ALBERT

Description: Key Points DLBCL patients carrying the HLA-B44 supertype have a worse progression-free and overall survival after R-CHOP-like treatment. The HLA-DRB1*01 allele increases the risk of DLBCL development.

Description: In Burkitt lymphoma/leukemia (BL), achievement of complete remission with first-line chemotherapy remains a challenging issue, as most patients who respond remain disease-free, whereas those refractory have few options of being rescued with salvage therapies. The mechanisms underlying BL chemoresistance and how it can be circumvented remain undetermined. We previously reported the frequent inactivation of the proapoptotic BIM gene in B-cell lymphomas. Here we show that BIM epigenetic silencing by concurrent promoter hypermethylation and deacetylation occurs frequently in primary BL samples and BL-derived cell lines. Remarkably, patients with BL with hypermethylated BIM presented lower complete remission rate (24% vs 79%; P = .002) and shorter overall survival (P = .007) than those with BIM-expressing lymphomas, indicating that BIM transcriptional repression may mediate tumor chemoresistance. Accordingly, by combining in vitro and in vivo studies of human BL-xenografts grown in immunodeficient RAG2−/−γc−/− mice and of murine B220+IgM+ B-cell lymphomas generated in Eμ-MYC and Eμ-MYC-BIM+/− transgenes, we demonstrate that lymphoma chemoresistance is dictated by BIM gene dosage and is reversible on BIM reactivation by genetic manipulation or after treatment with histone-deacetylase inhibitors. We suggest that the combination of histone-deacetylase inhibitors and high-dose chemotherapy may overcome chemoresistance, achieve durable remission, and improve survival of patients with BL.

Description: Background: Mantle cell lymphoma (MCL), an aggressive B-cell non-Hodgkin lymphoma, remains incurable with standard therapies. The highly selective, potent Bruton tyrosine kinase (BTK) inhibitor acalabrutinib was approved by the US Food and Drug Administration for the treatment of relapsed/refractory MCL based on clinical data showing a high rate of durable responses and a favorable safety profile (Lancet 2017;391:659-667). Here, we present long-term follow-up in these patients. Methods: Eligible patients were aged ≥18 years, had confirmed MCL, Eastern Cooperative Oncology Group performance status ≤2, and had relapsed and/or were refractory to 1-5 prior therapies. Exclusion criteria included prior BTK or BCL-2 inhibitor exposure and concomitant warfarin or equivalent vitamin K antagonists. Oral acalabrutinib 100 mg twice daily was administered until progressive disease or unacceptable toxicity. Response was assessed by investigators based on the Lugano classification (J Clin Oncol 2014;32:3059-3068).Analysis of minimal residual disease using next-generation sequencing (10-6) is ongoing for a subset of patients with available samples and will be presented upon completion. Results: A total of 124 patients were treated; 80% were men, and median age was 68 years (range, 42-90 years) with 65% aged ≥65 years. At baseline, 93% of patients had Eastern Cooperative Oncology Group performance status ≤1, 8% had bulky lymph nodes ≥10 cm, 72% had extranodal involvement, and 44%/17% had intermediate-/high-risk simplified MCL International Prognostic Index scores. The median number of prior therapies was 2 (range, 1-5); 24% were refractory to the most recent prior treatment. As of February 12, 2018, median time on study was 26.3 months (range, 0.3-35.1 months), and 40% of patients remain on treatment. Median relative dose intensity (ratio of actual to planned cumulative dose during drug exposure period) was 99% (range, 27%-100%). Investigator-assessed overall response rate was 81% (95% CI: 73%, 87%), with 43% (95% CI: 34%, 52%) achieving complete response (Table). Overall response rates were consistent across prespecified subgroups of tumor bulk, presence of refractory disease and number/type of prior treatment. Median duration of response was 25.7 months (95% CI: 17.5 months, not reached). Median progression-free survival (PFS) was 19.5 months (95% CI: 16.5 months, 27.7; Figure). Median overall survival (OS) was not reached; the estimated 24-month OS rate was 72% (95% CI: 64%, 80%). The most frequent adverse events (AEs; ≥20%) were primarily Grade 1/2 and included headache (38%), diarrhea (36%), fatigue (28%), cough (22%) and myalgia (21%). Grade 3/4 AEs (≥5%) included anemia (10%), neutropenia (10%) and pneumonia (6%). There were 13 patients (10%) with 16 cardiac events, including 4 Grade 3/4 events (3%) in 1 patient each (acute coronary syndrome, acute myocardial infarction, cardiorespiratory arrest, coronary artery disease). Four patients had hypertension events (3%); 1 event was Grade 3. The most common bleeding events were contusion (13%) and petechiae (9%); all bleeding events were Grade 1/2 except for 3 Grade 3 events (gastrointestinal hemorrhage, hematuria, hematoma). Grade 3/4 infections occurred in 15% of patients and none were Grade 