Lower Uric Acid Level At the Time of Allogeneic Hematopoietic Cell Transplantation (HCT) Is Protective Against Acute Graft-Vs-Host-Disease

ABSTRACT:

Acute graft-versus-host disease (aGVHD) is primarily a T-cell mediated process. Uric acid released from dying cells acts as a danger signal that alerts the immune system to cell death and promotes cytotoxic T cell responses. Elimination of uric acid in mouse models reduces this immune response. We hypothesized that lower serum uric acid levels at the time of transplant may decrease the incidence of aGVHD. Through record review, we recorded serum uric acid levels from day -7 through day +6 from 43 historical control patients who received myeloablative HCT (MRD, n=32; MUD, n=11) at the Massachusetts General Hospital between 2007 and 2010, these patients received standard allopurinol. We also obtained uric acid levels from 23 consecutive patients (19-59 years) with hematologic malignancies in complete remission (AML, n=13; ALL, n=8; MDS, n=1; MPD, n=1) who were treated in a pilot trial using rasburicase as part of a myeloablative conditioning regimen, followed by GCSF-mobilized HLA-matched (MRD, n=18; MUD, n=5) peripheral blood HCT. Urate oxidase (Rasburicase) was administered beginning on the first day of conditioning at a dose of 0.20 mg/kg IV daily for 5 days starting from day -7. GVHD prophylaxis for all patients consisted of cyclosporine or tacrolimus/MTX for MRD transplants and tacrolimus/MTX/ +/-ATG for MUD transplants. Out of the control group, patients who developed aGVHD (grade 2+) had a similar mean serum uric acid level over all days (2.82 mg/dl) compared to patients who did not have aGVHD (2.86 mg/dl, 2-tailed t-test p=0.74, Figure 1a). Results depend on the type of transplant received, however, as MUD transplants showed a differential expression in serum uric acid levels between the two groups (2.64mg/dl for aGVHD+ vs. 2.18 for aGVHD-, p=0.047, Figure 1b), while MRD transplants did not show a difference (2.97mg/dl for aGVHD+ vs. 2.98 for aGVHD-, p=0.95, Figure 1c). Patients given rasburicase had a lower serum uric acid level compared to the control arm (0.213mg/dl vs. 3.04 for d-7 to -2; 1.20mg/dl vs. 2.85 over all days, p<0.0001) as well as significantly less aGVHD (rasburicase: 22% vs. control: 48%, Fisher's exact test, p=0.033).  Lower serum uric acid level at the time of transplantation appears to be protective against the development of aGVHD among patients receiving matched unrelated donor transplants. Rasburicase, when administered during the conditioning, significantly lowers the serum uric acid level and appears to decrease aGVHD.

Figure 1

Mean uric acid levels from day-7 to day+6 between control patients who developed aGVHD2+ (Red) vs. no aGVHD2+ (Blue).