ALBERT

Description: Background Patients (pts) with DLBCL who have received rituximab (R) antibody in the first-line setting, have poorer treatment outcomes when they are re-treated with R-chemotherapy in the salvage setting. Resistance to R may have developed. Ofatumumab (O) is a human monoclonal antibody against CD 20 that targets a different epitope than R. We hypothesized that replacing R with O in second line setting may overcome R resistance. The primary end-point of this ongoing phase II study is the objective response rate (ORR) following two cycles of O in combination with ICE (Ifosfamide, Carboplatin and Etoposide) or O-ICE. Secondary end points include the assessments of the safety and tolerability of the combination, progression-free (PFS) and overall survival (OS). Methods This was a multi-center, non-randomized phase II open label study. Pts with histologically confirmed DLBCL who failed or were refractory to first line R-based anthracycline therapy were eligible. Pts were accrued according to a 2-stage Simon’s Optimal Design at the National Cancer Centre Singapore and 3 medical centres in South Korea; Samsung Medical Centre, Ajou University Hospital and Soonchunhyang University Hospital. Stage 1 will enrol 24 pts and if 14 or more pts respond, we will proceed to stage 2 where another 37 pts would be recruited. Pts receive 3-weekly ICE (Ifosfamide 5g/m2 on day 2, Carboplatin AUC = 5 on day 2, Etoposide 100 mg/m2 day 1-3) and O (1000 mg), infused on day 1 and 8 of cycle 1, and thereafter only on day 1 of each cycle. A restaging scan is performed after cycle 2. Pts who are candidates for high dose chemotherapy (HDC) and autologous stem cell rescue (ASCR) would receive additional 1 or 2 more cycles of O-ICE before stem cell mobilization. Pts who are not candidates for HDC and ASCR would receive up to 6 cycles of O-ICE. Results A total of 24 pts with a median age of 54.5 years (27-75) were enrolled. Among them, 14 (58%) were male and 14 (58%) had stage III/IV disease. A median of 4 (2-6) courses of O-ICE was administered and 11 pts underwent HDC+ASCR. The ORR after 2 cycles was 58.3%; complete response (CR) 29.2% and partial response (PR) 29.2%. On treatment completion, the best ORR became 62.5% (CR = 37.5%, PR = 25%). Grade 1/2 non-hematologic toxicities, independent of relation to study drug, occurring in at least 20% of pts included nausea (50%), pain (50%), fatigue (42%), rash (42%), anorexia (33%), vomiting (33%), diarrhea (25%), edema (29%), fever (21%), pruritus (21%), cough (21%) and paresthesia (21%). Grade 3/4 toxicities included neutropenia (50%), thrombocytopenia (71%) and 4 anemia (54%). Febrile neutropenia occurred in 12.5% and no treatment related deaths were reported. The median follow up time was 8.2months (95% CI 5.3-14.0). The median PFS was 8.2months (95% CI 4.2-17.8) and the median OS was not reached (95% CI 8.6-not reached). Conclusion The study regimen met the predefined threshold of 14 responding pts in stage 1. The ORR of O-ICE was comparable to that of RICE in the CORAL study and this result is significant considering that all pts in this study had received R prior to study entry. Together with the tolerability data and promising activity, continuation of study enrolment in stage 2 has started. Disclosures Tao: Medscape: Honoraria; Takeda: Honoraria. Quek:Novartis: Consultancy, Honoraria; Bayer: Honoraria. Kim:Novartis: Research Funding; Cellgene: Research Funding; Takeda: Research Funding.

