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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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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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[Kinetics of MDSC in Patients Treated Steroids-Ruxolitinib as the First Line Therapy for aGVHD]
Yang, J. J., Peng, B., Fang, S., Wei, Y., Wang, H., Zhao, Y. X., Qian, K., Wen, Y. N., Liu, D. H., Dou, L. P.
Zhongguo shi yan xue ye xue za zhi. 2022;30(1):276-285
Abstract
OBJECTIVE To analyze the kinetic characteristics of lymphocyte subsets and myeloid-derived suppressor cell (MDSC) in patients who newly diagnosed intermediate- to high-risk aGVHD and treated with steroids-ruxolitinib as the first line therapy from a single-arm, open clinical trial (NCT04061876). METHODS We prospectively observed the efficacy of 23 patients having intermediate- to high-risk aGVHD and treated with steroids-ruxolitinib as the first line therapy. The kinetic characteristics of lymphocyte subsets and MDSC were monitored, and then we compared them in steroids-ruxolitinib group (n=23), free-aGVHD group (n=20) and steroids group (n=23). RESULTS Of the 23 patients, the CR rate was 78.26% (18/23) on day 28 after first-line treatment with steroids-ruxolitinib. On day 28 after treatment, patients had lower level of CD4(+)CD29(+) T cells (P=0.08) than that of pre-treatment, whereas levels of other lymphocyte subsets in this study were higher than that of pre-treatment; CD4(+)CD29(+) T cells in CR patients decreased, compared with refractory aGVHD patients. On day 28 of treatment, CD8(+)CD28(-) T cells (P=0.03) significantly increased in patients with aGVHD than that in patients without aGVHD, so did CD8(+)CD28(-) T / CD8(+)CD28(+) T cell ratio (P=0.03). Compared with patients without aGVHD, patients with aGVHD had lower level of G-MDSC, especially on day 14 after allo-HSCT (P=0.04). Compared with pre-treatment, M-MDSC was higher in CR patients on day 3 and 7 post-treatment (P(3)=0.01, P(7)=0.03), e-MDSC was higher on day 28 post-treatment (P=0.01). Moreover, compared with CR patients, M-MDSC was lower in refractory aGVHD patients on day 3 post-treatment (P=0.01) and e-MDSC was lower on day 28 post-treatment (P=0.01). Compared with steroids group, MDSC in steroids-ruxolitinib group was higher, with the most significant difference in M-MDSC (P(3)=0.0351; P(7)=0.0142; P(14)=0.0369). CONCLUSION We found that patients newly diagnosed intermediate- to high-risk aGVHD receiving first-line therapy with steroids-ruxolitinib achieved high response rate. Moreover, the novel first-line therapy has a small impact on the immune reconstitution of patients after allo-HSCT. Elevated MDSC might predict a better response in aGVHD patients receiving this novel first-line therapy. M-MDSC responded earlier to steroids-ruxolitinib than e-MDSC, G-MDSC.
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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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5.
HLA-DQB1 mismatch increase risk of severe bleeding independently in recipients of allogeneic stem cell transplant
Qi, J., Zhang, R., Cai, C., Wang, H., Zhou, M., Shen, W., Tang, Y., Pan, T., Wu, D., Han, Y.
Annals of hematology. 2021
Abstract
Severe bleeding is a major cause of death in acute leukemia (AL) patients with graft-versus-host disease (GVHD) after allogene hematopoietic stem-cell transplantation (allo-HSCT). However, the prognostic value and prediction of HSCT-associated severe bleeding in GVHD patients have not been reported in cohort studies. We did a retrospective analysis of 200 AL patients with GVHD after allo-HSCT from Feb 1, 2014, to Dec 1, 2015. Multivariate analysis showed that the severe bleeding class was associated with the risk of death (HR 2.26, 95% CI 1.31-3.92, p<0.001***). In order to predict severe bleeding and figure out the solution to bleeding events, we established a multiple logistic regression model. HLA-DQB1 unmatching, megakaryocyte reconsititution failure, and III or IV GVHD were the independent risk factors for severe bleeding. Among all the variations above, OR of HLA-DQB1 was the highest (OR: 16.02, 95% CI: 11.54-48.68). Adding HLA-DQB1 to other factors improved the reclassification for predicting severe bleeding (NRI=0.195, z=2.634, p=0.008**; IDI=0.289, z=3.249, p<0.001***). Lasso regression was used to select variants. A nomogram of the logistic model was generated and displayed. Calibration curve demonstrated excellent accuracy in estimating severe bleeding (C index of 0.935). HLA-DQB1 showed excellent efficacy of predicting severe bleeding in HSCT patients.