Is There Any Impact of Uric Acid Levels during the Peri-Transplant Period on Acute Graft Vs. Host Disease Incidence and Allotransplant Outcome?

Background: Damage associated molecular patterns (DAMPs) are considered important contributors to acute Graft vs Host Disease (aGvHD) pathogenesis. Uric acid (UA), a DAMPs family molecule, upon its release from damaged tissues post high dose chemo/radio therapy, triggers activation of donor derived T-cells. Currently, only two published studies evaluated the association between UA levels at day 0 and aGvHD occurrence, with totally conflicting results. Given that aGvHD is a dynamic process which takes place during the whole early post-transplant period, contrasting to previous studies, we evaluated serum UA levels not only once but in 4 different time points during the early transplant period, at days -7, 0, +7, +14, and investigated its correlation to aGvHD incidence, non-relapse mortality (NRM) and survival rates.

Methods: We retrospectively evaluated 57 patients (pts), with a median age of 36.8 years (range, 17-62), who underwent allogeneic stem cell transplantation (alloSCT) from full matched sibling donors for malignant (n=48) or non-malignant (very severe aplastic anemia =9) hematological diseases. A median of 5.6 x10⁶/kg CD34+ cells were infused after a myeloablative (n=34) or reduced intensity (n=23) regimen. At the time of alloSCT, 42 pts were in remission (CR1: 30, CR2: 10, >CR2: 2). All pts received either allopurinol or rasburicase from the day of conditioning initiation till day -1. The ROC-curve method, t-test, Kaplan-Meir method, and log-rank test were used for the univariate while the binary logistic regression method for the multivariate statistical analysis. Disease phase [early (CR1) vs. intermediate (CR2) and advanced (>CR2 or presence of residual disease)], donor gender, patient and donor age, UA levels at day -7, 0, +7, +14, type of conditioning regimens and number of infused CD34+ cells were tested as possible factors that can affect aGvHD incidence.

Results: Median UA levels were 3.2, 2.4, 2.2 and 2.9 mg/dl at days -7, 0, +7 and +14 respectively; using the ROC curve method the cutoff point was determined at 4.4 mg/dl for day -7 and 2.2 mg/dl for days 0, +7 and +14. Overall, 20/57 (35%) pts developed aGvHD; 18 (31%) were assessed as gr ≥II, while 10 (17%) as gr III-IV. The incidence of the aGvHD gr ≥II was higher for pts with UA levels ≤ 4.4 mg/dl at day -7 (14 vs 4) and for pts with UA levels ≥2.2 mg/dl at days 0 (12 vs. 6 pts) and +14 (13 vs. 5 pts) however these differences did not reach statistical significance. UA levels at +7 day had no impact on aGvHD incidence. In multivariate analysis, only the number of CD34+ >6x10⁶/kg was an adverse factor for aGVHD gr≥II (p=0.04) while intermediate & advanced disease phase along with a number of CD34+ cells >6x10⁶/kg, proved to be significant contributors for severe aGvHD (gr III-IV) occurrence (p<0.03). We observed a better 4 years overall survival for patients with UA levels < 2.2 mg/dl at day +14 (85% vs. 55%, p=0.06). Fifteen pts succumbed to NRM causes; 8/15 deaths were attributed to aGvHD complications. The NRM was higher in patients who had UA levels ≥2.2 mg/dl at day +14 (32% vs. 15%) though this difference was not significant (p=0.2).

Conclusions: The present study bears the limitations of a small series of pts and it's retrospective nature. However, it has the advantage of evaluation of UA levels, as an aGvHD mediator, at multiple time points during the peri-transplant period. Our results, though not of strong statistical significance, demonstrated that UA levels might affect aGvHD incidence as well as survival and the NRM rates post alloSCT. Definitely, well designed prospective clinical trials are warranted to clarify the role of UA on alloSCT outcome.