ASH 2018 | Vedolizumab plus standard of care to prevent graft-versus-host disease – a phase Ib study

On Monday, 3 December 2018, an oral abstract session took place at the 60th American Society of Hematology (ASH) Annual Meeting in San Diego, CA. During Session: 722. Clinical Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: GVHD Treatment and Prevention Strategies, Abstract #605 was presented by Yi-Bin Chen, Massachusetts General Hospital, Boston, MA, entitled: A Phase 1b Study of Intravenous Vedolizumab Plus Standard of Care for Graft-Versus-Host Disease Prophylaxis in Subjects Undergoing Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies: 6-Month Results.

Vedolizumab is a monoclonal antibody for the treatment of ulcerative colitis and Crohn's disease. Vedolizumab blocks integrin α4β7 (lymphocyte Peyer's patch adhesion molecule). Binding to α4β7 integrin results in gut-selective anti-inflammatory activity. Preclinical murine models and human samples suggest that blocking integrin α4β7 may prevent lower gastrointestinal (GI) acute graft-versus-host disease (aGvHD). Doctor Chen presented the 6‑month results of a phase Ib study evaluating the safety, efficacy, and tolerability of vedolizumab in combination with standard GvHD prophylaxis.

Patients and methods:

• Cohort 1:
  • N = 3 patients
  • Median age: 22 years (range, 18–50)
  • Patients underwent human leukocyte antigen (HLA)-matched or 1 locus-mismatched, unrelated-donor myeloablative transplantation
  • Patients received intravenous (IV) vedolizumab (75 mg), on days –1, +13 and +42 of HCT
  • If no engraftment failures or dose-limiting toxicities (DLTs) were observed, then subsequent patients were enrolled into Cohort 2
• Cohort 2 (dose‑expansion cohort):
  • N = 21 patients
  • Median age: 58 years (range, 18–72)
  • Patients received IV vedolizumab (300 mg) following the same schedule as Cohort 1
• All patients received standard GvHD prophylaxis (tacrolimus and methotrexate)
• Primary objectives: describing initial tolerability, safety, and identify a recommended dose of IV vedolizumab
• Secondary objectives: characterize the PK of vedolizumab, determine cumulative incidence and severity of aGvHD
• Exploratory endpoints: determine overall survival (OS) and grade II-IV and III-IV aGvHD-free survival

Key findings:

• DLTs and PK
  • Cohort 1: all three patients received three doses of vedolizumab
  • Cohort 2: 19/21 patients received three doses of vedolizumab, two patients received two doses
  • No DLTs were observed and all patients were engrafted within 28 days
• Cumulative incidence of aGvHD
  • Day +100 aGvHD
    • Cohort 1:
      • Grade II-IV: 0/3
      • Grade III-IV: 0/3
    • Cohort 2:
      • Grade II-IV: 4/21
      • Grade III-IV: 1/21
    • aGvHD involving lower GI tract
      • Stage 1:
        • 3 patients in Cohort 2 at 100 days
        • 2 patients in Cohort 2 at 12 months
      • Stage 2: 1 patient in Cohort 2
    • Survival
      • Overall survival: 85% (95% CI, 59.7–94.8)
      • Non-relapse mortality: 6% (95% CI, 0.8–33.4)
      • Grade II-IV aGvHD-free survival: 63% (95% CI, 36.7–81.8)
      • Grade III-IV aGvHD-free survival: 80% (95% CI, 54.3–91.8)
      • GRFS: 36% (95% CI, 14.5–58.4)

Doctor Chen concluded that the observed TEAEs were consistent with the expected risks in this patient population, furthermore there were no DLTs observed. Doctor Chen added that “the low cumulative incidences of grade II-IV aGvHD and severe lower GI aGvHD (stage 2–4) reported in this study are promising.” The addition of 300 mg IV vedolizumab prophylaxis to standard of care to prevent GI aGvHD requires further study.