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1.
Higher cyclosporine-A concentration increases the risk of relapse in AML following allogeneic stem cell transplantation from unrelated donors using anti-thymocyte globulin
Lisak, M., Nicklasson, M., Palmason, R., Wichert, S., Isaksson, C., Andersson, P. O., Johansson, J. E., Lenhoff, S., Brune, M., Hansson, M.
Scientific reports. 2023;13(1):22777
Abstract
Cyclosporine-A (CsA) is used to prevent acute graft-versus-host disease (aGvHD). European Society for Blood and Marrow transplantation (EBMT) recommends a CsA target serum concentration of 200-300 µg/L during the first month after allogeneic hematopoietic stem cell transplantation (HSCT). With this study, we investigated whether a median CsA concentration > 200 µg/L (CsA(high)) the first month after HSCT, compared to ≤ 200 µg/L (CsA(low)), increased the relapse risk of acute myloid leukemia (AML), using unrelated donors (URD) and antithymocyte globulin (ATG). Data was collected from 157 patients with AML, transplanted 2010-2016. The cumulative incidence of relapse (CIR) at 60 months was 50% in the CsA(high) versus 32% in the CsA(low) group (p = 0.016). In univariate analysis, CsA(high) versus CsA(low) (p = 0.028), 10-unit increase of CsA as a continuous variable (p = 0.017) and high risk disease (p = 0.003) were associated with higher CIR. The results remained after adjusting for disease risk. Death following relapse occurred more frequently in the CsA(high) group (p = 0.0076). There were no significant differences in rates of aGvHD, chronic GvHD (cGvHD), EBV/CMV-infections or overall survival (OS) between the two groups. In conclusion, we found that a median CsA concentration > 200 µg/L, the first month after HSCT, results in higher CIR of AML when combined with ATG.
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Cyclophosphamide with cyclosporine A for graft-versus-host disease prophylaxis in adult patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation from human leucocyte antigen-matched donors
Sharaf El-Deen, M. O., Soliman, M. M., Al-Azab, G., Samra, M., Shams, M. E. E.
International immunopharmacology. 2023;120:110374
Abstract
BACKGROUND Graft-versus-host disease (GVHD) is one of the most severe complications in patients with acute myeloid leukemia (AML) who underwent allogenic hematopoietic stem cell transplantation (HSCT). This study addressed the effectiveness and safety outcomes of high dose post-transplant cyclophosphamide (PT-CY) followed by cyclosporine A (CSA) as a GVHD prophylaxis protocol. PATIENTS AND METHODS From January 2019 to March 2021, AML patients who underwent HSCT, and received high-dose PT-CY followed by CSA were prospectively recruited, assessed, and followed up for one-year post-transplantation (PT). The cumulative incidences of both acute GVHD (aGVHD) at 100 days PT, and chronic GVHD (cGVHD) at one-year PT were assessed. RESULTS This study included 52 patients. The cumulative incidence (95% CIs) of aGVHD was 2.3% (0.3 - 15.4%), while the cumulative incidence of cGVHD was 23.2% (12.2-41.5%). The cumulative incidence of relapse and non-relapse mortality were 15.6%, and 7.9%, respectively. The median duration to reach neutrophil and platelet engraftment was 17 and 13 days, respectively. The overall, progression-free, and GVHD-free/relapse-free survival rates (95% CIs) were 89.6% (76.6 - 95.6%), 77.7% (62.1-87.5%), and 58.2% (41.6 - 71.7%) respectively. The cumulative incidences of the main transplant-related complications were; neutropenic sepsis (48.3%), cytomegalovirus reactivation (21.7%), pneumonia (13.8%), hemorrhagic cystitis (17.8%), septic shock (4.9%), and CSA toxicity (48.9%). CONCLUSION PT-CY followed by CSA was associated with low cumulative incidences of both aGVHD and cGVHD without increase in either the relapse or transplant-related complications; so, considered as a promising protocol to be widely applied in the settings of HLA-matched donors.
