Patients

Patients eligible for the study were aged 12 years, weighed 30kg and had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 if aged 18 years34 and Karnofsky or Lansky PS60% if aged 16 years or 12 to <16 years35, respectively (see Supplementary Tables 5 and 6 for details of PS scoring systems). All patients were to receive either peripheral blood or bone marrow allo-HSCT for hematologic malignancy from unrelated donors who were 8 of 8 or 7 of 8 human leukocyte antigen (HLA)-matched (a single allele mismatch at HLA-A, HLA-B and HLA-C, and HLA-DRB1 was permitted). A total of 441 patients were screened for eligibility. After screening, 343 patients were randomly assigned 1:1 to receive vedolizumab (174 patients) or placebo (169 patients) treatment. Randomization was stratified by age (patients aged 18 years or aged 12 to <18 years); HLA match (8 of 8 versus 7 of 8); conditioning regimen intensity (myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC)); and anti-thymocyte globulin (ATG) use (with versus without ATG). Patients received either vedolizumab 300mg or placebo intravenously on day 1 and days +13, +41, +69, +97, +125 and +153 after allo-HSCT in addition to standard GVHD prophylaxis (CNI plus methotrexate or mycophenolate mofetil). Nine patients did not receive study treatment, five were randomized to vedolizumab and four were randomized to placebo treatment.

Of 334 patients who received 1 dose of study treatment (analyzed for safety study end points), 333 also received allo-HSCT (analyzed for efficacy study end points), 168 in the vedolizumab group and 165 in the placebo group. For patients discontinuing the study, reasons for discontinuation included death (26 out of 57 patients in the vedolizumab group and 34 out of 71 in the placebo group), withdrawal by the patient (16 versus 18) and adverse events (AEs; 6 versus 5) (Fig. 1). Median (range) exposure to treatment was 40.0 (18.142.1) weeks for vedolizumab and 39.7 (18.142.3) weeks for placebo. In the vedolizumab group, patients received a mean (s.d.) of 5.4 (2.1) and median (range) 7.0 (17) treatment doses; 52.7% of patients in the vedolizumab group received all seven doses. A mean (s.d.) of 5.1 (2.3) and median (range) 7.0 (17) doses were received in the placebo group; 50.9% of patients in this group received all seven doses. Patient numbers were reduced to 60% of the planned sample size of 558 because of early enrollment termination owing to the impact of COVID-19 on recruitment. Consequently, more patients (n=137, 41.1%) received ATG at baseline than the 25% planned.

Discontinuation of the study refers to all patients who discontinued before the end of the long-term follow-up safety survey period of the study, 6 months after the last dose of study treatment. Withdrawn by physician is noted as reason other. Patients included in the analysis for efficacy end points per protocol were those who received 1 dose of study treatment and also received allo-HSCT. One patient was randomized to receive vedolizumab but did not receive allo-HSCT; per protocol, this patient was not included in the analysis of efficacy end points but was included in the analysis of safety end points.

Patient and transplant characteristics were balanced between treatment groups (Table 1 and Extended Data Table 1). The median age was 55.0 years (range, 1674 years; 1 aged <18 years) and 62.8% were male. The most frequent underlying malignancies were acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoid leukemia (ALL). The conditioning regimen intensity was either MAC (52.4% in the vedolizumab group versus 53.9% in the placebo group) or RIC. GVHD prophylaxis (with or without ATG) was tacrolimus (TAC)+methotrexate (MTX; 42.3% versus 50.3%) or TAC+mycophenolate mofetil (MMF; 3.0% versus 3.0%); cyclosporine (CYS)+MTX (30.4% versus 23.0%) or CYS+MMF (14.3% versus 12.1%). The proportion of patients who received ATG prophylaxis was balanced between treatment groups: 42.3% (n=71) in the vedolizumab group versus 40.0% (n=66) in the placebo group; 57.7% versus 60.0% did not receive ATG.

Neutrophil engraftment occurred in 165 patients in the vedolizumab treatment group and 160 patients in the placebo group. The median (range) time to neutrophil engraftment was 16.0 (835) days in the vedolizumab group and 15.0 (831) days in the placebo group. Platelet engraftment occurred in 159 patients in the vedolizumab group and 148 patients in the placebo group. The median (range) time to platelet engraftment was 18.0 (1136) days in the vedolizumab group and 17.0 (0233) days in the placebo group.

