Search

Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Mantle cell lymphoma (MCL) accounts for approximately 6% of all newly diagnosed NHL cases. Radiation therapy with or without systemic therapy is a reasonable approach for the few patients who present with early-stage disease. Rituximab-based chemoimmunotherapy followed by high-dose therapy and autologous stem cell rescue (HDT/ASCR) is recommended for patients presenting with advanced-stage disease. Induction therapy followed by rituximab maintenance may provide extended disease control for those who are not candidates for HDT/ASCR. Ibrutinib, a Bruton tyrosine kinase inhibitor, was recently approved for the treatment of relapsed or refractory disease. This manuscript discusses the recommendations outlined in the NCCN Guidelines for NHL regarding the diagnosis and management of patients with MCL.

This phase 2, open-label, multicenter study evaluated the efficacy and safety of brentuximab vedotin, a CD30-directed antibody-drug conjugate, in relapsed/refractory CD30(+) non-Hodgkin lymphomas. The primary end point was objective response rate (ORR). Key secondary end points included safety, correlation of CD30 expression with response, response duration, and progression-free survival (PFS). Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks until progression or unacceptable toxicity. This planned subset analysis included patients with peripheral T-cell lymphomas (PTCLs; n = 35), specifically angioimmunoblastic T-cell lymphoma (AITL; n = 13) and PTCL not otherwise specified (n = 22). Median age was 64 years; 63% were refractory to most recent therapy. Of 34 evaluable patients, ORR was 41% (8 complete remissions [CRs], 6 partial remissions [PRs]), and ORR was 54% in AITL (5 CRs, 2 PRs) with median PFS of 6.7 months thus far. No correlation between CD30 expression per central review and response was observed. Safety data were consistent with the known profile of brentuximab vedotin, and included at least grade 3 events of neutropenia (14%), peripheral sensory neuropathy, and hyperkalemia (9% each). In summary, brentuximab vedotin showed antitumor activity in patients with relapsed PTCL particularly AITL. This trial was registered at www.clinicaltrials.gov as #NCT01421667.

BACKGROUND The objective of this study was to compare the outcomes of patients with classical Hodgkin lymphoma (cHL) who achieved complete remission with frontline therapy and then underwent either clinical surveillance or routine surveillance imaging. METHODS In total, 241 patients who were newly diagnosed with cHL between January 2000 and December 2010 at 3 participating tertiary care centers and achieved complete remission after first-line therapy were retrospectively analyzed. Of these, there were 174 patients in the routine surveillance imaging group and 67 patients in the clinical surveillance group, based on the intended mode of surveillance. In the routine surveillance imaging group, the intended plan of surveillance included computed tomography and/or positron emission tomography scans; whereas, in the clinical surveillance group, the intended plan of surveillance was clinical examination and laboratory studies, and scans were obtained only to evaluate concerning signs or symptoms. Baseline patient characteristics, prognostic features, treatment records, and outcomes were collected. The primary objective was to compare overall survival for patients in both groups. For secondary objectives, we compared the success of second-line therapy and estimated the costs of imaging for each group. RESULTS After 5 years of follow-up, the overall survival rate was 97% (95% confidence interval, 92%-99%) in the routine surveillance imaging group and 96% (95% confidence interval, 87%-99%) in the clinical surveillance group (P = .41). There were few relapses in each group, and all patients who relapsed in both groups achieved complete remission with second-line therapy. The charges associated with routine surveillance imaging were significantly higher than those for the clinical surveillance strategy, with no apparent clinical benefit. CONCLUSIONS Clinical surveillance was not inferior to routine surveillance imaging in patients with cHL who achieved complete remission with frontline therapy. Routine surveillance imaging was associated with significantly increased estimated imaging charges. Cancer 2014;120:2122–2129. © 2014 American Cancer Society.

Summary The multicentre, open-label, two-stage, single-arm, phase 2, PILLAR (PIvotaL Lymphoma triAls of RAD001)-1 study (NCT00702052) assessed the efficacy and safety of everolimus 10 mg/d in adults with confirmed mantle cell lymphoma (MCL) refractory to or intolerant of bortezomib who received ≥1 other antineoplastic agent, either separately or in combination with bortezomib. Primary endpoint was overall response rate (ORR) per investigator review according to the response criteria for malignant lymphoma. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Fifty-eight patients were enrolled from August 2008–January 2011. Five partial responses were observed (ORR 8·6%; 90% confidence interval [CI] 3·5–17·3%); the study did not meet the prespecified objective of ≥8 objective responses among 57 patients. Median PFS and OS were 4·4 months (95% CI 3·5–6·1) and 16·9 months (95% CI 14·4–29·9), respectively. Grade 3/4 non-haematological toxicities occurred in 70·7% of patients. Based on laboratory values, grade 3/4 thrombocytopenia, neutropenia and anaemia occurred in 13·8%, 13·8% and 8·6% of patients, respectively. Everolimus demonstrated modest activity and acceptable tolerability in heavily pretreated patients with MCL refractory to or intolerant of bortezomib. Future studies evaluating everolimus in a less refractory population or in combination with other targeted therapies in refractory MCL are warranted.

Introduction The role of body mass index (BMI) impacting clinical outcome among lymphoma patients is controversial. Two recent studies suggest that increased BMI is associated with significantly improved survival. In this study the association between BMI at study entry and failure-free survival (FFS) and overall survival (OS) was evaluated in three phase III Eastern Cooperative Oncology Group-led trials, among patients with DLBCL (E4494), follicular lymphoma (FL) (E1496) and Hodgkin's lymphoma (HL) (E2496). Patients and Methods 537 patients with DLBCL, 730 patients with HD and 282 patients with FL were included in the analysis. BMI was calculated as weight (kilograms) divided by the square of height (meters), using data at study entry. BMI was analyzed both as continuous and categorical variables (underweight Results Among patients with DLBCL, HL and FL, the median age was 70, 33 and 56; 29%, 29% and 37% were obese and 38%, 27% and 37% were overweight, respectively. Age was significantly different among BMI groups in all three studies. Higher BMI groups tended to have better prognosis at study entry among DLBCL and HL patients. BMI was not associated with clinical outcome, with p-values of 0.89, 0.30 and 0.40 for FFS, and p-values of 0.64, 0.67 and 0.09 for OS, for patients with DLBCL, HL and FL, respectively (Figure 1). In multivariate analysis adjusting for other clinical factors, BMI remains an insignificant predictor for all three histologies (Table 1). When limiting to patients treated with rituximab, the association remains non-significant for both FL patients (p=0.92 for PFS, p=0.36 for OS) and DLBCL patients (Figure 2). A subset analysis of males with DLBCL treated on R-CHOP, which matched the study cohort used in a recent report (Carson et al, 2012), revealed no differences in FFS (p=0.48) or OS (p=0.58) (Figure 2). Sensitivity analysis excluding patients with weight loss at study entry resulted in similar findings. Conclusion BMI was not significantly associated with clinical outcomes among patients with DLBCL, HL or FL, in three prospective phase III clinical trials. The findings contradict some previous reports of similar investigations. Further work is required to understand the observed discrepancies. Disclosures: Horning: Genentech: Employment.

Older adults constitute a significant proportion of the cancer population, but are underrepresented in clinical trials. We conducted a retrospective analysis of the safety and efficacy of brentuximab vedotin in adults ≥ 60 years with relapsed CD30-positive lymphomas. Baseline characteristics and safety data were compared for older (median age 66) and younger patients (60 years, median age 32). Exposure to brentuximab vedotin was comparable. Older patients had more preexisting conditions (median 11 vs. 6) and were receiving more concomitant medications (median 7.5 vs. 4). Higher rates of anemia (30% vs. 10%), peripheral sensory neuropathy (60% vs. 46%), fatigue (58% vs. 43%) and adverse events ≥ grade 3 (70% vs. 56%) occurred in older patients. Objective response rates were 56% and 100% in older patients with Hodgkin lymphoma and systemic anaplastic large cell lymphoma, respectively. With appropriate monitoring, brentuximab vedotin may represent a meaningful clinical option for older patients with relapsed CD30-positive lymphomas.

Background: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, is indicated for the treatment of several B-cell malignancies. In the phase 3 HELIOS trial, the addition of ibrutinib to a bendamustine plus rituximab regimen significantly improved patient outcomes, including quality of life, overall response, and progression-free survival, in patients with relapsed/refractory chronic lymphocytic leukemia (CLL; Chanan-Khan, Lancet Oncol 2016; 17:200-211). Here we report the results from analyses exploring the pharmacokinetic (PK) interactions between ibrutinib, bendamustine, and rituximab from the HELIOS trial. Methods: In total, 578 patients were randomized to 420 mg ibrutinib (n = 289) or placebo (n = 289) in combination with 6 cycles of bendamustine and rituximab until disease progression or unacceptable toxicity. The bendamustine intravenous (IV) dose was 70 mg/m2 on days 2-3 of cycle 1 and days 1-2 of cycles 2-6; the rituximab IV dose was 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 in cycles 2-6. Infusion durations were typically 30 min for bendamustine and varied based on tolerability and infusion rates for rituximab. Ibrutinib PK samples were collected from all patients at predose, 1, 2, and 4 hr on day 1 of cycles 1 and 2. In a subset of patients, bendamustine PK samples were collected on day 2 of cycles 1 and 2 at predose, end of infusion, and at 1, 2, and 4 hr. Rituximab PK samples were collected on days 1 (predose) and 15 of cycle 1, day 1 (predose) of cycles 2-6, and on day 1 of cycles 7-9. Dose-normalized bendamustine and rituximab concentration-time data were stratified by treatment to evaluate the effect of ibrutinib on the PK of these drugs. Descriptive statistics were calculated using R (www.R-project.org). Results:PK samples from 178 patients were analyzed; 84 patients from the placebo arm and 94 patients from the ibrutinib arm. The mean dose ± standard deviation (SD) of bendamustine was 68.2 ± 6.3 mg/m2 and 68.9 ± 4.7 mg/m2 in patients receiving ibrutinib and placebo, respectively; the doses of rituximab were 468.1 ± 55.3 mg/m2 and 465.2 ± 65.0 mg/m2, respectively. The dose-normalized plasma concentration-time data of bendamustine (a cytochrome P450 1A2 substrate) from both arms were comparable, indicating that ibrutinib did not alter bendamustine PK. In contrast, systemic exposure of rituximab was higher in patients coadministered with ibrutinib than in patients who received placebo; mean predose serum concentrations were 2- to 3-fold higher in the first three cycles and 1.2- to 1.7-fold higher in subsequent cycles (Figure). The systemic exposure of ibrutinib (n = 280; mean area under the plasma drug concentration-time curve at steady state ± SD = 447.5 ± 298.2 ng•h/mL) in patients receiving the 420 mg dose was comparable to exposures observed in studies of single agent ibrutinib (Marostica, Cancer Chemother Pharmacol 2015; 75:111-121), indicating that bendamustine and rituximab did not impact the PK of ibrutinib. No relevant differences in safety profile were observed between the ibrutinib and placebo arm with the increase in systemic exposure of rituximab. All-grade infusion-related reactions were more frequent with placebo than with ibrutinib (22% vs. 16.7%, respectively), and the incidence of chills was comparable (~11%). Dose interruptions, dose reductions, and discontinuations due to infusion-related reaction were more frequent in the placebo arm (34.8% vs. 27.9%). Additional analyses to model the rituximab PK data using metrics of tumor burden as covariates (e.g., sum of the products of diameters) are currently ongoing and will be presented. Conclusions:Coadministration of ibrutinib with bendamustine and rituximab did not affect the PK of bendamustine or ibrutinib but led to greater dose-normalized systemic exposure of rituximab when compared to patients who received placebo. Rituximab has been reported to be characterized by target-mediated drug disposition (TMDD; Li, J Clin Pharmacol 2012; 52:1918-1926), which may describe many rituximab PK features, such as PK differences in CLL, non-Hodgkin's lymphoma, and rheumatoid arthritis and the dependency of PK behavior on baseline tumor burden. TMDD may account for the rituximab PK findings from this study, with the early decreased tumor burden following ibrutinib resulting in decreased rituximab clearance and hence higher systemic exposure. The clinical significance of this finding needs additional exploration. Disclosures Cramer: Mundipharma: Other: Travel, Accommodations, Expenses; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Astellas: Other: Travel, Accommodations, Expenses; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Other: Travel, Accommodations, Expenses, Research Funding. Demirkan:Amgen: Consultancy. Fraser:Celgene: Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau. Bartlett:Pharmacyclics: Research Funding; Janssen: Research Funding. Dilhuydy:Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria. Loscertales:Roche: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goy:Genentech: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Ganguly:Seattle Genetics: Speakers Bureau; Janssen: Research Funding; Onyx: Speakers Bureau. Poggesi:Janssen: Employment, Equity Ownership. de Jong:Janssen: Employment. Neyens:Janssen: Employment. Salman:Janssen Research & Development: Employment, Equity Ownership, Other: Travel, Accommodations, Expenses. Howes:Janssen Research & Development: Employment. Mahler:Janssen Research & Development: Employment.

