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Acute graft-versus-host disease (aGvHD) is a life-threatening complication typically occurring within 100 days after allogeneic hematopoietic cell transplantation (allo-HCT). This hypothesis-generating, phase II, prospective, open-label, randomized study (clinicaltrials gov. Identifier: NCT03339297) compared defibrotide added to standard-of-care (SOC) GvHD prophylaxis (defibrotide prophylaxis arm) versus SOC alone (SOC arm) to prevent aGvHD post-transplant. This study estimated incidences of aGvHD and was not statistically powered to assess differences among treatment arms. Patients were randomized 1:1 to defibrotide prophylaxis arm (n=79; median age 57 years; range, 2-69 years) or SOC arm (n=73; median age 56 years; range, 2-72 years). Patient demographics in the two arms were similar except for conditioning regimen type (myeloablative: defibrotide, 76% vs. SOC, 61%) and stem cell source for allo-HCT (bone marrow: defibrotide, 34% vs. SOC, 26%). In the intent-to-treat primary endpoint analysis, the cumulative incidence of grade B-D aGvHD at day 100 post-transplant was 38.4% in the defibrotide prophylaxis arm versus 47.1% in the SOC arm (difference: –8.8%, 90% confidence interval [CI]: –22.5 to 4.9). The difference noted at day 100 became more pronounced in a subgroup analysis of patients who received antithymocyte globulin (defibrotide: 30.4%, SOC: 47.6%; difference: –17.2%; 90% CI: –41.8 to 7.5). Overall survival rates at day 180 post-transplant were similar between arms, as were the rates of serious treatment-emergent adverse events (defibrotide: 42%, SOC: 44%). While the observed differences in endpoints between the two arms were not substantial, these results suggest defibrotide prophylaxis may add a benefit to currently available SOC to prevent aGvHD following allo-HCT without adding significant toxicities.

T-helper 1 and T-helper 17 lymphocytes mediate acute graft-versus-host disease (GvHD). Interleukin 12 is critical for T-helper 1 differentiation and interleukin 23 for T-helper 17 maintenance. Interleukin 12 and 23 are heterodimeric cytokines that share the p40 subunit (IL-12/IL-23p40). In a randomized, blinded, placebo-controlled trial, we examined the biological impact and clinical outcomes following IL-12/IL-23p40 neutralization using ustekinumab. Thirty patients received peripheral blood mobilized hematopoietic cell transplantation (HCT) from HLA-matched sibling or unrelated donors, received sirolimus plus tacrolimus as GvHD prophylaxis, and were randomized to ustekinumab versus placebo with 1:1 allocation after stratification by donor type. The primary end point of the trial was the mean percentage (%) T-regulatory (Treg) cells on day 30 post HCT. Ustekinumab was delivered by subcutaneous injection on day −1 and day +20 after transplantation. On day 30 post transplant, no significant difference in % Treg was observed. Ustekinumab suppressed serum IL-12/IL-23p40 levels. Host-reactive donor alloresponse at days 30 and 90 after transplantation was polarized with significant reduction in IL-17 and IFN-α production and increase in IL-4. No toxicity attributed to ustekinumab was observed. Overall survival and National Institute of Health moderate/severe chronic GvHD-free, relapse-free survival were significantly improved among ustekinumab-treated patients. No significant improvements were observed in acute or chronic GvHD, relapse, or non-relapse mortality. These data provide first evidence that IL-12/IL-23p40 neutralization can polarize donor anti-host alloresponse in vivo and provide initial clinical efficacy evidence to be tested in subsequent trials. (Trial registered at clinicaltrials.gov identifier: 01713400.)

Graft-versus-host disease (GvHD) remains a major cause of transplant-related mortality. Interleukin-2 (IL-2) plus sirolimus (SIR) synergistically reduces acute GvHD in rodents and promotes regulatory T cells. This phase II trial tested the hypothesis that IL-2 would facilitate STAT5 phosphorylation in donor T cells, expand regulatory T cells, and ameliorate GvHD. Between 16th April 2014 and 19th December 2015, 20 patients received IL-2 (200,000 IU/m2 thrice weekly, days 0 to +90) with SIR (5–14 ng/mL) and tacrolimus (TAC) (3–7 ng/mL) after HLA-matched related or unrelated allogeneic hematopoietic cell transplantation (HCT). The study was designed to capture an increase in regulatory T cells from 16.0% to more than 23.2% at day +30. IL-2/SIR/TAC significantly increased regulatory T cells at day +30 compared to our published data with SIR/TAC (23.8% vs. 16.0%, P=0.0016; 0.052 k/uL vs. 0.037 k/uL, P=0.0163), achieving the primary study end point. However, adding IL-2 to SIR/TAC led to a fall in regulatory T cells by day +90 and did not reduce acute or chronic GvHD. Patients who discontinued IL-2 before day +100 showed a suggested trend toward less grade II-IV acute GvHD (16.7% vs. 50%, P=0.1475). We surmise that the reported accumulation of IL-2 receptors in circulation over time may neutralize IL-2, lead to progressive loss of regulatory T cells, and offset its clinical efficacy. The amount of phospho-STAT3+ CD4+ T cells correlated with donor T-cell activation and acute GvHD incidence despite early T-cell STAT5 phosphorylation by IL-2. Optimizing IL-2 dosing and overcoming cytokine sequestration by soluble IL-2 receptor may sustain lasting regulatory T cells after transplantation. However, an approach to target STAT3 is needed to enhance GvHD prevention. (clinicaltrials.gov identifier: 01927120).

Effective pharmacological strategies employed in allogeneic hematopoietic cell transplantation should prevent serious chronic graft-versus-host disease and facilitate donor-recipient immune tolerance. Based on demonstrated pro-tolerogenic activity, sirolimus (rapamycin) is an agent with promise to achieve these goals. In a long-term follow-up analysis of a randomized phase II trial comparing sirolimus/tacrolimus versus methotrexate/tacrolimus for graft-versus-host disease prevention in matched sibling or unrelated donor transplant, we examined the impact of prolonged sirolimus administration (≥ 1 year post-transplant). Median follow-up time for surviving patients at time of this analysis was 41 months (range 27–60) for sirolimus/tacrolimus and 49 months (range 29–63) for methotrexate/tacrolimus. Sirolimus/tacrolimus patients had significantly lower National Institutes of Health Consensus moderate-severe chronic graft-versus-host disease (34% vs. 65%; P=0.004) and late acute graft-versus-host disease (20% vs. 43%; P=0.04). While sirolimus/tacrolimus patients had lower prednisone exposure and earlier discontinuation of tacrolimus (median time to tacrolimus discontinuation 368 days vs. 821 days; P=0.002), there was no significant difference in complete immune suppression discontinuation (60-month estimate: 43% vs. 31%; P=0.78). Prolonged sirolimus administration represents a viable approach to mitigate risk for moderate-severe chronic and late acute graft-versus-host disease. Further study of determinants of successful immune suppression discontinuation is needed.