Human leukocyte antigens HLA DRB1 influence clinical outcome of chronic lymphocytic leukemia

Abstract

We investigated HLA DRB1 correlations with chronic lymphocytic leukemia (B-CLL) outcome in 90 patients. Neither of the alleles was associated with B-CLL clinical characteristics or mortality. HLA DRB1*01 and HLA DRB1*02-null were associated with shorter overall survival (p=0.007, p=0.002). Our results suggest that HLA-restricted adaptive immunity influences CLL outcome. Haematologica 2007; 92:5:710-711 B-cell chronic lymphocytic leukemia (B-CLL) is the most common adult leukemia in Western countries and North America. It is characterized by the clonal accumulation of CD5 + B-cells expressing CD19, CD23 and low surface IgM.1 Its origins still remains largely unknown, although genetic susceptibility appears to play an important role.2 The Human Leukocyte Antigen complex (HLA) is one of the inherited factors that influences the development of B-CLL and clinical outcome of diffuse large B-cell lymphoma.3-5 This led us to examine whether HLA antigens contribute to the clinical course of CLL.Allelic frequencies of HLA DRB1 were systematically examined in 90 B-CLL patients seen in the Department of Hematology during 2003-2004 for control visits, and in 94 ethnically-matched, healthy controls. Patients' confidentiality was maintained in accordance with Polish regulations for studies on human subjects. Clinical characteristics of CLL patients are presented in Table 1. Of 90 patients enrolled in the study, 58 required treatment and were available for an estimation of treatment response. Forty patients (69%) achieved complete or partial remission and 18 (31%) did not. Twenty-one patients (36%) experienced disease progression or relapse and 25 patients died. HLA DRB1 genotyping was performed using PCR-based reverse blot technology (RELI SSO; Dynal, Oslo, Norway) according to the manufacturer's protocol. Statistical tests were two-tailed with the level of significance p<0.05. Survival was estimated according to the KaplanMeier method. Comparison of survival was based on log-rank testing as previously described, with death for any cause as a censoring variable. 5The HLA DRB1 allelic frequencies and distributions were consistent with the Hardy-Weinberg equilibrium, and did not differ significantly between CLL patients and the control group. We assessed HLA DRB1 allele frequency using low (two-digit) typing resolution. We were therefore unable to detect previously reported associations of HLA DRB1*0401 and DRB1*0403 with CLL incidence, or DRB3 (DR52) and DRB4 (DR53) supertypical loci with age-at-onset of CLL. 3,6There were no associations between HLA DRB1 alleles and clinical characteristics of CLL patients at diagnosis, including age, clinical stage according to Rai classification, surface CD38 expression, serum levels of lactate dehydrogenase (LDH) and β2-microglobulin (data not shown). In patients with HLA DRB1*01 allele, there was a trend towards a shorter time from diagnosis to treatment (log-rank test, p=0.07, Figure 1A.) Neither of assessed HLA DRB1 alleles was associated with response to first-line treatment or morta...

The role of HLA variation in lymphoma aetiology and survival

“…Among Iranian patients, significant risk increase for disease progression was reported for HLA‐DRB1*04 and HLA‐DRB5 alleles, but they did not identify differences in HLA‐A or HLA‐B alleles or haplotypes . On the other hand, HLA‐DRB1*01 ( P ‐value = 0.007) and HLA‐DRB1*02‐null ( P ‐value = 0.002) were associated with shorter overall survival . One study of the nonclassical HLA loci suggested the presence of HLA‐E*01:03 allele and detection of soluble HLA‐E as an independent predictor of disease progression .…”

Human leukocyte antigen class II allele association to disease progression in Iranian patients with chronic lymphocytic leukemia

“…Previous investigations examining the frequency of the HLA system in CLL patients demonstrated inconsistent and controversial association of some HLA alleles with CLL [17][18][19]22,23]. Whereas some studies indicated no association of CLL with HLA molecules [24], others demonstrated association with a variety of HLA alleles [17][18][19][20][21][22][23].…”

“…These polymorphic antigens could also influence the pathogenesis of B-cell or T-cell malignancies through continuous clonal stimulation of antigen-specific lymphocytes [16]. Many studies examined the possible association of the HLA system with lymphoproliferative disorders, but few reported HLA frequencies in CLL [17][18][19][20][21][22][23][24]. Furthermore, the frequency of HLA alleles has not been well determined in Asian CLL patients.…”

“…Whereas some studies indicated no association of CLL with HLA molecules [24], others demonstrated association with a variety of HLA alleles [17][18][19][20][21][22][23].…”

Host immune response in B-cell lymphomas: friend or foe?

“…The absence of the the HLA-DRB*02 and presence of the DRB*01 allele were related to adverse outcome of NHL and CLL, respectively [38,49]. In an extended haplotype analysis, HLA A*01 and B*08 components of 8.1 HLA ancestral haplotype exhibited the strongest associations with shorter FFP and OS in DLBCL patients [65,66].…”