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ATG in HLA-matched, peripheral blood, hematopoietic cell transplantation in acute myeloid leukemia and myelodysplastic syndrome: a secondary analysis of a CIBMTR database
Arcuri, L. J., Kerbauy, M. N., Kerbauy, L. N., Santos, F. P. S., Ribeiro, A. A. F., Hamerschlak, N.
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND Peripheral blood stem cells (PBSC) are the preferred grafts for hematopoietic cell transplantation (HCT), according to the CIBMTR. Donor recovery is faster with PBSC harvest, but PBSC is associated with higher chronic graft-versus-host disease (GVHD) and poorer quality of life. Anti-T cell globulin (ATG) is polyclonal IgG from rabbits or horses immunized with human thymocytes or a human T-cell line which may reduce graft-versus-host disease in HCT and improve outcomes. OBJECTIVE The objective of this study was to analyze the impact of ATG in HLA-matched Related (MRD) and matched (HLA 8/8) unrelated donor (MUD) HCT. STUDY DESIGN We used a freely available CIBMTR database published online for secondary analyses. The database included patients ≥ 40 y/o who have undergone their first PBSC MRD or MUD HCT for acute myeloid leukemia or myelodysplastic syndrome with or without ATG between 2008 and 2017. Patients who received posttransplant cyclophosphamide or alemtuzumab were excluded. RESULTS Overall survival was not different with ATG (HR = 1.09, 95CI 1.00-1.19, p = 0.06) compared with no ATG. Relapse rate was higher with ATG (HR = 1.29, 95CI 1.17-1.43, p < 0.001) and NRM was lower with ATG (HR = 0.84, 95CI 0.72-0.98, p = 0.03). Grades II-IV acute GVHD was significantly lower with ATG (HR = 0.77, 95CI 0.69-0.87, p < 0.001) but not grades III-IV acute GVHD (HR = 0.85, 95CI 0.69-1.04, p = 0.11). Both chronic GVHD (HR = 0.54, 95CI 0.48-0.60, p < 0.001) and moderate/severe chronic GVHD (HR = 0.45, 95CI 0.38-0.52, p < 0.001) were lower with ATG. There was an interaction between ATG and conditioning regimen for relapse rate and overall survival. Relapse rate was higher in those who received reduced-intensity (RIC) or non-myeloablative (NMA) conditioning regimens and ATG, compared with MAC ± ATG or RIC without ATG (interaction test, p = 0.003). Overall survival was also poorer with ATG and RIC or NMA conditioning regimens (interaction test, p = 0.03). CONCLUSION Our results show that ATG can mitigate the more severe forms of chronic GVHD without impairing overall survival in HLA-matched HCT with PBSC grafts and myeloablative conditioning regimen. ATG should be standard in this population.
PICO Summary
Population
Adults over 40 years drawn from the CIBMTR database, undergoing first peripheral blood stem cell transplant from matched related donor or matched unrelated donor for acute myeloid leukemia or myelodysplastic syndrome with or without ATG (n=4320)
Intervention
Received Anti-T cell globulin (ATG) prophylaxis (n=1007)
Comparison
Received no ATG prophylaxis (n=3313)
Outcome
Overall survival was not different with ATG (HR = 1.09, 95CI 1.00-1.19) compared with no ATG. Relapse rate was higher with ATG (HR = 1.29, 95CI 1.17-1.43) and non-relapse mortality was lower with ATG (HR = 0.84, 95CI 0.72-0.98). Grades II-IV acute GVHD was significantly lower with ATG (HR = 0.77, 95CI 0.69-0.87) but not grades III-IV acute GVHD (HR = 0.85, 95CI 0.69-1.04). Both chronic GVHD (HR = 0.54, 95CI 0.48-0.60) and moderate/severe chronic GVHD (HR = 0.45, 95CI 0.38-0.52) were lower with ATG. Relapse rate was higher in those who received reduced-intensity (RIC) or non-myeloablative (NMA) conditioning regimens and ATG, compared with myeloablative conditioning with or without ATG or RIC without ATG. Overall survival was also poorer with ATG and RIC or NMA conditioning regimens.
