ALBERT

Description: 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, the screening for molecular markers suitable to identify the risk of refractory and relapse disease and specific 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. BCL2 exogenous expression was enough to partially rescue the death induce in cHL cells, which highlight the relevance of this alternative NFkB pathway target gene. Since the BCL2 data was obtained in human cHL cell lines established from patients with refractory and relapsed disease, we decided 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 disease. 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 a role in the refractory and relapsed classic Hodgkin Lymphoma disease, being BCL2 one of its key downstream target genes. BCL2 can be used as a prognosis marker determined by routine immunohistochemistry at diagnosis of the primary disease. BCL2 expression correlated with refractory disease to first line conventional therapy and disease progression. Based on the venetoclax effect in cHL cell lines we believe BCL2 directed-therapy in cHL should be considered in the subgroup of cHL patients that express this protein in ≥60% HRS cells in the lymph node biopsy performed at diagnosis. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: venetoclax used to specifically block BCL2.

Description: Background: The cure rate for advanced classical Hodgkin lymphoma (cHL) is approximately 70%, which is calculated based on data from clinical trials performed in North American and/or European countries (Canellos GP, et al. N Engl J Med. 1992;327:1478-84; Carde P, et al. J Clin Oncol. 2016;34:2028-36; Gordon LI, et al. J Clin Oncol. 2013;31:684-91). However, there are limited outcome data available in other countries, apart from some small hospital-based studies (Ramirez P, et al. Rev Bras Hematol E Hemoter. 2015;37:184-9; Law MF, et al. Arch Med Sci. 2014;10:498-504; Jaime-Pérez JC, et al. Oncologist. 2015;20:386-92; Omer Al-Sayes FM, Sawan A. J Taibah Univ Med Sci. 2006;1:48-56). The B-HOLISTIC retrospective chart review study seeks to address the paucity of data on cHL treatment patterns, clinical outcomes, and healthcare resource utilization in 13 countries across Latin America, Africa, Middle East, and the Asia-Pacific region. Methods: The study will collect data from approximately 2,600 patients aged ≥18 years and newly diagnosed with stage IIB-IV cHL or relapsed/refractory cHL (RRHL) between 01 January 2010 and 31 December 2013, and will follow them until death or chart review, whichever occurs first. The primary objective is to describe progression-free survival (PFS) in patients with RRHL. Secondary objectives include describing demographic and clinical characteristics, clinical outcomes (overall survival, best clinical response after completion of treatment, response duration), key adverse events associated with each line of therapy, and cHL-related healthcare resource use. Results: As of 14 May 2018, a total of 165 patients from 12 sites have been included in the interim analysis, predominantly from Turkey and South Korea. At this time, 150 patients had cHL and 24 patients had RRHL, including 9 patients who were enrolled in the cHL group and had a documented relapse/progression during the study period. Here, we report the results of the newly diagnosed cHL group; data from the RRHL group will be reported in subsequent publications. At diagnosis, 64.7% of the cHL group were male, with a median age of 36.5 years (range, 18-89 years); 22.7% had stage IV disease, 30% had extranodal disease, 59.3% had 'B' symptoms, and 34.9% had an International Prognostic Score (IPS) of ≥4. Patients were classified as 13.3% in stage I-IIA; 24% in stage IIB; 53.3% in stage IIIA-IVB; and 9.3% as unknown. Patients classified as stage I-IIA are a deviation from the clinical study protocol and will be removed from the final study analysis. The proportion of patients alive was 94%, with the cause of death reported as either HL-related (44.4%), due to an adverse event (11.1%), or other (44.4%). Positron emission tomography (PET) or PET-computed tomography (CT) imaging was performed in 58.5% of patients at baseline, 48% of patients at interim, and 36.6% at end-of-treatment; CT imaging was performed in 68.7% of patients at baseline, 83.6% of patients at interim, and 59.7% of patients at