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Posttransplant Cyclophosphamide for Prevention of Graft-versus-Host Disease: The Prospective Randomized HOVON-96 Trial
Broers, A. E. C., de Jong, C. N., Bakunina, K., Hazenberg, M. D., van Marwijk Kooy, M., de Groot, M., van Gelder, M., Kuball, J., van der Holt, B., Meijer, E., et al
Blood advances. 2022
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Editor's Choice
Abstract
Graft versus host disease (GVHD) is the most important complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). We performed a prospective randomized, multicenter, phase III trial to study whether posttransplant cyclophosphamide (PT-Cy) combined with a short course of cyclosporine A (CsA) would result in a reduction of severe GVHD and improvement of GVHD-free, relapse free survival (GRFS) as compared to the combination of CsA and mycophenolic acid (MPA) after non-myeloablative (NMA) matched related and unrelated peripheral blood alloHSCT. Between October 2013 and June 2018, 160 patients diagnosed with a high-risk hematological malignancy and having a matched related or at least 8 out of 8 HLA matched unrelated donor were randomized and allocated in a 1:2 ratio to CsA/MPA or PT-Cy/CsA. A total of 151 patients was transplanted (52 versus 99 patients). The cumulative incidence of grade II-IV acute GVHD at six months was 48% in recipients of CsA/MPA versus 30% following PT-Cy/CsA (Hazard ratio (HR): 0.48, 95% confidence interval (CI): 0.29-0.82, p=0.007). The two-year cumulative incidence of chronic extensive GVHD was 48% versus 16% (HR: 0.36, 95%CI: 0.21-0.64, p<0.001). The one-year estimate of GRFS was 21% (11%-32%) versus 45% (35%-55%), p<0.001. With a median follow-up of 56.4 months, relapse incidence, progression-free and overall survival were not significantly different between the two treatment arms. PT-Cy combined with a short course of CsA after NMA matched alloHSCT significantly improves GRFS due to a significant reduction in severe acute and chronic GVHD. The trial was registered as number NL2128 in the Dutch trial registry (www.trialregister.nl).
PICO Summary
Population
Patients with haematological malignancy due to undergo non-myeloablative allogeneic stem cell transplant with a matched related or at least 8/8 HLA matched unrelated donor, in six centres in the Netherlands (n=151)
Intervention
Posttransplant cyclophosphamide combined with a short course of cyclosporine A (PT-Cy/CsA, n=99)
Comparison
Cyclosporine A and mycophenolic acid (CsA/MPA, n=52)
Outcome
The cumulative incidence of grade II-IV acute GVHD at six months was 48% in recipients of CsA/MPA versus 30% following PT-Cy/CsA (Hazard ratio (HR): 0.48, 95% confidence interval (CI): 0.29-0.82). The two-year cumulative incidence of chronic extensive GVHD was 48% versus 16% (HR: 0.36, 95%CI: 0.21-0.64). The one-year estimate of GRFS was 21% (11%-32%) versus 45% (35%-55%), p<0.001. With a median follow-up of 56.4 months, relapse incidence, progression-free and overall survival were not significantly different between the two treatment arms.
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Graft-Versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide versus Cyclosporine A and Methotrexate in Matched Sibling Donor Transplantation
Nagler, A., Labopin, M., Dholaria, B., Wu, D., Choi, G., Aljurf, M., Ciceri, F., Gedde-Dahl, T., Meijer, E., Niittyvuopio, R., et al
Transplantation and cellular therapy. 2021
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Editor's Choice
Abstract
Cyclosporine A and methotrexate (CSA/MTX) is the standard graft-versus-host disease (GVHD) prophylaxis regimen for matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). Recently, post-transplant cyclophosphamide (PTCy) has been shown to be effective in GVHD prevention. In this registry-based study, we compared outcomes of 118 patients with PTCy and 1202 patients with CSA/MTX who underwent MSD allo-HCT for acute myeloid leukemia (AML). In a matched-pair analysis, PTCy was associated with a higher incidence of relapse at 2-year (41.1% versus 21.3%, p=0.039) compared to CSA/MTX. The incidence of day 180 grade II-IV acute GVHD (25.2% versus 25.4%, p=0.90) and 2-year chronic GVHD (42.6% versus 42.6%, p=0.84) were comparable between PTCy and CSA/MTX, respectively. Similarly, 2-year leukemia-free survival (LFS, 54.4% versus 74.32%, p=0.052), overall survival (OS, 70.6% versus 79.7%, p=0.15) and GVHD-free-relapse-free survival (GRFS, 38.1% versus 52.5%, p=0.49) were not statistically different between PTCy versus CSA/MTX. In conclusion, GVHD prophylaxis with PTCy is feasible, resulting in similar incidences of GVHD, GRFS, LFS, and OS compared to conventional CSA/MTX in patients undergoing allo-HCT from MSD. The higher relapse observed with PTCy needs further evaluation in a prospective study.