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: Hepatitis B virus (HBV) infection, defined by the presence of HBV surface antigen (HBsAg), increases the risk of HBV reactivation and current guidelines recommend that patients who are HBV-infected should receive antiviral prophylaxis during and after chemotherapy. As HBV infection is endemic in Asia, a proportion of patients may have had past HBV infection unknowingly. These patients have cleared HBsAg and are HBsAg negative but anti-Hepatitis B core antibody (anti-HBc) positive. The risk of HBV reactivation in lymphoma patients with past HBV infection undergoing immunochemotherapy has not been previously studied. We accrued 430 consecutive patients from our prospectively maintained data-base and an ongoing prospective epidemiological study from May 2006 to May 2008. All patients were tested for HBsAg. Prior to May 2006, anti-HBc test was performed at the discretion of the treating physician. After May 2006, anti-HBc test was performed for all patients. Stored sera from consented patients were genotyped for HBV DNA. Hepatitis attributable to HBV reactivation was defined as an increase in HBV DNA levels of tenfold, or an absolute increase greater than 105 copies/ml in the HBV DNA level. At presentation, characteristics of lymphomas and baseline liver function test in patients with HBV infection were similar to those with past HBV infection. Among the 430 patients tested for HBsAg, the prevalence of HBV infection is 7.2% (31/430). Overall, 233 patients had both tests performed and 80 (34%) were anti-HBc positive only. Among the 80 patients with past HBV infection, 67 patients received systemic treatment. Of these 67 patients, 58 had a HBV DNA test, which was positive in three (5.2%). 46 patients with past HBV infection were treated with rituximab immunochemotherapy. Of these 46 patients, one reactivated and died (1/46; 4.3%); this patient did not receive anti-viral prophylaxis and had undetectable HBV DNA at time of lymphoma diagnosis. Of the 26 patients with HBV infection receiving systemic treatment, 11 (42.3%) reactivated (p

Description: Introduction: Histone deacetylase (HDAC) inhibitors, by blocking HDAC enzymes, can regulate acetylation states of histones and other non-histone proteins. Hyperacetylation of histones in cells can cause transcriptional activation of tumor suppressor genes, as well as genes involved in cell cycle control, cell division, and apoptosis, resulting in antitumor activity. Currently, 3 HDAC inhibitors (HDACi), vorinostat, romidepsin, and belinostat, are approved for the treatment of relapsed or refractory peripheral or cutaneous T-cell lymphoma (T-CL). HDACi in development also show promising results in B-cell malignancies and solid tumors. Abexinostat, an orally available hydroxamate-containing HDACi with good tolerability, differs from approved HDACi due to its unique pharmacokinetic profile and oral dosing schedule, twice daily 4 hours apart, which allows for continuous exposure at concentrations required for efficient tumor cell killing (Mitsiades, et al. Blood. 2003; unpublished data). Abexinostat may, therefore, offer an active and potentially less-toxic treatment option for cancer with a wider therapeutic index than other HDACi in development. Abexinostat showed manageable toxicity and durable responses, including some complete responses (CR), particularly in patients (pts) with relapsed/refractory follicular lymphoma (FL) (Evens ICML 2013; Morschhauser, Invest New Drugs, 2015). Methods: In this phase 2 trial, pts aged ≥18 years with relapsed/refractory NHL or CLL received oral abexinostat at 80 mg BID for 14 days of a 21-day cycle and continued until progressive disease or unacceptable toxicity. The 80 mg BID dose, which corresponds to the recommended phase 2 dose of 45 mg/m2 BID, was identified in phase 1 of the study (Morschhauser, Invest New Drugs, 2015). The primary endpoint was overall response rate (ORR); secondary endpoints included overall survival, progression-free survival, time to tumor progression, duration of response, disease-free survival, and time to treatment failure. Results: A total of 100 pts (median age, 66.5 years; 52% 〉65 years; 55% male) were enrolled between Oct 2011 and Jul 2014, including 16 with CLL, 17 with diffuse large B-cell lymphoma (DLBCL), 18 with FL, 