Vedolizumab treatment for the prevention of acute GvHD following allogeneic hematopoietic stem cell transplantation

T cell trafficking to gut-associated lymphoid tissue has been shown to play a key role in acute graft-versus-host disease (aGvHD) establishment in experimental models.1 A key mediator of T-cell adhesion to gut endothelial cells is the integrin α4β1, which binds to mucosal addressin cell adhesion molecule 1 (MAdCAM-1) found specifically on gut endothelial cells.2,3 Vedolizumab, an anti-α4β1 humanized monoclonal antibody, has been shown to elicit gut-specific immunomodulatory activity and is currently approved for the treatment of moderate to severe ulcerative colitis and Crohn’s disease in adults.4

Yi-Bin Chen, Massachusetts General Hospital, Boston, US, and colleagues explored the potential benefits of coadministration of vedolizumab with standard GvHD prophylaxis in a phase Ib, open-label study (NCT02728895).4 The study evaluated the tolerability, safety, pharmacokinetics (PK) profile, and efficacy of vedolizumab in 24 patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Data from the study were published on August 26 2019, US.

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Study Design


  • All patients underwent either a myeloablative or reduced-intensity conditioning (Table 1) followed by standard GvHD prophylaxis (tacrolimus [recommended goal serum trough concentration of 5–10ng/dL] and MTX [recommended 10 mg/m2IV on Days +1, +3, +6 and +11 after allo-HSCT])
  • Patients received 75 mg (n= 3) or 300 mg (n= 21, dose-escalation) IV vedolizumab, on Days -1, +13, and +42 subsequent to the allo-HSCT procedure
  • Dose escalation:
    • Three participants were primarily enrolled on the 75 mg IV vedolizumab dosing regimen, on Days -1, +13, and +42 after the allo-HSCT procedure
    • If the first patient tolerated the basal dose and reached full neutrophil engraftment, two further participants were enrolled and observed for dose-limiting toxicities (DLTs)
    • A lack of DLTs across three patients resulted in the initiation of a dose-determining phase where additional 21 patients received 300 mg IV vedolizumab


  • Primary endpoints: to identify the tolerability and safety of vedolizumab and determine the recommended dose
  • Secondary endpoints: characterize PK profile of vedolizumab in participants and determine the cumulative incidence and the severity of aGVHD by 100 days after allo-HSCT
  • Patient characteristics
    • Patients (n= 24), median age 55 (range, 18–72) years, undergoing allo-HSCT were recruited (Table 1)
Table 1. Characteristics of study sample defined by vedolizumab dose cohort
Characteristic Vedolizumab 75 mg (n= 3) Vedolizumab 300 mg (n= 21) Total (N= 24)
Median age, years (range) 22 (18–50­) 58 (19–72) 55 (18–72)
Disease Type      
Myeloproliferative neoplasm 0 3 3
Myelodysplastic/myeloproliferative neoplasm 0 3 3
Myelodysplastic syndrome 0 2 2
AML or related precursor neoplasm 3 6 9
Precursor Lymphoid neoplasm 0 5 5
           Precursor T-ALL/LBL 0 3 3
           Precursor B-ALL/LBL 0 2 2
Other 0 2 2
Conditioning Regimen      
Myeloablative, busulfan + fludarabine 2 5 7
Myeloablative, cyclophosphamide + TBI 1 5 6
Reduced-intensity, busulfan + fludarabine 0 6 6
Reduced-intensity, fludarabine + melphalan 0 5 5
Source of stem cells      
Bone Marrow 3 6 9
Peripheral blood 0 15 15
HLA compatibility      
Matched 3 20 23
Mismatched 0 1 1
Donor relationship to study participant      
Related 0 4 4
Unrelated 3 17 20

B-ALL, B-cell acute lymphoblastic leukemia; HLA, human leukocyte antigen; LBL, lymphoblastic lymphoma; T-ALL, T-cell acute lymphoblastic leukemia; TBI, total body irradiation

  • Safety4
    • All participants experienced at least one grade III or higher TEAE, eight of which were considered related to vedolizumab (n= 2 and n= 6 in the 75 mg and 300 mg dose cohorts, respectively).
    • Serious TEAEs were observed in 13 of 24 participants. However, only in one patient in the 300 mg dose cohort it was considered to be related to study drug
    • No DLTs were observed for participants in either dose cohort
    • Cytomegalovirus- and Clostridium difficile-related infections were the most common TEAEs in the 300 mg dose cohort
    • Neutrophil engraftment was observed by Day +100 for all 24 participants. Time to engraftment was not significantly different between the 300 mg dose cohort (median 14; interquartile range 13–17 days) and the 75 mg dose cohort which saw one patient reaching engraftment at Day 15 and two at Day 22
    • Of the three deaths observed over the course of the study, none were believed to be related to vedolizumab
  • Efficacy
    • No participants in the 75 mg dose cohort developed grade II–IV aGvHD by 100 days post allo-HSCT
    • By Day 100, three of the 21 participants in the 300 mg dose cohort developed grade II aGvHD while one developed grade III acute GvHD (location: two skin only, two skin + intestinal tract, one skin + intestinal tract + liver). Grade I intestinal aGVHD occurred in three participants
    • At 12 months following allo-HSCT, three patients had grade II aGvHD and two patients had grade III aGvHD. However, no further participants developed aGvHD of the lower intestinal tract
    • One of the four deaths observed over the 12-month course of the study was a result of aGvHD
    • In the 300 mg dose cohort at 12 months, the overall survival was 84.7% and non-relapse mortality was 5.6%
  • PK profile
    • Vedolizumab IV at a dose of 300 mg was considered sufficient to maintain good α4β1 saturation. Therefore, no further dose escalation was required


  • Vedolizumab was well tolerated and did not interfere with engraftment when combined with standard GvHD prophylaxis in patients undergoing allo-HSCT
  • Despite the small study size, there were encouraging signs for a low intestinal aGVHD and overall grade III to IV aGVHD
  • Results from this study have justified a phase III randomized study (NCT03657160) investigating the administration of vedolizumab 300mg alongside standard GvHD prophylaxis in patients undergoing allo-HSCT
  1. Murai, M. et al., Peyer's patch is the essential site in initiating murine acute and lethal graft-versus-host reaction. Nat Immunol. 2003; 4(2): 154–160. DOI:10.1038/ni879
  2. Ueha, S. et al., Intervention of MAdCAM-1 or fractalkine alleviates graft-versus-host reaction associated intestinal injury while preserving graft-versus-tumor effects. J Leukoc Biol. 2006 Jan; 81(1): 176–185. DOI: 10.1189/jlb.0306231
  3. Waldman E. et al., Absence of beta7 integrin results in less graft-versus-host disease because of decreased homing of alloreactive T cells to intestine. Blood. 2006 Feb 15;107(4):1703-1711. DOI: 10.1182/blood-2005-08-3445
  4. Chen Y. et al., Vedolizumab for prevention of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Blood Adv. 2019; 3(23): 4136–4146. DOI: 10.1182/bloodadvances.2019000893
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