Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2021;:Jco2001086
PURPOSE Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD. METHODS ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days). RESULTS In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) (P = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, P = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, P < .001), and the SGFS was better (97.7% v 58.7%, P < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients. CONCLUSION Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.
Adults and children with haematologic malignancies enrolled in the ABA2 trial (n=185)
8/8 matched unrelated donor transplantation with CNI/MTX plus abatacept prophylaxis (abatacept, n=73)
CNI/MTX plus placebo (placebo, n=69); non-randomised cohort: 7/8 mismatched unrelated donor (7/8, n=43)
ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days). RESULTS: In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%), and the SGFS was better (97.7% v 58.7%). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients.
Post-transplant cyclophosphamide versus antithymocyte globulin in allogeneic hematopoietic cell transplantation: a meta-analysis
Annals of hematology. 2021
Graft-versus-host disease (GVHD) prophylaxis based on post-transplant cyclophosphamide (PTCy) or antithymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantations (allo-HCT). The differential impacts of PTCy and ATG on transplantation outcomes are not well characterized. Here we report a meta-analysis of PTCy versus ATG in allo-HCT. Ten studies were eligible, and a total of 1871 patients were included. The incidence of II-IV aGVHD, III-IV aGVHD, and NRM were significantly lower in PTCy arm (HR?=?0.63, 95% CI 0.45-0.89; HR?=?0.35, 95% CI 0.16-0.77; HR?=?0.59, 95% CI 0.48-0.73). PTCy was associated with a better OS and PFS (HR?=?0.62, 95% CI?=?0.53-0.73; HR?=?0.76, 95% CI 0.62-0.93). The relapse rate and cGVHD incidence were not significantly different between PTCy and ATG (HR?=?0.85, 95% CI 0.68-1.07; HR?=?0.65, 95% CI 0.38-1.12). Thus, compared with ATG, PTCy has a better aGVHD control and OS benefit, without increasing relapse risk, which needs further validation in prospective randomized trials.
Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease
The New England journal of medicine. 2021;384(1):11-19
BACKGROUND Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known. METHODS We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation. RESULTS A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation. CONCLUSIONS In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.).
Pediatric acute graft-versus-host disease prophylaxis and treatment: Real-life approach reveals dissimilarities compared to published recommendations
Transplant international : official journal of the European Society for Organ Transplantation. 2020
Pediatric allogeneic hematopoietic cell transplantation (HCT) practices differ from those of adults, particularly the heterogeneity of transplantable non-malignant diseases and the lower incidence of Graft-versus-Host-Disease (GVHD). Several guidelines regarding the management of acute (a) GVHD in adult HCT have been published. We aimed to capture the real-life approaches for pediatric aGVHD prophylaxis/treatment, and data from 75/193 (response rate 39%) EBMT centers (26 countries) were included, representing half (48%) of the pediatric EBMT-HCT activity. Results with ≥75% approval from respondents (74/75) for GVHD prophylaxis after myeloablative HCT for malignancies partially contradict published guidelines: single-agent cyclosporine A (CsA) was used for matched-sibling donor HCT in 47%; blood CsA levels were reported lower; the relapse risk in malignant diseases influenced GVHD prophylaxis with early withdrawal of CsA; distinct longer duration of CsA was employed in non-malignant diseases. Most centers used additional anti-thymocyte globulin for matched-unrelated and mismatched donor HCT, but not for matched-siblings. Regarding prophylaxis in non-myeloablative conditioning (mainly for non-malignant diseases) responses showed broad heterogeneity. High conformity was found for first-line treatment; however, results regarding steroid-refractory aGVHD indicate an earlier diagnosis in children. Our findings highlight the need for standardized pediatric approaches towards aGVHD prophylaxis/treatment differentiated for malignant and non-malignant underlying diseases.