5; there was one case of cytomegalovirus viremia and one case of pneumocystis jiroveci pneumonia (both Grade 2). Treatment discontinuation was primarily due to progressive disease (n=54; 44%) and AEs (n=10; 8%).Twelve AEs led to discontinuation in 10 patients; all of these AEs occurred in only 1 patient each.There were 43 deaths (35%), most commonly from progressive disease (n=29; 23%) or AEs (n=6; 5%). Deaths due to AEs included bilateral pulmonary embolism, critical aortic stenosis, myelodysplastic syndrome, pneumonia, suicide, and non-small cell lung cancer; none were considered to be related to acalabrutinib. Conclusion: Response to acalabrutinib remained consistent during long-term (〉24-month) follow-up, including high response rates, median PFS of 19.5 months, and a median OS that has not yet been reached, confirming efficacy in patients with relapsed/refractory MCL. The AE profile was largely similar to earlier reporting, with limited additional safety events observed with an additional year of follow-up. Disclosures Wang: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Research Funding; MoreHealth: Consultancy; Acerta Pharma: Honoraria, Research Funding; Kite Pharma: Research Funding; Novartis: Research Funding. Rule:Celltrion: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria; Kite: Membership on an entity's Board of Directors or advisory committees. Zinzani:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau. Casasnovas:MSD: Honoraria; Merck: Honoraria; Takeda: Honoraria; Roche: Honoraria; Gilead Sciences: Research Funding; Roche: Research Funding; Janssen: Consultancy; Gilead Sciences: Consultancy; MSD: Consultancy; merck: Consultancy; takeda: Consultancy; Roche: Consultancy; Gilead Sciences: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Smith:Genentech: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck Sharpe Dohme and Corp: Consultancy, Research Funding; Seattle Genetics: Research Funding; Acerta Pharma BV: Research Funding. Morschhauser:BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Panizo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Roche: Consultancy, Speakers Bureau. Davies:Janssen: Consultancy, Honoraria; Karyopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; ADC Therapeutics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding. Jacobsen:Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Merck: Consultancy. Kater:Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Acerta/AZ: Research Funding; Genentech: Honoraria, Research Funding. Robak:Gilead: Consultancy; Janssen: Consultancy, Honoraria; AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria. Dua:Acerta Pharma: Employment. Frigault:AstraZeneca: Employment, Equity Ownership. Izumi:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acerta Pharma, various patents for ACP-196. Nguyen:Acerta Pharma: Employment. Patel:Acerta Pharma: Employment, Equity Ownership. Yin:Acerta Pharma: Employment. Jurczak:European Medicines Agency: Consultancy; Astra Zeneca/Acerta: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Janssen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Afimed: Research Funding; Bayer: Research Funding; Beigene: Research Funding; Celgene: Research Funding; Epizyme: Research Funding; Nordic Nanovector: Research Funding; Merck: Research Funding; Morphosys: Research Funding; Pharmacyclics: Research Funding; Servier: Research Funding; Roche: Research Funding; TG Therapeutics: Research Funding.

Description: Abstract 1978 Background: Autologous stem cell transplantation (ASCT) is the treatment of choice for patients with relapsed diffuse large B-cell lymphoma (DLBCL). However, in the rituximab era, patients with persistent disease receiving ASCT have a very poor outcome. Recent studies including radioimmunotherapy as part of the conditioning treatment suggest an improved outcome for this group of patients. Methods: We have evaluated, in a prospective phase 2 study, the safety and efficacy of yttriumm-90-ibritumomab tiuxetan (Zevalin) combined with standard BEAM in refractory DLBCL patients. Thirty patients with induction failure (primary refractory; n=18) or refractory to salvage immunochemotherapy at relapse (n=12) were included in the study. Patients' response was evaluated with PET-CT according to 2007 Cheson's revised response criteria. Results: Patients with a median age of 53 years (range, 25–67) received Zevalin at a fixed dose of 0.4mCi/kg (maximum dose 32 mCi) 14 days prior to standard BEAM. Histology included de novo DLBCL (22) and transformed DLBCL (8). Patients received a median of 3 (range, 2–6) prior therapies before ASCT. All patients had active disease at the time of ASCT, with 25 patients considered to be chemorefractory to the last treatment. Median CD34+ cell dose infused was 3.9 × 106/kg (range, 2–18.3). All patients engrafted. Median time to neutrophil recovery (〉500/μl) was 11 days (9–21), and to platelet recovery (〉20.000/μl) was 13 days (11–35). Overall response at day +100 was 70% (95% CI, 