Page 236 - 2020_07-Haematologica-web

O. Penack et al.
Introduction
Endpoints and statistical analyses
Patient, disease, and transplant-related characteristics for the two cohorts (uric acid levels prior to alloSCT above median / uric acid levels below median) were compared by using 2 statistics for categorical variables and the Mann-Whitney test for continuous variables. The primary endpoint was the incidence of acute GvHD. Secondary endpoints were relapse incidence (RI), non- relapse mortality (NRM), overall survival (OS), progression free survival (PFS) and the incidence of chronic GvHD. PFS was defined as survival with no evidence of relapse or progression. RI was defined as the probability of having had a relapse during fol- low-up time. Death without experiencing a relapse was a compet- ing event. NRM was defined as death without evidence of relapse or progression. OS was defined as the time from alloSCT to death, regardless of the cause. Acute GvHD was graded according to the modified Seattle-Glucksberg criteria9 and chronic GvHD accord- ing to the revised Seattle criteria.10 Cumulative incidence was used to estimate the endpoints of NRM, RI, acute and chronic GvHD to accommodate for competing risks. To study acute and chronic GvHD, we considered relapse and death to be competing events. Probabilities of OS and PFS were calculated using the Kaplan– Meier method. Univariate analyses were done using the Gray test for cumulative incidence functions and the log rank test for OS and PFS. A Cox proportional hazards model was used for multi- variate regression. All variables differing significantly between the two groups or factors associated with one outcome in univariate analysis were included in the Cox model. The following variables entered the multivariate models as possible confounders: age, sex mismatch between recipient and donor, diagnosis, disease status, Karnofsky score, number of CD34 cells given, intensity of condi- tioning (EBMT definition: myeloablative conditioning (MAC) was defined as total body irradiation (TBI) >6 Grey or oral busulfan >8 mg/kg or intravenous busulfan >6.4 mg/kg), type of GvHD pro- phylaxis, ATG use, time from diagnosis to transplant, year of transplant and CMV status. As the number of variables was too high regarding the number of events, a stepwise selection using Akaike information criterion (AIC) was run for all the confound- ing factors. The difference between the two cohorts was then assessed in the final selected model.
Results were expressed as the hazard ratio (HR) with the 95% confidence interval (95% CI). Proportional hazards assumptions were checked systematically for all proposed models using the Grambsch-Therneau residual-based test. All tests were two-sided. The type I error rate was fixed at 0.05 for the determination of fac- tors associated with time-to-event outcomes. Statistical analyses were performed in November 2018 with R 3.4.2 (R Core Team (2017). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/.)
Results
Patients, transplant characteristics and uric acid measurement
The entry criteria for analysis of primary and secondary endpoints were fulfilled in 386 patients. We used the last uric acid serum level that was masured in the individual patients before start of conditioning. The median time point of measurement was three days before start of con- ditioning. The range was between 0 days (morning before start of conditioning) to 22 days before conditioning. The main patients and transplant characteristics that were included in the analysis of OS are described in Table 1. Most parameters were balanced between the two cohorts.
High treatment-associated complication rates remain an important challenge to the success of allogeneic hematopoietic stem cell transplantation (alloSCT). A com- mon mechanism of the major infectious- and non-infec- tious complications after alloSCT, such as graft-versus-host disease (GvHD) and sepsis, is severe inflammation. Critical to excess inflammation after alloSCT are host bio- molecules termed ‘endogenous danger signals’, which can initiate and maintain non-infectious inflammatory responses by acting as pro-inflammatory mediators.1,2 One such molecule is uric acid. During conditioning for alloSCT, uric acid is released from injured cells and reduced renal clearance may contribute to high uric acid serum levels.3,4 Uric acid acts as a danger signal by enhanc- ing T-cell responses via activation of the NOD-like recep- tor protein (NLRP) 3 inflammasome.5,6 A pre-clinical study has provided basic evidence on the regulation of GvHD by uric acid via Nlrp3 inflammasome–mediated IL-1 produc- tion.7 The significance of uric acid for alloSCT outcome has been underlined by results from a pilot study reporting reduced incidence of acute GvHD in patients undergoing alloSCT after depletion of uric acid using urate oxidase.8
Based on these results, and because uric acid is a routine laboratory parameter assessed in patients undergoing alloSCT, there is a strong rationale to investigate the use of uric acid as a biomarker and possibly as a therapeutic target during alloSCT. To study the role of uric acid levels in alloSCT, the Transplant Complications Working Party (TCWP) of the European Society for Blood and Marrow Transplantation (EBMT) performed a prospective, multi- center, non-interventional study. We hypothesized that a high uric acid level prior to alloSCT is an independent risk factor for increased mortality and for the development of severe acute GvHD.
Methods
Data source, study design and data collection
We asked EBMT centers performing more than 50 alloSCT per year if they were willing to participate in this prospective study. Twenty centers in ten countries agreed to participate. Data collec- tion for the EBMT registry was approved by the institutional review board and/or Ethics Committee in all centers. Data were prospectively collected between August, 2014 and February, 2018. Consecutive alloSCT recipients with acute leukemia, lym- phoma or myelodysplastic syndrome (MDS) receiving a first matched sibling alloSCT from peripheral blood, regardless of con- ditioning, were eligible, provided they had signed an informed consent document that permitted sharing of clinical data accord- ing to national rules. Basic data on patient and disease characteris- tics as well as longer term follow-up was taken from minimal essential data (MED-A) forms, which are submitted from all con- secutive patients to the central EBMT registry. In addition, we designed registration and MED-B/C forms that were prospectively collected and specific to this study (see the Online Supplementary Materials and Methods). The MED-B/C form contained detailed information on uric acid serum levels prior to alloSCT, patient characteristics, infectious- as well as non-infectious complications, GvHD staging, morbidity and mortality. Uric acid levels were determined at the time of hospital admission for alloSCT directly before the start of conditioning therapy. Treatment teams com- pleted the specific forms at the time of registration and at day +100 after alloSCT.
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haematologica | 2020; 105(7)