Serum Uric Acid Levels Can Serve As a Sensitive Biomarker for Immunologic Activity in Patients Undergoing Hematopoietic Cell Transplantation
Authors: Haen Sebastian P. , Eyb Vicky , Roth Nora , Faul Christoph , Rammensee Hans-Georg , Kanz Lothar , Bethge Wolfgang A. 
Published: October 2019

Abstract
Abstract 4558

Background:
Both, autologous and allogeneic hematopoietic cell transplantation (HCT) are important treatment options for patients with hematologic malignancies. During transplantation multiple humoral danger signals, chemokines and cytokines modulate immune reconstitution and post-regeneration immune responses. Uric acid crystals have been identified to act as strong endogenous danger signals. Local high concentrations of uric acid without crystal formation have immunoactivating properties which are reflected by only slight changes in uric acid serum levels. We here extended our previous studies (Haen et al, Blood 2010 (ASH Annual Meeting Abstracts), 116: 4701) and analyzed uric acid serum levels in patients during HCT and a control group during induction chemotherapy for acute leukemia to test the applicability of uric acid as a sensitive biomarker for immunological activity.

Patients and Methods:
We retrospectively analyzed daily serum levels of uric acid, creatinine and peripheral blood counts of 150 consecutive patients (mean age 47 years, range 18–74 years) with different hematologic malignancies after 202 interventions: In the evaluation group 50 patients after allogeneic HCT (53 transplantations; mean age 48 years, range 19–73 years) and 50 patients after autologous HCT (61 transplantations; mean age 51 years, range 20–69 years) were included. In the control group 50 patients after induction chemotherapy for acute myeloid leukemia (AML, n = 25; 39 chemotherapy cycles; mean age 51 years, range 18–74 years) and acute lymphoblastic leukemia (ALL, n = 25; 49 chemotherapy cycles; mean age 31 years, range 19–61 years) were included. In the transplantation group, indications for treatment were AML (n = 29), ALL (n = 7), multiple myeloma (n = 12), lymphoma (n = 28), myelodysplastic syndromes (n = 7), myeloproliferative disease (n = 3), chronic lymphatic leukemia (n = 2), chronic myeloid leukemia (n = 1), germinal cell cancer (n = 9), and Ewing-sarkoma (n = 2).

Results:
All patients presented with a significant decrease of uric acid serum levels during conditioning or induction therapy and subsequent aplasia (p < 0.001) with all but 5 patients (97%) developing hypouricemic serum levels (< 3.4 mg/dl, p < 0.001) occurring independently from allopurinol application. Post-treatment serum levels recovered to pre-treatment values (p = 0.08). In all patients the nadir of uric acid serum levels was observed significantly earlier than the detection of first increasing leukocytes (day 11 vs. day 13, p < 0.001; detection limit 50 cells/μl). Most patients undergoing allogeneic or autologous HCT only had one re-increase of uric acid during aplasia (mean 1 and 1.4 re-increases after allogeneic and autologous HCT, respectively). In allogeneic HCT patients this re-increase started earlier than detection of > 50/μl leukocytes (day 9.1 versus day 11.5, p < 0.001), while in autologous HCT the re-increase occurred concomitantly with increasing leukocytes (day 6.6 versus day 6.3, p = 0.26). In contrast, most patients treated with induction chemotherapy presented with more than one re-increase of uric acid serum levels between chemotherapy and hematopoietic regeneration (mean 2.7 and 2.9 re-increases in AML and ALL patients, respectively). Hence, a re-increase of uric acid was indicative for incipient immunologic activity and leukocyte recovery out of aplasia after HCT but not in the control group. Moreover, we observed a drop of uric acid levels in patients with transplant rejection (n = 3) and one patient with bone marrow failure after induction chemotherapy three to four days before vanishing of leukocytes.

Conclusion:
Uric acid serum levels can indicate early immunologic activity in patients undergoing HCT. A re-increase of uric acid after allogeneic HCT is indicative for immanent leukocyte recovery before > 50 leukocytes/μL can be detected in peripheral blood, while after autologous HCT this increase was observed concomitantly with leukocyte recovery. In contrast, uric acid serum levels did not indicate incipient leukocytic regeneration in patients undergoing induction chemotherapy for AML or ALL, possibly reflecting residual immunologic activity. Of note, a drop of leukocytes shortly after a decrease of serum uric acid may be a hallmark of graft failure or rejection.

Disclosures:
No relevant conflicts of interest to declare.