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Antilymphocyte globulin (ATG) added to the conditioning regimen before allogeneic hematopoietic stem-cell transplantation resulted in a lower rate of chronic graft-versus-host disease at 2 years than the rate without ATG (32% vs. 68%), with no apparent increased risk of relapse. Chronic graft-versus-host disease (GVHD) is a major complication of allogeneic stem-cell transplantation that results in later illness and death and a reduction in quality of life. 1 , 2 Risk factors for chronic GVHD are the use of peripheral blood as a source of stem cells, a history of acute GVHD, and the use of donated stem cells with high numbers of T cells. 3 – 7 In a meta-analysis, the Stem Cell Trialists’ Collaborative Group reported an incidence of extensive chronic GVHD of 47% after peripheral-blood stem-cell transplantation from an HLA-identical sibling. 4 In 2012, more than 70% of the stem-cell transplantations performed in . . .

Among patients undergoing stem-cell transplantation from matched related donors, cyclophosphamide plus cyclosporin led to significantly longer GVHD-free, relapse-free survival than standard prophylaxis.

Overcoming graft-versus-host disease (GvHD) without increasing relapse and severe infections is a major challenge after allogeneic hematopoietic stem-cell transplantation (HSCT). ATIR101 is a haploidentical, naïve cell-enriched T-cell product, depleted of recipient-alloreactive T cells to minimize the risk of GvHD and provide graft-versus-infection and -leukemia activity. Safety and efficacy of ATIR101 administered after T-cell-depleted haploidentical HSCT (TCD-haplo + ATIR101) without posttransplant immunosuppressors were evaluated in a Phase 2, multicenter study of 23 patients with acute leukemia and compared with an observational cohort undergoing TCD-haplo alone (n = 35), matched unrelated donor (MUD; n = 64), mismatched unrelated donor (MMUD; n = 37), and umbilical cord blood (UCB; n = 22) HSCT. The primary endpoint, 6-month non-relapse mortality (NRM), was 13% with TCD-haplo + ATIR101. One year post HSCT, TCD-haplo + ATIR101 resulted in lower NRM versus TCD-haplo alone (P = 0.008). GvHD-free, relapse-free survival (GRFS) was higher with TCD-haplo + ATIR101 versus MMUD and UCB (both P < 0.03; 1-year rates: 56.5%, 27.0%, and 22.7%, respectively) and was not statistically different from MUD (1 year: 40.6%). ATIR101 grafts with high third-party reactivity were associated with fewer clinically relevant viral infections. Results suggest that haploidentical, selective donor-cell depletion may eliminate requirements for posttransplant immunosuppressors without increasing GvHD risk, with similar GRFS to MUD. Following these results, a randomized Phase 3 trial versus posttransplant cyclophosphamide had been initiated.

In the randomized, double-blind, phase 3 GRAPHITE study (NCT03657160), anti-α 4 β 7 integrin antibody vedolizumab showed greater efficacy than placebo for prevention of lower-gastrointestinal (GI) acute graft-versus-host disease (aGVHD) after unrelated allogenic hematopoietic stem cell transplantation (allo-HSCT). This post hoc analysis assessed the efficacy and safety of vedolizumab versus placebo for lower-GI aGVHD prevention in Japanese and non-Japanese patients, when added to standard GVHD prophylaxis (calcineurin inhibitor + methotrexate/mycophenolate mofetil + / − anti-thymocyte globulin [ATG]). The analysis included 35 (18 vedolizumab-treated, 17 placebo-treated) Japanese and 298 (150 vedolizumab-treated, 148 placebo-treated) non-Japanese patients. Lower-GI aGVHD-free survival by day + 180 after allo-HSCT (primary endpoint) was 94% in vedolizumab-treated versus 81% in placebo-treated Japanese patients (HR 0.36; 95% CI 0.03–4.01; P = 0.2) and 84% in vedolizumab-treated versus 70% in placebo-treated non-Japanese patients (HR 0.47; 95% CI 0.28–0.78; P = 0.002). The number of events for the 5 key secondary endpoints (lower-GI aGVHD-free and relapse-free survival, Grade C–D aGVHD-free survival, non-relapse mortality, overall survival, and Grade B–D aGVHD-free survival) by day + 180 was lower in vedolizumab- versus placebo-treated Japanese patients. No safety concerns were identified for vedolizumab use as lower-GI aGVHD prophylaxis in Japanese patients.

