BCL2 as a marker to identify refractory and at risk of relapse disease in classic Hodgkin Lymphoma patients. Its inhibition as a potential directed-therapy.

GAMBOA-CEDEÑO, ANGÉLICA; CRISTALDO, NANCY; OTERO, VICTORIA; SCHUTZ, NATALIA; FANTL, DOROTEA; CUGLIARI, SILVANA; ZERGA, MARTA; ROJAS-BILBAO, ERICA; JAUK, FEDERICO; GARCÍA RIVELLO, HERNÁN; NUÑEZ, MYRIAM; RANUNCOLO, STELLA MARIS

Orlando, Florida

Congreso; 61st Annual Meeting of the American Society of Hematology (ASH).; 2019

American Society of Hematology (ASH)

Classic Hodgkin Lymphoma (cHL) is a germinal center derived lymphoma with 8,500-9,000 new cases/year diagnosed in the US. Despite 90% stage I cHL patients can respond to current systemic therapy, this drops to 60%, when diagnosed in advanced stages. Furthermore, 20-30% of diagnosed patients, would be refractory or would relapse and have a poor prognosis. Refractory and relapsed disease (RRD) is currently the challenge when treating cHL patients. There is no specific therapy to offer rather than rescue chemotherapy schemes, which fails in 50% of the cases and associates with high risk severe toxicity. This highlights the need to deeper understand the cHL molecular biology and the screening for prognosis biomarkers and therapeutic directed-targets. We have previously reported that the alternative NFkB pathway, mediated by Rel-B and NIK (NFkB Inducing Kinase), plays an important role in cHL survival. Its constitutive activation sustains high BCL2 expression levels and seems to be involved in the RRD. BCL2 was found as a specific Rel-B target gene in cHL cells by ChIP-Seq (Chromatin Immunoprecipitation sequencing) and expression arrays. We aimed to analyze whether mediators of this pathway and BCL2 could be useful as prognosis markers and would represent potential targetable factors in both refractory and relapsed patients.We analyzed NIK and BCL2 citoplasm expression in Hodgkin Reed-Sternberg cells (HRS) in the lymph node biopsies of 113 cHL naïve of therapy patients by inmunohistochemistry [52 female Md age and (range) 36 (6-88), 61 male 40.7 (9-78)]. The follow-up period range from 6 to 136 months.The univariate analysis showed no correlation between NIK or BCL2 expression and the prognosis clinical and pathological parameters, including the PET Scan indicated at the end of the first line treatment, neither the molecular markers routinely assayed. The statistical significance was maintained in multivariate analysis (Logistic and Cox Regression p=0.01). NIK expression did not associate with prognosis but the BCL2 expression level correlated with lack of response to conventional therapy and both early and late disease progression. The survival analysis, using the Kaplan-Meir curves, showed that patients with ≥60% positive HRS cells had a shorter disease-free survival (DFS) [Log Rank Test (Mantel Cox) p=0.002] and a reduced overall survival (OS) [Log Rank Test (Mantel Cox) p=0.02].L1236, U-H01, KM-H2, SUPDH1 and L540, human cHL cell lines that express BCL2 protein, were sensitive to venetoclax a specific BCL2 inhibitor. The drug induced a cell cycle arrest in S-Phase when treated with 1uM each 24 hours during 10 days, as compared to wild type cells and cells treated with the vehicle.In summary, we found that the alternative NFkB pathway plays an important role in the refractory and relapsed Hodgkin disease, being BCL2 a key downstream target. BCL2 performed well as a prognosis marker identifying refractory patients and those that relapsed being assayed at diagnosis of the primary disease. We believe BCL2 directed-therapy in cHL could be interested in patients that express this protein in ≥60% HRS cells in the lymph node biopsy performed at diagnosis.