53.6–86.4) with 60% (95% CI, 42.5–77.5) complete responses. Eleven patients have died. One due to a cerebral hemorrhage before ASCT and 1 due to sepsis immediately post-transplant. Seven patients died of disease progression, and 2 patients died due to late complications: bacterial sepsis and secondary acute leukemia. One patient developed a myelodysplastic syndrome (refractory anemia with excess blasts-2) 33 months after TASP, while being in CR of its lymphoma. After a median follow-up of 22.7 months for alive patients (range, 12.2–39.0), 2-year overall and progression-free survival is 65% (95% CI, 47.8–82.8) and 63% (95% CI, 45.5–80.4), respectively. Conclusion: ASCT with conditioning including Zevalin radioimmunotheray plus BEAM is safe, and results in a very high response rate with promising survival in this very poor prognosis group of refractory DLBCL patients. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Neurologic toxicities have resulted in restrictions in driving/engaging in hazardous occupations and activities for pts receiving marketed T-cell-engaging CD19-directed bispecific antibodies and chimeric antigen receptor T-cell (CAR-T) therapies. Mosunetuzumab (M; RG7828) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). Clinical trials investigating the safety and preliminary efficacy of M currently mandate a driving restriction for enrolled pts while receiving treatment. Data collected to date show that neurologic toxicities associated with M may be milder than for other CD19-directed therapies, which may be due in part to the step-up dosing regimens investigated (Budde et al. ASH 2018; Bartlett et al. ASCO 2019). We initiated a systematic review of neurologic adverse events (NAEs) in pts treated with M to characterize the nature of driving-impacting NAEs and to develop a more patient-centric approach to NAE risk-mitigation that would reduce the burden on pts in M clinical trials. Methods: A systematic review of NAEs observed in the ongoing Phase I/Ib study (GO29781; NCT02500407) of M in relapsed or refractory non-Hodgkin lymphoma (NHL) pts (n=205) was performed (data cutoff: Jan 31, 2019; median safety follow-up: 116 days). NAEs were defined as any AE reported as a Preferred Term (PT) within the System Organ Class (SOC) Nervous System Disorders and SOC Psychiatric Disorders, as recommended by FDA. NAEs were further classified by those that have impact on cognition and consciousness (CC-NAEs), and those that may impair driving (DI-CC-NAEs). In conjunction with an independent neurology consultant, DI-CC-NAEs were adjudicated based on medical judgement and determined a priori based on reported PTs. Univariate and multivariate logistic regression with a 5% significance level was performed to determine the association of demographic and disease characteristics with DI-CC-NAEs occurring in the first 3 cycles of M treatment, as 90% (27/30) of events occurred within this period. Results: NAEs were observed in 49% (100/205) of enrolled pts and were mostly grade (Gr) 1-2 (Gr 1, 69/205 [34%]; Gr 2, 24/205 [12%]). The most frequent NAEs were headache (32/205, 16%), dizziness (27/205, 13%), and insomnia (19/205, 9%). Gr ≥3 NAEs were rare (3%, all Gr 3) and occurred as clinical sequelae to non-NAEs (e.g. Gr 3 hepatic encephalopathy secondary to Gr 4 liver function test increased, Gr 3 seizure secondary to electrolyte disturbance, Gr 3 post-herpetic neuralgia). The majority of NAEs occurred early and were transient (median onset from first M infusion: 16 days; median duration: 10 days). Most resolved (11% were unresolved at time of data cut). Frequency of NAEs was not associated with M dose level (Figure) or exposure (Li et al. ASH 2019). At the time of data cut, 30 DI-CC-NAEs (Gr 1, 17/30 [57%]; Gr 2, 9/30 [30%]; Gr 3, 4/30 [13%]) were reported, including PTs of confusional state, delirium, disturbance in attention, encephalopathy, hallucination, memory impairment, and seizure. These events were observed in 24 (12%) pts, and were mostly Gr 1-2 (26/30, 87%). Three pts experienced four Gr 3 DI-CC-NAEs (confusional state, hepatic encephalopathy, encephalopathy, seizure). The majority of DI-CC-NAEs (67%) occurred in pts with aggressive NHL (aNHL) and who had elevated C-reactive protein (CRP) at baseline based on the local institutional upper limit of normal (sensitivity: 67%; specificity: 66%; positive predictive value: 23%; negative predictive value: 93%; Table). Other characteristics included in the multivariate analysis were age, sex, and tumor bulk, but these did not demonstrate association with occurrence of DI-CC-NAEs. Conclusion: Based on these analyses, the driving restriction that applied to all pts for the duration of M treatment was amended to a restriction covering the first 2 cycles only in a subset of pts who had aNHL and elevated CRP at baseline. This novel approach of individualized risk mitigation for driving based on in-depth assessment of NAEs allows for a more targeted and patient-centric mitigation strategy to optimize the