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1.
Low-dose PTCy plus low-dose ATG as GVHD prophylaxis after UD-PBSCT for hematologic malignancies: a prospective, multicenter, randomized controlled trial
Zu, Y., Gui, R., Li, Z., Wang, J., Zhang, Y., Yu, F., Zhao, H., Zhan, X., Wang, Z., Xing, P., et al
Blood Cancer Journal. 2023;13(1):10
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2.
Targeted dosing of anti-thymocyte globulin in adult unmanipulated haploidentical peripheral blood stem cell transplantation: A single-arm, phase 2 trial
Wang, H., Wang, N., Wang, L., Du, J., Li, F., Shao, Y., Peng, B., Luan, S., Wang, L., Jin, X., et al
American journal of hematology. 2023
Abstract
Anti-thymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantation to prevent severe graft-versus-host disease (GVHD) and graft failure. However, overexposure to ATG may increase cytomegalovirus (CMV), Epstein-Barr virus (EBV) reactivation, non-relapse mortality, and disease recurrence. To investigate the optimal dosing of ATG, we established a targeted dosing strategy based on ATG concentration monitoring for haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). The aim of this phase 2 trial is to evaluate the safety and efficacy of the ATG-targeted dosing strategy in adult unmanipulated haplo-PBSCT. ATG was administered for 4 days (-5 days to -2 days) during conditioning. The ATG doses on -3 days and -2 days were adjusted by our dosing strategy to achieve the optimal ATG exposure. The primary endpoint was CMV reactivation on +180 days. Between December 2020 and January 2022, 66 haplo-PBSCT patients were enrolled and 63 of them were evaluable with a median follow-up of 632 days. The cumulative incidence of CMV reactivation was 36.7% and that of EBV was 58.7%. The 1-year disease-free survival was 82.5%, overall survival was 92.1%, and CD4+ T-cell reconstruction on +100 days was 76.8%. The most common severe regimen-associated toxicities (> grade 3) were infections (51.5%) and gastrointestinal toxicity (25.5%). A total of 102 haplo-PBSCT patients who received the conventional fixed ATG dose (cumulative 10 mg/kg) comprised historical control. The outcomes in historical control were inferior to those of phase 2 trial cohort (CMV reactivation: 70.8%, p < .001; EBV reactivation: 76.0%, p = .024; CD4 + T-cell reconstruction: 54.1%, p = .040). In conclusion, ATG-targeted dosing strategy reduced CMV/EBV reactivation and improved survival without increasing GVHD after haplo-PBSCT. These advantages may be associated with accelerated immune reconstitution.
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3.
Effectiveness of in vivo T-cell-depleted regimen containing porcine anti-lymphocyte globulin or rabbit anti-thymocyte globulin in preventing acute graft-versus-host disease after haploidentical haematopoietic stem cell transplantation
Xu, Z., Zhou, X., Zhao, X., Lu, X., Wang, H.
British journal of haematology. 2023
Abstract
To compare the clinical efficacy of porcine anti-lymphocyte globulin (p-ALG) and rabbit anti-thymocyte globulin (r-ATG) in the treatment of haematological malignancies using haploidentical haematopoietic stem cell transplantation (haplo-HSCT), this study was conducted. The incidences of neutrophil and platelet engraftment, respectively, were 100%, 93.6% and 94.4%; 100%, 93.6% and 90.3% in p-ALG 75 mg/kg (n = 57), p-ALG 90 mg/kg (n = 49), and r-ATG 7.5 mg/kg (n = 72). The median time to neutrophil engraftment and platelet engraftment were 11, 12 and 12 days (p = 0.032); 13, 14 and 13 days (p = 0.013), respectively. The incidence of grades II-IV acute graft-versus-host disease and cumulative incidence of chronic graft-versus-host disease were 16.7% versus 12.5% versus 13.3% (p = 0.817) and 14.7% versus 12.1% versus 19.5% in p-ALG 75 mg/kg, p-ALG 90 mg/kg and r-ATG groups. Notably, the cytomegalovirus infection rate in the p-ALG 75 mg/kg group was significantly lower than the other two groups. The cumulative incidence of 2-year relapse and 2-year overall survival rates were similar (p = 0.901, p = 0.497). The lower dose of p-ALG (75 mg/kg) had a similar efficacy and safety profile compared with r-ATG (7.5 mg/kg) in the setting of haplo-HSCT. Therefore, p-ALG (75 mg/kg) may be an appropriate alternative to r-ATG in the conditioning regimen of haplo-HSCT.
