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A randomized study of cyclosporine and methotrexate with or without methylprednisolone for the prevention of graft-versus-host disease: Improved long-term survival with triple prophylaxis
Ruutu, T., Nihtinen, A., Niittyvuopio, R., Juvonen, E., Volin, L.
Cancer. 2018;124(4):727-733
Abstract
BACKGROUND In a previously published study, the authors randomized 108 adult patients with a malignant hematologic disorder undergoing allogeneic bone marrow transplantation from a human leukocyte antigen-identical sibling to receive methylprednisolone (53 patients; MP+) or not to receive methylprednisolone (55 patients; MP-) as a part of graft-versus-host disease (GVHD) prophylaxis. All patients received cyclosporine and methotrexate. The cumulative incidence of acute GVHD was found to be significantly lower among the patients given MP. METHODS In the current study, the authors performed a long-term follow-up to discover possible late effects of the intensified GVHD prophylaxis. RESULTS The median follow-up for surviving patients was 24.5 years. In the MP+ group, the overall survival and recurrence-free survival were higher (P = .021 and P = .028, respectively) and the nonrecurrence mortality was lower (P = .003) than in the MP- group. There was a trend toward a lower cumulative incidence and a significantly lower prevalence (P = .031) of chronic GVHD in the MP+ group. There was no difference noted with regard to the rate of disease recurrence or in the incidence of secondary malignancies. Eleven patients in the MP- group but none in the MP+ group died >15 years after transplantation. At the end of follow-up, the overall survival rates in the MP+ and MP- groups were 55% and 20%, respectively, and the recurrence-free survival rates were 49% and 15%, respectively. CONCLUSIONS Long-term survival was found to be higher among the patients given MP in addition to cyclosporine and methotrexate. There was marked late nonrecurrence mortality observed in the group not given MP. No adverse late effects caused by the addition of corticosteroid were observed. Cancer 2018;124:727-33. © 2017 American Cancer Society.
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Anti-thymocyte globulin improves survival free from relapse and graft-versus-host disease after allogeneic peripheral blood stem cell transplantation in patients with Philadelphia-negative acute lymphoblastic leukemia: An analysis by the Acute Leukemia Working Party of the EBMT
Czerw, T., Labopin, M., Giebel, S., Socie, G., Volin, L., Fegueux, N., Masszi, T., Blaise, D., Chaganti, S., Cornelissen, J. J., et al
Cancer. 2018
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Abstract
BACKGROUND Mobilized peripheral blood stem cells are currently the predominant source of grafts for allogeneic transplantation (allogeneic peripheral blood stem cell transplantation [allo-PBSCT]), although, in comparison with bone marrow, their use is associated with an increased risk of chronic graft-versus-host disease (cGVHD). Attempts to reduce the incidence of cGVHD include the addition of anti-thymocyte globulin (ATG) to the pretransplant conditioning regimen. METHODS The goal of this retrospective study was to analyze the effect of ATG on allo-PBSCT outcomes for adults with Philadelphia-negative acute lymphoblastic leukemia (Ph-neg ALL). The primary endpoint was survival free from relapse, grade 3 to 4 acute graft-versus-host disease (aGVHD), and cGVHD (ie, graft-versus-host disease-free/relapse-free survival [GRFS]). Nine-hundred twenty-four patients who underwent unmanipulated allo-PBSCT in their first complete remission between 2007 and 2016 were included. ATG was used in 97 of the 494 transplants from matched sibling donors (20%) and in 307 of the 430 transplants from human leukocyte antigen-matched (8 of 8 loci) unrelated donors (71%). RESULTS The use of ATG was an independent factor for an improved chance of GRFS (hazard ratio [HR], 0.70; P = .0009). Furthermore, it was associated with a reduced risk of both grade 2 to 4 (HR, 0.66; P = .005) and grade 3 to 4 aGVHD (HR, 0.58; P = .03). Similarly, its addition reduced the incidence of both total (HR, 0.45; P < 10(-5) ) and extensive cGVHD (HR, 0.30; P < 10(-5) ) as well as nonrelapse mortality (HR, 0.58; P = .01). No significant effect was found with respect to leukemia-free or overall survival. However, an increased risk of relapse was noted for those who received ATG (HR, 1.40; P = .04). CONCLUSIONS Patients with Ph-neg ALL treated with allo-PBSCT benefit from the use of ATG in terms of improved GRFS. Its use may, therefore, be considered in this setting. Cancer 2018. (c) 2018 American Cancer Society.