protection of pts at risk, and is useful during clinical development when the safety profile is being characterized. As further data are accumulated, the multivariate analysis can be updated to further refine the pts at risk for DI-CC-NAE. Disclosures Diefenbach: Bristol-Myers Squibb: Consultancy, Research Funding; Denovo: Research Funding; Genentech: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Trillium: Research Funding. Assouline:Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau. Bosch:Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cheah:F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Gilead: Honoraria; Janssen: Honoraria; Acerta: Honoraria; Loxo: Honoraria. Kim:J + J: Research Funding; Novartis: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. Matasar:Merck: Consultancy, Equity Ownership; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Juno Therapeutics: Consultancy. Panizo:Janssen: Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Speakers Bureau. Yoon:F. Hoffmann-La Roche Ltd: Research Funding. Bender:Genentech, Inc.: Employment, Equity Ownership. Hernandez:Genentech, Inc.: Employment, Equity Ownership. Li:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. McCall:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment, Equity Ownership. O'Hear:Genentech, Inc.: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Wei:Genentech, Inc./F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Yin:Genentech, Inc: Employment, Equity Ownership. Yousefi:F. Hoffmann-La Roche Ltd: Employment. Kwan:Genentech, Inc: Employment, Equity Ownership. Nastoupil:Celgene: Honoraria, Research Funding; Bayer: Honoraria; Spectrum: Honoraria; Janssen: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Gilead: Honoraria. OffLabel Disclosure: Mosunetuzumab (RG7828) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). Mosunetuzumab redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.

Description: Background: CC-122, a first in class PPM™ pleiotropic pathway modifier, has anti-tumor activity against B cell lymphomas. The molecular target of CC-122 is cereblon (CRBN) and CC-122 promotes ubiquitination of lymphoid transcription factor Aiolos in a CRBN-dependent manner, leading to its degradation in Diffuse Large B Cell Lymphoma (DLBCL) tumor tissue and immune cells. CC-122 also depletes Ikaros, which is expressed in immature stages of myeloid differentiation and regulates early neutrophil differentiation (Blood 101:2219 2003). Following establishment of CC-122 3mg daily (QD) as the maximum tolerated dose (MTD) on a continuous schedule (Blood 122:2905 2013), subjects with advanced lymphoma, myeloma, and select solid tumors were enrolled in parallel expansion. In DLBCL subjects, CC-122 treatment demonstrated promising clinical efficacy, however, dose reductions due to neutropenia were frequent with the QD schedule (Blood 124:3500 2014). Therefore, a second cohort of DLBCL subjects was enrolled to evaluate the tolerability and clinical activity of intermittent schedules. Methods: Subjects with relapsed/refractory DLBCL were enrolled in parallel dose escalation of CC-122 given orally at 4mg or 5mg on two intermittent schedules. CC-122 given 21/28 days was tested based on lenalidomide experience. In order to model a second schedule, human bone marrow CD34+ cells were cultured for two weeks in SCF, Flt3L and G-CSF for expansion towards granulocytic lineage followed by 6 days with media plus G-CSF for neutrophil maturation.CC-122 0.5 uM was added continuously or on a 5 out of 7 day (5/7d) schedule. Myeloid maturation stages were measured 14 days later by CD34, CD33 and CD11b flow cytometry. Continuous exposure to CC-122 led to reversible myeloid maturation arrest and 90% decreased mature neutrophils compared to vehicle, whereas, CC-122 exposure for 5/7d resulted in only 50% decreased mature neutrophils. Based on this rationale, CC-122 given 5/7d was selected as the second intermittent schedule tested in DLBCL. Results: As of June 25, 2015, 22 subjects with relapsed/refractory DLBCL were enrolled in the 2nd cohort; all were evaluable for safety, 16 were efficacy evaluable (EE) as of the cutoff date. The median age was 60 years and 54% were male. The median time since diagnosis was 14 months and all subjects were ECOG 0-1. For subjects treated with CC-122 4mg 21/28 days (N=3), there were no dose limiting toxicities (DLTs) in cycle 1, however, all subjects required dose reduction due to neutropenia and therefore this dose level was considered a non-tolerated dose (NTD). For subjects treated with CC-122 on a 5/7 days schedule, the NTD was at 5mg due to 2 DLTs in 2 of 5 subjects (grade 3 febrile neutropenia and grade 3 pneumonitis). CC-122 4mg was the MTD on 5/7d and was selected for ongoing expansion in up to 50 subjects (N=14 as of cutoff date). There were no DLTs in 12 DLT-evaluable subjects. Median relative dose intensity achieved for 4mg 5/7d vs 3mg QD was 99% vs 79%. The most common (≥ 10%) related adverse events (AEs) were neutropenia (36%), constipation (29%), asthenia (21%) and grade 3/4 related AEs were neutropenia (36%) and lipase elevation (14%). In addition, drug-related serious AEs included pneumonia, neck pain, and respiratory failure. AEs were an uncommon cause of discontinuation (7%, n=14). Response rates for the EE DLBCL subjects treated at 5mg 5/7d (N=3), 4mg 5/7d (N=10), and 3mg QD (N=22) was 67% (2 PR), 30% (1CR, 2 PR) and 23% (1CR, 4PR), respectively. Aiolos protein levels in peripheral T cells was measured by flow cytometry pre (baseline) and 5 hours post dosing on C1D1, C1D10 and C1D22. The median % change Aiolos levels at each of these visits were -47, -28 and -52%, respectively, indicating that Aiolos degradation occurs throughout the cycle. In addition, the median increase from baseline in cytotoxic memory T cells and helper memory T cells at cycle 1 day 22 in peripheral blood samples was 580% and 76%, respectively. Conclusion: In an in vitro myeloid differentiation assay, myeloid maturation arrest by CC-122, possibly due to Ikaros degradation, can be partially bypassed with a 2 day drug holiday. From a clinical standpoint, exploration of intermittent dosing confirmed that 5/7d schedule mitigates neutropenia-related dose reductions and improves CC-122 clinical activity in relapse/refractory DLBCL patients. Of note, the immunomodulatory effects of CC-122 are maintained on the 5/7d schedule. Disclosures Carpio: Celgene: Research Funding. Off Label Use: CC-122 is a first in class PPM(TM) pleiotropic pathway modifier with anti-tumor activity against B cell lymphomas.. Ysebaert:Celgene: Research Funding. Cordoba:Celgene: Research Funding. Santoro:Celgene: Research Funding. López-Martín:Celgene: Research Funding. Sancho:Celgene: Research Funding. Panizo:Celgene: Research Funding; Roche: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau. Gharibo:Celgene: Research Funding. Rasco:Asana BioSciences, LLC: Research Funding; Celgene: Research Funding. Stoppa:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Damian:Celgene: Research Funding. Wei:Celgene: Employment, Equity Ownership. Hagner:Celgene: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership. Carrancio:Celgene: Research Funding. Gandhi:Celgene: Employment, Equity Ownership. Pourdehnad:Celgene: Employment, Equity Ownership. Ribrag:Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; Celgene: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Abstract 2680 Introduction: The Human Leukocyte Antigen (HLA) system plays an important role in antitumor immune response. In the last years, different genome-wide association studies have suggested that 6p21.3 (which include HLA system), is a risk region for lymphoma susceptibility. It has been also reported that specific alleles could modify the prognosis in patients diagnosed of lymphoma, including diffuse large B cell lymphoma (DLBCL), treated without Rituximab. Aim: Our hypothesis is that HLA system could play an essential role in disease control of DLBCL. Here, we have evaluated the effect of HLA Class I (A, B and C) and II (DRB1 and DQB1) alleles in DLBCL incidence and survival. Patients and Methods: A total of 251 patients diagnosed of DLBCL according to the 2008 WHO classification were analyzed (68% of them received Rituximab-based regimens). Control population consisted in 1940 healthy donor individuals analyzed for HLA-A, B, and DRB1 alleles and 200 for HLA-C and HLA-DQB1. Overall survival (OS) was calculated from diagnosis until death for any cause. Event-free survival (EFS) was calculated from diagnosis until event defined as death for any cause, relapse or progression of the disease. Allele frequencies and Hardy-Weinberg equilibrium were estimated using the Arlequin software package, version 3.5.1.2. Comparison of allele and phenotype frequencies between populations was performed with the two-sided Fisher's exact test or χ2 test using GraphPad Prism 4.0 (GraphPad Software, Inc. San Diego, CA, USA) or SPSS software (SPSS 15.0, Inc. Chicago, IL, USA). P-value was adjusted applying a Bonferroni correction (Pc). The effect of biological and clinical variables on OS and EFS at five years was analyzed by univariate (two-sided log-rank test) and multivariate (Cox multivariate analysis) methods. Differences were considered to be statistically significant when P〈 0.05. Results: HLA specificities frequencies in patients and controls (Alcoceba et al, Tissue Antigens 2011) were consistent in all cases with the Hardy-Weinberg equilibrium. Phenotypic frequencies showed significant differences in DLBCL patients compared to control population. DRB1*01 frequency was increased in DLBCL patients (28.9% vs. 19.5%, p=0.0009, Pc=0.0117, OR: 1.68; 95% CI: 1.24–2.26). By contrast, DLBCL patients showed a lower frequency in C*03 allele as compared to the control population (6.4% vs. 18.3, p=0.0005, Pc=0.007, OR: 3.2, 95% CI: 1.62–6.3). As far as the outcome of patients was concerned, the presence of B*18 and/or B*44 was significantly associated with a worse EFS (32% vs. 60%, p