The primary study end point was lower-GI aGVHD-free survival by day +180 after allo-HSCT. There were 24 (14.3%) patients in the vedolizumab group with an event of lower-GI aGVHD or death by day +180 after allo-HSCT compared to 47 (28.5%) patients in the placebo group (Fig. 2a). The frequency of lower-GI aGVHD by maximum clinical stage (see Supplementary Table 1 for a description of clinical staging of aGVHD9) is shown in Fig. 2b for each treatment group, with four cases of stage 24 lower-GI aGVHD in the vedolizumab group compared to 14 cases observed in those who received placebo. The KaplanMeier (KM) estimate for lower-GI aGVHD-free survival by day +180 was 85.5% (95% confidence interval (CI) 79.290.1) for the vedolizumab group and 70.9% (63.277.2) for the placebo group (Fig. 2c). The risk of a lower-GI aGVHD event or death by day +180 after allo-HSCT was 55% less in the vedolizumab group compared to the placebo group (hazard ratio (HR) 0.45, 95% CI 0.270.73; P<0.001). Results were consistent for sensitivity analyses of the primary end point (Table 2), including events occurring within a 7-day time frame at day +187 after allo-HSCT, stratified log-rank tests by randomization stratification factors, analysis with corrected stratification information, competing risk analysis and an analysis excluding aGVHD events graded stage 0 or unknown. By day +180 after allo-HSCT, 23 patients (13.7%) in the vedolizumab group versus 43 (26.1%) in the placebo group had an event of death or lower-GI aGVHD (when aGVHD events graded stage 0 or unknown were excluded) (HR 0.47, 95% CI 0.280.78; P=0.0029). In subgroup analyses of the primary end point (Fig. 2d and Extended Data Fig. 1), HRs consistently favored vedolizumab over placebo regardless of HLA match, conditioning regimen intensity, use of ATG or stem-cell source (bone marrow or peripheral blood). The overall incidence of upper-GI aGVHD, skin aGVHD and aGVHD in the liver by day +180 after allo-HSCT was similar between treatment groups (Supplementary Table 7).

Analysis included all randomized patients who received 1 dose of study treatment and received allo-HSCT. All statistical tests were two-sided. a, Graph shows number and proportion of patients with a lower-GI aGVHD event or death; censored for patients who had not had the lower-GI aGVHD event or died or had the event after a prespecified time, for example, last contact or day +180 after allo-HSCT, whichever occurred first. If a patient had a lower-GI aGVHD event and died due to any cause, including lower-GI aGVHD, the time to event was derived as the time to the first qualifying event (lower-GI aGVHD event). b, Frequency of lower-GI aGVHD by maximum clinical stages 04 by day +180 after allo-HSCT for patients in vedolizumab and placebo treatment groups and also the corresponding frequency of skin aGVHD and liver aGVHD in these treatment groups by maximum clinical stages 04 by day +180 after allo-HSCT. CI was based on the ClopperPearson method. c, KM estimate for the primary study end point lower-GI aGVHD-free survival from first study treatment (day 1) to lower-GI aGVHD event or death due to any cause. Red line shows the vedolizumab group; blue line shows the placebo group; open circles indicate censored patients. HR obtained via a Cox proportional hazards model with treatment group, stratified by randomization stratification factors: HLA match (7 of 8 or 8 of 8), conditioning regimen (MAC or RIC), ATG (with or without) and P value from a log-rank test (P=0.0009). d, Forest plot of prespecified subgroup analyses for the primary study end point of lower-GI aGVHD-free survival by day +180 after allo-HSCT: conditioning regimen MAC or RIC, with or without ATG, CNI TAC or CYS, HLA match, and stem cell source peripheral blood or bone marrow. HRs plotted with 95% CIs were obtained via a Cox proportional hazards model with treatment group stratified by randomization strata. Results for the remaining prespecified subgroup analyses are shown in Extended Data Fig. 1.