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4.
Low-dose post-transplant cyclophosphamide with low-dose antithymocyte globulin for prevention of graft-versus-host disease in first complete remission undergoing 10/10 HLA-matched unrelated donor peripheral blood stem cell transplants: a multicentre, randomized controlled trial
Zu, Y., Li, Z., Gui, R., Liu, Y., Zhang, Y., Yu, F., Zhao, H., Fu, Y., Zhan, X., Wang, Z., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
The most widely used regimens of graft-versus-host disease (GVHD) prophylaxis in HLA-matched unrelated donor peripheral blood stem cell transplantation (MUD-PBSCT) are based on anti-thymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). To improve the efficiency of GVHD prophylaxis, a novel regimen, composed of low-dose PTCy (20 mg/kg on day +3 and +4) and low-dose ATG (6 mg/kg), was evaluted in patients with hematological malignancies ungoing 10/10 HLA MUD-PBSCT in first remission (CR1). In our prospective, multicenter study, 104 patients were randomly assigned one-to-one to low-dose PTCy-ATG (n = 53) or standard-dose ATG (10 mg/kg, n = 51). Both the cumulative incidences (CIs) of grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) at 2 years in low-dose PTCy-ATG cohort were significantly reduced (24.5% vs. 47.1%; P = 0.017; 14.1% vs. 33.3%; P = 0.013). The CI of non-relapse-mortality (NRM) was much lower (13.2% vs. 34.5%; P = 0.049) and GVHD-free, relapse-free survival (GRFS) was significantly improved at 2 years in low-dose PTCy-ATG arm (67.3% vs 42.3%; P = 0.032). The low-dose PTCy-ATG based GVHD prophylaxis is a promising strategy for patients in CR1 after 10/10 HLA MUD-PBSCT.
PICO Summary
Population
Participants aged 12-69 years with haematological malignancies receiving 10/10 matched unrelated donor (MUD) transplantation in three transplant centres in China (n=104)
Intervention
Post-transplant cyclophosphamide, 20 mg/kg on day +3 and +4 and low-dose (6mg/kg) antithymocyte globulin (low-dose PTCy-ATG, n=53)
Comparison
ATG 2.0 mg/kg/day on days −5 through -1 (standard-dose ATG, n=51)
Outcome
Both the cumulative incidences (CIs) of grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) at 2 years in low-dose PTCy-ATG cohort were significantly reduced (24.5% vs. 47.1%; 14.1% vs. 33.3%). The CI of non-relapse-mortality (NRM) was much lower (13.2% vs. 34.5%) and GVHD-free, relapse-free survival (GRFS) was significantly improved at 2 years in low-dose PTCy-ATG arm (67.3% vs 42.3%).