Role of ATG in patients with hematologic diseases undergoing umbilical cord blood transplantation: A systematic review and meta-analysis
Clinical transplantation. 2020;:e13876
The role of antithymocyte globulin (ATG) in patients with hematologic diseases undergoing umbilical cord blood transplantation (UCBT) remains controversial. This systematic review and meta-analysis were conducted to comprehensively evaluate this issue. PubMed, Embase and the Cochrane Library were systematically searched. Clinical studies reporting the impact of ATG- vs. non-ATG-containing conditioning regimens on transplantation outcomes were identified. Twenty-five studies were included. ATG significantly prevented grades II-IV and III-IV acute graft-versus-host disease (GVHD) (11 studies, 5020 patients, HR: 0.49, 95% CI: 0.42 to 0.56, P < 0.001; 5 studies, 5490 patients, HR: 0.60, 95% CI: 0.46 to 0.80, P < 0.001) but not chronic GVHD (8 studies, 5952 patients, HR: 0.78, 95% CI: 0.51 to 1.20, P = 0.266). However, use of ATG was associated with increased transplantation-related mortality and inferior overall survival (9 studies, 4244 patients, HR: 1.79, 95% CI: 1.38 to 2.33, P < 0.001; 8 studies, 5438 patients, HR: 1.96, 95% CI: 1.56 to 2.46, P < 0.001). Our study did not recommend routine use of ATG in UCBT. Individualizing the ATG timing and dose based on patient characteristics to retain the prophylactic effects of ATG on GVHD without compromising the survival of UCBT recipients may be reasonable.
Twice-daily intravenous bolus tacrolimus infusion: A safe and effective regimen for graft-versus-host disease prophylaxis
Hematology/oncology and stem cell therapy. 2020
OBJECTIVE/BACKGROUND Among patients undergoing allogeneic hematopoietic cell transplant, continuous intravenous (IV) tacrolimus infusion is frequently used for graft-versus-host disease (GvHD) prophylaxis. Twice-daily intermittent IV tacrolimus dosing may confer safety and convenience benefits. METHODS We performed a retrospective chart review of 66 patients who received twice-daily IV bolus tacrolimus for GvHD prophylaxis. The primary end point of the study was safety, as measured by renal toxicity. The secondary end points included mean tacrolimus serum concentrations, incidence of grades II-IV acute GvHD, electrolyte abnormalities, hyperglycemia, hypertension, and neurologic toxicity. RESULTS There was acceptable, possibly favorable, incidence of renal toxicity (42%) and no significant difference in grades II-IV GvHD (37%), compared with published data. Mean tacrolimus blood concentrations were not affected by occurrence of renal toxicity. CONCLUSION We conclude that administration of IV tacrolimus twice daily over 4 h may be safe and effective in preventing GvHD in allogeneic hematopoietic cell transplant.
Comparison of ATG-thymoglobulin with ATG-Fresenius for Epstein-Barr virus infections and graft-versus-host-disease in patients with hematological malignances after haploidentical hematopoietic stem cell transplantation: a single-center experience
Annals of hematology. 2020
Two anti-thymocyte globulin (ATG) forms are used in graft-versus-host disease (GVHD) prophylaxis during haploidentical hematopoietic stem cell transplantations (haplo-HSCTs): ATG-thymoglobulin (ATG-T) and ATG-fresenious (ATG-F). However, comparable dosages for haplo-HSCT remain unclear. We compared and evaluated the effects of ATG-T (7.5 mg/kg) or ATG-F (20 mg/kg) dosages in a relatively homogenous population in haplotype HSCT settings. Patients administered ATG-T 7.5 mg/kg (n = 81) or ATG-F 20 mg/kg (n = 35) as part of GVHD prophylaxis during haplo-HSCT were enrolled. Incidence and severity of GVHD, Epstein-Barr virus (EBV) infection, and immune cell recovery were compared using the Mann-Whitney U rank test and chi-square test. Cumulative incidences of GVHD, EBV infection and its subgroups, and relapse mortality were computed; overall survival (OS) was analyzed using the Kaplan-Meier method, with the log-rank test used for univariate comparison. Risk factors for OS were analyzed by the Cox proportional hazards model. Incidence and cumulative incidence of all grades of acute GVHD and subgroups were comparable in both groups (all p > 0.05); however, cumulative incidence of any grade and limited chronic GVHD was significantly higher in the ATG-T group (p = 0.002, p = 0.007, respectively). Cumulative incidences of EBV infections, EBV-DNAemia, and EBV-related diseases were similar; relapse mortality and OS rates were comparable between both groups (all p > 0.05). ATG-T dosage (7.5 mg/kg) appeared comparable to ATG-F dosage (20 mg/kg) for haplo-HSCT. Currently approved ATG-T and ATG-F doses appear efficient to balance the risk-benefit ratio of GVHD, OS, relapse mortality, and EBV infection in haplo-HSCT.