end-of-treatment. At frontline treatment, 95.3% of patients received chemotherapy (mostly doxorubicin, bleomycin, vinblastine, dacarbazine [ABVD], 92.3% [median number of cycles, 6; range, 2-8]), 22.7% of patients received radiotherapy, with 22% of patients receiving radiotherapy and chemotherapy (median total dose, 34.5 Gy; range, 24-45 Gy). The majority of patients received involved-field radiotherapy (53.1%), with other modalities including involved-node (21.9%), involved-site (18.8%), whole body (3.1%), or other (3.1%). The proportion of patients who achieved a complete or partial response to frontline treatment was 52.1% and 21.1%, respectively. The PFS for treatment in frontline cHL in the overall patient population at 48 months was 81% (95% CI, 73.1-86.7; Figure 1), with a median duration of follow-up of 58.9 months (range, 2.6-128.3 months). The PFS for treatment in frontline cHL excluding ineligible patients classified as stage I-IIA (13.3%) at 48 months was 78.9% (95% CI 69.7-85.6). Due to the retrospective nature of this study, adverse events were under-reported and will be presented once the data are mature. Conclusion: The B-HOLISTIC study is ongoing, with final patient enrolment anticipated in December 2018. These interim data provide real-world information on the incidence, treatment, and outcomes of cHL in countries where little is known about this patient population. Disclosures Ferhanoglu: Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Yeh:GNT Biotech & Medicals Crop.: Research Funding. Brittain:Takeda: Membership on an entity's Board of Directors or advisory committees. Karduss:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Kwong:Bayer: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Song:Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Zerga:Bristol Myers Squibb: Other: Conference fees; Roche: Other: Conference fees; Janssen: Other: Conference fees; Takeda: Other: Conference fees. Blair:Takeda Pharmaceuticals International Co.: Employment. Dalal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA: Employment, Equity Ownership. Wan:Takeda Pharmaceuticals International Co.: Employment. Hertzberg:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees.

Description: Introduction Estimated incidence of cHL in Argentina is 842 cases/year (Globocan 2018). There is no local data regarding response rates (RR) to FL. GATLA (Grupo Argentino de Tratamiento de Leucemia Aguda) reported 3 years progression free survival (PFS) rates of 90% and overall survival (OS) of 98% regardless of stage. HL has a high cure rate; 10% are primary refractory and 30% relapse after achieving complete remission (CR). In stage I-IIa, 5 years OS is estimated around 90% and 60% in stage IV (Ann Hematol 2019). Objectives Primary: To learn the RR, PFS and associated variables after FL of cHL in public (PuI) and private institutions (PrI) in Argentina. Secondary: To learn the OS rates. To study epidemiological characteristics of the patients (Pts) in participating institutions and reveal differences which may affect the response to treatment. Materials and methods Retrospective analysis of consecutive Pts with diagnosis of cHL from 1/1/2008 to 2/1/2019 with available follow up data. Descriptive statistics was performed in clinical variables and histopathological findings. Quantitative variables were expressed as median an interquartile range (IQR) and qualitative variables as total number and percentage (%). Survival rates were estimated by the Kaplan-Meier method and compared by the log-rank test. OS was measured from the date of diagnosis to date of death or last follow-up visit. Results 520 Pts from 7 PuI and PrI in Buenos Aires and Rosario were examined. 22 Pts had nodular lymphocyte predominant HL. Data on the 498 Pts with cHL is presented. Median follow up: 37.4 months (CI95% 17.7-63.5). Pts characteristics: Table 1. The median time from diagnosis to FL was 22 days (IQR 14-42), significantly shorter in PrI (32.5 (IC95% 27-38) vs. 49.3 (IC95% 38.5-60.2); p=0.0027). 