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Reduced Risk of Chronic Graft-Versus-Host Disease (cGVHD) by Rabbit Anti-Thymocyte Globulin (ATG) in Patients Undergoing Matched Sibling Donor Transplantation in Hematological Malignancies
Fang, S., Wang, N., Wang, L., Du, J., Yang, J., Wen, Y., Wei, Y., Qian, K., Wang, H., Jiao, Y., et al
Annals of transplantation. 2022;27:e937356
Abstract
BACKGROUND With the addition of anti-thymocyte globulin (ATG) to GVHD prophylaxis in patients undergoing transplantation of peripheral blood stem cells (PBSCT), the incidence of cGVHD decreases. However, the optimal dose and timing of ATG remain undetermined. MATERIAL AND METHODS In this historical controlled trial, data from 85 patients who had hematological malignancies and underwent matched sibling donor (MSD)-PBSCT were used to analyze the effectiveness of rabbit ATG (rATG) for prophylaxis of GVHD. Forty patients received 5 mg/kg rATG used for days -5 to -2, and 45 patients did not receive ATG. RESULTS All patients had successful engraftment except for 2 in the non-ATG group, who had platelet engraftment failure. The 2-year cumulative incidence of chronic GVHD (cGVHD) in the ATG group versus non-ATG group was 19.3% (95% CI, 8.4-33.6%) versus 61.4% (95% CI, 45.4-73.9%) (P<0.001), and in those with moderate to severe cGVHD it was 11.0% (95% CI, 3.4-23.6%) versus 31.8% (95% CI, 18.8-45.6%) (P=0.029), respectively. The 2-year cumulative incidence of non-relapse mortality and relapse (CIR) were 0% versus 15.5% (95% CI, 6.8-27.5%) (P=0.018), and 53.3% (95% CI, 35.6-68.1%) versus 26.7% (95% CI, 14.9-40.0%) (P=0.019), respectively. No differences were found in other survival outcomes. In the multivariate analysis, ATG was an independent protective factor for moderate to severe cGVHD (HR=0.314, 95% CI, 0.103-0.958, P=0.042), and was an independent poor risk factor for CIR (HR=2.337, 95% CI, 1.133-4.822, P=0.022). CONCLUSIONS ATG in our strategy was effective for prophylaxis of cGVHD, whereas the relapse rate was increased in patients with rATG.
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Comparisons Between modified PTCY and G-CSF/ATG Regimens for Haploidentical Transplantation in Patients with Aplastic Anemia
Li, Y., Lu, X., Wang, N., Zhang, X., Cao, Y., Xiao, Y., Meng, F., Zhang, D., You, Y., Zou, L., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Haploidentical transplantation has become an alternative treatment option for aplastic anemia patients without matched sibling donors or matched unrelated donors. Recently, the post-transplantation cyclophosphamide (PTCY) regimen and granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG) regimen have become the most common protocols used worldwide. OBJECTIVE We designed this retrospective study to compare the outcomes of patients receiving a modified post-transplantation cyclophosphamide (mPTCY) regimen versus the G-CSF/ATG regimen. STUDY DESIGN We retrospectively reviewed and analyzed the clinical data of 130 aplastic anemia patients who underwent haplo-HSCT and received the mPTCY regimen (n=55) or G-CSF/ATG regimen (n=75) between Jan 2013 and Jun 2021 across seven transplant centers. RESULTS Neutrophil engraftment was successful in all patients within 30 days in the G-CSF/ATG group. The cumulative neutrophil engraftment rate in the mPTCY group was 96.36% (95% CI, 94.57-97.57, P=0.010). The median time of neutrophil engraftment in the G-CSF/ATG group was 10 (7-28) days, which was more rapid than that observed in the mPTCY group (P <0.001). There were no significant differences in the incidence of graft versus host disease (GVHD) between the two groups. The cumulative incidence of II-IV acute GVHD was 18.40% (95% CI, 4.27-40.31) in the mPTCY group and 19.32% (95% CI, 5.86-38.58) in the G-CSF/ATG group, while the cumulative incidence of III-IV acute GVHD was 7.31% (95% CI, 0.09-37.48) in the mPTCY group and 7.57% (95% CI, 0.20-34.19) in the G-CSF/ATG group. Similarly, no significant difference was observed between the two groups in terms of overall survival (OS), failure-free survival (FFS), and GVHD relapse-free survival (GRFS). The 2-year OS, FFS and GRFS rates were 95.91% (95% CI, 84.59-98.96), 92.25% (95% CI, 80.59-97.03) and 86.68% (95% CI, 73.98-93.44), respectively, in the mPTCY group and 86.67% (95% CI, 76.64-92.59), 81.28% (95% CI, 70.45-88.46) and 77.20% (95% CI, 65.89-85.16), respectively, in the G-CSF/ATG group. The transplantation-related mortality (TRM) rate was significantly higher in the G-CSG/ATG group than in the mPTCY group (13.33% in the G-CSG/ATG group versus 1.96% in the mPTCY group, P=0.022). In multivariate analysis, female donors, a higher hematopoietic cell transplantation comorbidity index (HCT-CI) and III-IV aGVHD were associated with worse survival outcomes. CONCLUSIONS In conclusion, the mPTCY and G-CSF/ATG regimens led to similar outcomes in AA patients, but quicker engraftment was observed with the ATG/G-CSF regimen, and a lower incidence of TRM was observed with the mPTCY regimen.