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4.
Post-transplant cyclophosphamide and sirolimus based graft-versus-host disease prophylaxis after allogeneic stem cell transplantation for acute myeloid leukemia
Lazzari, L., Balaguer-Roselló, A., Montoro, J., Greco, R., Hernani, R., Lupo-Stanghellini, M. T., Villalba, M., Giglio, F., Facal, A., Lorentino, F., et al
Bone marrow transplantation. 2022
Abstract
Post-transplant cyclophosphamide (PTCy) has emerged as a promising graft-versus-host disease (GvHD) prophylaxis in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, no studies have reported the efficacy of a GvHD prophylaxis based on PTCy with sirolimus (Sir-PTCy) in patients with acute myeloid leukemia (AML). In this retrospective study, we analyze the use of sirolimus in combination with PTCy, with or without mycophenolate mofetil (MMF), on 242 consecutive adult patients with AML undergoing a myeloablative first allo-HSCT from different donor types, in three European centers between January 2017 and December 2020. Seventy-seven (32%) patients received allo-HSCT from HLA-matched sibling donor, 101 (42%) from HLA-matched and mismatched unrelated donor, and 64 (26%) from haploidentical donor. Except for neutrophil and platelet engraftment, which was slower in the haploidentical cohort, no significant differences were observed in major transplant outcomes according to donor type in univariate and multivariate analysis. GvHD prophylaxis with Sir-PTCy, with or without MMF, is safe and effective in patients with AML undergoing myeloablative allo-HSCT, resulting in low rates of transplant-related mortality, relapse/progression, and acute and chronic GvHD in all donor settings.
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Post-Transplant Cyclophosphamide Combined with Anti-Thymocyte Globulin as Graft-versus-Host Disease Prophylaxis for Allogeneic Hematopoietic Cell Transplantation in High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome
Alanazi, W., Chen, S., Lipton, J. H., Kim, D. D., Viswabandya, A., Kumar, R., Lam, W., Law, A. D., Al-Shaibani, Z., Mattsson, J., et al
Acta haematologica. 2020;:1-8
Abstract
BACKGROUND Allogeneic hematopoietic cell transplantation (HCT) is curative for high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) but with significant non-relapse mortality (NRM) and relapse. We compared the combination of anti-thymocyte globulin (ATG; 4.5 mg/kg) and post-transplant cyclophosphamide (PTCy; 50 mg/kg on day +3 and +4) with other graft-versus-host disease (GvHD) prophylaxis regimens used for these patients. METHODS We retrospectively analyzed 159 patients, aged 22-73 (median 56) years, having undergone transplantation for high-risk AML (n = 120) or MDS (n = 39). The donors were matched related (33%), unrelated (55%) and haploidentical (12%). Almost all patients used peripheral blood stem cells. Conditioning was myeloablative (34%) or reduced intensity (66%). ATG + PTCy was used in 69 patients (43%), and other GvHD prophylaxis regimens in 90 patients (57%). RESULTS Grade III-IV acute GvHD occurred in 4% of the ATG + PTCy patients versus 20% of those using other regimens (p = 0.004), and chronic GvHD in 19% of the ATG + PTCy patients versus 41% of those using other regimens (p = 0.003). Two-year GvHD-free relapse-free survival (GRFS) was 30% with ATG + PTCy versus 18% with other regimens (p = 0.04). Multivariable analysis demonstrated that while ATG + PTCy had no significant influence on overall survival, cumulative incidence of relapse or NRM, there was a significant influence on GRFS in favor of ATG + PTCy (HR = 0.69, 95% CI 0.45-0.99, p = 0.04). CONCLUSIONS We conclude that the ATG + PTCy combination significantly improved GRFS in allogeneic HCT for high-risk AML and MDS without influencing other outcomes.