Background: The DIAL study is testing the efficacy of dual immunomodulation in patients with advanced aggressive B cell non-Hodgkin lymphoma (B-NHL). Sponsored by the Cancer Therapy Evaluation Program (CTEP), the trial combines the use of a programmed cell death protein 1 (PD-1) inhibitor (nivolumab) with an agonist of the CD27 receptor (varlilumab) in a randomized phase 2 design. CD27, a co-stimulatory receptor, regulates T cell activation in the context of T cell receptor (TCR) engagement through interaction with CD70. T cell exhaustion plays a major role in immune evasion in B-NHL. Varlilumab is an agonistic IgG1 monoclonal antibody that recognizes CD27 leading to prevention or reversal of exhaustion in pre-clinical models. Varlilumab also demonstrates direct anti-tumoral activity in xenograft models of human lymphoma cell lines via antibody-dependent cell-mediated cytotoxicity. Phase 1 data supports the safety and tolerability of single-agent varlilumab in advanced hematologic malignancies (NCT01460134). We hypothesize that CD27 activation synergizes with PD-1 inhibition resulting in a superior anti-lymphoma effect compared to PD-1 blockade alone. The study will also evaluate the effect of these agents on tumor and immune cells using immunohistochemistry (IHC), mass cytometry (CyTOF), multiplex ELISA, imaging mass cytometry (IMC), and whole exome sequencing. Methods: The trial is enrolling patients with advanced aggressive B-NHL. Standard inclusion criteria and prior treatment with at least 2 lines of standard therapy are required. Prior autologous stem cell transplant and/or chimeric antigen receptor (CAR) T cell therapy is allowed. Patients with active CNS disease are excluded. Eligible patients are randomized to treatment with single-agent nivolumab (group 1) or dual immunotherapy with nivolumab and varlilumab. Group 1 is allowed to cross-over at the time of progression. Nivolumab will be administered intravenously (IV) every 2 weeks (240 mg) for 4 months followed by monthly dosing thereafter (480 mg). Varlilumab will be given IV every 4 weeks (3 mg/kg). Response assessment will be done by PET-CT scan every 12 weeks. Primary outcome is overall response rate (ORR) according to the LYRIC criteria. The trial will enroll 48 patients per arm, allowing 80% power to detect at least 20% increase in ORR in the experimental arm (group 2) assuming a 25% ORR in the control arm (group 1). The trial is registered (NCT03038672) and open to participation to members of the Experimental Therapeutics Clinical Trials Network (ETCTN) and Early Drug Development Opportunity Program (EDDOP). Figure Disclosures Tun: BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Mundi-pharma: Research Funding; DTRM Biopharma: Research Funding. Bartlett:Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Millennium: Research Funding; Kite Pharma: Research Funding; Janssen: Research Funding; Immune Design: Research Funding; Affimed: Research Funding; Autolus: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Genentech, Inc.: Research Funding; Gilead: Research Funding. Kline:Merck: Honoraria; Merck: Research Funding. Awan:Janssen: Consultancy; Gilead: Consultancy; Sunesis: Consultancy; Genentech: Consultancy; Abbvie: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Speakers Bureau. Lazaryan:Kadmon: Consultancy. Ansell:Affimed: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding. 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.

Background: In the SCHOLAR-1 study, the largest published retrospective analysis of outcomes in patients with refractory large B-cell lymphoma (LBCL), the objective response rate (ORR) was 26% and complete response (CR) rate was 7% with available salvage therapies in the pre-chimeric antigen receptor (CAR) T cell therapy era (Crump et al. Blood. 2017). These results served as a benchmark for assessing novel therapies. ZUMA-1 (NCT02348216) is the pivotal, multicenter, single-arm Phase 1/2 study evaluating axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 CAR T cell therapy, in patients with refractory LBCL that supported the approval of axi-cel in the United States and Europe. At a median follow-up of 27.1 months, the ORR in ZUMA-1 was 83% and the CR rate was 58% (Locke et al. Lancet Oncol. 2019). Here, we describe comparative analyses of outcomes in ZUMA-1 and SCHOLAR-1 after adjusting for potential imbalances in refractory status between the 2 studies. Methods: Patients in both studies had refractory LBCL defined as stable disease of ≤ 6 months with ≥ 4 cycles of frontline or ≥ 2 cycles of later-line therapy, progressive disease as best response, or relapse ≤ 12 months post autologous stem cell transplant (SCT). To address potential imbalances between studies in refractory status which could affect response and survival outcomes, standardized analyses were performed which equally weighted the proportions of patients by refractory categorization (primary refractory, refractory to ≥ second-line therapy, or relapse after SCT) and presence of post-refractory SCT in each study. Stratified Cochran-Mantel-Haenszel (CMH) tests and Cox models were used to compare the odds ratio for response and hazard ratio (HR) for survival between ZUMA-1 and SCHOLAR-1. P values were descriptive and were not adjusted for multiplicity. Results: Axi-cel was administered to 101 patients in the pivotal Phase 2 portion of ZUMA-1. In the SCHOLAR-1 analysis, 508 patients were evaluable for response and 497 were evaluable for survival. The median follow-up in ZUMA-1 was 2.3 years, and the median follow-up from the overall SCHOLAR-1 study ranged from 7.6 to 14.8 years across different cohorts. In general, ZUMA-1 patients were more heavily pretreated with more patients receiving ≥ 3 lines of therapy as compared with SCHOLAR-1 (69% vs 23%). ZUMA-1 also had more patients who were refractory to second- or later-line therapy compared with SCHOLAR-1 (76% vs 62%). Fewer patients in ZUMA-1, however, were classified as primary refractory vs those in SCHOLAR-1 (26% vs 45%), and a similar proportion of patients between studies relapsed within 1 year of SCT (21% vs 18%). After standardization, the ORR and CR rate in ZUMA-1 vs SCHOLAR-1 were 72% and 54% vs 22% and 7%, respectively. The odds ratios for ORR and CR rate were 7.2-fold and 11.5-fold higher, respectively in ZUMA-1 vs SCHOLAR-1 (CMH test; P < .0001 for both ORR and CR rate). The 2-year survival rate after standardization was 50% (95% CI, 40% - 59%) in ZUMA-1 and 12% (95% CI, 9% - 15%) in SCHOLAR-1, which translated to a 73% reduction in the risk of death in ZUMA-1 relative to SCHOLAR-1 (HR, 0.27; P < .0001). Conclusions: This standardized analysis of the ZUMA-1 and SCHOLAR-1 studies indicates that treatment with axi-cel in this selected population results in 11.5-fold higher odds of CR and a 73% reduction in the risk of death compared with standard salvage regimens in an unselected population. Although limited by retrospective evaluation and cross-study comparisons, these results support the previous literature indicating that axi-cel is a highly effective treatment option for patients with refractory LBCL. Disclosures Neelapu: Pfizer: Consultancy; BMS: Research Funding; Cellectis: Research Funding; Precision Biosciences: Consultancy; Allogene: Consultancy; Acerta: Research Funding; Cell Medica: Consultancy; Celgene: Consultancy, Research Funding; Karus: Research Funding; Novartis: Consultancy; Poseida: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Incyte: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Consultancy, Research Funding. Locke:Novartis: Other: Scientific Advisor; Kite: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy. Bartlett:Genentech, Inc.: Research Funding; Gilead: Research Funding; Autolus: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Affimed: Research Funding; Immune Design: Research Funding; Incyte: Research Funding; Janssen: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Miklos:Celgene-Juno: Consultancy; Novartis: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Janssen: Consultancy; Miltenyi: Consultancy, Research Funding; AlloGene: Consultancy; Kite, A Gilead Company: Consultancy, Research Funding; Pharmacyclics: Consultancy, Patents & Royalties, Research Funding; Becton Dickinson: Consultancy; Precision Bioscience: Consultancy. Jacobson:Pfizer: Research Funding; Celgene: Consultancy, Other: travel support; Humanigen: Consultancy, Other: travel support; Precision Biosciences: Consultancy, Other: travel support; Bayer: Consultancy, Other: travel support; Novartis: Consultancy, Honoraria, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. Siddiqi:BeiGene: Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Kite, A Gilead Company: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Speakers Bureau; Juno Therapeutics: Consultancy, Other: travel support, Research Funding; PCYC: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Crump:Kite/Gilead: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Servier: Consultancy. Kuruvilla:Seattle Genetics: Honoraria; Roche: Honoraria; Novartis: Honoraria; Merck: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria; BMS: Honoraria; Astra Zeneca: Honoraria; Amgen: Honoraria; Seattle Genetics: Consultancy; Roche: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Janssen: Research Funding; Roche: Research Funding. Van Den Neste:Gilead: Other: travel support. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding. Navale:Kite, A Gilead Company: Employment, Equity Ownership; Gilead: Equity Ownership; Allogene: Equity Ownership; Cellectis: Equity Ownership; Bluebird Bio: Equity Ownership; Amgen: Equity Ownership; Organesis: Equity Ownership; Jounce: Equity Ownership; Editas: Equity Ownership; Intellia: Equity Ownership. DePuy:Kite, A Gilead Company: Consultancy, Other: travel support. Kim:Kite, A Gilead Company: Employment.

Background: Histone deacetylase inhibitors (HDACi) and combination chemotherapy are independently used to treat relapsed/refractory (R/R) lymphoma. In vitro studies suggest that the addition of HDACi to platinum-based chemotherapy is synergistic. We conducted a phase I study of the combination of romidepsin, gemcitabine, oxaliplatin and dexamethasone in R/R lymphomas with an expansion cohort in T-cell lymphomas. Here we present the initial efficacy results. The maximum tolerated dose (MTD) determination was presented at ASH 2018. Methods: The safety and tolerability of the combination of romidepsin, gemcitabine, oxaliplatin, and dexamethasone was assessed in this phase I study to determine the MTD with a 9 pt cohort expansion at the MTD. The treatment schedule included: gemcitabine 1000 mg/m2 (day 1), oxaliplatin 100 mg/m2 (day 1); romidepsin (day 2), dexamethasone 20 mg (days 1-4) and pegfilgrastim 6 mg (day 3) of a 21-day cycle. A 3+3 dose escalation was followed with 3 dose levels (DL) of romidepsin: 1) 8 mg/m2, 2) 10 mg/m2, 3) 12 mg/m2. The study originally included romidepsin administration on days 2 and 8 but due to prolonged cytopenias, the day 8 dose was eliminated after the first 6 pts. Dose-limiting toxicity (DLT) was defined in cycle 1 as ≥ gr3 non-hematologic toxicity, any gr4 hematologic toxicity, gr≥ 3 related laboratory changes not responsive to supportive measures, and gr≥2 toxicity resulting in a >14 day treatment delay. Patients could be treated until progression, intolerance, or response adequate to allow autologous or allogeneic transplantation, to a maximum of 8 cycles. Those in complete remission at restaging could limit treatment to 2 cycles beyond complete response. Results: 24 patients with R/R lymphoma (10 PTCL-NOS, 7 AITL, 6 DLBCL, 1 ALCL) were enrolled with all patients evaluable for toxicity and 23 for response (1 AITL pursued supportive care without progression in cycle 1). The median age was 70 years (range 53-81) with 50% men. The median number of prior therapies was 2 (range: 1-4). DL 2 was the MTD. There was 1 DLT in 6 pts treated in DL 1 (pneumonia); 1 DLT in 6 pts treated in DL 2 (bleeding); and 2 DLTs in 3 pts treated in DL 3 (neutropenic fever, grade 4 thrombocytopenia). SAEs included hospitalizations for pneumonia (1), nausea/vomiting (1), fever (1), tumor lysis (1), eosinophilic pneumonia (1), febrile neutropenia (1), post-procedural bleeding (1) and for complications of disease progression (7). Other grade 3-4 treatment related toxicities included thrombocytopenia (79%), neutropenia (21%), anemia (13%), hypophosphatemia (21%), hyperglycemia (8%), hypoglycemia (8%), hypokalemia (8%), diarrhea (4%), peripheral neuropathy (4%), and hypernatremia (4%). The overall response rate (ORR) was 52% (12/23) with complete response (CR) rate 43% (10/23) and the partial response (PR) rate 9% (2/23). At the MTD, ORR was 53% (8/15) and CR 40% (6/15). In patients with TCL, ORR was 58% (10/17) and CR 47% (8/17). CRs were seen in AITL (6/6), PTCL-NOS (2/10) and DLBCL (2/6). PR was seen in PTCL-NOS (2/10). CRs were since in 3 pts refractory to their most recent therapy. The median progression free survival (mPFS) for all pts was 2.8 months (95% CI: 1.3-10.3) and median overall survival (mOS) was 10.4 months (95% CI: 2.8-33.4) and 10.4 months (95% CI: 1.7-N/A) and 3.3 months (95% CI: 1.2-30.4) respectively in TCL. The median duration of response for all patients was 5.8 months (range: 0.7 - 45.1). At the MTD, mPFS and mOS were 7.6 months (95% CI: 1.2-10.3) and 10.4 (95% CI: 1.7-20.8). 4 patients proceeded to transplant after study treatment (2 allogeneic and 2 autologous) and were censored at transplant. The median time to response was 6.0 weeks. Of others, who achieved a complete response: 2 remain in CR at 18.6 (PTCL) and 37.6 (AITL) months. Three others progressed after >6 months: 45.1 mo (DLBCL), 29.5 mo (AITL), 9.0 mo (AITL). Conclusions: MTD was identified as romidepsin 10 mg/m2 in combination with gemcitabine 1000 mg/m2, oxaliplatin 100 mg/m2, and dexamethasone 20 mg. There were no unexpected toxicities. The ORR and CR rates of this regimen are promising, particularly in AITL where 6/6 patients had a CR. Durable responses were seen in AITL, PTCL-NOS and DLBCL. Four patients have had responses for >12 months, 4 proceeded to transplant, and 2 remissions are ongoing. Given the durable complete remissions seen in this difficult to treat patient population, this regimen warrants further study. Figure Disclosures Mehta-Shah: Verastem Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding; Kiowa Hakka Kirin: Consultancy; Celgene: Research Funding; Roche/Genentech: Research Funding; Bristol Myers Squibb: Research Funding. Riedell:Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Bayer: Honoraria, Speakers Bureau; Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bartlett:Pharmacyclics: Research Funding; Bristol-Myers Squibb: Research Funding; Forty Seven: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Janssen: Research Funding; Genenetech: Research Funding; Affimed: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Seattle Genetics: Research Funding; Millenium: Research Funding; Merck: Research Funding. Cashen:Celgene: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau. Kahl:ADC Therapeutics: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Consultancy; Seattle Genetics: Consultancy. Fehniger:Cyto-Sen Therapeutics: Consultancy; Horizon Pharma PLC: Other: Consultancy (Spouse). Carson:Flatiron Health, Inc., which is an independent subsidiary of the Roche Group: Employment, Research Funding; Roche: Equity Ownership.