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7.
Optimal Active Anti-Thymocyte Globulin Exposure Associated with Minimum Risk of Virus Reactivation and Comparable Acute Graft-Versus-Host Disease under Adult Myeloablative Haploidentical Peripheral Blood Stem Cell Transplantation
Wang, H., Zhao, Y., Fang, S., Wang, L., Peng, B., Yang, J., Wang, N., Du, J., Li, F., Jin, X., et al
Transplantation and cellular therapy. 2022
Abstract
Anti-thymocyte globulin (ATG) is often included in the conditioning regimen to prevent graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HCT). Meanwhile, the risk of virus reactivation increased significantly. We conducted a single-center prospective study to identify the optimal ATG exposure that ensures engraftment, effectively prevent aGVHD, and reduces the risk of virus reactivation without increasing relapse of malignant diseases in haplo-PBSCT. From September 2018 to June 2020, 106 patients (median age: 32 years) with malignant hematological diseases who received haplo-PBSCT for the first time were enrolled. All patients received 10 mg/kg rabbit-ATG (thymoglobulin) divided for 4 days (Day -5 to -2). Pre-transplant, post-transplant, and total areas under the concentration-time curve (AUCs) of active ATG were calculated. Total AUC of active ATG was shown to be the best predictor for virus reactivation and aGVHD of grades II-IV or III-IV. The optimal total AUC range of active ATG was 100-148.5 UE/mL•day. The median time was 14 versus 13 days (P = .184) for myeloid engraftment and 13 versus 13 days (P = .263) for platelet engraftment in the optimal and non-optimal AUC group, respectively. The optimal AUC group showed a lower CI of CMV reactivation and persistent CMV viremia than the non-optimal AUC group [60.6% (95%CI, 48.3%-73.1%) versus 77.1% (95%CI, 64.5%-87.7%), P = .016, and 31.5% (95%CI, 21.2%-45.3%), versus 56.3% (95%CI, 42.9%-70.4%), P = .007, respectively]. The CI of persistent EBV viremia in the optimal AUC group was significantly lower than the non-optimal total AUC group [33.1% (95%CI, 22.5%-46.8%) versus 52.6% (95%CI, 39.3%-67.2%), P=0.048], but there was no difference in EBV reactivation (P=0.752). Similar outcomes were observed for Grade II-IV and grade III-IV aGVHD between the two groups (48.6% (95%CI, 36.8%-62.0%) versus 37.0% (95%CI, 24.8%-52.5%), P = 0.113, and 10.4% (95%CI, 4.8%-21.7%) versus 4.2% (95%CI, 1.0%-15.6%), P = 0.234, respectively). Relapse, non-relapse mortality, and disease-free survival had no significant differences between the two groups. But overall survival at 2years tended to increase in optimal AUC group (75.7% [95%CI, 62.4%-84.8%] vs. 57.8% [95%CI, 42.4%-70.4%], P=0.061). These data support an optimal active ATG exposure of 110-148.5 UE/mL•day in haplo-PBSCT. Individualized dosing of ATG in allo-HCT might reduce the risk of virus reactivation and effectively prevent aGVHD simultaneously.
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8.