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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., Socié, 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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Posttransplantation cyclophosphamide improves transplantation outcomes in patients with AML/MDS who are treated with checkpoint inhibitors
Oran, B., Garcia-Manero, G., Saliba, R. M., Alfayez, M., Al-Atrash, G., Ciurea, S. O., Jabbour, E. J., Mehta, R. S., Popat, U. R., Ravandi, F., et al
Cancer. 2020
Abstract
BACKGROUND There have been concerns regarding increased peritransplantation complications, especially severe acute graft-versus-host disease (aGVHD), in patients with prior use of checkpoint inhibitors (CPI) before hematopoietic stem cell transplantation (HSCT). METHODS The authors performed a retrospective study of 43 patients with acute myeloid leukemia and/or myelodysplastic syndromes who were treated with an antiprogrammed cell death protein 1 (PD-1) (32 patients) or anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (9 patients) blockade or both (2 patients) prior to HSCT with the primary outcome of aGVHD by day 100 after HSCT. Outcome analyses were stratified by GVHD prophylaxis as use of post-HSCT cyclophosphamide (PTCy) (22 patients) or not (non-PTCy) (21 patients). RESULTS The PTCy group demonstrated a trend toward lower grade 3 to 4 aGVHD when compared with the non-PTCy group (5% vs 22%), although the rates of grade 2 to 4 aGVHD were comparable (49% vs 56%). The interval between CPI and HSCT did not appear to impact the incidence of aGVHD. However, a higher incidence of grade 3 to 4 aGVHD was observed in patients who received >4 treatments of CPI prior to HSCT if they were not given PTCy as GVHD prophylaxis (43% vs 12%). Matched control analyses using patients with no prior use of CPI confirmed the increase in grade 3 to 4 aGVHD with those agents. However, that increased risk was limited to patients who did not receive PTCy and was not observed in patients who received PTCy as GVHD prophylaxis. Despite persistent improvement in GVHD with the use of PTCy, disease control was not compromised and progression-free survival at 1 year was found to be superior for patients treated with PTCy compared with those not receiving PTCy among patients with prior use of CPI (55% vs 22%). CONCLUSIONS The results of the current study indicated that HSCT with prior use of CPI appears feasible in patients with acute myeloid leukemia and/or myelodysplastic syndromes and the use of PTCy as GVHD prophylaxis improves outcomes.
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The impact of anti-thymocyte globulin on the outcomes of Patients with AML with or without measurable residual disease at the time of allogeneic hematopoietic cell transplantation
Nagler, A., Dholaria, B., Labopin, M., Socie, G., Huynh, A., Itala-Remes, M., Deconinck, E., Yakoub-Agha, I., Cahn, J. Y., Bourhis, J. H., et al
Leukemia. 2019
Abstract
Measurable residual disease (MRD) status pre-allogeneic hematopoietic cell transplantation (allo-HCT) has been shown to predict transplant outcomes. We investigated the effect of Anti-Thymocyte Globulin (ATG) on acute myelogenous leukemia (AML) relapse by pretransplant MRD status. AML patients undergoing allo-HCT in first complete remission from either a matched sibling or unrelated donor during the 2006-2017 period were selected. Outcomes of 1509 patients (MRD(+), n = 426) were studied. ATG was used in 561 (52%) and 239 (58%) patients within the MRD(-) and MRD(+) cohorts, respectively. In MRD(-) patients, ATG did not affect relapse incidence (RI) (HR = 0.80, p = 0.17), but was associated with reduced incidence of grade II-IV acute GVHD, grade II-IV and chronic GVHD, reduced nonrelapse mortality (HR = 0.66, p = 0.05), improved leukemia-free survival (HR = 0.74, p = 0.02), overall survival (HR = 0.69, p = 0.01), and GVHD-relapse free survival (HR = 0.62, p < 0.01). In MRD(+) patients, ATG was associated with a lower incidence of chronic GVHD (total, HR 0.56 p = 0.03; extensive, HR 0.40 P = 0.01), without an impact on other allo-HCT outcome parameters, including RI(HR = 1.02, p = 0.92). The use of ATG was associated with reduced risk for GVHD. ATG did not increase RI, even in high-risk AML patients who were MRD(+) before allo-HCT.