Background: Patients with follicular lymphoma (FL) have a heterogenous prognosis. Recently a simple score, the PRIMA-PI, was developed based on the PRIMA clinical trial (Bachy et al Blood. 2018). With only two factors (beta-2-microglobulin level > 3 mg/L and bone marrow involvement), this index was at least as discriminatory as FLIPI on the training and validation cohorts. The validity of the PRIMA-PI was confirmed on Czech and German FL cohorts and a patient group from the Nordic Lymphoma Group. However, further validation is needed to confirm the use of PRIMA-PI in place of FLIPI for prognostic assessment. Indeed, in the era of new chemo-free treatments, it seems important to challenge the potency of traditional prognostic factors and scores. Recently, rituximab combined with lenalidomide (R2) was compared to conventional immunochemotherapy (R-chemo) in the phase III RELEVANCE trial. The aim of our study was to validate PRIMA-PI in the RELEVANCE trial cohort and compare its performance with FLIPI (Solal-Celigny et al. Blood. 2004) and FLIPI2 (Federico et al. JCO. 2009). A secondary objective was to evaluate potential differences in terms of prognostic bio-clinical parameters between the R2 and R-chemo arms. Methods: All patients with available data for FLIPI, FLIPI2, and PRIMA-PI from the intention to treat population of the RELEVANCE study were included in the analysis. PFS according to each prognostic score were assessed in the total population and by treatment arms. Data were not mature enough to compare OS distributions. Performance metrics (log-rank p value and Net Reclassification Improvement [NRI]) were calculated for each group to assess concordance and discriminating ability of each score. Results: Median follow-up time for the study was 38 months. Overall, 846 RELEVANCE patients were included in the analysis. Data were available for 845 patients for FLIPI score assessment, 832 for FLIPI2 and 807 for PRIMA-PI. Group repartition according to the FLIPI and the FLIPI2 were largely imbalanced compared with PRIMA-PI. FLIPI classified very few patients in the low risk group (15% LR) while 49% of the patients were at high risk (HR), and 36% were at intermediate risk (IR). Similarly, FLIPI2 risk categories were as follow: 8% LR, 50% IR, and 42% HR. On the contrary, PRIMA-PI divided the study population into three equal groups (33%, 33% and 34%). In the total population, FLIPI and PRIMA-PI were predictive of PFS (p=0.029 and p=0.004, respectively); FLIPI2 showed poor performance (p=0.094). PFS curves based on each score are shown in Figure 1. NRI index indicated that the PRIMA-PI yielded analogous segregation for PFS with FLIPI (NRI 0.16; 95% CI: -0.008, 0.318; Table 1). In the R-chemo arm, both FLIPI and PRIMA-PI could isolate different prognostic groups for PFS, whereas FLIPI2 could not. Conversely, none of the indices were able to significantly discriminate outcomes for patients treated with R2. Interestingly, analysis showed that some usual prognostic factors, especially those likely to reflect tumor burden such as beta-2 microglobulin and LDH, were not predictive for PFS in the R2 arm. In contrast, low albumin ( Conclusion: For patients with FL treated upfront with immunochemotherapy, the PRIMA-PI is a valid scoring system that allows to segregate patients as efficiently as the FLIPI while using only two factors. These results confirm that the PRIMA-PI could substitute for the FLIPI for patients treated with upfront R-chemo. Athough our data have to be interpreted in light of the short median follow-up time, they also suggest that other clinical/biological parameters might be considered and new prognostic indexes established for patients treated with R2. Considering possible mechanisms of action of lenalidomide, prognostic factors related to the underlying patient's immunological status might be more predictive. Disclosures Fowler: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bachy:Roche: Consultancy; Janssen Cilag: Honoraria; Gilead Science: Honoraria; Amgen: Honoraria; Roche: Honoraria; Janssen Cilag: Other: Travel, accomodation, Expense. Feugier:abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau. Tilly:roche: Membership on an entity's Board of Directors or advisory committees; servier: Honoraria; merck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Astra-Zeneca: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding. Palomba:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights ; Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees. Libby:Akcea: Consultancy; Alnylam: Consultancy; Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy. Casasnovas:Merck Sharp and Dohme: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Flinn:TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding. Haioun:Novartis: Honoraria; Janssen: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Servier: Honoraria; Takeda: Honoraria; Miltenyi: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Bartlett:Pharmacyclics: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Celgene: Research Funding; Millenium: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Forty Seven: Research Funding; Bristol-Myers Squibb: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Genenetech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Janssen: Research Funding. Bouabdallah:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Brice:BMS: Honoraria; Millennium Takeda: Research Funding; Takeda France: Consultancy, Honoraria. Ribrag:Nanostring: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Research Funding; ArgenX: Research Funding; Roche: Other: Travel, accommodations, and expenses ; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses ; MSD: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees. Le Gouill:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Martín:Teva: Research Funding; Gilead: Consultancy, Honoraria; Kiowa Kirin: Consultancy; Roche: Consultancy, Honoraria, Other: Travel Expenses; iQone: Consultancy; Servier: Honoraria, Other: Travel Expenses; Janssen: Honoraria, Other: Travel Expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Lopez-Guillermo:Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Research Funding. Larouche:Bayer; Gilead Sciences; Merck; Roche: Research Funding. Ando:Eisai: Research Funding. Maria:Janssen Cilag: Consultancy, Other: Travel support; Gilead Sciences: Other: Travel support, Research Funding; Abbvie: Consultancy, Other: Travel support; Celgene: Consultancy; Roche: Consultancy, Other: Travel support. André:Takeda: 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding; Takeda Millenium: Research Funding; Chugai: Research Funding; Celgene: Other: Travel grants, Research Funding. Sehn:Merck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Janssen-Ortho: Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria. Tobinai:Daiichi Sankyo: Consultancy, Honoraria; Eisai: Honoraria, Research Funding; Verastem: Honoraria; Mundi Pharma: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; Yakult: Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; HUYA Bioscience: Consultancy, Honoraria; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; AbbVie: Research Funding; Solasia: Honoraria; Meiji Seika: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding. Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Delarue:Celgene Corporation: Employment, Equity Ownership. Czuczman:Celgene Corporation: Employment, Equity Ownership. Salles:BMS: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; Epizyme: Consultancy, Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, 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.

Introduction Brentuximab vedotin (BV) targets CD30, a receptor expressed on the Reed-Sternberg cells of classic Hodgkin lymphoma (cHL). Nivolumab (Nivo) restores antitumor immunity by blocking the PD-1 receptor on activated T-cells. In this phase 1/2 study, combination treatment (tx) with BV + Nivo demonstrated durable efficacy in patients (pts) with relapsed/refractory (R/R) cHL (Herrera, Blood 2018; NCT02572167). Biomarkers consistent with innate and adaptive immune activation were observed in the peripheral blood of pts treated with the combination regimen. Herein, we associate biomarkers in the peripheral blood with clinical response, and present follow-up results for pts who received BV + Nivo under staggered and concurrent dosing schedules. Methods Enrolled pts had cHL that relapsed or was refractory to frontline chemotherapy. In Parts 1 and 2 (staggered dosing), pts received up to 4 cycles of BV 1.8 mg/kg and Nivo 3.0 mg/kg given on Days 1 and 8 of Cycle 1, respectively, and together on Day 1 of Cycles 2-4. Pts in Part 3 (concurrent dosing) received the same dose of both agents on Day 1 of all 4 cycles. After investigators assessed response (Cheson 2014, with the incorporation of LYRIC [Cheson 2016] for pts in Part 3), pts could undergo ASCT. Results Demographics and baseline characteristics were similar across all treated pts (N=91) in the staggered and concurrent dosing cohorts; median age 34 years (yrs, range; 18-69), 42% with primary refractory disease, and 30% with relapse within 1 yr of frontline therapy. All 91 pts are off-tx and have been observed through the 100-day safety reporting period. A total of 86 pts (92%) completed all 4 cycles of BV + Nivo. Early tx discontinuations were due to; AE (peripheral neuropathy and increased GGT [1 pt each]), progressive disease (PD), investigator decision, and pt decision (1 pt each). Most common AEs prior to ASCT or additional salvage therapy were nausea (52%) and infusion-related reactions (IRRs, 43%). Excluding IRRs, 14% of pts had immune-related AEs requiring tx with systemic steroids, including rash (8%), pneumonitis (4%), and AST increased, diarrhea, and Guillain-Barre syndrome (1% each). The ORR for all-treated pts was 85%, with 67% complete response (CR). A total of 67 pts (74%) underwent ASCT after tx with BV + Nivo. There were 22 pts who received additional salvage therapy after BV + Nivo (7 PD, 6 partial response, 5 stable disease, and 4 CR at EOT), 17 of whom later underwent ASCT. At a median of 22.6 months (range; 1.2, 41.2) from the start of tx, the estimated 2-yr PFS rate in all treated pts was 78%, and for pts who underwent ASCT after tx with BV + Nivo was 91% (Figure 1). At 2 years, the estimated OS rate for all treated pts was 93%. Staggered and concurrent dosing of BV + Nivo resulted in increased levels of activated and dividing CD4+ T cells, activated and dividing CD8+ T cells (concurrent dosing-only), regulatory T cells (Tregs), and circulating plasmablasts in blood. We did not observe any associations between the magnitude of these changes and clinical response. Pts with CR exhibited trends for higher pre-tx blood levels of CD30+ Tregs and CD30+ Th subsets compared to pts without CR, suggesting BV depletion of these populations may have a role in the clinical mode of action of BV + Nivo. Although pre-tx levels of cytotoxic lymphocytes (CTLs) in blood did not differentiate pts with CR from other pts, pts in the lower quartile of pre-tx CTL levels showed significantly shorter PFS than other pts, suggesting a potential association between CTLs and disease control. Changes in blood cytokine and chemokine levels were observed after BV + Nivo, including increased levels of IL-18, IP-10, I-TAC, and sCD30, and decreased levels of TARC, IL-2Ra, and IL-6. Our analyses support strong correlations between pre-tx cytokine/chemokine levels and clinical benefit including trends linking lower pre-tx levels of IL-18, I-TAC, and IL-2RA to achieving CR and longer PFS. Conclusion BV + Nivo, both staggered and current dosing, showed tolerability and high CR rates with durable remissions among pts with R/R cHL. Analysis of blood biomarkers identified trends potentially linking baseline levels of CD30+ immune cells and the baseline pt inflammatory state with the activity of BV + Nivo. Together, these encouraging results support further investigation of BV + Nivo as initial salvage therapy in pts with R/R cHL. Figure 1 Disclosures Moskowitz: Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Merck: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Incyte: Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding. Advani:Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Forty-Seven: Research Funding; Infinity Pharma: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Merck: Research Funding; Kura: Research Funding; Bayer: Consultancy, 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, Research Funding; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; Cell Medica, Ltd: Consultancy; Stanford University: Employment, Equity Ownership; Seattle Genetics: Consultancy, Research Funding; Millennium: Research Funding; Janssen: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bartlett:Affimed Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Dynavax: Research Funding; Forty-Seven: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medimmune: Research Funding; Merck: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Vose:Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Legend Pharmaceuticals: Honoraria. Ramchandren:Genentech: Research Funding; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Pharmacyclics LLC, an Abbvie company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Sandoz-Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Feldman:Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Trillium: Research Funding; Viracta: Research Funding. LaCasce:BMS: Consultancy; Research to Practice: Speakers Bureau; Humanigen: Consultancy; Seattle Genetics: Consultancy, Research Funding. Christian:Bristol-Myers Squibb: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Research Funding; Janssen: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Triphase: Research Funding; Millennium Pharmaceuticals Inc: Research Funding; Merck: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding. Moskowitz:ADC Therapeutics: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding. Brown:Seattle Genetics, Inc.: Employment, Equity Ownership. Taft:Seattle Genetics, Inc.: Employment, Equity Ownership. Ansari:Seattle Genetics, Inc.: Employment, Equity Ownership. Zak:Seattle Genetics, Inc.: Employment, Equity Ownership. Sacchi:Seattle Genetics, Inc.: Research Funding. Manley:Seattle Genetics: Employment, Equity Ownership. Herrera:Merck: Consultancy, Research Funding; AstraZeneca: Research Funding; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding.

