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Exploration of efficacy and safety of combined therapy of basiliximab with ruxolitinib for grade 3-4 steroid-refractory acute graft-versus-host disease: a registered clinical trial (NCT05021276)
Zhou, F., Pan, T., Li, X., Du, F., Ma, X., Zhang, Y., Wu, D., Han, Y., Xue, S., Miao, M., et al
Bone marrow transplantation. 2023
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Safety and Efficacy of Fecal Microbiota Transplantation for Grade IV Steroid Refractory GI-GvHD Patients: Interim Results From FMT2017002 Trial
Zhao, Y., Li, X., Zhou, Y., Gao, J., Jiao, Y., Zhu, B., Wu, D., Qi, X.
Frontiers in immunology. 2021;12:678476
Abstract
Gastrointestinal (GI) tract graft-versus-host disease (GvHD) is a major cause of post-allo-HSCT (hematopoietic stem cell transplantation) morbidity and mortality. Patients with steroid-refractory GI-GvHD have a poor prognosis and limited therapeutic options. FMT2017002 trial (#NCT03148743) was a non-randomized, open-label, phase I/II clinical study of FMT for treating patients with grade IV steroid-refractory GI-GvHD. A total of 55 patients with steroid-refractory GI-GvHD were enrolled in this study. Forty-one patients with grade IV steroid-refractory GI-GvHD were included in the final statistical analysis. Of them, 23 patients and 18 patients were assigned to the FMT group and the control group, respectively. On days 14 and 21 after FMT, clinical remission was significantly greater in the FMT group than in the control group. Within a follow-up period of 90 days, the FMT group showed a better overall survival (OS). At the end of the study, the median survival time was >539 days in the FMT group and 107 days in the control group (HR=3.51; 95% CI, 1.21-10.17; p=0.021). Both the event-free survival time (EFS) (HR=2.3, 95% CI, 0.99-5.4; p=0.08) and OS (HR=4.4, 95% CI, 1.5-13.04; p=0.008) were higher in the FMT group during the follow-up period. Overall, the mortality rate was lower in the FMT group (HR=3.97; 95% CI, 1.34-11.75; p=0.013). No differences in the occurrence of any other side effects were observed. Our data suggest that the diversity of the intestinal microbiota could be affected by allo-HSCT. Although its effectiveness and safety need further evaluation, FMT may serve as a therapeutic option for grade IV steroid-refractory GI-GvHD. CLINICAL TRIAL REGISTRATION [ClinicalTrials.gov], identifier [NCT03148743].
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Efficiency and Toxicity of Ruxolitinib as the Salvage Treatment in Steroid-Refractory Acute Graft-Versus-Host Disease after Haplo-Identical Stem Cell Transplantation
Liu, Y., Fan, Y., Zhang, W., Chen, J., Cheng, Q., Ma, X., Lin, Z., Wu, D., Xu, Y.
Transplantation and cellular therapy. 2021;27(4):332.e1-332.e8
Abstract
Haplo-identical stem cell transplantation (haplo-SCT) for hematological malignancies has ushered in a new era in which everyone has a potential donor. However, the occurrence of steroid-refractory acute graft-versus-host disease (SR-aGVHD), with no priority among second-line therapies, leads to late mortality after haplo-SCT. Ruxolitinib is the first drug recommended for SR-aGVHD. Here, we report the outcome data from 40 patients after haplo-SCT following the Beijing Protocol who had received ruxolitinib as a salvage therapy for grades II to IV SR-aGVHD in our center between November 2017 and May 2019. The overall response rate was 85% (34/40; 95% confidence interval [CI], 73.4% to 96.6%), including 25 patients with complete response. The median time to first response was 10 days. The levels of inflammatory cytokines and T cell activation declined, and the percentage of regulatory T cells increased. The rate of GVHD relapse was 26.5% (9/34; 95% CI, 10.8% to 42.1%) in responders. Cytomegalovirus reactivation and cytopenia were the major adverse events after ruxolitinib was begun (57.5% and 60%, respectively). The 6-month overall survival estimate was 56.8% (95% CI, 41.5% to 72.1%), and the event-free survival was 45% (95% CI, 29.7% to 60.3%). Liver GVHD was associated with a worse response rate and poor survival. Collectively, ruxolitinib could be an effective treatment for SR-aGVHD patients after haplo-SCT.
