Abstract 6235: BCL2 blockade in refractory and relapsed classic Hodgkin Lymphoma; Venetoclax sensitize cells to first line treatment
Authors: Cedeño-Gamboa Angélica M. , Díaz Mariángeles , Otero Victoria , Schutz Natalia , Fantl Dorotea , Jauk Federico , Nuñez Myriam , Ranuncolo Stella M. 
Published: September 2020

Abstract
Classic Hodgkin Lymphoma (cHL) is a germinal center derived lymphoma with 9,000 new cases diagnosed each year in the US. Despite 70-80% early stage cHL patients respond to current systemic treatment, 10% of patients are refractory to first-line therapy and 30-40% relapse. Refractory and relapsed disease is currently the challenge when treating cHL patients. There are no biomarkers suitable to identify patients that would be refractory or that could relapse at the primary diagnosis. Furthermore, there is no specific therapy 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 innovative approaches.
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.
We analyzed NIK and BCL2 citoplasm expression in Hodgkin Reed-Sternberg cells (HRS) in the lymph node biopsies of 112 cHL naïve of therapy patients by immunohistochemistry [51 female Md age and (range) 36 (6-88), 61 male 40.7 (9-78)]. The median follow-up period was 512, months (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).
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]. NIK expression did not correlate with prognosis.
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 cell cycle arrest in S-Phase and G2-M when treated with 1uM each 24 hours during 10 days, as compared to wild type cells and cells treated with the vehicle. Furthermore, venetoclax sensitized cHL cell lines to vincristine and doxorubicin, two drugs used in the first-line chemotherapy scheme ABVD (Adriamycin, Bleomycin, vincristine, doxorubicin).
In summary, we found that the alternative NFkB pathway plays an important role in the refractory and relapsed Hodgkin disease biology, being BCL2 a key downstream target. BCL2 performed well as a prognosis biomarker 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. Furthermore venetoclax sensitized cHL cells to conventional chemotherapy.
Citation Format: Angélica M. Cedeño-Gamboa, Mariángeles Díaz, Victoria Otero, Natalia Schutz, Dorotea Fantl, Federico Jauk, Myriam Nuñez, Stella M. Ranuncolo. BCL2 blockade in refractory and relapsed classic Hodgkin Lymphoma; Venetoclax sensitize cells to first line treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6235.