Relationship Between HLA Class I and II Polymorphisms with Susceptibility and Clinical Outcome in Diffuse Large B-Cell Lymphoma.
Authors: Alcoceba Miguel , Sebastián Elena , Marín Luis , Balanzategui Ana , Caballero M. Dolores , González-Barca Eva , Pardal Emilia , Martin Alejandro , Grande Carlos , Bello José Luis , Albo Carmen , de la Cruz Fatima , Panizo Carlos , Conde Eulogio , Sarasquete M. Eugenia , Chillón M. Carmen , Jiménez Cristina , Puig Noemí , Corral Rocío , Miguel Jesús F. San , García-Sanz Ramón , González Marcos 
Published: October 2019

Abstract
Abstract 2680

Introduction:
The Human Leukocyte Antigen (HLA) system plays an important role in antitumor immune response. In the last years, different genome-wide association studies have suggested that 6p21.3 (which include HLA system), is a risk region for lymphoma susceptibility. It has been also reported that specific alleles could modify the prognosis in patients diagnosed of lymphoma, including diffuse large B cell lymphoma (DLBCL), treated without Rituximab.

Aim:
Our hypothesis is that HLA system could play an essential role in disease control of DLBCL. Here, we have evaluated the effect of HLA Class I (A, B and C) and II (DRB1 and DQB1) alleles in DLBCL incidence and survival.

Patients and Methods:
A total of 251 patients diagnosed of DLBCL according to the 2008 WHO classification were analyzed (68% of them received Rituximab-based regimens). Control population consisted in 1940 healthy donor individuals analyzed for HLA-A, B, and DRB1 alleles and 200 for HLA-C and HLA-DQB1.
Overall survival (OS) was calculated from diagnosis until death for any cause. Event-free survival (EFS) was calculated from diagnosis until event defined as death for any cause, relapse or progression of the disease.
Allele frequencies and Hardy-Weinberg equilibrium were estimated using the Arlequin software package, version 3.5.1.2. Comparison of allele and phenotype frequencies between populations was performed with the two-sided Fisher's exact test or χ2 test using GraphPad Prism 4.0 (GraphPad Software, Inc. San Diego, CA, USA) or SPSS software (SPSS 15.0, Inc. Chicago, IL, USA). P-value was adjusted applying a Bonferroni correction (Pc).
The effect of biological and clinical variables on OS and EFS at five years was analyzed by univariate (two-sided log-rank test) and multivariate (Cox multivariate analysis) methods. Differences were considered to be statistically significant when P< 0.05.

Results:
HLA specificities frequencies in patients and controls (Alcoceba et al, Tissue Antigens 2011) were consistent in all cases with the Hardy-Weinberg equilibrium.
Phenotypic frequencies showed significant differences in DLBCL patients compared to control population. DRB1*01 frequency was increased in DLBCL patients (28.9% vs. 19.5%, p=0.0009, Pc=0.0117, OR: 1.68; 95% CI: 1.24–2.26). By contrast, DLBCL patients showed a lower frequency in C*03 allele as compared to the control population (6.4% vs. 18.3, p=0.0005, Pc=0.007, OR: 3.2, 95% CI: 1.62–6.3).
As far as the outcome of patients was concerned, the presence of B*18 and/or B*44 was significantly associated with a worse EFS (32% vs. 60%, p<0.001 and 53% vs. 72%, p=0.025, respectively) and OS (41% vs. 78%, p<0.001, and 53% vs. 86%, p=0.006, respectively). These statistical differences were also observed in the group of patients receiving Rituximab-based regimens. The Cox multivariate analysis identified high International Prognostic Index and the presence of any B*18 or B*44 as independent adverse prognostic factors for EFS and OS.

Conclusions:
Our data revealed that HLA specificities could influence the incidence (DRB1*01 and C*03) and outcome (B*18 and B*44) of DLBCL. These results suggest a role for HLA in the immune-surveillance of DLBCL and, also open possibilities for future investigations to answer how a specific HLA allele could affect in DLBCL.

Disclosures:
No relevant conflicts of interest to declare.