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Efficiency and Toxicity of Ruxolitinib as a Salvage Treatment for Steroid-Refractory Chronic Graft-Versus-Host Disease
Wang, D., Liu, Y., Lai, X., Chen, J., Cheng, Q., Ma, X., Lin, Z., Wu, D., Xu, Y.
Frontiers in immunology. 2021;12:673636
Abstract
Graft-versus-host disease (GVHD), especially steroid-refractory GVHD, remains a life-threatening complication after hematopoietic stem cell transplantation (HSCT). The effect of the JAK1/2 kinase inhibitor ruxolitinib on treating steroid-refractory acute GVHD has been verified by the REACH1/2 study; however, its safety and efficacy in patients with steroid-refractory chronic GVHD (SR-cGVHD) remain unclear. In this retrospective study, 70 patients received ruxolitinib as a salvage therapy for SR-cGVHD. Twenty-four weeks after ruxolitinib treatment, the overall response rate (ORR) was 74.3% (52/70), including 34 patients who achieved complete remission (CR) and 18 who achieved partial remission (PR). The main adverse event was cytopenia, which occurred in 51.4% (36/70) of patients. After ruxolitinib treatment, the percentage of CD4 cells increased from 18.20% to 23.22% (P<0.001), while the percentages of NK (CD16(+)CD56(+)) cells and regulatory T cells (CD4(+)CD127 (±) CD25(+)) decreased (P<0.001, P<0.001). Among the B cell subsets, the proportion of total B cells approximately tripled from 3.69% to 11.16% (P<0.001). Moreover, we observed a significant increase in IL-10 levels after ruxolitinib treatment (P=0.025) and a remarkable decrease in levels of suppression of tumorigenicity 2 (ST2) from 229.90 ng/ml to 72.65 ng/ml. The median follow-up after the initiation of ruxolitinib treatment was 401 (6-1076) days. The estimated one-year overall survival rate of the whole group was 66.0% (54.4-77.6%, 95% CI), and the one-year overall survival rate of patients with mild and moderate cGVHD was 69.6% (57.4-81.8%, 95% CI), which was better than that of patients with severe cGVHD (31.3%, 0.0-66.2%, 95% CI) (P=0.002). Patients who achieved a CR and PR achieved better survival outcomes (84.5%, 73.9-95.1%, 95% CI) than those who showed NR to ruxolitinib treatments (16.7%, 0-34.3%, 95% CI) (P<0.001). At the final follow-up, cGVHD relapse occurred in six patients after they reduced or continued their ruxolitinib doses. Collectively, our results suggest that ruxolitinib is potentially a safe and effective treatment for SR-cGVHD.
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Combining therapeutic antibodies using basiliximab and etanercept for severe steroid-refractory acute graft-versus-host disease: A multi-center prospective study
Tan, Y., Xiao, H., Wu, D., Luo, Y., Lan, J., Liu, Q., Yu, K., Shi, J., He, J., Zheng, W., et al
Oncoimmunology. 2017;6(3):e1277307
Abstract
Acute graft versus host disease (aGVHD) remains a major problem after allogeneic hematopoietic stem cell transplantation. Standard frontline therapy for aGVHD involves corticosteroids. However, fewer than half of patients have a lasting complete response. The long-term mortality rate of steroid-refractory aGVHD (SR-aGVHD) remains around 70%. To date, no consensus has been reached regarding the optimal salvage treatment for SR-aGVHD. We performed the first prospective, multi-center clinical trial to assess the efficacy and safety of a novel approach to treat severe (grades III-IV) SR-aGVHD with the combination of basiliximab and etanercept. Sixty-five patients with severe SR-aGVHD from six centers were included. The median number of basiliximab infusions was 4 (range 2-11) and of etanercept was 9 (range 2-12). At day 28 after starting the combination treatment, overall response (complete and partial response: CR+PR) to second-line treatment was 90.8% with 75.4% being CR. The incidences of CR per organ were 100%, 73.8%, and 79.7% for skin, liver, and gut involvement, respectively. Patients >30-y old (p = 0.043, RR = 3.169), development of grades III-IV liver aGVHD (p = 0.007, RR = 5.034) and cytomegalovirus (CMV) reactivation (p = 0.035, RR = 4.02) were independent predictors for incomplete response. Combined treatment with basiliximab and etanercept resulted in improved CR to visceral aGVHD and significantly superior 2-y overall survival (54.7% vs. 14.8%, p <0.001) compared with classical salvage treatments. Our data suggest that the combination of basiliximab and etanercept may constitute a promising new treatment option for SR-aGVHD.