Introduction: A positive interim PET scan (PET2) following 2 cycles of ABVD for Hodgkin lymphoma (HL) is associated with a poor prognosis; several studies in advanced stage demonstrate benefit from escalating therapy. Definition of positivity (Deauville 3 (D3) vs Deauville 4/5 (D4/5)), initial treatment and response adaptive decisions may vary among clinicians. Data examining practice patterns in managing positive PET2 scans is lacking. We report practice patterns and outcomes for patients (pts) with positive PET2 results including D3 and D4/5 outcomes. Methods: Adult pts with classical HL and PET2 findings of D3, D4, and D5 after initial therapy between 01/01/2015 and 07/01/2019 were identified. Pts enrolled in clinical studies were excluded. Retrospective demographic, clinical, and treatment data were obtained and described from 14 academic and community sites across North America (NA). Progression-free survival (PFS) and overall survival (OS) were summarized by Kaplan-Meier curves and compared by log-rank test. Results: 166 PET2 positive pts were identified. Clinical characteristics included 54% (89/166) with advanced stage (III/IV) and 46% (77/166) with early stage (IA-IIB) disease. 152 pts (92%) were treated with initial ABVD like therapy and 14 pts (8%) with an alternate regimen (Table 1). After initial treatment, 163 pts demonstrated PET2 scores of D3 (n=33), D4 (n=99) and D5 (n=31). Of the 130 D4/5 pts; 23% (30/130) underwent therapeutic escalation and 77% (100/130) did not escalate. The complete response rate (CR) at end of treatment (EOT) for all D4/5 patients receiving escalation was 37% (11/30) compared to 45% (45/100) without escalation (p=0.43). (Table 2) The 12 month PFS was 54% (38.2-76.3) versus (vs) 69.2% (60.4-79.2) for escalation and no escalation respectively. Of the 66 D4/5 pts with advanced stage disease; 21% (14/66) had therapeutic escalation and 79% (52/66) did not escalate. CR at EOT was noted in 29% (4/14) with escalation vs 31% (16/52) without escalation (p=0.88). (Table 2) The 12 month PFS was 54.2% (32.9-89.3) vs 57.5% (44.9-73.7) for escalation and no escalation respectively. (Figure 1; Log Rank p=0.38). Of the 64 D4/5 pts with early stage disease; 75% (48/64) did not undergo escalation and 25% (16/64) had escalation. CR at EOT was noted in 44% (7/16) with escalation vs 60% (29/48) without escalation (p=0.26). (Table 2) The 12 month PFS was 54.7% (34.5-86.7) vs 80.8% (70.2-92.9) for escalation and no escalation respectively. Of the 33 D3 pts; 52% (17/33) de-escalated with the remainder (16/33) continuing on initial therapy. No D3 pt underwent escalation. In the 12 D3 pts with early stage disease, 50% (6/12) de-escalated. Of the 21 D3 pts with advanced stage disease; 52% (11/21) had de-escalation and 48% (10/21) did not de-escalate. CR at EOT was noted in 71% (12/17) with de-escalation vs 81% (13/16) without de-escalation (p=0.50). (Table 2) Progression was noted in 29% (5/17) of patients who underwent de-escalation compared to 38% (6/16) without de-escalation. The 12 month PFS was 76.5% (85.8-99.6) vs 72.1% (52.2-99.7) for de-escalation and no de-escalation respectively. Conclusion: This is the first study evaluating clinical practice patterns and outcomes of PET adaptive therapy in NA. In this retrospective study, less than a quarter of advanced stage ABVD-treated D4/5 pts had therapy escalation despite prior studies reporting benefit. Our data suggest that outcomes for advanced stage PET positive pts are suboptimal irrespective of therapeutic escalation. In addition, pts with D3 findings represent a heterogeneous population and demonstrate favorable outcomes compared to D4/5 pts. Longer follow up time and further studies with larger numbers of pts are essential for confirming the reported findings. Disclosures Rutherford: Seattle Genetics: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Heron: Consultancy, Honoraria; Janssen Scientific Affairs: Consultancy, Honoraria; Juno Therapeutics Inc: Consultancy, Honoraria. Bartlett:ADC Therapeutics: Consultancy, Research Funding; Affimed: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; Genenetech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Merck: Research Funding; Millenium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding. Maddocks:Novartis: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; BMS: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Feldman:Takeda: Honoraria, Speakers Bureau; Viracta: Research Funding; Trillium: Research Funding; Roche: Research Funding; Portola Pharma: Research Funding; Pfizer: Research Funding; Kyowa Hakko Kirin: Research Funding; Eisai: Research Funding; Corvus: Research Funding; Roche: Research Funding; Cell Medica: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Magarelli:Tevan Oncology: Speakers Bureau. Advani:Merck: Research Funding; Infinity Pharma: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Millennium: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agensys: Research Funding; Seattle Genetics: Consultancy, Research Funding; Stanford University: Employment, Equity Ownership; Bayer: Consultancy, 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, Research Funding; Celgene: Research Funding; Regeneron: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cell Medica, Ltd: Consultancy; Forty-Seven: Research Funding; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stephens:Karyopharm: Research Funding; Gilead: Research Funding; Acerta: Research Funding. Patel:Sunesis: Consultancy; Genentech: Consultancy, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Tees:Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau. Karmali:Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution; Astrazeneca: Speakers Bureau. Cheson:Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Trillium: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yazdy:Bayer: Honoraria, Speakers Bureau; Octapharma: Consultancy; Genentech: Research Funding; Abbvie: Consultancy. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Ramchandren:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Merck: Research Funding; Sandoz-Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an Abbvie company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction: As previously reported, the combination of brentuximab vedotin with doxorubicin, vinblastine and dacarbazine (A+AVD) demonstrated a statistically significant improvement in modified progression free survival (modified PFS) compared with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in patients with newly diagnosed Stage III or IV classical HL in the phase 3 ECHELON-1 trial (NCT01712490). The benefit of A+AVD in the ITT population observed in the primary analysis was maintained at 3-years median follow-up [3-year PFS: A+AVD: 83.1% (79.9-85.9), ABVD: 76% (72.4-79.2)] and appears independent of interim PET status, disease stage, and prognostic risk factors. Here we present the efficacy and safety results of longer follow-up at a median 43.3 months. Methods: Newly diagnosed patients with Stage III or IV cHL were randomized 1:1 to receive A+AVD (n=664) or ABVD (n=670) intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. The primary endpoint of the study was modified PFS per independent central review. The present follow-up PFS analysis is exploratory and per investigator assessment, with a cutoff date of June 17th, 2019. Patients with ongoing peripheral neuropathy (PN) at end of treatment were followed for resolution or improvement (defined as improved by ≥1 grade from worst grade as of the latest assessment) during the post-treatment follow-up period. Results: With a median follow-up of 43.3 months, the 42-month PFS per investigator for all patients was 82.4% (95% CI, 79.1-85.2) on the A+AVD arm and 76.2% (95% CI, 72.6-79.4) on the ABVD arm [overall HR 0.697 (95% CI, 0.547-0.890)]. Exploratory subgroup analyses of PET2(+) and PET2(-) patients showed a treatment effect in favor of A+AVD. The 42-month PFS in PET2(-) patients was 85.0% (95% CI, 81.6-87.7) for A+AVD and 79.6% (95% CI, 75.9-82.8) for ABVD [overall HR 0.695 (95% CI, 0.526-0.919)]; in PET2(+) patients 42-month PFS was 68.3% (95% CI, 54.5-78.7) for A+AVD and 51.5% (95% CI, 38.2-63.4) for ABVD [overall HR 0.552 (95% CI, 0.308-0.989)]. Upon continued follow-up, 81% (356/442) of patients with PN in the A+AVD arm had either complete resolution (64%, 283/442) or improvement (17%, 73/442) of their PN events compared with 83% (236/286) with either complete resolution (74%, 212/286) or improvement (8%, 24/286) in the ABVD arm. Among patients with ongoing PN after continued follow-up, the majority were Grade 1/2 events, with 89% (141/159; 59% Grade 1) and 95% (70/74; 65% Grade 1) on the A+AVD and ABVD arms, respectively. Overall survival data are not yet mature; per protocol, the final analysis will be performed after 112 deaths have occurred. Additional follow-up at an estimated median of ~4 years, including data from prespecified subgroups, will be presented. Conclusions: With a median follow-up of 43.3 months, A+AVD continues to provide a robust, durable benefit for patients with previously untreated Stage III or IV cHL compared with ABVD; the benefit is evident regardless of patient status at interim PET [PET2(+) or PET2(-)] and without the need for treatment intensification. PN continued to completely resolve or improve in patients on the A+AVD and ABVD arms. Together, these data further support the clinical advantages of A+AVD versus ABVD as treatment for patients with previously untreated Stage III or IV cHL. Disclosures Bartlett: Affimed Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Dynavax: Research Funding; Forty-Seven: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medimmune: Research Funding; Merck: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria. Dlugosz-Danecka:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Macrogenomics: Research Funding; Roche: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Illes:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Janssen: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: 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. Feldman:Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Cell Medica: Research Funding; Amgen: Research Funding; Viracta: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Eisai: Research Funding; Corvus: Research Funding; Roche: Research Funding; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Kyowa Hakko Kirin: Research Funding; Trillium: Research Funding. Smolewski:Roche: Other: Travel Expenses. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding; BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria. Walewski:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Takeda: Honoraria, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Gilead: Other: Travel Expenses; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zinzani:Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: 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; Janssen-Cilag: 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; Sanofi: Consultancy; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Hutchings:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Radford:AstraZeneca: Equity Ownership, Research Funding; Novartis: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; GSK: Equity Ownership. Munoz:AstraZeneca: Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Portola: Research Funding; Incyte: Research Funding. Kim:Roche: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J&J: Research Funding; Mundipharma: Research Funding; Celltrion: Research Funding; Donga: Research Funding. Advani:Cell Medica, Ltd: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Kura: Research Funding; Infinity Pharma: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; Stanford University: Employment, Equity Ownership; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Regeneron: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ansell:Mayo Clinic Rochester: Employment; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Trillium: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment. Younes:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding. Gallamini:Takeda: Consultancy; Roche: Consultancy. Miao:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Liu:Takeda: Employment. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Forero-Torres:Seattle Genetics: Employment, Equity Ownership, Honoraria, Research Funding.

Mantle cell lymphoma (MCL) is an incurable B-cell lymphoma characterized by the chromosomal translocation (11;14)(q13;q32), resulting in aberrant expression of cyclin D1 and dysregulated cell cycle progression. In a phase I clinical trial in patients with previously treated MCL, the combination of the cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor palbociclib and the Bruton tyrosine kinase inhibitor ibrutinib was safe and active. We hypothesized that clinical responses are in part attributed to dynamic changes in the immune landscape and tumor-immune interaction, given accumulating evidence that inhibition of CDK4/6 augments anti-tumor immunity. In a patient (Pt 17) treated with palbociclib and ibrutinib for over 3 years and experiencing a complete response (CR), there was an over 4-fold increase in circulating CD3+ T cells over time. For the first 19 treatment cycles, the absolute CD3+ T cell count was 862 ± 322 compared to 4,027 ± 253 between cycles 31 and 40, with no clinical suspicion of infection for at least 3 months prior. To investigate the T-cell receptor (TCR) repertoire over the course of treatment, high-throughput sequencing of the TCRB CDR3 region was performed, revealing a more oligoclonal repertoire in the peripheral blood over time. The cumulative frequency of the top 10 TCR clones during cycles 3, 7, and 31 were 3.9%, 6.5%, and 25.8%, respectively. These clones were mapped to single-cell RNA sequencing (scRNA-seq) data and determined to be CD8+ effector and central memory T cells. Furthermore, there appears to not only be increased numbers of CD4+ and CD8+ T cells but also enhanced activation as evidenced by scRNA-seq expression of CD69. These findings suggest a predominant cytotoxic T-cell response, which is consistent with recent preclinical studies using CDK4/6 inhibitors. A similar, less dramatic, pattern of T cell expansion was observed in three additional responding patients, including one with non-leukemic MCL (Pt 25) who achieved a CR with subsequent progression of disease at cycle 25. This patient had a 2-fold increase in the absolute number of circulating CD3+ T cells with a baseline count of 442 ± 168 during cycles 1 to 2 compared to 915 ± 104 between cycles 4 and 23, prior to a substantial decrease to 452 during cycle 24 and further to 114 during cycle 25. There was no evidence of clonal T cell expansion in the peripheral blood samples from cycles 4, 20, and 24. Whether this is related to a lack of circulating tumor cells remains to be determined. Interestingly, scRNA-seq analysis revealed a remarkable increase in PDCD1 (encoding PD-1) expression upon disease progression (abstract by Di Liberto et al.). Our findings offer potential new insights into the tumor-immune interaction associated with a durable treatment responses and drug resistance in targeting CDK4/6 and BTK in MCL. In preclinical models, CDK4/6 inhibition has been linked to changes in the tumor microenvironment to enhance the immune response, and here we present the first longitudinal data obtained from patients within the context of a clinical trial. Expansion of the cohort from the ongoing phase II trial, cytokine profiling, and functional assays are underway to further characterize the oligoclonal CD8+ T cell and other immune populations as well as to explore the potential therapeutic role of combinations with immune checkpoint blockade in lymphoma. Figure 1. Differential T-cell responses in relapsed/refractory MCL patients on palbociclib and ibrutinib combination therapy, including a leukemic MCL patient with a CR (Pt 17) and a non-leukemic MCL patient with a CR and subsequent progression of disease (Pt 25). A, Absolute B-cell and T-cell counts during various treatment cycles for Pt 17 (top) and Pt 25 (bottom). B, Cumulative productive frequency of the top 10 clonal TCR rearrangements in a given treatment cycle. C, Change in abundance of the top 10 TCR clones across a given treatment cycle. D, Differential abundance of productive TCR clones that have significantly increased or decreased in frequency between treatment cycles. Abbreviations: CR, complete response. MCL, mantle cell lymphoma. PD, progression of disease. Pt, patient. TCR, T-cell receptor. Figure 1 Disclosures Bartlett: Pharmacyclics: Research Funding; Pfizer: Research Funding; Millennium: Research Funding; Merck: Research Funding; Kite Pharma: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Immune Design: Research Funding; Gilead: Research Funding; Genentech, Inc.: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Autolus: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding. Maddocks:Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; BMS: Research Funding. Leonard:MorphoSys: Consultancy; Epizyme, Inc: Consultancy; Celgene: Consultancy; Bayer Corporation: Consultancy; MorphoSys: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; Merck: Consultancy; Miltenyi: Consultancy; Nordic Nanovector: Consultancy; ADC Therapeutics: Consultancy; BeiGene: Consultancy; Nordic Nanovector: Consultancy; Sandoz: Consultancy; Sandoz: Consultancy; Akcea Therapeutics: Consultancy; Miltenyi: Consultancy; Akcea Therapeutics: Consultancy; Celgene: Consultancy; Merck: Consultancy; Karyopharm Therapeutics: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Sutro Biopharma: Consultancy; Karyopharm Therapeutics: Consultancy; AstraZeneca: Consultancy; AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Epizyme, Inc: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Sutro Biopharma: Consultancy; BeiGene: Consultancy; Gilead: Consultancy. Galluzzi:Luke Heller TECPR2 Foundation: Consultancy; Astra Zeneca: Consultancy; Inzen: Consultancy; OmniSEQ: Consultancy, Membership on an entity's Board of Directors or advisory committees. Martin:I-MAB: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Teneobio: Consultancy; Sandoz: Consultancy. OffLabel Disclosure: Palbociclib, a CDK4/6 inhibitor, was used off-label in combination with ibrutinib in a phase I clinical trial in patients with relapsed/refractory mantle cell lymphoma.