Description: Background:Ibrutinib, a potent inhibitor of Bruton's tyrosine kinase, is indicated for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (including 17p deletion), and Waldenström's macroglobulinemia. Because ibrutinib is extensively cleared by cytochrome P450 (CYP) 3A4, concomitant treatment with CYP3A inhibitors has been shown to increase ibrutinib exposure in healthy adults. However, sparse PK data from uncontrolled phase 2 studies with moderate CYP3A inhibitors showed a lower magnitude of drug-drug interactions (DDI) than observed in studies with healthy subjects or in silico simulations under nonfasted conditions (data on file). This phase 1 study was conducted to evaluate potential DDIs between ibrutinib and CYP3A inhibitors in patients with B-cell malignancies and to confirm recommended dose adjustments. Methods: This was an open-label, multicenter, DDI study of ibrutinib with erythromycin (moderate CYP3A inhibitor) and voriconazole (strong CYP3A inhibitor) in patients (≥ 18 years) with relapsed/refractory B-cell malignancy. During the first treatment cycle, patients received an oral dose of 560 mg ibrutinib on days 1-4 (steady-state) and days 14-18. On days 5-13 and 19-27, the dose was reduced to 140 mg ibrutinib and combined with erythromycin (500 mg tid on days 5-11) and then with voriconazole (200 mg bid on days 19-25). On PK sampling days (days 4 [alone], 11 [with erythromycin], and 25 [with voriconazole]), ibrutinib was administered 30 min before a standard breakfast. On these PK sampling days, the morning doses of voriconazole and erythromycin were administered 1 hr prior to ibrutinib and together with ibrutinib, respectively. PK samples were taken pre- and up to 24 hr postdose; key PK parameters were summarized for ibrutinib, PCI-45227 (ibrutinib metabolite), erythromycin, and voriconazole. After completion of the DDI assessment during cycle 1, patients continued treatment with ibrutinib monotherapy at therapeutic doses. Safety was evaluated throughout the study. Results:All patients (N = 26) completed the PK assessments in cycle 1; 54% were men, and the median age was 65 years. The geometric mean ratio (GMR) for dose-normalized maximum concentration (Cmax) and area under the plasma concentration-time curve from time 0 to 24 hr (AUC24h) for ibrutinib was 3.35 and 2.99, respectively, when given in combination with erythromycin (Table). When ibrutinib was coadministered with voriconazole, the GMR for Cmax and AUC24h was 6.71 and 5.74, respectively (Table). Four out of 26 patients showed either no interaction between ibrutinib and erythromycin or a lower ibrutinib exposure (AUC ratios 0.27-0.99). Three of these 4 patients also displayed minimal interaction with voriconazole (AUC ratios 1.08-1.96); baseline ibrutinib AUCs for the 3 patients were at the high end of the range, indicating lower CYP3A abundance and thus less impact from CYP inhibition. Physiologically-based PK modeling under fed conditions predicted a 5.5- and 7.1-fold increase in the GMR for ibrutinib Cmax and AUC, respectively, when dosed with erythromycin and an increase of 6.3- and 7.6-fold, respectively, when dosed with voriconazole. The simulated interaction factor for voriconazole is contained in the 90% CI of the observed GMRs (borderline for AUC), whereas the model over-predicted Cmax and AUC by ~50% and ~130%, respectively. Treatment-emergent adverse events (TEAEs) were reported in 22/26 patients (85%); The most common TEAEs (all causality, ≥ 10% of patients) were diarrhea (27%); neutropenia (23%); abdominal pain, fatigue, pyrexia, and thrombocytopenia (15% each); anemia, dry mouth, cough, dyspnea, and hypertension (12% each). Drug-related TEAEs ≥ grade 3 were neutropenia (15.4%); hypertension (7.7%); and diarrhea, thrombocytopenia, herpes zoster, cough, dyspnea, atrial fibrillation, and cardiac failure (3.8% each). Conclusions:PK data indicate that 140 mg ibrutinib, when combined with a moderate or strong CYP3A inhibitor, achieved exposures generally consistent with those after a 560 mg dose given alone. Coadministration of 140 mg ibrutinib with erythromycin or voriconazole demonstrated an acceptable safety profile, and the adverse event profile was consistent with the ibrutinib safety profile at therapeutic doses. These findings support the 140 mg/day ibrutinib dose when given in combination with erythromycin or voriconazole. Disclosures de Jong: Janssen: Employment. Hellemans:Janssen: Employment, Equity Ownership. De Wilde:Janssen: Employment. Patricia:Janssen: Employment. Masterson:Janssen: Employment. Osmanov:Seattle Genetics: Research Funding. Cordoba:Janssen: Research Funding, Speakers Bureau. Panizo:Roche Pharmaceuticals: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. de Zwart:Janssen: Employment. Snoeys:Janssen: Employment, Equity Ownership. Chauhan:Janssen: Consultancy. Jiao:Janssen: Employment. Sukbuntherng:Pharmacyclics, LLC: Employment, Equity Ownership; Global Blood Therapeutics: Equity Ownership. Ouellet:Janssen: Employment.