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Long-term outcomes after standard graft-versus-host disease prophylaxis with or without anti-human-T-lymphocyte immunoglobulin in haemopoietic cell transplantation from matched unrelated donors: final results of a randomised controlled trial
Finke, J., Schmoor, C., Bethge, W. A., Ottinger, H., Stelljes, M., Volin, L., Heim, D., Bertz, H., Grishina, O., Socie, G.
The Lancet Haematology. 2017;4(6):e293-e301
Abstract
BACKGROUND Previously, we demonstrated that the addition of anti-human-T-lymphocyte immunoglobulin (ATLG) to standard ciclosporin and methotrexate prophylaxis reduced graft-versus-host disease (GvHD) in adult patients treated with allogeneic haemopoietic cell transplantation from matched unrelated donors without negatively affecting relapse and survival. Since reports on long-term results from randomised trials testing anti-thymocyte globulin are scarce, we performed an extended follow-up of the trial. 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 to receive ciclosporin and methotrexate with or without ATLG. 201 patients who underwent transplantation with peripheral blood (n=164; 82%) or bone marrow (n=37; 18%) grafts after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATLG n=103, non-ATLG n=98). We assessced chronic GvHD, non-relapse mortality, relapse, relapse mortality, disease-free survival, overall survival, severe GvHD-free (acute GvHD III-IV, and extensive chronic GvHD) and relapse-free survival, and time under immunosuppressive therapy after long-term follow-up. The trial is registered with the German Clinical Trials Register (DRKS00000002), ClinicalTrials.gov (NCT00655343), and EudraCT (2004-000232-91). FINDINGS Median follow-up was 8.6 years (IQR 8.0-9.3). Only patients at risk for chronic GvHD (ie, patients who were alive and without a second transplant at 100 days) were included in the analyses of chronic GvHD (90 patients in the ATLG group, 80 patients in the non-ATLG group). At 8 years, the incidence of extensive chronic GvHD was 14% (95% CI 8-29) in the ATLG group versus 52% (42-64) in the non-ATLG group (adjusted hazard ratio [HR] 0.18, 95% CI 0.09-0.34; p<0.0001). Non-relapse mortality was 21% (95% CI 14-30) versus 34% (26-45; adjusted HR 0.66, 95% CI 0.38-1.16; p=0.15), incidence of relapse was 35% (95% CI 27-46) versus 30% (22-41; adjusted HR 1.17, 95% CI 0.71-1.93; p=0.54), relapse mortality was 31% (95% CI 23-41) versus 29% (21-40; adjusted HR 1.03, 95% CI 0.61-1.76; p=0.90), disease-free survival was 44% (95% CI 35-54) versus 36% (27-46) (adjusted HR 0.91, 95% CI 0.63-1.31; p=0.60), overall survival was 49% (95% CI 39-59) versus 37% (27-47; adjusted HR 0.82, 95% CI 0.56-1.20; p=0.31), and severe GvHD-free and relapse-free survival was 34% (25-43) versus 13% (7-21) (adjusted HR 0.55, 95% CI 0.39-0.76; p=0.0003). The probability of being alive and free of immunosuppressive therapy was 47% (95% 37-57) in the ATLG group and 11% (5-18) in the non-ATLG group at 8 years. INTERPRETATION ATLG in addition to standard ciclosporin and methotrexate as GvHD prophylaxis improves severe GvHD-free and relapse-free survival in the long term. The use of ATLG in unrelated donor transplantation after myeloablative conditioning substantially increases the probability of surviving free of immunosuppressive therapy, and thus reduces the risk associated with long-term immunosuppression. FUNDING Neovii Biotech.Copyright © 2017 Elsevier Ltd. All rights reserved.
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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
Finke, J., Bethge, W. A., Schmoor, C., Ottinger, H. D., Stelljes, M., Zander, A. R., Volin, L., Ruutu, T., Heim, D. A., Schwerdtfeger, R., et al
The Lancet. Oncology. 2009;10(9):855-64
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.