Mantle cell lymphoma (MCL) is incurable due to the development of drug resistance. MCL cells proliferate without constraint on disease progression, fueled by aberrant cyclin D1 expression due to (11;14)(q13;q32) chromosomal translocation and dysregulation of CDK4 (CDK6 is silenced) that accelerate cell cycle progression through G1. Previously, we demonstrated that selective inhibition of CDK4/6 with palbociclib leads to prolonged early G1 arrest that sensitizes MCL cells to partner drugs including the BTK inhibitor ibrutinib. In our phase I clinical trial of palbociclib + ibrutinib (PALIBR) in recurrent MCL, complete response (CR) was achieved in 10/28 patients with only 5/19 responding patients progressing in 5 years. CDK4/6 inhibition thus appears to prolong and deepen the clinical response to ibrutinib. To determine the tumor-intrinsic mechanism that discriminate sensitivity from resistance to PALIBR, we performed integrative analysis of longitudinal whole exome- and whole transcriptome- sequencing (WES/WTS) of MCL cells isolated from the tissue and peripheral blood of patients before, during therapy and on progression. To reveal tumor heterogeneity, clonal evolution, and the tumor-immune interaction during the clinical response, we undertook single cell RNA-sequencing (scRNA-seq) of the corresponding peripheral blood mononuclear cells (PBMCs) in conjunction with flow cytometry. Integrative WES/WTS analysis demonstrated that CR (n=8) was achieved despite copy number gain of CDK4, BCL6 or MYC, or hemizygous deletion (h-del) of RB1, CDKN2A (encoding CDK4/6 inhibitor p16), ATM or TP53. However, composite CDK4 gain + CDKN2A and RB1 h-del, coupled with ATM or TP53 h-del before treatment was associated with loss of cell cycle control in 3 of 4 evaluable primary resistant patients, on progression at cycle 5 after a transient CR (Pt 18) and cycle 30 after a durable partial response (PR) (Pt 2). The other PR patients harbor various copy number variations (CNV) but not the resistance composite CNV. Thus, by perturbing the stoichiometry of CDK4/p16/Rb, composite CNV of CDK4, CDKN2A and RB1 predisposes MCL to resistance to dual CDK4/6 and BTK inhibition. scRNA-seq analysis further revealed 5 transcriptionally distinct MCL clusters (cyclin D1+CD19+) in PBMCs of treatment-naïve patients (n=4) as well as PBMCs, bone marrow and tissue samples of recurrent MCL patients before PALIBR. Cluster 3 (mC3) and cluster 4 (mC4) were absent in PBMCs of normal subjects (n=4) but expanded with disease progression. mC3 was enriched for a cytokine signaling, interferon and inflammatory response signature and mC4 was enriched for a cell cycle signature. Unexpectedly, PDCD1 was expressed in MCL cells in all patients before PALIBR, modestly in mC3 in responding patients and strongly in both mC3 and mC4 in primary resistant patients. Loss of MCL cells in a durable CR (Pt 17) correlated with marked expansion of CD8+ T cells, whereas re-emergence of PDCD1- expressing mC3 and mC4 on progression after a durable PR (Pt 11) or CR (Pt 25) was preceded by loss of CD8+T cells (Lee et al Abstract # 122322). Flow cytometry confirmed that PD-1 was expressed on the surface of MCL cells. WTS of purified MCL cells further revealed that PDCD1 was regulated by the cell cycle, being repressed in MCL cells by palbociclib alone in patients responding to a separate sequential palbociclib-bortezomib therapy and elevated in mC3 on progression after a durable PR. In summary, we have demonstrated, for the first time, that composite gain of CDK4 and hemizygous deletion of CDKN2A and RB1, but not each alone, predisposes MCL to resistance to dual CDK4/6 and BTK inhibition, and identified the resistant MCL clusters. The discovery of PD-1 expression in MCL cells suggests the existence of a clinically relevant tumor-intrinsic program that impinges on immunomodulation. A failure to curb the expansion of PD-1+ MCL clusters may fuel resistance by restricting cytotoxic T cell expansion. Conversely, repressing PD-1 expression in MCL cells and eliminating MCL cells in G1 arrest induced by CDK4/6 inhibition may augment ibrutinib's antitumor immunity by favoring T cell expansion. As the first integrative analysis of longitudinal scRNA-seq, WES and WTS in the context of clinical response to CDK4/6 inhibitor therapy in human cancer, our study provides new insights into tumor-intrinsic and -extrinsic mechanisms for targeting CDK4/6 in cancer. Disclosures Bartlett: Merck: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Genenetech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Pfizer: Research Funding; Millenium: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding. Maddocks:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; BMS: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding. Park:Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Seattle Genetics: Research Funding, Speakers Bureau; G1 Therapeutics: Consultancy; Teva: Consultancy, Research Funding; Gilead: Speakers Bureau. Ruan:Juno: Consultancy; Kite: Consultancy; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Galluzzi:Inzen: Consultancy; Luke Heller TECPR2 Foundation: Consultancy; Astra Zeneca: Consultancy; OmniSEQ: Consultancy, Membership on an entity's Board of Directors or advisory committees. Leonard:Sutro Biopharma: Consultancy; Bayer Corporation: Consultancy; AstraZeneca: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Bayer Corporation: Consultancy; MorphoSys: Consultancy; Karyopharm Therapeutics: Consultancy; Miltenyi: Consultancy; Akcea Therapeutics: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Merck: Consultancy; Akcea Therapeutics: Consultancy; Gilead: Consultancy; Sutro Biopharma: Consultancy; BeiGene: Consultancy; MorphoSys: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Karyopharm Therapeutics: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Nordic Nanovector: Consultancy; ADC Therapeutics: Consultancy; Sandoz: Consultancy; BeiGene: Consultancy; Sandoz: Consultancy; Gilead: Consultancy; ADC Therapeutics: Consultancy; Nordic Nanovector: Consultancy; Merck: Consultancy; Miltenyi: Consultancy. Martin:Janssen: Consultancy; Teneobio: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; I-MAB: Consultancy; Sandoz: Consultancy. OffLabel Disclosure: Palbociclib is a CDK4/6 inhibitor FDA-approved for breat cancer treatment. It was used off-label in combination with ibrutinib in a phase I clinical trial in patients with relapsed/refractory mantle cell lymphoma.

Introduction: Improved treatments are needed for relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) pts. Options are particularly limited for pts with B-cell NHLs who are R/R to CAR-T therapies or for whom a delay in effective therapy precludes this approach. 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). In an ongoing Phase I/Ib study (GO29781; NCT02500407), promising efficacy and favorable tolerability were observed in R/R NHL pts (Budde et al. ASH 2018; Bartlett et al. ASCO 2019). We report complete remissions (CRs) with M in NHL pts who are R/R to CAR-T therapy, as well as activity with M re-treatment. Methods: GO29781 is an open-label, multicenter, Phase I/Ib, dose escalation and expansion study of M in R/R B-cell NHL. Data is presented from Group B, in which M is administered with step-up dosing on Days 1, 8, and 15 of Cycle 1, and then as a fixed dose on Day 1 of each subsequent 21-day cycle (maximum 17 cycles). Outcome measures include best objective response rate (ORR) by revised International Working Group criteria, maximum tolerated dose (MTD), and tolerability. Results: As of June 4, 2019, 218 pts in Group B had received any amount of M. Indolent NHL (iNHL) pts (n=72) were mainly follicular lymphoma (FL, n=69). Aggressive NHL (aNHL) pts (n=141) were mainly diffuse large B-cell lymphoma (DLBCL, n=87) or transformed FL (trFL, n=29). Median prior systemic therapies was 3 (range: 1-14). Twenty-three pts had prior CAR-T therapy (12 DLBCL, 6 trFL, 5 FL), and 16 were efficacy evaluable (7 DLBCL, 5 trFL, 4 FL). ORR and CR rates were 43.8% (7/16) and 25.0% (4/16, 2 DLBCL and 2 FL), respectively. Expansion of previously administered CAR-Ts after M administration was detected by quantitative PCR, in line with the mechanism of action of M. Dose escalation is ongoing, supported by a positive exposure-response relationship for efficacy and broad therapeutic window with step-up dosing (Li et al. ASH 2019). Among efficacy-evaluable pts across all dose levels, ORR and CR rates were 64.1% (41/64) and 42.2% (27/64) in iNHL pts and 34.7% (41/119) and 18.6% (22/119) in aNHL pts, respectively. CRs appeared durable, with 25/27 (92.6%) iNHL pts (median time from first CR: 5.8 months; range: 0.2-28.9) and 15/22 (68.2%) aNHL pts (median time from first CR: 8.8 months; range: 0.0-25.4) who achieved CR remaining in remission. Re-treatment with M was allowed in CR pts who relapsed. Four pts, including 1 in Group A who was initially treated with a fixed, non-step-up dosing schedule, received M re-treatment. One CR and 2 partial responses were observed. All three responses are ongoing, with the CR pt in second remission for 314 days. The MTD of M has not been reached at doses up to 1/2/60mg (Cycle 1 Day 1, 8, and 15). Adverse events (AEs) leading to treatment withdrawal were uncommon (12/218, 5.5%). Cytokine release syndrome (CRS), graded by Lee criteria (Lee et al. Blood 2014;124:188-95), was observed in 28.4% of pts, and was mostly Grade (Gr) 1 (21.1%) or Gr 2 (6.0%); Gr 3 CRS occurred in 1.4% of pts. Most CRS events occurred in Cycle 1; 5 pts (2.7%) had CRS during or after Cycle 2. Three of 218 pts (1.4%) received tocilizumab for CRS management; all 3 events resolved without sequelae (for 1 pt, CRS resolved after the cutoff date). Neurological AEs (NAEs) were reported in 44% of pts (Gr 1, 28.0%; Gr 2, 12.8%; Gr 3, 3.2%). Common NAEs were headache (14.7%), insomnia (10.1%), and dizziness (9.2%). Potential immune effector cell-associated neurotoxicity syndrome (ICANS)-like NAEs of Gr 1 or Gr 2 confusional state occurred in 3 pts (1.4%) during cycles 1 and 2. The frequency of CRS and NAEs did not correlate with M exposure, likely due to step-up dosing, which effectively mitigates acute toxicities and allows administration of higher doses (Bartlett et al. ASCO 2019; Li et al. ASH 2019). Among the 4 pts who were re-treated with M, no CRS was observed and NAEs were reported in 1 pt (Gr 1 headache and insomnia). Among the 23 pts who were R/R to CAR-T therapy, CRS occurred in 5 pts (21.7%; Gr 1, 13.0%; Gr 2, 4.3%; Gr 3, 4.3%) and NAEs in 8 pts (34.8%; Gr 1, 17.4%; Gr 2, 13.0%; Gr 3, 4.3%), with no ICANS-like events. Conclusions: M has favorable tolerability and durable efficacy in pts with heavily pre-treated R/R B-cell NHL, including CRs in pts with disease progression after CAR-T therapies. Preliminary data support the possibility for re-treatment with M. Disclosures Schuster: Novartis: Honoraria, Patents & Royalties: Combination CAR-T and PD-1 Inhibitors, Research Funding; Nordic Nanovector: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding. Bartlett:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Incyte: Research Funding; Janssen: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Autolus: Research Funding; Forty Seven: Research Funding; Genentech, Inc.: Research Funding. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau. Yoon:Kyowa Hako Kirin: Research Funding; Genentech, Inc.: Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MSD: Consultancy; Janssen: Consultancy; Yuhan Pharma: Research Funding. 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; Celgene: Honoraria, Research Funding; Janssen: 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; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; AstraZeneca: 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. Sehn:Acerta: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Apobiologix: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Janssen-Ortho: Honoraria; TG Therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria. Cheah:Janssen: Honoraria; Acerta: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Gilead: Honoraria; Loxo: Honoraria. Shadman:Mustang Biopharma: Research Funding; Gilead: Research Funding; AbbVIe: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy; Sound Biologics: Consultancy; Pharmacyclics: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Atara: Consultancy; Bigene: Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Verastem: Consultancy; Acerta: Research Funding; Emergent: Research Funding; Sunesis: Research Funding; Merck: Research Funding. Gregory:MSD: Other: grant pending, Research Funding; Beigene: Other: Grant pending, Research Funding; Celgene: Other: grant pending, Research Funding; Monash University: Research Funding; Roche: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: grant pending, Research Funding; Janssen: Other: grant pending, Research Funding; Melbourne Haematology: Consultancy, Honoraria, Other: Travel fees and conference support, Speakers Bureau. Wei:Genentech, Inc./F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Yin:Genentech, Inc: Employment, Equity Ownership. Kwan:Genentech, Inc: Employment, Equity Ownership. Yousefi:F. Hoffmann-La Roche Ltd: Employment. Hernandez:Genentech, Inc.: Employment, Equity Ownership. Li:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. O'Hear:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Off Label 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.