The KM estimates for the five key secondary end points analyzed at day +180 after allo-HSCT are shown in Fig. 3.

ae, KM estimates for the secondary efficacy end points. Analyses included all randomized patients who received 1 dose of study treatment and allo-HSCT. In the fixed-sequence hierarchical testing procedure, once 1 efficacy end point was not significant (P0.05), testing of subsequent end points was not performed. P values were obtained using a log-rank test unless otherwise stated. All statistical tests were two-sided. *P value is significant for vedolizumab versus placebo. HR and 95% CI values were obtained from a Cox proportional hazards model with treatment group stratified by randomization strata: HLA match (7 of 8 or 8 of 8), conditioning regimen (MAC or RIC) and ATG (with or without). Time to first documented lower-GI aGVHD, relapse of underlying malignancy or death from any cause. Sensitivity analysis, excluding lower-GI aGVHD events classified as clinical grade 0 or unknown. NRM was a competing risk in this competing risk sensitivity analysis; P value for comparison of vedolizumab with placebo was obtained by a Grays test. Time to first documented IBMTR grade CD aGVHD (any organ) or death from any cause. **Death and relapse were competing risks in this sensitivity analysis; an event was defined as IBMTR grade CD aGVHD (any organ) or death. P value was obtained by a Grays test. Death from first dose of study treatment without occurrence of a relapse. Relapse was a competing risk in this sensitivity analysis; NRM was the time from first study treatment to death without occurrence of a relapse; P value was obtained by a Grays test. Overall survival by day +180 was the analysis of the time from the first dose of study treatment to death from any cause. All deaths were defined as events in this analysis. Time to first documented IBMTR grade BD aGVHD (any organ) or death from any cause. Death and relapse were competing risks in this sensitivity analysis; an event was defined as IBMTR grade BD aGVHD (any organ) or death. P value was obtained by a Grays test.

There was a statistically significant difference favoring vedolizumab over placebo for lower-GI aGVHD-free and relapse of the underlying malignancy-free survival by day +180 after transplant. The KM estimated survival for this end point was 78.9% for the vedolizumab treatment group versus 65.4% for the placebo group. Events of lower-GI aGVHD, relapse or death for this end point occurred in 11, 18 and 6 patients, respectively from the vedolizumab group (total of 35, 20.8%) and 31, 13 and 12 (total of 56, 33.9%) in the placebo group (HR 0.56, 95% CI 0.370.86; P=0.0043). A statistically significant treatment difference favoring vedolizumab for this end point was also maintained after a sensitivity analysis excluding stage 0 and unknown lower-GI aGVHD events (HR 0.59, 95% CI 0.380.91; P=0.0130) (Fig. 3). The secondary end point of IBMTR grade CD aGVHD of any organ-free survival by day +180 (see Supplementary Table 3 for description of aGVHD severity grading using the IBMTR severity index), also demonstrated a statistical difference between vedolizumab and placebo treatment groups. The KM estimated survival for this end point was 78.9% for vedolizumab the treatment group versus 67.7% in the placebo group. Events of grade CD aGVHD of any organ or death counted for this end point occurred in 35 patients (20.8%) receiving vedolizumab versus 52 (31.5%) receiving placebo (HR 0.59, 95% CI 0.390.91; P=0.0204). In a competing risk analysis (death and relapse as competing risks), cumulative incidence of IBMTR grade CD aGVHD by day +180 was lower for the vedolizumab group (13.2%, 95% CI 8.618.8) than the placebo group (21.6%, 95% CI 15.628.2; P=0.0446) (Fig. 3). Secondary end point sensitivity analyses (Supplementary Table 8) and subgroup analyses (Extended Data Fig. 2) showed consistent results with decreased risk in the vedolizumab group compared to the placebo treatment group. The secondary end point of non-relapse mortality (NRM) by day +180 did not meet statistical significance, with 10 patients (6.0%) in the vedolizumab group and 19 (11.5%) in the placebo group (HR 0.48, 95% CI 0.221.04; P=0.0668) dying of non-relapse causes. Following the hierarchical statistical testing procedure, the subsequent fourth and fifth secondary end points were not tested for statistical significance. The KM estimate for the fourth secondary end point of overall survival was 89.7% for the vedolizumab treatment group and 84.4% in the placebo group. All-cause deaths by day +180 counted for this analysis occurred in 17 patients (10.1%) in the vedolizumab group and 25 (15.2%) in the placebo group (HR 0.63, 95% CI 0.341.17; P=0.1458). For the fifth secondary end point of IBMTR grade BD aGVHD of any organ-free survival by day +180, KM estimated survival was 66.4% for the vedolizumab treatment group and 52.3% in the placebo group. Grade BD aGVHD events in any organ counted for this end point occurred in 47 patients (28.0%) in the vedolizumab group and 64 (38.8%) in the placebo group with deaths also counted in 9 and 13 patients in the vedolizumab and placebo groups, respectively (HR 0.64, 95% CI 0.460.91; P=0.0105).