16 with mantle cell lymphoma (MCL), 18 with T-CL, and 15 with marginal zone lymphoma (MZL) or other NHL subtypes. The median number of prior regimens across all lymphoma subtypes was 3 (range, 1-11) with a median of 4.5 prior regimens (range, 1-11) for FL pts. All pts received at least one dose of study drug; 55% discontinued due to progressive disease and 25% due to adverse events. Seven pts remain on treatment. Among the 87 pts evaluable for efficacy, ORR was 28% (CR, 5%). Responses by histology are shown in the table. Highest responses were observed in FL, T-CL, and DLBCL with ORRs of 56%, 40%, and 31% and median durations of response of 26.0 weeks (range, 0.1-90.4), 32.1 weeks (range, 6.3-51.3), and 8.1 weeks (range, 3.1-59.0), respectively. Grade ≥3 adverse events (AEs) and any serious AEs (SAEs) were reported in 86% and 46% of pts, respectively. The most frequently reported grade ≥3 treatment-emergent AEs were thrombocytopenia (80%), neutropenia (27%), and anemia (22%). The incidence of any-grade diarrhea was 47% (grade ≥3, 3%). The most commonly reported SAEs included thrombocytopenia (15%), anemia (7%), and pneumonia (6%). The most frequent toxicities that led to discontinuation included hematologic events, such as thrombocytopenia and neutropenia. Gastrointestinal toxicities leading to discontinuation were infrequent with 1 episode of vomiting being reported. Conclusions: Abexinostat has a manageable toxicity profile in pts with various NHL subtypes that is similar to other HDACi and comparable to other single-agent therapies currently in development. Promising efficacy was observed with abexinostat, especially in FL, T-CL, and DLBCL, with an ORR ≥30% in these subtypes, consistent with the results of an independent study of abexinostat in lymphomas that used a week-on-week-off schedule (Evens ICML 2013). Further investigation of the safety and efficacy of abexinostat in these indications implementing the less dose-intense interval on a week-on-week-off schedule is planned. Table. Response With Abexinostat by Tumor Type Tumor type ORR, % (CR, %) Overall (N=87) 28% (5%) FL (n=16) 56% (6%) T-CL (n=15) 40% (7%) DLBCL (n=16) 31% (6%) MCL (n=13) 15% (8%) MZL/other (n=13) 15% (0%) CLL (n=14) 0% (0%) Disclosures Ribrag: Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: abexinostat in NHL and CLL. Coiffier:CELLTRION, Inc.: Consultancy, Honoraria. Luan:Pharmacyclics LLC, an AbbVie Company: Employment. Graef:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Genentech Inc./Roche: Other: Advisory boards.

Description: Non-Hodgkin lymphomas (NHL) are a diverse group of blood cancers on the rising trend both worldwide and in Singapore. Better understanding of the pathogenesis and biology of these tumors is urgently required to improve the diagnosis and prognostication. Moreover, the outcome using currently available therapies is poor and there is an immediate need for better treatment options. With an increasing number of genomic studies published, there is a growing demand to bring these discoveries into in vitro and in vivo models. However, the lack of publicly available cell lines and/or animal models for the majority of the NHL subtypes makes these studies difficult to proceed. With that objective, we have started collecting fresh NHL tumor samples and implanting them into NOD scid gamma (NSG) mice to generate patient-derived xenograft (PDX) models. After tumor dissemination, the cells are injected either subcutaneously or intraperitoneally into 6-10 week old mice. Each passage is thoroughly immunohistochemically characterized by a senior hematopathologist and contrasted to the primary patient specimen. Whole exome sequencing (WES) is performed and compared to the primary patient data where possible. A model is considered stable if it has not changed its phenotype for at least 3 passages. A full list of currently available stable models is listed in Table 1. Efforts are also under way to generate stable cell lines based on these models. Strategies tested are spontaneous immortalization, human telomerase reverse transcriptase (TERT), Herpesvirus saimiri (HVS) or Epstein-Barr virus (EBV) transduction and feeder culture. We have recently reported a comprehensive molecular profiling of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL; previously also known as type II