Introduction Approximately 20% of patients (pts) with classical Hodgkin lymphoma (cHL) are age ≥ 60 years (yrs) at diagnosis (dx). Standard anthracycline-based therapies (ABTx) have historically shown lower efficacy and greater toxicity in this older population compared with younger pts, especially for unfit or frail pts. However, prior analyses have pre-dated the use of brentuximab vedotin (BV) and other novel targeted agents in the front-line setting and there remains no clearly defined or unified standard of care for this pt population. Studies in older lymphoma pts have also defined specific categories of pt fitness that may potentially guide therapy, although continued validation of these definitions in cHL are needed. We performed a large, multicenter retrospective study to identify current practice patterns in the US in older untreated cHL pts with specific attention to pt fitness using established definitions and to outcomes with ABTx versus non-ABTx. Methods Following IRB approval at each site, detailed pathologic and clinical data, including geriatric assessments (GAs) for the latter, were collected across 10 US academic medical centers. Eligible pts included: cHL dx on or after 1/1/2010, age ≥ 60 yrs at dx, and no preceding hematologic malignancy. Subjects with inadequate clinicopathologic and outcomes data or with dx other than cHL were excluded. A multivariable Cox proportional hazards model was developed to study the association of PFS and OS with various factors of interest, and survival rates were estimated by Kaplan-Meier using SPSS. Associations were considered significant for two-sided P values ≤ 0.05. Results Among 254 eligible older cHL pts with newly diagnosed disease, clinical features included: median age 67 yrs (range 60-90+), 54% male, 64% stage III/IV, 46% B symptoms, and 86.1% ECOG PS 0-1. 68.9% had nodular sclerosis, 18.9% mixed cellularity, and 12.2% other subtypes; EBV was detectable by IHC or peripheral blood in 39.3% of evaluable cases (n=98). In terms of geriatric measures, 31 pts (12.2%) had loss of at least one ADL; 40 (15.8%) had a geriatric syndrome; and 16 (6.3%) had both. Of note, only one pt underwent a comprehensive GA prior to treatment. Using established fitness definitions in lymphoma (Tucci et al, 2015), pts were classified as "Fit" (n=129; 50.8%), "Unfit" (n=8; 3.2%), or "Frail" (n=112 (44.1%); 5 (2%) were unclassifiable due to incomplete data (Table 1). Front-line regimens included ABVD (n=145; 57.1%), AVD (n=33; 13.0%), and CHOP (n=18; 7.1%). 6 pts (2.4%) received BV monotherapy; 21 (8.3%) received BV with AVD, the latter either concurrently (N=11) or sequentially (n=10). 11 pts did not receive systemic tx, of whom 9 received radiation alone; 58 pts received radiation with systemic tx. ABVD recipients received an average of 7.4 doses of bleomycin (range 1-14) and 18.4% (n=26) had pulmonary toxicity. In addition, 56.7% (n=130) of pts experienced at least one tx-related toxicity, which was similar across all fitness groups (Table 1). 15.1% (n=38) of pts stopped tx due to toxicity, which was noted more often in "frail" pts though it was relatively uncommon. 11 pts (4.3%) experienced treatment-related mortality (TRM). Compared with pts receiving non-ABTx, ABTx was associated with significantly improved PFS (HR 0.391, P=0.008) and OS (HR 0.195, P=0.0004). ECOG PS >1 was associated with inferior PFS (HR=1.96, P=0.017) and OS (HR=3.09, P=0.002). Pts defined as "frail" had no apparent difference in PFS compared with fit pts (Figure 1A;P=0.169), although decreased OS was seen (Figure 1B; P=0.01). Discussion To the best of our knowledge, these data represent one of the largest analyses of older cHL pts in the modern era. Our real-world analysis shows that in those who are able to receive them, anthracyclines provide meaningful survival benefit in this older cHL patient population and can be well-tolerated for many pts. The impact of dose intensity and backbone regimen are not yet known. In addition, current definitions of "fitness" incompletely identified pts at risk for poor outcomes or greater toxicity. Further studies are planned to better delineate fitness in this population. Disclosures Bartlett: Celgene: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Affimed: Research Funding; Merck: Research Funding; Janssen: Research Funding; Immune Design: Research Funding; Gilead: Research Funding; Millenium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Forty Seven: Research Funding; Genenetech: Research Funding; Bristol-Myers Squibb: Research Funding. Grover:Seattle Genetics: Consultancy. Bennani:Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board. Hill:Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding. Advani:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Kura: Research Funding; Janssen: Research Funding; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Regeneron: Research Funding; Infinity Pharma: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Agensys: Research Funding; Stanford University: Employment, Equity Ownership; Seattle Genetics: Consultancy, Research Funding; Cell Medica, Ltd: Consultancy; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Magarelli:Tevan Oncology: Speakers Bureau. Feldman:Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Trillium: Research Funding; Viracta: Research Funding. Cohen:Astra Zeneca: Research Funding; ASH: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; Lymphoma Research Foundation: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Janssen Pharmaceuticals: Consultancy; Genentech, Inc.: Consultancy, Research Funding. Evens:Seattle Genetics: Consultancy, Honoraria, Research Funding; Tesaro: Research Funding; Epizyme: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria. Portell:AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding.

Introduction Limited stage disease accounts for 30-40% of Diffuse Large B-cell Lymphoma (DLBCL), with better overall survival than advanced stage disease, but with increased late relapses regardless of treatment strategy (Stephens 2016). Preferred treatment for these patients (pts) per NCCN guidelines is abbreviated R-CHOP followed by radiotherapy. Based on promising results of radioimmunotherapy consolidation in SWOG S0313 (Persky 2015), and of PET-directed experience by the BC Cancer Agency (Sehn 2011), we designed a National Clinical Trials Network (NCTN) PET-directed study to tailor therapy after 3 cycles of R-CHOP, to improve outcomes and decrease toxicities. Methods Pts had non-bulky (< 10 cm) stage I/II untreated DLBCL. Mediastinal, HIV-associated, testicular, central nervous system, and indolent lymphoma were excluded. Pts received standard R-CHOP therapy and had an interim PET scan on day 15-18 of cycle 3, which was centrally reviewed in real time. Pts with negative PET scan (Deauville 1-3, iPET-neg) proceeded with 1 additional cycle of R-CHOP. Pts with positive PET scan (Deauville 4-5, iPET-pos) initiated 36 Gy of involved field radiation therapy (IFRT), plus additional boost to FDG-avid area up to 9 Gy, within 5 weeks of 3rd cycle of R-CHOP. This was followed by ibritumomab tiuxetan (IFRT-Zevalin) 3-6 weeks after completing IFRT. Final PET scan was performed 12 weeks after treatment completion. Results The study completed accrual in June 2016. Safety, response, interim PET, and immunohistochemistry-based cell of origin (COO) and MYC/BCL2 analyses were presented previously (Persky 2017, Stephens 2017). Of 159 pts enrolled, 1 was upstaged by PET, and 26 pts were ineligible - due to incorrect histology (mostly concurrent indolent or follicular lymphoma grade 3B) (21), lack of diagnostic tissue submission for central pathology review (3), and bulky disease (2). In 132 eligible pts, median age was 62 years, 62% had stage I, 17% had B symptoms, 14% had elevated LDH, 43% had extranodal involvement, and 66% had exclusive involvement of the head and neck region. Stage modified IPI (smIPI, Miller 1998) was 0 in 27%, 1 in 42%, 2 in 28%, and 3 in 4% of the pts. COO by Lymph2Cx was assessable in 87 pts - 68% were GCB, 23% were ABC, and 9% were unclassifiable. Double protein expressers (MYC and BCL2, DPE) were 16%, while 4 (3%) pts had "double hit" lymphoma (DHL) - 2 with MYC/BCL2 and 2 with MYC/BCL6 rearrangements - none of which were DPE. Of 132 eligible pts, 128 had an interim PET scan centrally reviewed, of which 110 were iPET-neg. Only 18 were iPET-pos, 4 of them due to infection (Deauville X) which were treated as iPET-neg. Of 14 truly iPET-pos pts (11%), 2 refused radiation, and 12 pts received IFRT-Zevalin. Eight pts (67%) converted from PR to CR after IFRT-Zevalin and 4 (33%) had PR, for an overall CR of 92% and PR of 4% (with 4% unevaluable). With median follow up of 4.5 yrs (range 1.1 - 7.5 yrs), only 5 pts progressed and 2 died from lymphoma. Of 5 progressors, 3 received R-CHOP x 4, 1 was iPET-pos but declined radiation, and 1 went off treatment after 1 cycle of R-CHOP. Eleven pts died from non-lymphoma causes, including 1 pt from secondary AML (iPET-neg arm), and 1 of lung adenocarcinoma diagnosed upon iPET. S1001 5-yr PFS estimate is 87% and OS estimate is 90% (figure 1), with iPET-pos and iPET-neg pts having similar outcomes - PFS 86% vs. 88%, OS 93% vs. 91%, respectively. Five-yr PFS by smIPI was 97% for smIPI of 0, 86% for 1-2, and 30% for 3. GCB had 5-yr PFS of 95%, vs. 70% for ABC and 47% for unclassifiable. DPE pts had 5-yr PFS of 70, vs. 89% for non-DPE pts. All 4 DHL pts maintain remission. Conclusions S1001 is the largest US study of limited stage DLBCL in the rituximab era, with best NCTN results in this disease subset. Only 5 patients progressed and 2 died from lymphoma. Our study confirms the distinct biology of limited stage DLBCL, with predominance of GCB origin (68%), and head and neck location (66%). Due to small number of lymphoma events, no strong conclusions about prognostic ability of smIPI, COO, DPE, or DHL, could be made. S1001 demonstrated that 89% of pts maintained excellent outcomes after R-CHOP x 4 with PET-directed therapy. Only 11% of pts were iPET-pos and required radiation, but they also had excellent outcomes. Together with the FLYER trial in younger pts (Poeschel 2018), this NCTN trial establishes R-CHOP x 4 alone as the new standard approach to limited stage disease for majority of the pts. Disclosures Persky: Sandoz: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy. Stephens:Acerta: Research Funding; Karyopharm: Research Funding; Gilead: Research Funding. Park:BMS: Consultancy, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Teva: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Bartlett:Seattle Genetics: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Millenium: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Genenetech: Research Funding; Immune Design: Research Funding; Gilead: Research Funding; Forty Seven: Research Funding; Janssen: Research Funding; Affimed: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding. Swinnen:Pharmacyclics: Consultancy; AbbVie: Consultancy. Barr:Celgene: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Astra Zeneca: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Leonard:Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; BeiGene: Consultancy; Gilead: Consultancy; Miltenyi: Consultancy; ADC Therapeutics: Consultancy; Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; Sandoz: Consultancy; ADC Therapeutics: Consultancy; Miltenyi: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Karyopharm Therapeutics: Consultancy; Epizyme, Inc: Consultancy; Sutro Biopharma: Consultancy; AstraZeneca: Consultancy; AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Bayer Corporation: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Celgene: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Merck: Consultancy; MorphoSys: Consultancy; Karyopharm Therapeutics: Consultancy; Gilead: Consultancy; Sutro Biopharma: Consultancy; BeiGene: Consultancy; Merck: Consultancy; MorphoSys: Consultancy; Sandoz: Consultancy. Kahl:TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; BeiGene: Consultancy. Fisher:Celgene: Consultancy; AstraZeneca: Consultancy; Barclays: Honoraria; prIME: Honoraria. Rimsza:NanoSting: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution]. Smith:Portola Pharmaceuticals: Research Funding. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee. OffLabel Disclosure: Ibritumomab tiuxetan in diffuse large B-cell lymphoma