Description: Background: Rituximab, administered intravenously (IV), is the mainstay of treatment for CD20+ B-cell non-Hodgkin lymphoma (NHL). A subcutaneous (SC) formulation has been approved in Europe and other countries based on the SABRINA study, which showed non-inferior pharmacokinetics and comparable safety and efficacy for rituximab SC compared with IV in treatment-naïve patients with follicular lymphoma (FL) (Davies A, et al. Lancet Oncol 2014;15:343-52). Furthermore, rituximab SC reduces healthcare resource burden (De Cock et al. PLoS One 2016;11:eD157957) and improves patient satisfaction and convenience compared with IV (Rummel et al. Blood 2015;18:A469). MabRella is a global umbrella study comprising three local open-label, single-arm, Phase 3b studies evaluating the safety of first-line (1L) rituximab SC treatment in patients with FL or diffuse large B-cell lymphoma (DLBCL) with a focus on administration-related reactions (ARRs). The studies share a core protocol, study endpoints, and timepoints, but have flexibility for modifications at local level. Data from participating countries is pooled for pre-defined global analyses. Methods: Patients were aged 18-80 years with grade 1-3a FL or DLBCL, and ECOG PS of ≤3. All patients had received ≥1 full dose of rituximab IV as 1L induction or maintenance prior to study entry, and were eligible to receive at least 4 additional cycles of induction or 6 additional cycles of maintenance. Patients with FL or DLBCL receiving induction therapy were treated with rituximab SC 1400mg every cycle (14, 21, or 28 days) for 4-7 cycles, in combination with standard chemotherapy. FL patients undergoing maintenance treatment received single-agent rituximab SC 1400mg every 2 months for 6-12 cycles. The primary endpoint was incidence of ARRs following multiple doses of rituximab SC; ARRs were defined as all adverse events (AEs) occurring within 24 hours of rituximab administration and considered related to the study drug by the investigator. Secondary safety endpoints included grade ≥3 AEs and serious AEs (SAEs). The safety analysis included all patients who received ≥1 dose of study treatment. Safety data were not collected for rituximab IV, as patients entered the trial after they had switched to SC. Data are presented from a planned interim analysis of safety (cut-off March 31, 2016). Results: At the data cut-off, the safety population comprised 336 patients: 157 from Italy; 139 from Spain; and 40 from North Africa (Tunisia and Algeria). The median (range) age was 59 (19-80) years and 50% patients were male; 205 patients had FL and 131 had DLBCL. With respect to patients with FL, 84 completed ≥1 cycle of rituximab SC induction (37 completed all 7 cycles) and 190 completed ≥1 cycle of maintenance (169 completed 6 cycles and 26 completed all 12 cycles). Among DLBCL patients, 37 completed all 7 cycles of induction. Overall, 282 patients (84%) experienced an AE during treatment (Table 1). ARRs were observed in 75 patients (22%), the most common of which (≥2% incidence) were erythema (12%) and injection-site erythema (4%). Other AEs reported in ≥10% of patients were neutropenia, asthenia, erythema, pyrexia, and diarrhea (Table 1). Grade ≥3 AEs occurring in ≥5% of patients were neutropenia (24%) and febrile neutropenia (6%). Grade ≥3 ARRs were observed in 4 patients (1%). SAEs were reported in 29% of patients (8% drug-related). Of 11 deaths attributed to AEs, 2 were considered to be related to treatment (Klebsiella infection and sepsis). The safety profile of rituximab SC was generally comparable between FL and DLBCL patients, although neutropenia (any grade and grade ≥3) was more prevalent in DLBCL patients, while erythema (any grade) was more common in FL patients (Table 1). The profile of AEs was similar during induction and maintenance, but the intensity and seriousness of events was lower during maintenance (Table 2). Geographic location (Spain, Italy, North Africa) of study sites did not appear to impact on the safety profile of rituximab SC. Conclusions: In line with previous reports (Davies et al. 2014), rituximab SC is well tolerated during the 1L treatment of patients with NHL. The safety profile of 1L rituximab SC is similar to reports for IV administration, with the exception of an expected increase in ARRs, the majority of which are mild or moderate in intensity, and resolve spontaneously. Disclosures Panizo: Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche Pharmaceuticals: Speakers Bureau. Rigoroso Mendoza:F Hoffmann La Roche Ltd: Employment. Truman:Aurinia Pharmaceuticals: Consultancy; F Hoffmann La Roche Ltd: Consultancy, Equity Ownership. Smith:F. Hoffmann La Roche Ltd.: Employment.