PICO Summary
Population
Patients who underwent matched sibling donor (MSD) allogeneic transplant for acute myeloid leukemia, (AML) reported to the EBMT registry (n=1320)
Intervention
Post-transplant cyclophosphamide (PTCy, n=118)
Comparison
Cyclosporine A and methotrexate (CSA/MTX, n=1202)
Outcome
In a matched-pair analysis, PTCy was associated with a higher incidence of relapse at 2-year (41.1% versus 21.3%) compared to CSA/MTX. The incidence of day 180 grade II-IV acute GVHD (25.2% versus 25.4%) and 2-year chronic GVHD (42.6% versus 42.6%) were comparable between PTCy and CSA/MTX, respectively. Similarly, 2-year leukemia-free survival (LFS, 54.4% versus 74.32%), overall survival (OS, 70.6% versus 79.7%) and GVHD-free-relapse-free survival (GRFS, 38.1% versus 52.5%) were not statistically different between PTCy versus CSA/MTX. In conclusion, GVHD prophylaxis with PTCy is feasible, resulting in similar incidences of GVHD, GRFS, LFS, and OS compared to conventional CSA/MTX in patients undergoing allo-HCT from MSD. The higher relapse observed with PTCy needs further evaluation in a prospective study.
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Post-transplantation cyclophosphamide versus antithymocyte globulin in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation from HLA-identical sibling donors: A retrospective analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Battipaglia, G., Labopin, M., Hamladji, R. M., Blaise, D., Chevallier, P., Brissot, E., Gerbitz, A., SociƩ, G., Afanasyev, B., Ciceri, F., et al
Cancer. 2020
Abstract
BACKGROUND Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Addition of antithymocyte globulin (ATG) or post-transplantation cyclophosphamide (PTCY) to standard immunosuppressive agents reduces GVHD in different donor settings. METHODS We compared the outcomes of adults with acute myeloid leukemia undergoing allo-HSCT from HLA-identical sibling donors after the use of PTCY (n = 197) or ATG (n = 1913). RESULTS Patients in the PTCY group were younger than those in the ATG group (median age, 47 vs 54 years; P < .01). Peripheral blood was the most frequently used stem cell source, being significantly more frequent in the ATG group than in the PTCY group (95% vs 70% P < .01). The conditioning regimen was more frequently myeloablative in the PTCY group than in the ATG group (59% vs 48%; P < .01). Time to neutrophil engraftment was shorter in the ATG group than in the PTCY group (17 vs 20 days; P < .01). No differences were observed according to the other transplantation outcomes, except for chronic GVHD of all grades and extensive chronic GVHD at 2 years, which were significantly lower in the ATG group compared with the PTCY group (P < .02). CONCLUSION PTCY is feasible in an HLA-identical sibling setting, and despite similar outcomes, ATG may be associated with lower incidence of chronic GVHD.
