Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Nov 23;5(22):4594-4604.
doi: 10.1182/bloodadvances.2021005231.

Graft rejection markers in children undergoing hematopoietic cell transplant for bone marrow failure

Anthony Sabulski  1   2 , Kasiani C Myers  1   2 , Jack J Bleesing  1   2 , Alexandra Duell  1   2 , Adam Lane  1   2 , Ashley Teusink-Cross  1   2 , Stella M Davies  1   2 , Sonata Jodele  1   2
Affiliations

Graft rejection markers in children undergoing hematopoietic cell transplant for bone marrow failure

Anthony Sabulski et al. Blood Adv. .

Abstract

Graft rejection (GR) is a poorly understood complication of hematopoietic cell transplant (HCT). GR risk factors are well published, but there are no reliable biomarkers or therapies known. Fever is the most common symptom of GR, but no study has evaluated fever kinetics as a diagnostic marker of GR. The objectives of this study were to identify mechanisms, biomarkers, and potential therapies for GR after HCT. Chemokine ligand 9 (CXCL9), B-cell activating factor (BAFF), and complement markers (sC5b-9, C3a, and C5a) were measured in 7 patients with GR and compared with 15 HCT controls. All patients had a diagnosis of aplastic anemia, Fanconi anemia, or genetically undefined chromosomal fragility syndrome. All patients with GR were febrile during GR; therefore, control patients who underwent HCT were matched for diagnosis and early fevers after HCT. Patients withh GR had significantly higher CXCL9, BAFF, and sC5b-9 at the time of fever and GR compared with control patients who underwent HCT at the time of fever. The maximum fever was significantly higher and occurred significantly later in the transplant course in patients with GR compared with febrile HCT controls. These data support the use of CXCL9, BAFF, sC5b-9, and fever kinetics as GR markers. Two patients with GR underwent a second HCT that was complicated by high fevers. Both patients received interferon and complement blockers during their second HCT, and both preserved their graft. These laboratory and clinical findings support larger studies to evaluate the safety and efficacy of interferon, complement, and BAFF inhibitors for the prevention and treatment of GR after HCT.

PubMed Disclaimer

Figures

None
Graphical abstract
Figure 1.
Figure 1.
CXCL9, BAFF, and sC5b-9 are higher in patients with graft rejection compared with febrile HCT controls. CXCL9, BAFF, and sC5b-9 levels at the time of fever are shown. Fever samples were obtained at the closest available time point to when fevers rose above 102.2°F (39°C) or at the closest time point to Tmax if less than 102.2°F. The median value with 95% confidence interval is marked (A-E). ROC curves are shown for each marker at time of fever (F).
Figure 2.
Figure 2.
Tmax is higher and occurs later in patients with graft rejection compared with febrile patients who underwent HCT without graft rejection. Tmax magnitude (A) and timing relative to HCT (B) are shown with corresponding ROC curves (C-D).
Figure 3.
Figure 3.
Clinical outcomes in 2 patients treated with eculizumab and emapalumab for graft rejection. Two patients in our cohort (19 and 22) experienced high fevers again after their second HCT. Based on our data showing elevated interferon and terminal compliment activation in graft rejection with high fevers, each of these patients received 1-time doses of eculizumab and emapalumab at the time of fever and both maintained engraftment. ANC, absolute neutrophil count; MP, methylprednisolone.
Figure 4.
Figure 4.
Proposed mechanism of graft rejection in patients with BMF syndromes.
See this image and copyright information in PMC

References

    1. Woodard P, Tong X, Richardson S, et al. . Etiology and outcome of graft failure in pediatric hematopoietic stem cell transplant recipients. J Pediatr Hematol Oncol. 2003;25(12):955-959. - PubMed
    1. Lowsky R, Messner H.. Mechanisms and treatment of graft failure. In: Forman SJ, Negrin RS, Antin JH, Appelbaum FR, eds. Thomas’ Hematopoietic Cell Transplantation. Hoboken, NJ: John Wiley & Sons Inc; 2015:944-958.
    1. Olsson R, Remberger M, Schaffer M, et al. . Graft failure in the modern era of allogeneic hematopoietic SCT [correction published in Bone Marrow Transplant. 2013;48:616]. Bone Marrow Transplant. 2013;48(4):537-543. - PubMed
    1. Mattsson J, Ringdén O, Storb R.. Graft failure after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2008;14(1 suppl 1):165-170. - PMC - PubMed
    1. Remberger M, Ringdén O, Ljungman P, et al. . Booster marrow or blood cells for graft failure after allogeneic bone marrow transplantation. Bone Marrow Transplant. 1998;22(1):73-78. - PubMed

MeSH terms