Allogeneic hematopoietic stem-cell transplantation offers a potentially curative treatment modality for aggressive hematologic malignancies. However, severe donor T-cell allo-reactivity frequently precipitates life-threatening tissue destruction known as acute graft-versus-host disease. Patients lacking human leukocyte antigen-matched sibling donors routinely undergo alternative donor transplantation, including haploidentical and matched unrelated donor procedures. Although antithymocyte globulin regimens have substantially diminished post-transplant complications, significant clinical burdens persist. Consequently, clinicians urgently need non-toxic immunomodulatory agents that effectively suppress alloreactive donor immune responses without impairing marrow engraftment or abolishing vital graft-versus-tumor effects. A landmark phase III randomized trial has evaluated the clinical impact of repurposing the dipeptidyl peptidase-4 inhibitor sitagliptin to resolve this therapeutic challenge.

Mechanisms of CD26 Inhibition in Acute Graft-Versus-Host Disease

Dipeptidyl peptidase-4, widely recognized as the cell-surface glycoprotein CD26, functions as a critical co-stimulatory molecule during T-cell activation. When donor T lymphocytes encounter foreign recipient host antigens, CD26 interaction drives intracellular signaling cascades that amplify cytotoxic proliferation and pro-inflammatory cytokine production. Consequently, CD26 overexpression correlates strongly with mucosal tissue injury and donor immune hypersensitivity. Preclinical murine models established that targeted down-regulation or enzymatic inhibition of CD26 markedly mitigates acute graft-versus-host disease. Crucially, this selective targeted blockade preserves underlying antineoplastic immunity and graft-versus-leukemia activity.

Pharmacologic inhibition using sitagliptin exerts potent immunomodulatory actions by cleaving key chemokine ligands and blunting T-helper cell trafficking into target organs. Furthermore, systemic inhibition impairs donor T-cell homing toward the liver and intestinal mucosa. Because sitagliptin functions through enzymatic suppression rather than broad pan-cellular lymphodepletion, it spares regulatory T-cell compartments. Therefore, sitagliptin effectively dampens destructive alloreactivity while simultaneously avoiding excessive systemic immunosuppression. These biologic insights prompted investigators to test whether adjunct sitagliptin could significantly enhance conventional pharmacologic prophylaxis.

Phase III Trial Design and Patient Demographics

To establish definitive clinical evidence, investigators initiated a prospective, multicenter, open-label, randomized phase III trial across tertiary academic centers. The study protocol screened 251 transplant candidates and ultimately enrolled 190 adult patients aged 18 to 60 years diagnosed with high-risk hematologic malignancies. Every participant received standard myeloablative conditioning chemotherapy followed by peripheral-blood stem-cell transplantation from either haploidentical or unrelated donors. Investigators randomly assigned participants in a 1:1 ratio to receive standard prophylaxis alone or standard prophylaxis combined with adjunct sitagliptin therapy.

The standard control arm utilized four-drug antithymocyte globulin-based prophylaxis consisting of antithymocyte globulin, a calcineurin inhibitor, methotrexate, and mycophenolate mofetil. Meanwhile, participants in the experimental intervention arm received identical four-drug prophylaxis plus oral sitagliptin administered at 600 mg every 12 hours from day -1 through day +14 post-transplant. The primary study endpoint measured the cumulative incidence of grade II to IV acute graft-versus-host disease occurring by day +100. Secondary endpoints encompassed severe organ staging, graft failure rates, infectious toxicities, chronic manifestations, relapse rates, and overall patient survival.

Key Efficacy Findings: Reduction in Grade II to IV Events

At a median clinical follow-up duration of 29.8 months, adjunct sitagliptin demonstrated profound protective efficacy. The cumulative incidence of grade II to IV acute graft-versus-host disease at day +100 reached only 14.7% in the sitagliptin group compared with 31.6% in the standard control group. This substantial reduction yielded a statistically significant subdistribution hazard ratio of 0.41, confirming that sitagliptin more than halved the overall relative risk. Moreover, the absolute risk reduction approached nearly 17 percentage points, showing an immediate clinical benefit in heavily conditioned cohorts.

In addition, secondary efficacy outcomes mirrored these primary improvements. The incidence of severe grade III to IV disease declined dramatically from 18.9% in the control arm to 6.3% in the sitagliptin cohort. Intestinal tissue involvement dropped noticeably from 29.5% to 12.6%, highlighting selective gut protection. Furthermore, patients receiving sitagliptin achieved superior day +180 graft-versus-host disease-free, relapse-free survival at 86.3% versus 72.6% in controls. Although long-term survival curves converged beyond two years, early clinical morbidity decreased substantially.