Introduction: 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). It drives tumor B-cell killing independent of T-cell specificity and has been shown clinically to have single-agent activity in relapsed or refractory non-Hodgkin lymphoma, with durable complete responses (CR) at doses as low as 1.2mg (Budde et al. ASH 2018). We present biomarker data from the ongoing first-in-human multicenter Phase I/Ib study GO29781 (NCT02500407), highlighting acute pharmacodynamic effects that confirm mechanism of action (MOA), support Cycle 1 step-up dosing to mitigate cytokine-driven toxicities, and potentially predict response. Methods: Patients (pts) with biomarker data in Group A (0.05 to 2.8mg q3w dosing, n=30) and Group B (0.4/1/2.8 to 1/2/40.5mg Cycle 1 Day 1/8/15 step-up dosing, followed by q3w dosing) were included in the analyses. Peripheral biomarkers were evaluated using whole blood flow cytometry, plasma cytokine ELISA, and ex-vivo single-cell cytokine assay of cryopreserved peripheral blood mononuclear cells. Tumor biomarkers were assessed through CD20 immunohistochemistry and CD8/Ki67 immunofluorescence staining. Average CD20 receptor occupancy (RO%), which takes into account residual levels of rituximab that may compete with M for target binding, was used to characterize the exposure-pharmacodynamic response relationship (Li et al. ASH 2019). Results: Pharmacodynamic changes were observed in peripheral blood by 4 hours (hrs) after infusion of sub-efficacious doses of M in Group A. Transient reduction of circulating T cells was evident starting at the lowest doses administered of 0.05-0.2mg, with decreased cell numbers by 4 hrs after infusion and recovery by 72 hrs. At doses between 0.4-0.8mg, T-cell activation was observed in some pts, as evidenced by upregulation of CD69 on both CD8+ and CD4+ T cells and elevation of IFN-γ in plasma. At 1.2mg (minimal efficacious dose) to 2.8mg, all of these changes were detected in the majority of pts. M induced depletion of circulating B cells immediately after the first dose, which was sustained for the duration of treatment, even in pts refractory to prior anti-CD20 therapy. IL-6 levels peaked within 24 hrs of the Cycle 1 Day 1 dose and the kinetics of IL-6 increase were associated with the onset of cytokine release syndrome (CRS). Hence, step-up dosing at Cycle 1 was implemented in Group B to maintain the IL-6 peak at reasonably low levels and reduce the risk of toxicity. With step-up dosing, pharmacodynamic changes, including transient T-cell decrease, T-cell activation, and cytokine production, remained strongest within 4 hrs of the Cycle 1 Day 1 dose, despite higher subsequent and total cumulative doses. IL-6 peaks were similar in Group A and Group B and were in line with the low grades of CRS observed to date (Schuster et al. ASH 2019). In pts for whom the Cycle 1 Day 1 dose was fixed at 1mg, the acute pharmacodynamic changes were found to be associated with RO% at Day 1. In a subset of diffuse large B-cell lymphoma pts, functional assays showed that peripheral T cells taken at baseline from pts who achieved CR secreted multiple effector cytokines, such as IFN-γ, TNF-α, and Granzyme B, upon M stimulation ex vivo, whereas T cells from pts with progressive disease did not show this capacity. Analysis of tumor biopsies showed similar baseline levels of CD8+ tumor infiltrating T-cells (TILs) between responders and non-responders. M induced increases in CD8+ TILs, which were mostly Ki67-, as early as Cycle 1. The median on-treatment CD8+ TIL level was significantly higher in responders than non-responders. Conclusions: T-cell activation, cytokine elevation, and B-cell depletion in the periphery are among the earliest biomarkers of M activity and precede clinical responses. Acute pharmacodynamic changes confirm the MOA and inform dose/schedule selection. In particular, the 1mg Cycle 1 Day 1 dose, which was chosen to mitigate CRS and to dissociate toxicity and efficacy at higher subsequent doses, still induced potent pharmacodynamic changes. Finally, the data suggest a model whereby clinical efficacy may be critically dependent on activation and migration of functional T cells from the periphery into the tumor bed. Disclosures Hernandez: Genentech, Inc.: Employment, Equity Ownership. Huw:Roche/ Genentech: Employment, Equity Ownership. Belousov:Roche: Employment. Wilson:Genentech, Inc.: Employment. Koeppen:Genentech, Inc.: Employment; Roche: Equity Ownership. McCord:Roche: Equity Ownership; Genentech, Inc.: Employment. Peng:Genentech inc. / Roche: Employment, Equity Ownership. Bartlett:Affimed: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Merck: Research Funding; Millennium: Research Funding; Gilead: Research Funding; Genentech, Inc.: Research Funding; Pharmacyclics: Research Funding; Autolus: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Immune Design: Research Funding; Incyte: Research Funding; Janssen: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Millennium: Research Funding; Merck: Research Funding; Kite Pharma: Research Funding; Kite Pharma: Research Funding. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Assouline:Pfizer: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau. Nastoupil:Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria. Yoon:F. Hoffmann-La Roche Ltd: Research Funding. Matasar:Juno Therapeutics: Consultancy; Merck: Consultancy, Equity Ownership; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Bayer: Other: Travel, accommodation, expenses. Bender:Genentech, Inc.: Employment, Equity Ownership. Kwan:Genentech, Inc: Employment, Equity Ownership. Li:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. O'Hear:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. Yin:Genentech, Inc.: Employment, Equity Ownership. Wei:Genentech, Inc./F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Adamkewicz:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. 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.

7543 Background: Brentuximab vedotin (BV), an antibody-drug conjugate targeting CD30, has been evaluated in multiple trials in patients (pts) with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), or B-cell lymphoma. We examined the ability of CD30 expression level to predict response to BV across these patient populations. Methods: Data were integrated from 275 pts with PTCL, CTCL, and B-cell lymphoma treated with BV from 5 prospective clinical trials. Study SGN35-012 evaluated BV plus rituximab or BV monotherapy in pts with relapsed/refractory non-Hodgkin lymphoma. The ALCANZA study compared BV to physician’s choice of methotrexate or bexarotene in pts with mycosis fungoides (MF) or primary cutaneous anaplastic large cell lymphoma (pcALCL). Three investigator-sponsored trials evaluated BV monotherapy in pts with relapsed PTCL, MF, and pcALCL (35-IST-030, 35-IST-001, 35-IST-002). Exploratory analyses were conducted to examine the relationship between CD30 expression and objective response rate (ORR) for pts with CD30 expression ≥10%

7518 Background: T-cell directed therapies (e.g., CAR-T, blinatumomab) are associated with significant risk of Grade (Gr) ≥3 neurotoxicity and CRS/infusion-related reaction (IRR). Mosunetuzumab is a CD20/CD3 bispecific antibody that directs T-cells to engage and eliminate malignant B-cells. We report safety results from an ongoing phase 1/1b study of mosunetuzumab in patients (pts) with R/R B-cell NHL. Methods: Pts received ascending doses on Day 1, Day 8, and Day 15 of Cycle 1 (step-fractionation), then a fixed dose on Day 1 of every 21-day cycle thereafter, up to a maximum of 17 cycles. Primary outcome measures included safety and efficacy. Results: As of October 23, 2018, 114 pts who received step-fractionated dosing of mosunetuzumab were evaluable for safety (Table). The majority of adverse events (AE) occurred during Cycle 1 and 2. Neurologic AEs (NAE), defined from Nervous System or Psychiatric System Organ Classes, were mostly low grade, transient (median duration 4 days) and reversible; most common ones were headache (14%) and dizziness (8%). Gr ≥3 NAEs occurred in 4 pts (4%) with only 1 treatment-related event (hepatic encephalopathy). CRS/IRR was reported in 25% of pts, with only 1 Gr 3 event. Most common CRS symptoms were pyrexia (86%), chills (38%), and tachycardia and headache (14% each). There were no Gr 5 events related to CRS or NAEs. No apparent dose toxicity relationship was observed with step-fractionation in these pts, despite escalation of the Cycle 1 Day 15 dose to 20 mg, consistent with observed peak IL-6 levels after a low Cycle 1 Day 1 dose. In these pts, objective responses were observed in 24/73 (33%; complete response [CR], 13 [18%]) aggressive NHL and 17/32 (53%; CR, 10 [31%]) indolent NHL pts. Conclusions: Step-fractionation has enabled continued dose escalation of mosunetuzumab with no apparent increases in toxicity, exhibiting a promising risk-benefit profile. Clinical trial information: NCT02500407; GO29781. [Table: see text]

7555 Background: Axi-cel is a US FDA-approved, autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for the treatment of pts with relapsed or refractory LBCL with ≥ 2 prior systemic therapies. In the 2-y follow-up of ZUMA-1, the objective response rate (ORR) was 83% with a complete response (CR) rate of 58%, and 39% of pts were in ongoing response (Locke et al. Lancet Oncol. 2019). Here we report efficacy and safety outcomes by age. Methods: Eligible pts with refractory LBCL underwent leukapheresis and conditioning chemotherapy followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg. The Phase 2 primary endpoint was investigator-assessed ORR. Additional key endpoints were adverse events (AEs), overall survival (OS), and levels of CAR gene-marked cells in peripheral blood. Efficacy was evaluated for Phase 2 pts; safety was evaluated for all treated pts (Phases 1 and 2). Pts were analyzed by ≥ 65 y vs < 65 y of age. Results: As of 8/11/2018, 108 pts were treated. Pts ≥ 65 y (n = 27) vs < 65 y (n = 81) had a median age of 69 y vs 55 y, respectively, were 81% vs 63% male, 70% vs 36% had an IPI score 3-4, 59% vs 57% had ECOG 1, 67% vs 72% had ≥ 3 prior therapies, and median tumor burdens were 3790 mm2 vs 3574 mm2. Median follow-up was 27.1 mo for Phase 2 pts (n = 101). The ORR for pts ≥ 65 y (n = 24) and < 65 y (n = 77) was 92% and 81% (CR rate 75% and 53%), respectively, with ongoing responses in 42% and 38% of pts (ongoing CR 42% and 35%). The 24-mo OS rate was 54% for pts ≥ 65 y and 49% for pts < 65 y. Most pts experienced Grade ≥ 3 AEs (100% of pts ≥ 65 y; 98% of pts < 65 y), and 4% of each group (1/27 pts ≥ 65 y and 3/81 pts < 65 y) died due to AEs as previously reported. Grade ≥ 3 neurologic events and cytokine release syndrome occurred in 44% vs 28% and 7% vs 12% of pts ≥ 65 y vs < 65 y, respectively. CAR T cell expansion by peak level (43 vs 35 cells/μl) or area under the curve (562 vs 448 d × cells/μl) was similar in pts ≥ 65 y vs < 65 y, respectively. Conclusions: The 2-y follow-up of ZUMA-1 demonstrates that axi-cel can induce high rates of durable responses with a manageable safety profile for pts ≥ and < 65 y. Axi-cel offers substantial clinical benefit for older pts with refractory LBCL who otherwise have limited treatment options. Clinical trial information: NCT02348216.

Background: Burkitt lymphoma (BL) is a rare, highly aggressive B-cell malignancy treated most successfully with brief-duration, high-intensity chemotherapeutic regimens. The benefit of the addition of rituximab to these regimens remains uncertain. We sought to examine the effectiveness of chemotherapy with and without rituximab in patients with BL. Methods: This study is a retrospective cohort study of all adult patients with BL diagnosed and treated with modern, dose-intense chemotherapeutic regimens from 1998–2008 at two tertiary care institutions. All cases were confirmed by application of WHO 2008 criteria by hematopathologists. Medical records were reviewed for patient-, disease-, and treatment- related factors as well as treatment response and survival. Factors associated with survival were analyzed using Cox proportional hazards modeling. Results: A total of 35 patients were analyzed: 18 patients received rituximab with chemotherapy (R-chemo) and 17 received chemotherapy (chemo) alone. The median age was 42 (range 20–74 years); 57% were male; 71% had Ann Arbor Stage IV disease; 33% had central nervous system involvement; 78% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. R-chemo was associated with significantly longer overall survival (OS) than chemo alone (5-year OS 70% and 29%, respectively, p = 0.040). On multivariate regression analysis, poor performance status and central nervous system involvement were associated with poorer survival. Conclusions: The addition of rituximab to chemotherapy was associated with improved OS in patients with Burkitt lymphoma. Poor performance status and central nervous system involvement were prognostically significant on multivariate analysis.

Rituximab-based chemoimmunotherapy using R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is the standard frontline treatment for patients with diffuse large B-cell ly...

High-dose methotrexate (HDMTX), defined by doses of methotrexate (MTX) ≥ 1 g/m(2), is a widely used regimen known to cause renal toxicity. The reported incidence of renal toxicity in patients with osteosarcoma is 1.8%, but the incidence in hematologic malignancies is not well characterized. In this retrospective study of 649 cycles of HDMTX in 194 patients, renal toxicity occurred in 9.1% of cycles in patients with lymphoma compared to 1.5% in patients with sarcoma. Older age, male sex, decreased baseline creatinine clearance (CrCl) and increased proton pump inhibitor use among the lymphoma population likely contributed to the observed difference. The incidence of renal toxicity was independent of the incidence of delayed MTX elimination, suggesting that kidney function is only one factor involved in MTX clearance. Renal toxicity prolonged the duration of hospitalization but severe renal insufficiency was uncommon. No significant impact on progression-free or overall survival was observed.

Epstein-Barr virus (EBV) is associated with Hodgkin lymphoma (HL) and can be detected by in situ hybridization (ISH) of viral nucleic acid (EBER) in tumor cells. We sought to determine whether plasma EBV-DNA could serve as a surrogate for EBER-ISH and to explore its prognostic utility in HL. Specimens from the Cancer Cooperative Intergroup Trial E2496 were used to compare pretreatment plasma EBV-DNA quantification with EBV tumor status by EBER-ISH. A cutoff of >60 viral copies/100 µL plasma yielded 96% concordance with EBER-ISH. Pretreatment and month 6 plasma specimens were designated EBV(-) or EBV(+) by this cutoff. Patients with pretreatment EBV(+) plasma (n = 54) had inferior failure-free survival (FFS) compared with those with pretreatment EBV(-) plasma (n = 274), log-rank P = .009. By contrast, no difference in FFS was observed when patients were stratified by EBER-ISH. Pretreatment plasma EBV positivity was an independent predictor of treatment failure on multivariate analyses. At month 6, plasma EBV(+) patients (n = 7) had inferior FFS compared with plasma EBV(-) patients (n = 125), log-rank P = .007. These results confirm that plasma EBV-DNA is highly concordant with EBER-ISH in HL and suggest that it may have prognostic utility both at baseline and after therapy. This trial was registered at www.clinicaltrials.gov as #NCT00003389.

Approximately 90% of patients with early-stage Hodgkin lymphoma (HL) will be cured with first-line therapy. Chemotherapy alone or combined-modality therapy are both acceptable standard treatment options for nonbulky early-stage HL. Combined-modality therapy is associated with more serious late effects and, in at least one study, showed inferior survival rates compared with chemotherapy alone. Modern radiotherapy fields and doses are likely to result in fewer complications, but given the common involvement of the mediastinum in HL, complete avoidance of the heart, lungs, and breasts in the radiotherapy field is unlikely. In patients receiving chemotherapy alone, four to six cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD), with fewer cycles being given to those with an early complete remission, is recommended. Three cycles of ABVD may be adequate in those with an early negative PET, but these results have been published only in abstract form. Current standards for combined-modality therapy include two cycles of ABVD and 20 Gy of involved field radiotherapy in those with a favorable risk profile and four cycles of ABVD plus 30 Gy for unfavorable HL in early-stage patients. Standard of care for bulky early-stage HL remains combined-modality therapy. Whether an interim PET will allow selection of patients with nonbulky HL who will benefit most from consolidative radiotherapy is still under investigation.