High Risk of Recurrence of Malignancy Noted in 4-day rATG Regimen after Allogeneic PBSCT from Matched Sibling Donors
Wang, N., Wang, H., Fang, S., Du, J., Huang, S., Li, F., Jin, X., Jia, M., Xu, L., Dou, L., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Hitherto, the optimal timing of rabbit anti-thymocyte globulin (rATG) in matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT) remains to be elucidated. OBJECTIVE To evaluate the effect of a new timing strategy of rATG in MSD-PBSCT patients on transplantation outcomes. STUDY DESIGN In this prospective single-arm phase 2 clinical trial, 45 consecutive MSD-PBSCT patients were enrolled from February 1, 2019, to January 31, 2021. rATG was administered intravenously at a total dose of 5 mg/kg from day -5 to day -2 before graft infusion (4d-ATG group). While 37 MSD-PBSCT patients receiving rATG at the same total dose of 5 mg/kg from day -5 to day -4 before graft infusion from December 1, 2014, to January 31, 2019 served as historical control (2d-ATG group). RESULTS No graft failure occurred in either group. In 4d-ATG group, median timing to neutrophil and platelet engraftment were 12 days. The cumulative incidences (CI) of grade 2-4 and grade 3-4 acute graft-versus-host disease (acute GVHD) at day +100 were 37.8% and 4.4%. The 2-year CIs of severe chronic GVHD and extensive chronic GVHD were 2.2% and 9.6%. The rates of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation at day +180 were 24.4% and 37.8%, respectively. No patient died of non-relapse causes. Twenty-one patients relapsed at a median of 203 days after transplantation and the 2-year cumulative incidence of relapse (CIR) was 51.4%. The 2-year probabilities of overall survival (OS), disease-free survival (DFS), and GVHD-free and relapse-free survival (GRFS) were 72.4%, 48.6% and 40.8%, respectively. There were no significant differences between the 4d-ATG group and 2d-ATG group with regard to timing of neutrophil and platelet engraftment, incidences of CMV reactivation, EBV reactivation, acute GVHD, chronic GVHD, probabilities of OS and GRFS. While 2-year CIR was significantly increased and the 2-year DFS was significantly reduced in 4d-ATG group compared with the control group (CIR: 51.4% vs 13.5%, p <0.001; DFS: 48.6% vs 75.7%, p =0.014). CONCLUSION High CIR and worse DFS were noted in MSD-PBSCT receiving 4d-ATG regimen compared with historical control (2d-ATG regimen). Inappropriate rATG timing may increase the risk of relapse after MSD-PBSCT in patients with hematologic malignancies.
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9.
Antithymocyte globulin improves the survival of patients with myelodysplastic syndrome undergoing HLA-matched unrelated donor and haplo-identical donor transplants
Wang, H., Liu, H., Zhou, J. Y., Zhang, T. T., Jin, S., Zhang, X., Chen, S. N., Li, W. Y., Xu, Y., Miao, M., et al
Scientific Reports. 2017;7:43488
Abstract
Significant advances have been achieved in the outcomes of patients with myelodysplastic syndromes (MDS) after both HLA-matched sibling donor transplants (MSDT) and non-MSDT, the latter including HLA-matched unrelated donor (MUDT) and haplo-identical donor transplants (HIDT). In this retrospective study, we analyzed the data of 85 consecutive patients with MDS who received allogeneic HSCT between Dec 2007 and Apr 2014 in our center. These patients comprised 38 (44.7%) who received MSDT, 29 (34.1%) MUDT, and 18 (21.2%) HIDT. The median overall survival (OS) was 60.2 months, the probabilities of OS being 63%, 57%, and 48%, at the first, second, and fifth year, respectively. Median OS post-transplant (OSPT) was 57.2 months, the probabilities of OSPT being 58%, 55%, and 48% at the first, second, and fifth year, respectively. The survival of patients receiving non-MSDT was superior to that of MSDT, median OSPT being 84.0 months and 23.6 months, respectively (P=0.042); the findings for OS were similar (P=0.028). We also found that using ATG in conditioning regimens significantly improved survival after non-MSDT, with better OS and OSPT (P=0.016 and P=0.025). These data suggest that using ATG in conditioning regimens may improve the survival of MDS patients after non-MSDT.