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Post-transplant cyclophosphamide after matched sibling, unrelated and haploidentical donor transplants in patients with acute myeloid leukemia: a comparative study of the ALWP EBMT
Sanz, J., Galimard, J. E., Labopin, M., Afanasyev, B., Angelucci, E., Ciceri, F., Blaise, D., Cornelissen, J. J., Meijer, E., Diez-Martin, J. L., et al
Journal of hematology & oncology. 2020;13(1):46
Abstract
BACKGROUND The use of post-transplant cyclophosphamide (PTCy) is highly effective in preventing graft-versus-host disease (GVHD) in the haploidentical (Haplo) transplant setting and is being increasingly used in matched sibling (MSD) and matched unrelated (MUD) transplants. There is no information on the impact of donor types using homogeneous prophylaxis with PTCy. METHODS We retrospectively compared outcomes of adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) who received a first allogeneic stem cell transplantation (SCT) with PTCy as GVHD prophylaxis from MSD (n = 215), MUD (n = 235), and Haplo (n = 789) donors registered in the EBMT database between 2010 and 2017. RESULTS The median follow-up was 2 years. Haplo-SCT carried a significantly increased risk of acute grade II-IV GVHD (HR 1.6; 95% CI 1.1-2.4) and NRM (HR 2.6; 95% CI 1.5-4.5) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9) that translated to no differences in LFS (HR 1.1; 95% CI 0.8-1.4) or GVHD/relapse-free survival (HR 1; 95% CI 0.8-1.3). Interestingly, the use of peripheral blood was associated with an increased risk of acute (HR 1.9; 95% CI 1.4-2.6) and chronic GVHD (HR 1.7; 95% CI 1.2-2.4) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9). CONCLUSIONS The use of PTCy in patients with AML in CR1 receiving SCT from MSD, MUD, and Haplo is safe and effective. Haplo-SCT had increased risk of acute GVHD and NRM and lower relapse incidence but no significant difference in survival.
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Post-transplant cyclophosphamide versus antithymocyte globulin in patients with acute myeloid leukemia in first complete remission undergoing allogeneic stem cell transplantation from 10/10 HLA-matched unrelated donors
Brissot, E., Labopin, M., Moiseev, I., Cornelissen, J. J., Meijer, E., Van Gorkom, G., Rovira, M., Ciceri, F., Griskevicius, L., Blaise, D., et al
Journal of hematology & oncology. 2020;13(1):87
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Editor's Choice
Abstract
BACKGROUND Graft-versus-host disease (GVHD) remains a major contributor to mortality and morbidity after allogeneic stem-cell transplantation (allo-HSCT). The updated recommendations suggest that rabbit antithymocyte globulin or anti-T-lymphocyte globulin (ATG) should be used for GVHD prophylaxis in patients undergoing matched-unrelated donor (MUD) allo-HSCT. More recently, using post-transplant cyclophosphamide (PTCY) in the haploidentical setting has resulted in low incidences of both acute (aGVHD) and chronic GVHD (cGVHD). Therefore, the aim of our study was to compare GVHD prophylaxis using either PTCY or ATG in patients with acute myeloid leukemia (AML) who underwent allo-HSCT in first remission (CR1) from a 10/10 HLA-MUD. METHODS Overall, 174 and 1452 patients from the EBMT registry receiving PTCY and ATG were included. Cumulative incidence of aGVHD and cGVHD, leukemia-free survival, overall survival, non-relapse mortality, cumulative incidence of relapse, and refined GVHD-free, relapse-free survival were compared between the 2 groups. Propensity score matching was also performed in order to confirm the results of the main analysis RESULTS No statistical difference between the PTCY and ATG groups was observed for the incidence of grade II-IV aGVHD. The same held true for the incidence of cGVHD and for extensive cGVHD. In univariate and multivariate analyses, no statistical differences were observed for all other transplant outcomes. These results were also confirmed using matched-pair analysis. CONCLUSION These results highlight that, in the10/10 HLA-MUD setting, the use of PTCY for GVHD prophylaxis may provide similar outcomes to those obtained with ATG in patients with AML in CR1.
PICO Summary
Population
Patients from the EBMT registry underoing 10/10 matched unrelated stem cell transplantation for AML (n=1626)
Intervention
Post-transplant cyclophosphamide (PTCY, n=174)
Comparison
Antithymocyte globulin (ATG, n=1452)
Outcome
No statistical difference between the PTCY and ATG groups was observed for the incidence of grade II-IV aGVHD. The same held true for the incidence of cGVHD and for extensive cGVHD. In univariate and multivariate analyses, no statistical differences were observed for all other transplant outcomes.
