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The addition of tacrolimus to Treg graft for GvHD prophylaxis

May 10, 2024
Learning objective: After reading this article, learners will be able to cite a new clinical development in acute graft-versus-host disease.

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Calcineurin inhibitors can be used alongside donor regulatory T cells (Tregs) for the prevention of graft-versus-host disease (GvHD) in patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT). Regulatory T cells restrain excessive immune responses in patients and have shown promise as a form of GvHD prophylaxis. However, it remains unclear if the addition of immunosuppressive prophylaxis, for example with single agent tacrolimus (TAC), adds any GvHD preventative benefit to the use of a Treg graft alone.

Here, we summarize an article by Bader et al.,1 published in Blood Advances, evaluating the use of T-reg graft vs Treg graft + TAC for the prevention of acute GvHD (aGvHD) (NCT01660607).

Study design1

  • A randomized, open-label, phase II trial comparing Treg graft and Treg graft + TAC in patients who received myeloablative conditioning regimens with 10/10 human leukocyte antigen-matched, related and unrelated donors or 9/10 human leukocyte antigen-matched, unrelated donors.
  • Patients were randomized 1:1 to receive Treg graft or Treg graft plus GvHD prophylaxis.
    • All patients received fresh hematopoietic stem and progenitor cells, and T-regs, on Day 0, followed by conventional T cells on Day +2.  
    • In the prophylaxis group, TAC was initiated at 0.015 mg/kg per day on Day +3.
  • Blood samples were collected at baseline and at defined times after allo-HCT.
  • The primary endpoint was determining the safety, efficacy, and feasibility of Treg graft alone and Treg graft + TAC for the prevention of GvHD.
  • The secondary endpoints were the incidence and severity of aGvHD and chronic GvHD, and the incidence of serious adverse events.

Key findings1

  • In total, 24 patients aged 13–72 years, were randomized to receive Treg graft alone (n = 12) or T-reg graft + TAC (n = 12).
  • All patients achieved a CD34+ dose >2.5 × 106 cells per kg, with a median dose of 6.3 × 106 cells per kg.

aGvHD and cGvHD

  • The use of Treg graft alone was inferior to the use of Treg graft + TAC as worse GvHD outcomes were observed, for example, patients in the Treg graft + TAC group had fewer incidences of GvHD than patients who received Treg graft alone posttransplant (Table 1).

Table 1. Cumulative incidence of GvHD in patients who received Treg graft vs Treg graft + TAC*


Treg graft
(n = 12)

Treg graft + TAC
(n = 12)

p value

Grade 2─4 aGvHD



p = 0.006

Grade 3─4 aGvHD



p = 0.149

Moderate-to-severe cGvHD at 1 year



p = 0.058

aGvHD, acute graft-versus-host disease; cGvHD, chronic GvHD; TAC, tacrolimus; Treg; T-regulatory cell.
*Data from Badar, et al.1

  • Non-relapse mortality was 8% in the Treg graft group and 0% in the Treg graft + TAC group.
  • Relapse occurred in 1 patient in the Treg graft group at a median of 217 days whereas relapse occurred in 4 patients in the Treg + TAC group at a median of 241 days (range: 82–375; p = 0.42).
    • 1-year post-allo-HCT relapse-free survival was similar between both groups; 83% in the Treg graft group and 75% in the Treg + TAC group.
  • At 1 year, the unadjusted GvHD-free relapse-free survival was lower in the Treg graft group (37%) compared with the Treg + TAC group (75%).
  • Times to neutrophil and platelet engraftment were similar between groups
  • The median time from transplant to patient discharge was longer in the Treg graft group compared with the Treg graft + TAC group (17 vs 14 days, respectively).
  • All patients achieved full donor whole-blood and CD15 chimerism.
    •  Full CD3+ T-cell chimerism was observed by Day +90 in 100% of patients in the T-reg graft group, and in 63% of patients who received T-reg + TAC.
  • Patients in the Treg graft group had a higher CD4+ T-cell to Treg ratio than patients in the Treg graft + TAC group on Day +14 (p = 0.056) which precedes the onset of aGvHD.
  • Overall, seven non-hematologic Grade ≥3 serious adverse events occurred in five patients within 100 days after graft infusion.
    • There were no cases of exceptional infections or cytomegalovirus reactivation with organ involvement.

Key learnings

  • In this study, the authors suggest that the use of Treg graft alongside TAC is more effective than Treg graft alone for the prevention of aGvHD in patients undergoing allo-HCT.
  • As this study included a small group of patients, it would be of benefit to conduct a larger study to better understand the impact of Treg graft on GvHD, relapse risk as well as overall survival.

  1. Badar CS, Pavlova A, Lowsky R, et al. Single-center randomized trial of T-reg graft alone vs T-reg graft plus tacrolimus for the prevention of acute GvHD. Blood Adv. 2024;8(5):1105-1115. DOI:1182/bloodadvances.2023011625


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