Cytokine Gene Polymorphisms and Outcome of Patients with Hodgkin Lymphoma: A Prospective Study of the Groupe D’Etude Des Lymphomes De L’Adulte
Authors: Ghesquieres Herve , Casasnovas Olivier , Fournier Marion , Cox David , Brice Pauline , Morschhauser Franck , Borrel Anne-Laure , Sebban Catherine , Ribrag Vincent , Haioun Corinne , Feugier Pierre , Tilly Herve , Ferme Christophe , Salles Gilles Andre 
Published: April 2020

Background. Although Hodgkin lymphoma is a highly curable malignancy, about 15% and 30% of patients with respectively localized or disseminated disease do not respond or relapse after initial treatment. Several scoring systems using conventional biological and clinical parameters have been developed for limited and advanced stages in order to adapt the therapeutic strategy. However, the identification of patients with adverse outcome needs to be improved. Cytokines have an important role in the pathogenesis of Hodgkin lymphoma. Several studies have shown that plasma cytokine dosage at diagnosis has prognostic relevance. Various cytokine genes variants are known to influence cytokine productions and have been associated with lymphoma outcomes. We then evaluated the influence of cytokine gene polymorphisms on response to treatment and outcome in patients with Hodgkin lymphoma.

Methods. Between 1998 and 2002, we prospectively investigated the prognostic role of plasma cytokines and soluble receptors in Hodgkin lymphoma patients (Casasnovas et al. JCO 2007). A sample was collected at diagnosis specifically to investigate single nucleotide polymorphisms (SNPs) in cytokine genes. Ten SNPs that could be functionally important in seven genes (IL10, TNF-alpha, IL6, IL1B, IL1RN, INF-gamma, CCL17) were studied. DNA was extracted from venous blood samples. All genotyping experiments were performed in duplicate using Taqman technology (ABI Prism 7000, Applied Biosystems): IL10 rs1800890 (−3584&gt;A), 448 pts; IL10 rs1800896 (−1116A&gt;G), 459 pts; IL10 rs1800871 (−853C&gt;T), 446 pts; IL10 rs1800872 (−626C&gt;A), 447 pts; TNFalpha rs1800629 (−487G&gt;A), 464 pts; IL6 rs1800795 (−236G&gt;C), 201 pts; IL1B rs16944 (−1060T&gt;C), 198 pts; ILRNrs419598 (Ex5–35T&gt;C), 199 pts; INF-gamma rs2430561 (+874A&gt;T), 200 pts; CCL17rs223828 (−431T&gt;C), 198 pts. We estimated the prognostic value of each individual SNP and the IL10 haplotype for response to treatment, relapse and overall survival (OS).

Results. The median age of the 464 patients studied was 32 years (range, 15–93); 263 (57%) were male. At diagnosis, 335 patients (72%) were in Ann Arbor stage I–II and 206 (44%) presented with B symptoms. Histology was nodular sclerosis in 384 patients (84%). Treatment consisted of 4 to 6 courses of anthracycline-based chemotherapy (CT) followed by involved-field radiotherapy for stages I–II and 8 courses of anthracycline-based CT for stages III–IV. Complete response (CR) and uncertain CR (uCR) were observed in 417 patients (90%), partial response in 15 (3%) and stable and progressive disease in 32 (7%). Relapse occurred in 71 patients (15%) and 35 patients (8%) died, 24 of whom (5%) of Hodgkin lymphoma. After a median follow-up of 3.6 years months, the 4-year progression free survival (PFS) and OS were 83.4% and 93.6%, respectively. Regarding treatment response, only the IL10-1082AA genotype was associated with a better CR + uCR than other IL10 genotypes (95% vs. 88% p=0.02). Neither individual SNPs or IL10 haplotype influenced OS and PFS.

Conclusions. In this large series of Hodgkin lymphoma patients with particularly favorable outcome, the IL10-1082AA genotype was associated with better response to initial treatment. These data indicate that some genes associated with non-Hodgkin lymphoma outcome do not predict Hodgkin lymphoma outcome and that other target need to be analyzed to decipher the putative role of host’s immunogenetic background in this disease.