Description: Introduction and Objective: Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL-NT) is associated with Epstein-Barr virus (EBV) and is much more common in Asia and Latin America than in western countries. Data on disease presentation and outcome from European series are very limited. The objective of the study is to analyze the clinical characteristics at diagnosis, treatment received and outcome of a series of patients from Spain. Patients and Methods: Eigthy-seven patients with ENKTL-NT diagnosed from 2000 to 2017 were identified in 24 academic centers in Spain. Clinical data were collected retrospectively. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Variables included in the univariate analysis were: race, gender, age, previous sinusitis, nasal localization, Ann Arbor stage, ECOG performance status (PS), B symptoms, LDH, beta2-microglobulin, albumin and C-reactive protein. Multivariate analyses were performed by Cox proportional hazard regression model. Results: Clinical characteristics at diagnosis are shown in Table 1. Seventy-seven patients received active treatment, 31 (40%) with chemotherapy (CT) alone, 39 (51%) with CT and radiotherapy (RT), 7 (9%) with RT alone (median dose 50 Gy). First line therapies were: CHOP/CHOP-like in 30 (42%) patients, high-dose L-Asparaginase-containing regimens in 27 (38%), and other regimens in 14 (20%); 12 patients proceeded to stem-cell transplant in first line (10 auto / 2 allo). Response rate was evaluable in 70 patients (by PET/TC in 55%): CR 35 (50%), PR 9 (13%), SD/progression 26 (37%). Median number of CT lines was 2 (1-6). With a median follow-up of 38 months, 3 yr OS was 38% (95% CI 27-49), and 3 yr PFS 25% (95% CI 14-35). Causes of death were: progression 35 (67%), toxicity 12 (23%), second neoplasms 5 (10%). The variables at diagnosis significantly associated with poor OS were: age ≥ 60 yr, extranasal disease, Ann Arbor III-IV, ECOG PS 2-4, increased LDH, and decreased albumin. In the multivariate analysis including all the previous variables, ECOG 2-4 PS (HR 3.3, 95% CI 1.4-7.0) and low albumin (HR 3.6, 95% CI 1.4-9.3) maintained the negative influence in OS. Patients treated with regimens that included high dose L-Asparaginase had 3 yr OS of 61% (95%CI 40-82), compared with patients treated with CHOP/CHOP-like 3 yr OS of 19% (95%CI 5-32) (p=0.009). These differences were statistically significant both in patients with nasal involvement (3 yr OS 82% with L-Asparaginase vs 21% with CHOP, p=0.01) or with localized disease (3 yr OS 71% with L-Asparaginase vs 24% with CHOP, p=0.03). Differences were not statistically significant in patients with extranasal involvement (3 yr OS 48% with L-Asparaginase vs 14% with RCHOP, p=0.2), or advance disease (3 yr OS 48% with L-Asparaginase vs 14% with CHOP, p=0.2), probably because the low number of patients. Conclusion: This is the largest series reported of Caucasian patients with ENKTL-NT. Patients are young at diagnosis and one fourth had a previous history of chronic sinusitis. This population has a poor outcome, being progression the main cause of death. Poor clinical condition at diagnosis (high ECOG PS and low albumin level) is the main factor related with poor survival. Therapies with high dose L-Asparaginase improve the survival in this western population compared with the classical CHOP regimen. Disclosures González-Barca: Roche: Speakers Bureau; Celtrion: Consultancy; Gilead: Consultancy; janssen: Consultancy, Speakers Bureau. Martín:Celgene: Consultancy, Honoraria, Other: Travel expenses; Roche: Consultancy, Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Servier: Honoraria, Other: Travel expenses. Panizo:BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta Pharma: Research Funding; Roche: Consultancy, Speakers Bureau. Sanchez Blanco:Gilead: Honoraria; Roche: Honoraria; Janssen: Honoraria. Marin Niebla:Roche: Consultancy, Other: Medical education of Staff, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Medical education of Staff, Speakers Bureau; Celgene: Other: Medical education of Staff, Speakers Bureau; Amgen: Other: Medical education of Staff, Speakers Bureau. Queizan:Janssen: Consultancy. Lopez:Roche: Research Funding.