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Post-transplantation cyclophosphamide GvHD prophylaxis after hematopoietic stem cell transplantation from 9/10 or 10/10 HLA-matched unrelated donors for acute leukemia
Lorentino, F., Labopin, M., Ciceri, F., Vago, L., Fleischhauer, K., Afanasyev, B., Kroger, N., Cornelissen, J. J., Lovira, M., Meijer, E., et al
Leukemia. 2020
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Editor's Choice
Abstract
HLA-matching largely contributes to unrelated donor hematopoietic cell transplantation (UD-HCT) success but, due to the selective deletion of alloreactive T-cells, post-transplantation cyclophosphamide (PTCy) could modulate its negative impact on outcomes. We retrospectively compared acute leukemia patients receiving 10/10 or 9/10 HLA allele-matched UD-HCT with PTCy-GvHD prophylaxis between 2010 and 2017, reported to EBMT registry. The 100-day incidence of grade ≥2 and grade ≥3 aGvHD were comparable for 10/10 and 9/10 UD (28% versus 28%, p = 0.8 and 10% versus 8%, p = 0.5, respectively). The 2-year cGvHD and extensive cGvHD were similar between 10/10 and 9/10 UD (35% versus 44%, p = 0.2 and 21% versus 20%, p = 0.6, respectively). The 2-year nonrelapse mortality was 20% after 10/10 and 16% after 9/10 UD-HCT (p = 0.1). Relapse incidence at 2-year was 24% for 10/10 and 28% for 9/10 UD-HCT (p = 0.4). Leukemia-free survival at 2-year was the same for 10/10 and 9/10 UD (56 and 56%, p = 0.6, respectively), with comparable overall survival (62 and 59%, p = 0.9, respectively). Multivariate analysis showed no effect of HLA-matching on outcomes. An advanced disease status and patient disability remained the most important factors portending a worse survival. PTCy could alleviate the detrimental effect of HLA-allele mismatching in UD-HCT, potentially expanding the donor pool for acute leukemia patients.
PICO Summary
Population
Acute leukemia patients receiving unrelated donor HSCT with PTCy-GvHD prophylaxis between 2010 and 2017 reported to EBMT registry (n=464)
Intervention
10/10 allele-matched unrelated donor (n=305)
Comparison
9/10 allele-matched unrelated donor (n=159)
Outcome
The 100-day incidence of grade >/=2 and grade >/=3 aGvHD were comparable for 10/10 and 9/10 UD (28% versus 28% and 10% versus 8%, respectively). The 2-year cGvHD and extensive cGvHD were similar between 10/10 and 9/10 UD (35% versus 44%, and 21% versus 20%, respectively). The 2-year nonrelapse mortality was 20% after 10/10 and 16% after 9/10 UD-HCT. Relapse incidence at 2-year was 24% for 10/10 and 28% for 9/10 UD-HCT. Leukemia-free survival at 2-year was the same for 10/10 and 9/10 UD (56 and 56%, respectively), with comparable overall survival (62 and 59%, respectively). Multivariate analysis showed no effect of HLA-matching on outcomes. An advanced disease status and patient disability remained the most important factors portending a worse survival.
