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O. Penack et al.
Table 4. Univariate global comparison of overall survival, non-relapse mortality, relapse incidence as well as chronic graft-versus-host disease incidence and severity at one year after allogeneic stem cell transplantation.
Group OS (95% CI)
Uric acid </=4.3 mg/dL 81% (75-88)
PFS (95% CI)
71% (64-79)
RI (95% CI)
19% (13-26)
NRM (95% CI)
10% (6-16)
cGvHD (95% CI)
28% (20-36)
Extensive cGvHD (95% CI)
16% (10-24)
Uricacid 66% 56% 27% 17% 26% 18%
>4.3 mg/dL (59-74) (48-64) (20-34) (12-24) (19-33) (12-25)
P-value <0.001 0.001 0.09 0.02 0.43 0.85 OS: overall survival; PFS: progression free survival; NRM: non-relapse mortality; RI: relapse incidence: cGvHD: chronic graft-versus-host disease; CI: confidence intervall.
alloSCT in European centres increased recently.11 This trend is reflected by a higher frequency of ATG use in the present study (41-46%) than we had initially expected. Another likely reason is a hyperinflammatory status con- nected to high uric acid levels not restricted to acute GvHD with a negative impact on different relevant clini- cal situations after alloSCT, such as sepsis12 and adult res- piratory distress syndrome (ARDS).13 This view is sup- ported by our observation that death due to both infec- tious and non-infectious complications after alloSCT was increased in patients with high uric acid levels. Interestingly, an association of uric acid levels with decreased solid organ transplant survival has been described further underlining the significance of uric acid for transplantation biology.14,15 Our study extends these findings to the setting of alloSCT.
Our study contradicts results from a previous retrospec- tive single centre study, which did not show any signifi- cant association of uric acid levels prior to transplantation to mortality after alloSCT.16 Differences in study designs between the current larger, multicentre and prospective study versus the already published smaller, single centre and retrospective study may be the reason for the differ- ing results.
A limitation of this clinical study is the lack of mecha- nistic insight on the role of uric acid in development of complications after alloSCT. The study design did not allow the investigation of whether the impaired outcome in the high urid acid cohort is due to an active role of uric acid in causing inflammation or whether it is because uric acid primarily is a surrogate biomarker reflecting a hyper- inflammatory status and/or activity of the underlying malignancy. However, we found no significant differences regarding the disease status as well as disease risk index (DRI) (complete remission [CR] vs. non-CR) in between the two groups (high uric acid vs.low uric acid). In addition there were no significant differences in the performance status as well as the alloSCT-CI in between the two groups. This data is no proof, but rather points in the direction that high uric acid values were not merely a reflection of advanced disease or increased co-morbidity in our study.
A further limitation of our results is that our patient
Table 5. Causes of death in both cohorts.
Uric acid ≤4.3
Uric acid >4.3 mg/dL (n=180)
106 (58.9%)
74 (41.1%) 38 (21.1%) 36 (20.0%) 20 (11.1%) 10 (5.6%) 5 (2.8%)
1 (0.5%)
Alive at last follow up
Dead
Dead due to relapse
Dead without relapse
Dead due to infection
Dead due to GvHD
Dead due to infection and GvHD
Dead due to other causes or unknown
GvHD: graft-versus-host disease.
(n=186) mg/dL
155 (83.3%)
31 (16.7%) 13 (6.9%) 18 (9.7%) 5 (3.2%) 2 (1.0%) 3 (1.6%) 8 (4.3%)
References
1. Apostolova P, Zeiser R. The role of purine metabolites as DAMPs in acute graft-ver- sus-host disease. Front Immunol. 2016; 7:439.
2.
3.
Zeiser R, Blazar BR. Acute graft-versus-host disease - biologic process, prevention, and therapy. N Engl J Med. 2017;377(22):2167- 2179.
Cannell PK, Herrmann RP. Urate metabolism during bone marrow transplantation. Bone
Marrow Transplant. 1992;10(4):337-339.
4. Joo SH, Park JK, Lee EE, et al. Changes in serum uric acid levels after allogeneic hematologic stem cell transplantation: A retrospective cohort study. Blood Res.
2016;51(3):200-203.
population was restricted to alloSCT from HLA-identical sibling donors. We are therefore unable to draw definite conclusions from these results regarding the association of uric acid levels with outcome in matched unrelated donor alloSCT or in haploidentical alloSCT, which are increas- ingly used. Another limitation is the incomplete under- standing of the effects of uric acid on post alloSCT immu- nity. While previous studies showed that uric acid leads to a inflammatory status in leukocytes and our results demonstrate impaired survival in alloSCT recipients with uric acid levels above median, it may be premature to con- clude that uric acid is a negative factor at any time around alloSCT. There are clinical situations where immune acti- vation is necessary and desired – e.g. in anti-infectious and anti-tumor immunity. The impact of depleting uric acid on immune activity in these situations remains to be deter- mined. In addition, it is possible that uric acid is involved in immune reconstitution as it has been suggested recently that changes in uric acid serum levels can indicate incipi- ent or remaining immunological activity after SCT or induction therapy in patients with hematologic malignan- cies.17
In conclusion, this study supports the use of serum uric acid levels as biomarker for alloSCT outcome.
Acknowledgments
JP acknowledges the support of the Imperial NIHR-BCR.
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haematologica | 2020; 105(7)