Results for the main exploratory end points at day +180 and day +365 after transplant are summarized (Extended Data Tables 3 and 4). The cumulative incidence of all chronic GVHD events by day +180 was 20.7% (95% CI 14.827.2) in the vedolizumab group versus 21.9% (95% CI 15.828.6) in the placebo group (death and relapse as competing risks; nominal P=0.7555). Chronic GVHD requiring systemic immunosuppression by day +180 occurred in three (1.8%) patients in the vedolizumab group (severity was moderate in two patients and severe in one) and four (2.4%) in the placebo group (one mild, two moderate and one patient had severe chronic GVHD) (Extended Data Table 3). KM estimates for GVHD (any organ)-free and relapse (of the underlying malignancy)-free survival by day +180 were 80.1% in the vedolizumab group and 69.7% in the placebo group; events for this end point occurred in 33 (19.6%) of patients in the vedolizumab group and 49 (29.7%) in the placebo group (HR 0.61, 95% CI 0.390.96; nominal P=0.0243). Events of clinical stage 24 lower-GI aGVHD or death by day +180 occurred in fewer patients in the vedolizumab group (19, 11.3%) than in the placebo group (33, 20.0%) (HR 0.52, 95% CI 0.290.91; nominal P=0.0222). KM estimates for clinical stage 24 lower-GI aGVHD-free survival were 88.5% and 79.5%, respectively. By day +180 grade 24 aGVHD-free survival (per MAGIC criteria10, see Supplementary Table 4) also seemed to favor vedolizumab over placebo; KM estimates were 74.1% for vedolizumab and 63.3% for placebo, with events occurring in 43 (25.6%) and 59 (35.8%) patients, respectively (HR 0.67, 95% CI 0.450.99; nominal P=0.0421). Frequency of lower-GI aGVHD by maximum MAGIC grade were also reported for each treatment group, with corresponding values for maximum MAGIC grade of skin and liver aGVHD (Extended Data Table 2).

Progression-free survival in vedolizumab and placebo treatment groups by day +180 were 83.1% (95% CI 76.588.0) versus 77.6% (95% CI 70.483.3), respectively. Cumulative incidence of all relapse and death events for time to relapse (of the underlying malignancy) by day +180 were similar across treatment groups 10.9% (95% CI 6.716.2) for vedolizumab versus 10.6% (95% CI 6.416.0) for placebo (death as a competing risk; nominal P=0.9090). By day +180, there was no significant difference in relapse of the underlying malignancy between treatment groups, occurring in 18 (10.7%) patients from the vedolizumab group and 17 (10.3%) from the placebo group (HR 1.32, 95% CI 0.513.40; nominal P=0.9821; Extended Data Table 3).

Consistent results were obtained for primary and secondary efficacy end points when these were assessed as exploratory study end points 1 year after allo-HSCT (Extended Data Table 4). By day +365 after allo-HSCT, 21.4% of patients in the vedolizumab group and 33.9% in the placebo group had an event of lower-GI aGVHD or death (HR 0.53, 95% CI 0.350.81; nominal P=0.0041). KM estimates for lower-GI aGVHD-free survival 1 year after transplant were 78.1% for vedolizumab and 65.1% for placebo. Events of IBMTR grade CD aGVHD of any organ or death by day +365 occurred in 47 (28.0%) of patients in the vedolizumab group and 59 (35.8%) of patients in the placebo group (HR 0.68, 95% CI 0.461.00; nominal P=0.0709). Death without relapse occurred in 15 patients (8.9%) in the vedolizumab group and 25 (15.2%) in the placebo group (HR 0.49, 95% CI 0.250.95; nominal P=0.0670). All-cause deaths by day +365 occurred in 28 patients (16.7%) in the vedolizumab group and 36 (21.8%) in the placebo group (HR 0.67, 95% CI 0.411.11; nominal P=0.1741). IBMTR grade BD aGVHD in any organ or death events occurred in 69 patients (41.1%) in the vedolizumab group and 82 (49.7%) in the placebo group (HR 0.71, 95% CI 0.520.99; nominal P=0.0534). Incidence of relapse of the underlying malignancy at day +365 was also comparable between treatment groups occurring in 19.6% of patients in the vedolizumab group versus 13.3% for placebo (HR 2.13, 95% CI 0.974.65; nominal P=0.2097; Extended Data Table 4).

