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Effects of defibrotide preventive treatment on acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Mar 13, 2020

Graft- versus-host disease (GvHD) is a common complication observed after allogeneic hematopoietic stem cell transplant (allo-HSCT). 1 Endothelial damageas 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

Methods 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

Experimental treatment:

  • 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)

Results 3

aGvHD group treated with defibrotide vsvehicle control showed

  • better survival: 83.34% vs54.55% 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 vscontrols demonstrated a better disease-free survival (DFS), with 24.5 days median DFS vs14 days median DFS, respectively.

Conclusion 3

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.

  1. Jacobsohn D.A. &  Vogelsang G.B. Acute graft versus host disease. Orphanet J Rare Dis. 2007 Sep 4; 2:35. DOI: 10.1186/1750-1172-2-35
  2. Richardson P.G. et al. The use of defibrotide in blood and marrow transplantation. Blood Adv.2018 Jun 26; 2(12):1495–1509. DOI: 10.1182/bloodadvances.2017008375
  3. Palaniyandi S. et al. Endothelial Protective Effects of Defibrotide Reduce Acute Graft Versus Host Disease after Experimental Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant.2020 Mar 01;26(3):S52. DOI: 10.1016/j.bbmt.2019.12.125