aGvHD

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

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

Methods3

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)

Results3

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.

Conclusion3

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.

 

References
  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
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