enteropathy-associated T-cell lymphoma; Nairismagi et al., Leukemia, 2016). MEITL, a newly recognized WHO entity, is a rare aggressive primary intestinal disease with poor prognosis and a median overall survival of only 7 months. Frequent alterations were identified in the JAK-STAT and G-protein-coupled receptor signaling pathways and a number of epigenetic regulators. Specifically, 60-30% mutation frequencies were found in the STAT5B, JAK3, SETD2, GNAI2 and CREBBP genes. Tumor tissue was collected from a 55 year old Chinese male with relapsed MEITL. The cells have been propagated in the NSG mouse by subcutaneous or intraperitoneal injection up to 6 and 3 passages, respectively. All passages have been histologically characterized and maintained their CD3+ CD8alpha-alpha+ cytotoxic granules+ MATK+ and EBER- phenotype with aberrant expression of both TCR beta and gamma. WES was performed both in the patient primary sample and in passage 1 (P1) PDX sample. There were 83 somatic mutations present in the primary sample, all of which were also identified in the P1 PDX sample. Furthermore, Sanger sequencing was used to validate the presence of all 83 mutations in the remaining passages. There was only 1 mutation lost in the P6 subcutaneous PDX model compared to the primary patient specimen demonstrating the outstanding stability of this model. Using peritoneal fluid cells from P2 we have previously performed ex vivo studies and identified novel treatment modalities for this deadly disease (Nairismagi et al., Leukemia, 2016). Efforts are currently under way to test these regimens also in in vivo setting. In summary, we have generated a number of NHL PDX models with the objective to enhance drug testing. MEITL presents a real life situation where clinical trials are not possible due to the rarity of the disease; however, the availability of PDX models allows for efficient testing of novel therapies and can lead to improved patient outcome. Efforts are under way to further characterize the existing models and tissue collection is ongoing to establish more models. Table 1 List of available stable non-Hodgkin lymphoma models. AITL, angioimmunoblastic T-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus; GC, germinal center; MCL, mantle cell lymphoma; MEITL, monomorphic epitheliotropic intestinal T-cell lymphoma; NK/TCL, natural killer/T-cell lymphoma and PTCL NOS, peripheral T-cell lymphoma not otherwise specified. Table 1. List of available stable non-Hodgkin lymphoma models. AITL, angioimmunoblastic T-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus; GC, germinal center; MCL, mantle cell lymphoma; MEITL, monomorphic epitheliotropic intestinal T-cell lymphoma; NK/TCL, natural killer/T-cell lymphoma and PTCL NOS, peripheral T-cell lymphoma not otherwise specified. Disclosures No relevant conflicts of interest to declare.

Description: Background: Peripheral T-cell lymphomas (PTCL) typically have a dismal outcome when treated with conventional combination chemotherapy. However, the role of HDC with ASCT in patients who attained CR1 following induction chemotherapy remains controversial. Methods: This is a retrospective analysis performed using a prospective database of newly diagnosed PTCL patients treated at our centres from 1993 to 2015. After excluding patients with NK/T cell lymphoma, ALK-positive anaplastic large cell lymphoma, cutaneous T cell lymphoma and composite lymphomas, we identified 164 PTCL patients who were treated with curative intent. Among them, 73 patients achieved CR1 following induction chemotherapy. We compared the characteristics and outcomes of those who went on to receive further ASCT with those who did not receive further consolidation ASCT. Fisher's exact test and Student's T test was used to compare the baseline characteristics such as age, stage, international prognostic index risk group (IPI), prognostic index for PTCL (PIT), lactate dehydrogenase (LDH) and treatments between the two cohorts. Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test. Cox proportional hazard regression analysis was performed to estimate the hazard ratios (HR). Results: Of the 164 patients treated with curative intent, the median OS of patients who achieved CR1 was not reached compared to 1.23 years among those who did not achieve CR1 with a HR of 5.24 (95% CI: 3.11-8.83, p