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Post-Transplantation Cyclophosphamide after Allogeneic Hematopoietic Stem Cell Transplantation: Results of the Prospective Randomized HOVON-96 Trial in Recipients of Matched Related and Unrelated Donors
De Jong, C. N., Meijer, E., Bakunina, K., Nur, E., van Marwijk Kooij, M., de Groot, M. R., van Gelder, M., Maertens, J. A., Kuball, J. H. E., Deeren, D., et al
Blood. 2019;134(Supplement_1):1
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Antilymphocyte Globulin for matched sibling donor transplantation in patients with myelofibrosis
Robin, M., Chevret, S., Koster, L., Wolschke, C., Yakoub-Agha, I., Bourhis, J. H., Chevallier, P., Cornelissen, J. J., Remenyi, P., Maertens, J., et al
Haematologica. 2019
Abstract
Antihuman T-lymphocyte immunoglobulin is still much debated in the setting of transplant from an HLA matched related donor. Acute and chronic graft-versus-host disease are the main cause of morbidity and mortality after allogeneic hematopoietic stem cell in patients with myelofibrosis. The aim of this study was to evaluate the effect of antihuman T-lymphocyte immunoglobulin in a large cohort of patients with myelofibrosis. 287 patients were included in the study. Cumulative incidence of grade 2-4 acute graft-versus-host disease was 26% and 41% with or without antihuman T-lymphocyte immunoglobulin. Chronic graft-versus-host disease incidence was 52% and 55%. Non-adjusted overall Survival, Disease Free Survival and non-relapse mortality were 55% vs 53%, 49% vs 45%, and 32% vs 31%, respectively with or without antihuman T-lymphocyte immunoglobulin. An adjusted model confirmed that acute graft-versus-host disease risk was lower following antihuman T-lymphocyte immunoglobulin (Hazard ratio : 0.54, p=0.010) whilst it did not decrease the risk of chronic graft-versus-host disease. Hazard ratio for overall survival and non-relapse mortality were 0.66 and 0.64, with p-value at 0.05 and 0.09, respectively. Antihuman T-lymphocyte immunoglobulin did not influence disease-free survival, graft-versus-host disease and relapse free survival and relapse risk. In conclusion, in the setting of matched related transplantation in myelofibrosis patients, this study demonstrates that antihuman T-lymphocyte immunoglobulin decreases acute graft-versus-host disease risk without increasing relapse risk.
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Post-transplant cyclophosphamide for graft-versus-host disease prophylaxis in HLA matched sibling or matched unrelated donor transplant for patients with acute leukemia, on behalf of ALWP-EBMT
Ruggeri, A., Labopin, M., Bacigalupo, A., Afanasyev, B., Cornelissen, J. J., Elmaagacli, A., Itala-Remes, M., Blaise, D., Meijer, E., Koc, Y., et al
Journal of hematology & oncology. 2018;11(1):40
Abstract
BACKGROUND Experience using post-transplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis in allogeneic stem cell transplantation (HSCT) from matched sibling donors (MSD) or unrelated donors (UD) is limited and with controversial results. The study aim was to evaluate PT-Cy as GVHD prophylaxis post-HSCT from MSD and UD transplants. We analyzed 423 patients with acute leukemia who received PT-Cy alone or in combination with other immunosuppressive (IS) drugs as GVHD prophylaxis. Seventy-eight patients received PT-Cy alone (group 1); 204 received PT-Cy in combination with one IS drug-cyclosporine-A (CSA) or methotrexate (MTX) or mycophenolate-mofetil (MMF) (group 2), while 141 patients received PT-Cy in combination with two IS drugs-CSA + MTX or CSA + MMF (group 3). Transplants were performed from 2007 to 2015 and median follow-up was 20 months. RESULTS Probability of overall survival (OS) at 2 years was 50, 52.2, and 62.4%, for the three groups, respectively, p = 0.06. In multivariate analysis, in comparison to PT-Cy alone, the addition of two IS drugs was associated with reduced risk of extensive cGVHD (HR 0.25, p = 0.02). Use of bone marrow (BM) and anti-thymocyte globulin were independently associated with reduced risk of extensive cGVHD. Prognostic factors for non-relapse mortality (NRM) were the addition of two IS drugs to PT-Cy (HR 0.35, p = 0.04), diagnosis of AML, disease status at transplant, and patient CMV serology. Factors associated with increased OS were the use of PT-Cy with two IS drugs (HR 0.49, p = 0.02), AML, and disease status at transplant. CONCLUSION For GVHD prophylaxis in MSD and UD HSCT, the addition of IS drugs to PT-Cy enhances its effect and reduces the risk of severe cGVHD, reducing mortality and improving survival.
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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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Editor's Choice
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.