Is DPP-4 inhibition a feasible strategy for preventing acute GvHD?

Dipeptidyl peptidase 4 (DPP-4) is a transmembrane receptor (also called CD26), found on a variety of cell types and also present in its active form in the plasma. Engagement of CD26/DPP-4 with its ligand, caveolin 1, acts as a costimulatory signal on T cells, and downregulation of CD26 has been associated with reduced acute graft-versus-host disease (aGvHD) without impacting graft-versus-leukemia effect in preclinical mouse studies.  

The selective DPP-4 inhibitor, sitagliptin, is approved for the treatment of patients with type II diabetes mellitus. A trial evaluating sitagliptin for the promotion of engraftment following cord-blood transplants remarkably highlighted reduced incidences of aGvHD in patients who received the agent.

Sherif Farag and colleagues carried out a phase II trial to evaluate the safety and efficacy of sitagliptin in combination with tacrolimus and sirolimus for the prevention of aGvHD in patients undergoing myeloablative allogeneic peripheral blood stem cell (PBSC) transplantation. The results were published in the New England Journal of Medicine,¹ and the GvHD Hub is happy to provide a summary.

Study design

• With a current incidence of 30% and higher for Grade II–IV aGvHD when using standard GvHD prophylaxis regimens (calcineurin inhibitor plus methotrexate or sirolimus), the investigators tested the hypothesis that the addition of sitagliptin to tacrolimus and sirolimus would reduce aGvHD by Day 100 to below 15%.
• Patients aged 18–60 years with acute myeloid leukemia or acute lymphoblastic leukemia, a myelodysplastic disorder,* or chronic myeloid leukemia** were eligible to participate in the study if they had adequate organ function and performance status and a suitable donor for allogeneic PBSC transplant.
• Patients received tacrolimus and sirolimus prophylaxis from Day −3 (with respect to transplant day) prior to myeloablative conditioning and infusion of PBSCs on Day 0.
• Sitagliptin (600 mg) was administered orally every 12 hours from Day −1 to Day 14.
• Primary endpoint: Grade II–IV aGvHD by Day 100.
• Secondary endpoints: Neutrophil and platelet engraftment, non-relapse mortality, relapse, overall survival, and chronic GvHD.

*With a Revised International Prognostic Scoring System score >3.
**Refractory to >2 tyrosine kinase inhibitors or beyond the first chronic phase.

Results

• All evaluable patients (Table 1) demonstrated engraftment, with median times to neutrophil and platelet engraftment of 13 days and 15 days, respectively.

Table 1. Baseline patient characteristics*

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; HCT, hematopoietic cell transplantation; MDS, myelodysplastic syndromes. *Data from Farag et al.1
Characteristic	All patients (N = 36)
Median age, years (range)	46 (20–59)
Female sex, %	53
Karnofsky performance status score, %               ≥90%	94
HCT-specific comorbidity index score, %               0               1–2               3–4               ≥5	31 25 36 8
Disease risk index group, %               Low               Intermediate               High and very high	6 67 28
Median time from diagnosis to transplantation, days (range)	138 (41–2,227)
Donor type, %               Matched related               Matched volunteer unrelated	36 64

aGvHD

• At Day 100, two patients who received PBSCs from unrelated donors had developed aGvHD:
  • one patient experienced Grade II aGvHD by Day 81 (gut, stage 1; liver, stage 1; skin, stage 3)
  • one patient experienced Grade IV aGvHD by Day 29 (skin, stage 3; gut, stage 4; liver, stage 4)
• On Day 140, one patient who received PBSCs from a related donor experienced late-onset Grade II aGvHD following termination of immunosuppressive therapy on Day 110 due to low donor chimerism.

Safety

• Throughout the study, no toxic side effects were associated with sitagliptin. Of note, based on the drug’s mechanism of action, hypoglycemia was not observed in any of the patients.
• The 1-year non-relapse mortality was 0%, and all toxic effects not attributed to treatment with sitagliptin were reversible.
• Grade 3 and 4 non-hematologic adverse events that occurred by Day 30 are shown in Table 2.

Table 2. Grade 3/4 adverse events by Day 30 posttransplant*

*Data from Farag et al.1
Adverse events, n	Grade 3	Grade 4
Gastrointestinal event               Anorexia, nausea, or vomiting               Oropharyngeal mucositis               Diarrhea               Ileus               Hemorrhage	10 19 3 1 1	1 2 0 0 0
Cardiovascular event               Hypotension               Hypertension               Fluid overload or edema               Chest pain               Arrhythmia (supraventricular tachycardia)	2 3 1 1 1	0 0 1 0 0
Renal or urologic event               Acute kidney injury               Urinary tract infection	6 4	3 0
Neurologic event               Headache               Syncope	1 2	0 0
Neutropenic fever	4	0
Sepsis	0	3

Secondary endpoints

• Median follow-up: 700 days (range, 327–1,313).
• Patient outcomes are shown in Table 3.
• In total, nine patients experienced relapse at a median 243 days. There was no difference in the incidence of relapse between patients transplanted from related donors (four of 13 patients relapsed) and patients transplanted from unrelated donors (five of 23 patients relapsed)
• Of the 34 patients who survived without relapse after Day 100, 15 developed chronic GvHD (mild, n= 5; moderate, n = 7; severe, n = 3).
• Plasma DPP-4 inhibition levels were not significantly different between the patients who developed aGvHD by Day 100 and those who did not.

Table 3. Outcomes of patients who received sitagliptin plus sirolimus and tacrolimus as aGvHD prophylaxis prior to matched allogenic PBSC transplantation*

aGvHD, acute GvHD; CI, confidence interval; GvHD, graft-versus-host disease; PBSC, peripheral blood stem cell. *Adapted from Farag et al.1 †In patients who received systemic glucocorticoids for the treatment of chronic GvHD.
1-year outcomes, %	All evaluable patients (N = 36)	95% CI
Cumulative incidence               Relapse               Chronic GvHD	26 37	13–41 22–53
Non-relapse mortality	0	—
GvHD-free, relapse-free survival†	46	29–62
Overall survival	94	79–98

Conclusion

Data from this phase II trial suggest that GvHD prophylaxis with sitagliptin plus sirolimus and tacrolimus is safe and can strongly reduce aGvHD in patients receiving matched allogeneic PBSC transplantation following myeloablative conditioning. Although data are limited, there is currently no evidence that the addition of sitagliptin has an impact on graft-versus-leukemia effect leading to higher relapse rates. Also, rates of cGvHD, overall survival, and GvHD-free, relapse-free survival compare favorably with other commonly used GvHD prophylaxis regimens, such post-transplant cyclophosphamide, in combination with tacrolimus and mycophenolate.

This study supports the further investigations comparing sitagliptin-based regimens with standard GvHD prophylaxis in randomized trials.