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Impact of antithymocyte globulin on outcomes of allogeneic hematopoietic cell transplantation with TBI
Nagler, A., Labopin, M., Dholaria, B., Niittyvuopio, R., Maertens, J., Poire, X., Cornelissen, J., Remenyi, P., Bourhis, J. H., Beguin, Y., et al
Blood advances. 2019;3(13):1950-1960
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Abstract
The impact of the use of antithymocyte globulin (ATG) following a total body irradiation (TBI)-based myeloablative conditioning regimen has been poorly explored. We retrospectively analyzed 724 patients who underwent a first allogeneic hematopoietic cell transplantation (allo-HCT) following a TBI-based conditioning regimen for acute myeloid leukemia (AML) and compared the outcomes of 251 (35%) patients who received ATG (ATG group) with 473 (65%) patients who did not (non-ATG group). Median follow-up of surviving patients was 59 months (interquartile range, 28-83). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) for non-ATG and ATG groups in the first 100 days was 33% vs 24%, respectively (P = .0098). The 2-year cumulative incidence of chronic graft-versus-host disease (cGVHD) was reduced significantly in the ATG group in comparison with the non-ATG group (46% vs 34%, P = .003). Using multivariate analysis, in vivo T-cell depletion (ATG group) was independently associated with a decreased incidence of grade II-IV aGVHD (hazard ratio [HR], 0.28; P < .001), grade III-IV aGVHD (HR, 0.21; P < .001), cGVHD (HR, 0.63; P = .02), and nonrelapse mortality (NRM) (HR, 0.54; P = .02). Relapse risk, overall survival, and leukemia-free survival were similar between the 2 groups. Our results suggest that the addition of ATG to TBI-based myeloablative conditioning for allo-HCT in AML patients results in a significant reduction in aGVHD and cGVHD, translating into a significant reduction in NRM without increasing the relapse rate.
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Impacts of thymoglobulin in patients with acute leukemia in remission undergoing allogeneic HSCT from different donors
Wakamatsu, M., Terakura, S., Ohashi, K., Fukuda, T., Ozawa, Y., Kanamori, H., Sawa, M., Uchida, N., Ota, S., Matsushita, A., et al
Blood advances. 2019;3(2):105-115
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Abstract
Antithymocyte globulin (ATG) is widely used to reduce acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD). To clarify the different impacts of ATG for conditioning across different donor types, we retrospectively analyzed patients with acute leukemia (n = 6617) who underwent hematopoietic stem cell transplantation between 2008 and 2015 with ATG (n = 279) or without ATG (n = 6338). Because thymoglobulin is the only ATG drug approved for GVHD prophylaxis in Japan since September 2008, we included thymoglobulin alone in the present analysis. The survivors' median follow-up time was 1081 days. Patients were categorized into 5 groups: cord blood (CB; n = 1915), matched related donor (n = 1772), 1-antigen mismatched related donor (1-MMRD; n = 225), matched unrelated donor (MUD; n = 1742), and 1-allele mismatched unrelated donor (1-MMUD; n = 963). In multivariate analysis, ATG decreased overall survival (hazard ratio [HR], 1.403; P = .054) and GVHD-free/relapse-free survival (GRFS) (HR, 1.458; P = .053) in association with increased nonrelapse mortality (NRM) (HR, 1.608; P =03) with CB, whereas it improved GRFS (HR, 0.515; P < .01) and decreased grades II to IV aGVHD (HR, 0.576; P < .01), extensive cGVHD (HR, 0.460; P = .02), and NRM (HR, 0.545; P = .03) with 1-MMUD. ATG did not impact survival with 1-MMRD and MUD. The use of ATG in conditioning is beneficial due to the reduction in acute/chronic GVHD without increasing NRM or disease relapse only in 1-MMUD transplantation. On the other hand, ATG is not recommended for CB transplantation.