Safety Profile and Impact on Viral Reactivation

Intensive post-transplant immunosuppression frequently elevates the danger of life-threatening opportunistic infections and marrow graft rejection. Nevertheless, adjunct sitagliptin demonstrated an exceptionally benign safety profile during the peri-transplant period. Analysis of secondary safety outcomes showed that sitagliptin administration did not impede myeloid or platelet engraftment kinetics. Specifically, median days to sustained absolute neutrophil count recovery remained identical across both treatment cohorts. Nonrelapse mortality at two years likewise displayed no statistically meaningful divergence between groups.

Importantly, the trial investigated latent herpesvirus recrudescence to evaluate whether CD26 suppression hindered antimicrobial viral surveillance. Surveillance testing revealed that rates of cytomegalovirus viremia and Epstein-Barr virus reactivation remained comparable between study arms. Furthermore, overall hematologic, renal, and hepatic adverse event profiles showed no increased toxic burden attributable to sitagliptin. The brief two-week dosing duration effectively circumvented prolonged metabolic disruptions or delayed drug-drug interactions with concurrent calcineurin inhibitors, ensuring outstanding clinical feasibility.

Clinical Implications for Alternative Donor Transplantation

These phase III results establish an actionable strategy for clinical oncologists managing haploidentical and unrelated donor transplantation. In regions where access to fully matched family donors remains severely constrained, alternative donor grafts represent standard life-saving pathways. However, transplant-related mortality stemming from gut injury and acute alloreactivity has historically limited widespread application. By adding an accessible, low-cost oral agent during the peri-engraftment phase, clinicians can meaningfully blunt life-threatening inflammatory complications without increasing financial toxicity.

Nevertheless, clinicians must recognize the specific boundaries of these phase III findings. Adjunct sitagliptin demonstrated marked success in mitigating early grade II to IV disease and improving day +180 graft-free survival. However, it did not significantly alter two-year chronic graft-versus-host disease rates, long-term relapse-free survival, or overall survival. Consequently, sitagliptin represents an effective preventative adjunct for early inflammatory complications rather than a standalone cure for malignant recurrence. Future multi-center protocols will likely evaluate optimal dosing duration and combinations with targeted biologics.

Frequently Asked Questions

What dosage and schedule of sitagliptin was utilized in the trial?

Patients received oral sitagliptin at a dose of 600 mg every 12 hours. This high-dose schedule commenced on day -1 prior to stem cell infusion and continued through day +14 post-transplantation. This specific dosing window safely achieved target systemic dipeptidyl peptidase-4 inhibition throughout initial donor immune engraftment without provoking unexpected drug-related toxicities.

Does sitagliptin increase infection risks or blunt immune reconstitution?

No, sitagliptin did not heighten infectious complications or delay immune recovery. The trial observed identical rates of cytomegalovirus reactivation, Epstein-Barr virus viremia, and nonrelapse mortality between study cohorts. Neutrophil and platelet engraftment kinetics remained entirely unaffected, demonstrating that brief CD26 inhibition avoids broader systemic lymphodepletion.

How does sitagliptin affect graft-versus-leukemia effects and long-term relapse?

The trial demonstrated that sitagliptin preserved antineoplastic immune surveillance effectively. Malignant disease recurrence rates and two-year relapse-free survival showed no statistically significant differences compared with standard antithymocyte globulin prophylaxis. Thus, suppressing acute tissue inflammation via dipeptidyl peptidase-4 blockade did not compromise essential graft-versus-leukemia protective responses.

Disclaimer: This content is for informational and educational purposes only and should not be construed as clinical or diagnostic advice. Healthcare providers must evaluate individual patient needs using independent professional judgment. Refer to the latest local and national guidelines for clinical practice.

References

1. Qiao M et al. Sitagliptin for Acute Graft-Versus-Host Disease Prevention in Alternative Donor Transplantation: A Randomized Phase III Trial. J Clin Oncol. 2026 Oct 06. doi: 10.1200/JCO-26-00670. PMID: 42837636.


2. Farag SS, Nelson R, Konger R, et al. Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease. N Engl J Med. 2021;384(1):11-19. doi:10.1056/NEJMoa2027372.


3. Farag SS, Srivastava S, Messina-Graham S, et al. High-dose sitagliptin for systemic inhibition of dipeptidylpeptidase-4 to enhance engraftment of single cord umbilical cord blood transplantation. Oncotarget. 2017;8(66):110350-110357.