ATOS is a prospective observational study evaluating the outcome of patients receiving anti-human T-lymphocyte immunoglobulin (ATLG) in unrelated donor transplantation. Primary endpoint was severe GvHD and relapse-free survival (SGRFS). GvHD prophylaxis consisted of ATLG and CSA/ MTX or MMF. Outcome was compared to the ATLG arm of our prospective randomized phase III multicenter trial trial (RCT) [ 1 , 2 ]. 165 patients, median age 54 (18; 77) years, with haematological malignancies with early (45.5%), intermediate (17.6%), and advanced (37.0%) disease were included. ATLG dose differed between centers according to local practise (median total ATLG dose of 46 (IQR 32–60, range 15–91) mg/kg). Median follow-up was 70 months. Estimated probabilities at 5 years follow up were for SGRFS 0.27, OS 0.52, DFS 0.43, NRM 0.23, relapse 0.34, acute GvhD °III/IV 0.13, severe chronic GvHD 0.27. OS rates differed dependent on disease status. An effect of the given ATLG dose could not be separated from potential center effects. Despite higher age and more advanced disease in ATOS, outcome was similar to the ATLG arm of our RCT. This long-term, multicenter, experience in routine clinical practice confirms the GvHD-protective effect of ATLG without compromising relapse and non-relapse mortality rates. Clinical Trial Registry: German clinical trials register DRKS00004581.

We previously showed that minimal residual disease (MRD) detection pre-hematopoietic cell transplant (HCT) and acute GvHD (aGvHD) independently predicted risk of relapse in pediatric ALL. In this study we further define risk by assessing timing of relapse and the effects of leukemia risk category and post-HCT MRD. By multivariate analysis, pre-HCT MRD <0.1% and aGvHD by day +55 were associated with decreased relapse and improved event-free survival (EFS). Intermediate leukemia risk status predicted decreased relapse, and improved EFS and overall survival (OS). Patients with pre-HCT MRD ⩾0.1% who did not develop aGvHD compared with those with MRD <0.1% who did develop aGvHD had much worse survival (2 years EFS 18% vs 71%; P =0.001, 2 years OS 46 vs 74%; P =0.04). Patients with pre-HCT MRD <0.1% who did not experience aGvHD had higher rates of relapse than those who did develop aGvHD (40% vs 13%; P = 0.008). Post-HCT MRD led to a substantial increase in relapse risk (HR=4.5, P <0.01). Patients at high risk of relapse can be defined after transplant using leukemia risk category, presence of MRD pre or post HCT, and occurrence of aGvHD. An optimal window to initiate intervention to prevent relapse occurs between day +55 and +200 after HCT.

Chronic graft-versus-host-disease (cGVHD) is divided into two subtypes: classic (absence of acute GVHD features) and overlap cGVHD (‘ocGVHD’), in which both chronic and acute GVHD clinical features are present simultaneously. While worse outcomes with ocGVHD have been reported, there are few recent analyses. We performed a secondary analysis of data from the ABA2 trial ( N  = 185), in which detailed GVHD data were collected prospectively and systematically adjudicated. Analyses included cumulative incidence of classic versus ocGVHD, their specific organ manifestations, global disease severity scores, non-relapse mortality (NRM), disease-free survival (DFS) and overall survival (OS) in these two cGVHD subtypes. Of 92 patients who developed cGVHD, 35 were classified as ocGVHD. The 1-year cumulative incidence, organ involvement, and global severity of classic and ocGVHD were similar between ABA2 patients receiving CNI/MTX+placebo and CNI/MTX+abatacept; thus, cohorts were combined for ocGVHD evaluation. This analysis identified ocGVHD as having significantly higher severity at presentation and at maximum global severity compared to classic cGVHD. OS and DFS were significantly lower for ocGVHD versus classic cGVHD. OcGVHD is associated with increased cGVHD severity scores, and is associated with decreased OS and DFS compared to classic cGVHD, underscoring the high risks with this cGVHD subtype.

Posttransplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis is an effective strategie for patients receiving matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) and haploidentical HSCT (haplo-HSCT). We evaluated the effectiveness and safety of reduced-dose cyclophosphamide, 20 mg/kg for 13 patients in MSD-HSCT cohort and 25 mg/kg for 22 patients in haplo-HSCT cohort, on days + 3, + 4 combined with cotransplantation of peripheral blood stem cells (PBSCs) and human umbilical cord-derived mesenchymal stem cells (UC-MSCs) for severe aplastic anemia (SAA). In MSD-PTCy cohort, the times to neutrophil and platelet engraftment were significantly shorter than those in the MSD-control cohort (P < 0.05). The cumulative incidence of acute GVHD (aGVHD) at day + 100 (15.4%) was lower than that in the MSD-control cohort (P = 0.050). No patient developed chronic GVHD (cGVHD). The 1-year overall survival (OS) and event-free survival (EFS) rates were 100% and 92.3%. In haplo-PTCy cohort, the times to neutrophil and platelet engraftment were significantly shorter than those in the haplo-control cohort (P < 0.05). The cumulative incidences of aGVHD at day + 100 and 1-year cGVHD were 31.8% and 18.2%, and the 1-year OS and EFS rates were 81.8% and 66.9%. Reduced-dose PTCy and cotransplantation of PBSCs and UC-MSCs is an acceptable alternative to patients with SAA.

We conducted a multicenter phase I/II study using mesenchymal stem cells (MSCs) manufactured from the bone marrow of healthy unrelated volunteers to treat steroid-refractory acute graft-versus-host disease (aGVHD). Fourteen patients with hematological malignancies who suffered from grade II (9 patients) or III aGVHD (5) were treated. Affected organs were gut (10 patients), skin (9 patients), and liver (3 patients). Seven patients had two involved organs. The median age was 52. No other second-line agents were given. MSCs were given at a dose of 2 × 10 6 cells/kg for each infusion twice a week for 4 weeks. If needed, patients were continuously given MSCs weekly for an additional 4 weeks. By week 4, 13 of 14 patients (92.9 %) had responded to MSC therapy with a complete response (CR; n  = 8) or partial response (PR; n  = 5). At 24 weeks, 11 patients (10 with CR and 1 with PR) were alive. At 96 weeks, 8 patients were alive in CR. A total of 6 patients died, attributable to the following: underlying disease relapse (2 patients), breast cancer relapse (1), veno-occlusive disease (1), ischemic cholangiopathy (1), and pneumonia (1). No clear adverse effects associated with MSC infusion were observed. Third party-derived bone marrow MSCs may be safe and effective for patients with steroid-refractory aGVHD.

Previous studies have suggested that tacrolimus (TAC) is more potent than cyclosporine (CSA) for prophylaxis against acute GVHD after allogeneic hematopoietic stem cell transplantation (HSCT). However, the target blood concentrations of these drugs in these studies were not consistent with the current recommendations. Therefore, we performed a randomized controlled trial to compare CSA and TAC with target blood concentrations of 500 and 15 ng/ml, respectively, to prevent acute GVHD after unrelated HSCT. A total of 107 patients were randomized into a CSA group ( n =53) or a TAC group ( n =54). During the first 4 weeks after HSCT, more than 90% of the patients achieved a mean blood concentration of between 80 and 120% of the target concentration. The incidences of grade II–IV and grade III–IV acute GVHD were 39.6 and 7.5% for the CSA group and 33.3 and 9.4% for the TAC group, respectively ( P =0.41 and P =0.76). Other clinical outcomes, including overall survival, disease-free survival and the incidences of relapse, non-relapse mortality, and organ toxicities, were also equivalent. We concluded that the combinations of CSA and TAC with strict dose adjustment showed similar efficacies and toxicities as prophylaxis against acute GVHD after unrelated HSCT.