The safety analyses included 334 patients (169 patients in the vedolizumab group and 165 in the placebo group) who received 1 dose of study treatment and were assessed up to 18 weeks after the last dose of study treatment. Median (range) treatment exposure was 280.0 (127295) days for the vedolizumab group (mean (s.d.) of 5.4 (2.05) doses) and 278.0 (127296) days for the placebo group (mean 5.1 (2.25) doses). AEs of grade 3 or higher occurred in 92.3% of patients who received vedolizumab and 89.1% who received placebo (Table 3); the most frequent AEs of grade 3 or higher were anemia (29.6% versus 31.5%); neutropenia (31.4% versus 29.7%); febrile neutropenia (43.8% versus 42.4%); stomatitis (27.2% versus 26.7%); and decreased platelet count (21.9% versus 24.8%). Serious AEs occurred in 120 patients (71.0%) who received vedolizumab and 114 (69.1%) who received placebo (Extended Data Table 5). AEs led to treatment discontinuation in 44 (26.0%) versus 51 patients (30.9%) (Extended Data Table 6).

Table 3 lists serious infections among other AEs (serious and non-serious) prespecified as being of special interest (AESIs) in the study. Occurrence of post-transplant lymphoproliferative disease and Clostridioides infections are also reported in Table 3. AESIs included cytomegalovirus (CMV) colitis, which was reported in one patient from each treatment group (0.6% of patients in vedolizumab group 0.6% in the placebo group). Overall, CMV reactivation was reported in 23.7% of patients in the vedolizumab group and 18.2% in the placebo group. Most of the CMV reactivation events were grade 1 to grade 2 and none was above grade 3. The proportions of patients with grade 3 CMV reactivation were similar in both treatment groups. CMV infections were analyzed in subgroups of patients who received ATG prophylaxis or not (Supplementary Table 9). For those receiving ATG, grade 3 CMV infections occurred in seven patients (4.1%) in the vedolizumab group and six patients (3.6%) in the placebo group and serious CMV infections in seven (4.1%) versus three patients (1.8%), respectively. For patients treated without ATG, the frequency of grade 3 CMV infections was numerically lower in vedolizumab-treated versus placebo-treated patients (1 (0.6%) versus 3 (1.8%), respectively), one patient in the vedolizumab treatment group had a serious CMV infection. Other serious infections (excluding CMV colitis) occurred in 125 (74.0%) of patients receiving vedolizumab versus 111 (67.3%) receiving placebo. These are listed by infection type (Extended Data Table 7). The most common serious infections were CMV reactivation (23.7% versus 18.2%); pneumonia (7.7% versus 8.5%); sepsis (5.3% versus 7.3%); and bacteremia (4.7% versus 5.5%) (Table 3). Serious abdominal and GI infections occurred in eight patients receiving vedolizumab (4.7%) and three receiving placebo (1.8%). Clostridioides infections occurred in 14 (8.3%) patients in the vedolizumab treatment group and six (3.6%) patients in placebo treatment group; of these 2.4% of patients in each treatment group had Clostridioides colitis (C.difficile colitis or Clostridioides colitis). For safety end points, statistical analyses were not adequately powered for comparisons between treatment groups. There were five patients with an AE of human polyomavirus infection; none of these was diagnosed as progressive multifocal leukoencephalopathy (PML). One patient with AML relapse and subsequent additional therapy developed PML, with a fatal outcome ~6 months after the last dose of vedolizumab. An independent adjudication committee deemed the most probable cause of this event to be the immunosuppressive treatment for AML. Secondary malignancies occurred in seven patients (4.1%) in the vedolizumab group and 16 (9.7%) in the placebo group. Post-transplant lymphoproliferative disease occurred in three patients (1.8%) in the placebo group only (Table 3).

Overall, 48 patients died during the period from first dose of study treatment to 18 weeks after last dose: 21 (12.4%) in the vedolizumab group and 27 (16.4%) in the placebo group. Leading causes of death were multiple organ dysfunction syndrome (3.0% versus 1.8%); AML recurrence (0.6% versus 2.4%); respiratory failure (1.8% versus 1.2%); pneumonia (1.2% versus 1.2%); and sepsis (0.0% versus 1.8%). Intestinal aGVHD was listed as cause of death in 0.0% versus 1.2% patients, aGVHD in liver (0.6% versus 0.6%) and aGVHD (0.6% versus 0.0%). An additional 17 patients died during the period from 18 weeks post-treatment to 12 months after HSCT: eight in the vedolizumab group and nine in the placebo group (Extended Data Table 8).

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