; 18%) grafts from unrelated donors after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATG-F n=103, control n=98). The primary endpoint was severe acute GVHD (aGVHD) grade III-IV or death within 100 days of transplantation. The trial is registered with the numbers DRKS00000002 and NCT00655343. FINDINGS: The number of patients in the ATG-F group who had severe aGVHD grade III-IV or who died within 100 days of transplantation was 12 and 10 (21.4%, 95% CI 13.4-29.3), respectively, compared with 24 and nine (33.7%, 24.3-43.0) patients, respectively, in the control group (adjusted odds ratio 0.59, 95% CI 0.30-1.17; p=0.13). The cumulative incidence of aGVHD grade III-IV was 11.7% (95% CI 6.8-19.8) in the ATG-F group versus 24.5% (17.3-34.7) in the control group (adjusted hazard ratio [HR] 0.50, 95% CI 0.25-1.01; p=0.054), and cumulative incidence of aGVHD grade II-IV was 33.0% (n=34; 95% CI 25.1-43.5) in the ATG-F group versus 51.0% (n=50; 95% CI 42.0-61.9) in the control group (adjusted HR 0.56, 0.36-0.87; p=0.011). The 2-year cumulative incidence of extensive chronic GVHD was 12.2% (n=11; 95% CI 7.0-21.3) versus 42.6% (n=34; 95% CI 33.0-55.0; adjusted HR 0.22, 0.11-0.43; p<0.0001). There were no differences between treatment groups with regard to relapse, non-relapse mortality, overall survival, and mortality from infectious causes. INTERPRETATION: The addition of ATG-F to GVHD prophylaxis with ciclosporin and methotrexate resulted in decreased incidence of acute and chronic GVHD without an increase in relapse or non-relapse mortality, and without compromising overall survival. The use of ATG-F is safe for patients who are going to receive a haematopoietic cell transplantation from matched unrelated donors. FUNDING: Fresenius Biotech GmbH. SN - 1474-5488 UR - https://www.unboundmedicine.com/medline/citation/19695955/Standard_graft_versus_host_disease_prophylaxis_with_or_without_anti_T_cell_globulin_in_haematopoietic_cell_transplantation_from_matched_unrelated_donors:_a_randomised_open_label_multicentre_phase_3_trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1470-2045(09)70225-6 DB - PRIME DP - Unbound Medicine ER -