96.5% of Pts received ABVD as FL, dose modifications or transitory suspension were required in 17.1%, and 82.1% received all cycles properly. CR was achieved in 83.4% of Pts and partial remission (PR) in 6.3%. The % achieving CR was higher in PrI; more PR were achieved in PuI. 10.3% had progressive disease (PD) at the end-of FL. 85.4% (n=373) had negative end-of-treatment FDG-PET results (DS1-3). Interim PET scan was performed in 70% of Pts (n=357), with 83.8% achieving metabolic CR but only 15.5% (n=70) being treated with response-adapted strategies (6.5% deescalated to AVD). Regarding hematologic toxicity, anemia, neutropenia and thrombocytopenia were found in 28.5%, 56.4% and 7.2% of Pts, respectively. Febrile neutropenia was reported in 9 Pts. 28.6% developed non-hematologic toxicities (41/144 pulmonary toxicity). 51 Pts had primary refractory disease and 69 (14%) relapsed during follow-up (median time to relapse 4.4 months (CI95% 0-13)). 65 Pts died (12.5%), 34 due to lymphoma progression and the remaining 31 due to toxicity. 2 years OS rate was 91% (CI95% 88% - 94%) and 85% at 5 years (CI95% 80% - 89%). There was no difference in OS between PrI and PuI (p=0.27); every day of delay in the beginning of FL increased 0.89 (IC95% 0.6-1.8) the risk of achieving PR or PD at the end of FL. 5 years PFS rate was 76% (CI95% 70-81) (figure 1-2: OS according to risk group and PFS). Outcomes were statistically better in women, age younger than 60, non-bulky disease, absence of extranodal disease or risk factors such as leukocytosis, lymphopenia and hipoalbuminemia. Pts with normal ESD, stage I-III, early favorable and advanced favorable stages and Charlson score

Description: Despite 90% stage I Hodgkin Lymphoma (HL) patients can respond to current systemic therapy, this drops to 60%, when diagnosed in advanced stages. Nevertheless and independently of the lymphoma stage, the real challenge when treating these patients, is the refractory and relapsed disease. There is no molecular biomarker to identify patients that would be non-responsive to conventional treatment or that would relapse. Furthermore, rescue chemotherapy schemes for refractory and relapsed patients, associate with acute and late toxicity high risk. This highlights the need to deeper understand the HL molecular biology and the screening for predictive biomarkers as well as potential therapeutic directed-targets. We have previously reported that HL relies on the alternative NFkB pathway, mediated by RelB and NIK, to survive. Depletion of either RelB or NIK by shRNAs or pharmacological NIK inhibitors induce HL cell death. ChIP-Seq analysis uncovered RelB target genes showing RelB bound to BCL2 promoter. A significant downregulation of BCL2 mRNA and protein levels, following RelB or NIK knockdown was observed, indicating that RelB regulates BCL2 expression in human HL cell lines. Our molecular studies suggested that NFkB alternative pathway constitutive signaling could at least partially explain the non-responding HL cases. We aimed to analyze whether mediators of this pathway could be useful as predictive biomarkers 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 lymphatic node biopsies of 96 patients by inmunohistochemistry [50 female Md age and (range) 59 (6-82), 46 male 42 (9-78)]. The univariate analysis showed no correlation between NIK or BCL2 expression and the prognosis clinical and pathological parameters, neither the molecular markers routinely assayed. A positive correlation was found between NIK and BCL2 expression (p=0.01). NIK and BCL2 correlated with lack of response to conventional therapy and both early and late disease progression. The analysis of survival, applying the Kaplan-Meier Curves, showed 〉 60% NIK positive HRS cells associated with shorter Disease Free Survival (DFS) [Log Rank Test (p=0.000)] and predicted overall survival (OS) as well [Log Rank Test (p=0.01)]. Furthermore, 〉 60% BCL2 positive HRS cells correlated with poor prognosis in terms of OS [Log Rank Test (p=0.002)]. The statistical significance was maintained in the multivariate analysis [Cox Regression and Logistic Regression (p=0.001)]. NIK and BCL2 performed successfully as useful predictive markers to identify refractory or risk of relapse HL patients at diagnosis. They represent attractive molecules to further analyse their potential as directed-therapy targets, since we have already reported that HL is sensitive to NIK inhibitors and BCL2 blockers have already been approved for clinical use in other hematological pathologies. Disclosures Zerga: Bristol Myers Squibb: Other: Conference fees; Janssen: Other: Conference fees; Roche: Other: Conference fees; Takeda: Other: Conference fees.