Comparative efficacy of 20 graft-versus-host disease prophylaxis therapies for patients after hematopoietic stem-cell transplantation: A multiple-treatments network meta-analysis
Critical reviews in oncology/hematology. 2020;150:102944
BACKGROUND Graft-versus-host disease (GVHD) is a leading cause of death in patients after hematopoietic stem-cell transplantation (HSCT). Previous studies have shown different efficacy of GVHD prophylaxis therapies. METHODS We reviewed 46 randomized controlled trials (including 8050 participants) systematically from Jun 20, 2004 to Aug 20, 2019. These investigations compared the following drugs or their combination at therapeutic dose range for GVHD after HSCT. The main results were based on the proportion of patients who respond to these therapies. RESULTS Cyclosporine + methotrexate + Anti-T cell globulin (ATG), tacrolimus + methotrexate + ATG, tacrolimus + bortezomib + sirolimus and cyclosporine + marrow mesenchymal stem cells (MMSCs) were significantly more efficacious than corticosteroids alone (OR: 12.15, 6.71, 6.25, 3.73). corticosteroids alone were less efficacious than all the other GVHD prophylaxis therapies tested. CONCLUSION Cyclosporine + methotrexate + ATG may be the best choice when starting treatment for GVHD.
Post-transplant cyclophosphamide versus anti-thymocyte globulin for graft-versus-host disease prevention in haploidentical transplantation for adult acute lymphoblastic leukemia
Graft-versus-host disease (GVHD) prophylaxis for unmanipulated haploidentical hematopoietic cell transplantation (haplo-HCT) include post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG). Utilizing EBMT registry, we compared ATG versus PTCy based GVHD prophylaxis in adult acute lymphoblastic leukemia (ALL) patients undergoing haplo-HCT. Included were 434 patients; ATG (n=98) and PTCy (n=336). Median follow-up was ~2 years. Baseline characteristics were similar between the groups except that the ATG-group was more likely to have relapsed/refractory ALL (P=0.008), non-TBI conditioning (P<0.001), peripheral blood graft source (P=<0.001) and transplanted at an earlier time-period (median year of HCT 2011 vs. 2015). The 100-day grade II-IV and III-IV acute-GVHD was similar between ATG and PTCy, as was 2-year chronic-GVHD. On multivariate analysis (MVA), leukemia-free survival (LFS) and overall survival (OS) was better with PTCy compared to ATG prophylaxis. Relapse incidence (RI) was lower in the PTCy group (P=0.03), while non-relapse mortality (NRM) was not different. Advanced disease and lower performance score were associated with poorer LFS and OS and advanced disease with inferior GVHD-free/relapse-free survival (GRFS). Peripheral grafts were associated with higher GVHD compared to bone marrow grafts. In ALL patients undergoing unmanipulated haplo-HCT, PTCy for GVHD prevention resulted in lower RI and improved LFS and OS compared to ATG.
Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with relatively low incidence of GVHD. Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haploHCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with AML, ALL, MDS, or CML who underwent PTCy-based haploHCT (2013-2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced intensity (RIC) conditioning and bone marrow (BM) or peripheral blood (PB) graft source. 646 patients were identified (MA-BM=79, MA-PB=183, RIC-BM=192, RIC-PB=192). The incidence of grade 2-4 aGVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (p=0.002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (p<0.001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2-4 acute GVHD; however, older donor age (30-49 versus <29 years) was significantly associated with higher rates of grade 2-4 acute GVHD (HR 1.53, 95% CI 1.11-2.12, p=0.01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR 1.70, 95% CI 1.11-2.62, p=0.01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haploHCT. Our results indicate that in RIC haploHCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
Adult patients with AML, ALL, MDS, or CML who underwent PTCy-based haploHCT (n=646)
Myeloablative conditioning with a bone marrow graft source (MA-BM, n=79), Myeloablative conditioning with a peripheral blood graft source (MA-PB, n=183)
Reduced intensity conditioning with a bone marrow graft source, (RIC-BM, n=192) Reduced intensity conditioning with a peripheral blood graft source, (RIC-PB, n=192).
The incidence of grade 2-4 aGVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively. In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2-4 acute GVHD; however, older donor age (30-49 versus <29 years) was significantly associated with higher rates of grade 2-4 acute GVHD. In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD in the RIC setting. There were no differences in relapse or overall survival between groups.