Graft-versus-host disease (GvHD) is a common complication observed after allogeneic hematopoietic stem cell transplant (allo-HSCT).1 Endothelial damage as a consequence of GvHD is induced by an inflammatory T-cell response, leading to organ damage and contributing to poorer outcomes. The protection from endothelial damage may, therefore, improve the outcomes of patients with GvHD.
Defibrotide is a mixture of predominantly single-stranded nucleotides with endothelial protective properties.2 Senthilnathan Palaniyandi, University of Kentucky, Lexington, US, presented a study in mice, investigating the role of defibrotide as preventive treatment of acute GVHD (aGvHD) after allo-HSCT, during the 2020 Transplantation & Cellular Therapy (TCT) meetings.3
B10.BR mice received:
- Day −3 and −2: cyclophosphamide, 120 mg/kg per day
- Day 0: lethal total body irradiation (750 cGy)
- Infusion of donor C57BL/6 T-cell depleted (TCD) bone marrow (BM) cells
- Control group received BM cells only
- GvHD group was co-infused with splenocytes to induce GvHD
- Defibrotide at the dose of 800 mg/kg or vehicle control for the first week daily and then three times/week
Testing graft-versus-leukemia (GvL) activity:
- C57BL/6 recipients received lethal total body irradiation (12 Gy) and were then transplanted with C3H.SW donor TCD BM alone or in combination with T cells along with acute myeloid leukemia (AML) tumor cells (C1498-luc)
aGvHD group treated with defibrotide vs vehicle control showed
- better survival: 83.34% vs 54.55% on Day +28, respectively
- better clinical GvHD scores after Day +14
- less organ GvHD in gut, lung, and liver (p < 0.05) at Day +7 and +28
- decreased T-cell infiltration in ileum and colon
- reduced pathology scores on Day +28
- reduced level of TNF (p < 0.05) and IL-6 (p = 0.05) at Day +7
- reduced serum levels of ICAM-1 (p < 0.05), angiopoietin-2 (p < 0.05), and reduced VCAM-1 (p < 0.05) in gut on Day +28
In an AML tumor model for testing GvL, mice treated with defibrotide after allo-HSCT vs controls demonstrated a better disease-free survival (DFS), with 24.5 days median DFS vs 14 days median DFS, respectively.
The results of this study, conducted in mice, demonstrated that the anti-inflammatory and endothelial protective properties of defibrotide can be useful in preventing aGVHD after allo-HSCT. Furthermore, treatment with defibrotide after allo-HSCT appears to preserve GvL effect.