Relapsed Hodgkin lymphoma remains a clinical challenge, with few non-cytotoxic treatment options. CD80 is a surface antigen that normally functions as a co-stimulatory molecule but is aberrantly and uniformly expressed on Reed–Sternberg cells. Galiximab is a primatized monoclonal antibody against CD80, with a favorable toxicity profile demonstrated in other lymphomas. Cancer and Leukemia Group B (CALGB) 50602 (Alliance) tested single-agent galiximab in a highly refractory group of patients with Hodgkin lymphoma (median 3 prior regimens, 83% failing after prior stem cell transplant) to determine the efficacy. The overall response rate was 10.3% and the median progression-free survival was 1.6 months. Galiximab was well-tolerated, with minimal grade 3 or 4 toxicities. Despite this preclinical rationale, single-agent galiximab had limited activity in heavily pretreated Hodgkin lymphoma.

This phase 2 study evaluated brentuximab vedotin monotherapy in CD30-expressing DLBCL; after several patients with little to no CD30 achieved a complete remission (CR), the study evaluated treatment of DLBCL with undetectable CD30 (CD30u) by local visual immunohistochemistry (vIHC). Sixteen of 52 CD30u DLBCL patients (31%) had an objective response (6 CRs [12%]). Median progression-free survival (PFS) was 1.4 months (range, 0.4-15.6) and median overall survival (OS) was 7.5 months (range, 0.7-18.6+). Subsequent CD30 expression quantitated by computer-assisted digital image analysis (cIHC) showed that 11 of 16 CD30u DLBCL responders had ≥1% CD30. Correlative analyses of CD30u and CD30-expressing DLBCL combined demonstrated that ≥1% CD30 expression by cIHC resulted in a trend toward a higher response rate and significantly longer median PFS and OS. A minimum CD30 expression threshold appears to be required for antitumor activity in DLBCL; however, other factors also likely contribute to activity. (NCT01421667).

Peripheral T-cell lymphomas (PTCLs) represent a relatively uncommon heterogeneous group of non-Hodgkin's lymphomas (NHLs) with an aggressive clinical course and poor prognosis. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by first-line consolidation with high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) is the standard approach to most of the patients with newly diagnosed PTCL. Relapsed or refractory disease is managed with second-line systemic therapy followed by HDT/ASCR or allogeneic stem cell transplant, based on the patient's eligibility for transplant. In recent years, several newer agents have shown significant activity in patients with relapsed or refractory disease across all 4 subtypes of PTCL. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for NHL, specific to the management of patients with relapsed or refractory PTCL.

Chemoimmunotherapy in follicular lymphoma is associated with significant toxicity. Targeted therapies are being investigated as potentially more efficacious and tolerable alternatives for this multiply-relapsing disease. Based on promising activity with rituximab and lenalidomide in previously untreated follicular lymphoma (overall response rate [ORR] 90%-96%) and ibrutinib in relapsed disease (ORR 30%-55%), the Alliance for Clinical Trials in Oncology conducted a phase 1 trial of rituximab, lenalidomide, and ibrutinib. Previously untreated patients with follicular lymphoma received rituximab 375 mg/m 2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 4, 6, 8, and 10; lenalidomide as per cohort dose on days 1 to 21 of 28 for 18 cycles; and ibrutinib as per cohort dose daily until progression. Dose escalation used a 3+3 design from a starting dose level (DL) of lenalidomide 15 mg and ibrutinib 420 mg (DL0) to DL2 (lenalidomide 20 mg, ibrutinib 560 mg). Twenty-two patients were enrolled; DL2 was determined to be the recommended phase II dose. Although no protocol-defined dose-limiting toxicities were reported, a high incidence of rash was observed (all grades 82%, grade 3 36%). Eleven patients (50%) required dose reduction, 7 because of rash. The ORR for the entire cohort was 95%, and the 12-month progression-free survival was 80% (95% confidence interval, 57%-92%). Five patients developed new malignancies; 3 had known risk factors before enrollment. Given the increased toxicity and required dose modifications, as well as the apparent lack of additional clinical benefit to the rituximab-lenalidomide doublet, further investigation of the regimen in this setting seems unwarranted. The study was registered with www.ClinicalTrials.gov as #NCT01829568.

Brentuximab vedotin is an anti-CD30 monoclonal antibody-drug conjugate approved for treating relapsed or refractory Hodgkin lymphoma. The pivotal trial demonstrated brentuximab vedotin's efficacy and manageable toxicity profile with peripheral neuropathy and neutropenia being the most common side effects. The phase I study of brentuximab vedotin combined with ABVD or AVD revealed its contraindication with bleomycin due to pulmonary toxicity. As trials continue to investigate the drug in frontline and relapsed settings, emerging safety data will further define brentuximab vedotin's role in managing Hodgkin lymphoma.This article reviews the current literature on brentuximab vedotin in Hodgkin lymphoma treatment, both as a single agent and in combination regimens. The review focuses on safety findings from clinical trials, expected adverse events, and rare serious toxicities.Brentuximab vedotin is a breakthrough antibody-drug conjugate that may provide new options in earlier lines of therapy for Hodgkin lymphoma. Results from the ongoing phase III trial comparing ABVD to AVD + brentuximab vedotin will inform whether brentuximab vedotin adds benefit to frontline therapy over the current standard of care. The optimal duration of treatment and brentuximab vedotin's potential as an alternative to radiation in early stage disease still warrant investigation.

Robert Chen,1 Suzanne Allibone,2 Nancy L Bartlett,3 Pauline Brice,4 Andy Chen,5 Katrina Pose,6 Lynn Rich,7 Vijay Bonthapally,8 Phillip M Garfin,9 Michelle Fanale10 1Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA; 2The Lymphoma Service of the Christie NHS Foundation Trust, Manchester, UK; 3Department of Medical Oncology, Washington University School of Medicine, St Louis, MO, USA; 4Department of Hemato-Oncology, Hôpital Saint-Louis, Paris, France; 5Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 6Lymphoma and Cancer Survivorship Stanford Comprehensive Cancer Center, Stanford, CA, 7Lymphoma Program, James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 8Millennium Pharmaceuticals Inc., Cambridge, MA, 9Seattle Genetics, Inc., Bothell, WA, 10Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Background: Patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) or R/R systemic anaplastic large-cell lymphoma (sALCL) treated with brentuximab vedotin (BV) experienced high remission rates in two Phase II trials. With increased response rates and survival times, patient-reported outcomes (PROs) and health-related quality of life (HRQoL) are becoming increasingly important and can help inform treatment decisions to enhance care of cancer patients.Objective: The objective was to qualitatively assess HRQoL in long-term survivors treated with BV.Methods: An eight-question survey assessing PRO-related aspects was developed and fielded to a subset of patients with HL or sALCL who remained in long-term follow-up after completing BV treatment in the two pivotal studies.Results: The survey was completed by 25 of 38 patients (12 with HL, 13 with sALCL). The majority of patients reported that their energy level, outlook on life, difficulties with daily activities, ability to participate in physical activities, and overall HRQoL improved compared to those before BV treatment.Limitations: Small sample size and lack of a baseline questionnaire or validated assessment instrument limit broad applicability of these findings to large populations of patients with HL or sALCL.Conclusion: This is the first report of BV PRO data in R/R HL and sALCL. Given the patients’ poor prognostic outcomes before stem cell transplant, these encouraging results warrant formal evaluation of PRO end points in BV trials. Keywords: patient well-being, brentuximab vedotin, health-related quality of life, pilot study, activities of daily living

Diffuse large B-cell lymphomas (DLBCL) are now considered a heterogeneous group of distinct molecular subtypes (germinal center B-cell DLBCL, activated B-cell DLBCL, and primary mediastinal large B-cell lymphoma (PMBL) with varied natural history and response to therapy. In addition, a subset of patients with DLBCL have concurrent MYC and/or BCL2 gene rearrangements (double-hit lymphomas; DHL) and others have a dual expression of both MYC and BCL2 proteins (double-expressing DLBCL; DEL). The standard of care for the treatment of patients with PMBL, DHL, or DEL has not been established. Adequate immunophenotyping and molecular testing (in selected circumstances) are necessary for the accurate diagnosis of different subtypes of DLBCL. The NCCN Guidelines included in this issue, part of the NCCN Guidelines for non-Hodgkin's lymphomas, address the diagnosis and management of DLBCL and its subtypes.

Increased tumor-associated macrophages (TAMs) are reported to be associated with poor prognosis in classic Hodgkin lymphoma (CHL). We investigated the prognostic significance of TAMs in the E2496 Intergroup trial, a multicenter phase 3 randomized controlled trial comparing ABVD and Stanford V chemotherapy in locally extensive and advanced stage CHL. Tissue microarrays were constructed from formalin-fixed, paraffin-embedded tumor tissue and included 287 patients. Patients were randomly assigned into training (n = 143) and validation (n = 144) cohorts. Immunohistochemistry for CD68 and CD163, and in situ hybridization for EBV-encoded RNA were performed. CD68 and CD163 IHC were analyzed by computer image analysis; optimum thresholds for overall survival (OS) were determined in the training cohort and tested in the independent validation cohort. Increased CD68 and CD163 expression was significantly associated with inferior failure-free survival and OS in the validation cohort. Increased CD68 and CD163 expression was associated with increased age, EBV-encoded RNA positivity, and mixed cellularity subtype of CHL. Multivariate analysis in the validation cohort showed increased CD68 or CD163 expression to be significant independent predictors of inferior failure-free survival and OS. We demonstrate the prognostic significance of TAMs in locally extensive and advanced-stage CHL in a multicenter phase 3 randomized controlled clinical trial.

Purpose Obesity increases the risk of death from many malignancies, including non-Hodgkin's lymphoma (NHL). In diffuse large B-cell lymphoma (DLBCL), the most common form of NHL, the association between body mass index (BMI) at diagnosis and survival is unclear. Patients and Methods We evaluated the association between BMI at diagnosis and overall survival in a retrospective cohort of 2,534 United States veterans diagnosed with DLBCL between October 1, 1998 and December 31, 2008. Cox modeling was used to control for patient- and disease-related prognostic variables. Results Mean age at diagnosis was 68 years (range, 20 to 100 years); 64% of patients were overweight (BMI, 25 to < 30) or obese (BMI, ≥ 30). Obese patients were significantly younger, had significantly fewer B symptoms, and trended toward lower-stage disease, compared with other BMI groups. Cox analysis showed reduced mortality in overweight and obese patients (overweight: hazard ratio [HR], 0.73; 95% CI, 0.65 to 0.83; obese: HR, 0.68; 95% CI, 0.58 to 0.80), compared with normal-weight patients (BMI, 18.5 to < 25). Treatment during the rituximab era reduced the risk of death without affecting the association between BMI and survival. Disease-related weight loss occurred in 29% of patients with weight data 1 year before diagnosis. Cox analysis based on BMI 1 year before diagnosis continued to demonstrate reduced risk of death in overweight and obese patients. Conclusion Being overweight or obese at the time of DLBCL diagnosis is associated with improved overall survival. Understanding the mechanisms responsible for this association will require further study.

Dacetuzumab, a CD40-targeted, humanized antibody, mediates antitumor activity through effector cell functions and direct apoptotic signal transduction. Preclinical studies demonstrated synergistic activity between dacetuzumab, gemcitabine and rituximab against non-Hodgkin lymphoma in vivo. A phase 1b safety/efficacy study of dacetuzumab in combination with rituximab and gemcitabine was conducted in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients received dacetuzumab at doses of 8 or 12 mg/kg IV weekly with rituximab (375 mg/m(2) IV weekly in cycle 1, then every 28 days) and gemcitabine (1000 mg/m(2) IV, days 1, 8 and 15, or days 1 and 15). Thirty-three patients with a median age of 67 years were enrolled. Common adverse events (≥ 15%) were grade 1/2 cytokine release syndrome, nausea, fatigue, thrombocytopenia, headache, decreased appetite, dyspnea, neutropenia, pyrexia, anemia, diarrhea, edema, constipation and cough. Dacetuzumab-related grade 3/4 adverse events occurred infrequently. Six of 30 evaluable patients achieved a complete response (CR) and eight a partial response (PR) per investigator assessment for an overall response rate (ORR) of 47%.

Systemic anaplastic large-cell lymphoma (ALCL) is a rare, mature T-cell non-Hodgkin lymphoma. Anaplastic large-cell lymphoma cells express the surface antigen CD30, and more than half express the anaplastic lymphoma kinase (ALK) protein. These 2 proteins provide unique therapeutic targets in ALCL. Remission rates in ALCL with combination chemotherapy are approximately 80%, but relapse after first-line therapy is common. Brentuximab vedotin is a US Food and Drug Administration-approved, antibody-drug conjugate that combines an anti-CD30 antibody with monomethylauristatin E, a potent antimicrotubule agent. Response rates to brentuximab vedotin in patients with relapsed/refractory ALK and ALK ALCL have exceeded 80% with frequent complete responses and a median duration of response greater than 1 year. Brentuximab vedotin in combination with chemotherapy is being explored as a first-line therapy in ALCL. Crizotinib is an inhibitor of ALK tyrosine kinase that has been approved for the treatment of ALK non-small cell lung cancer. Successful treatment of ALK ALCL with crizotinib has been reported in pediatric patients and small case series leading to ongoing trials in relapsed/refractory ALCL. Brentuximab vedotin and crizotinib represent major advances in the treatment of ALK and ALK ALCL and will likely result in marked improvement in prognosis for this subset of aggressive lymphomas.

A 47-year-old human immunodefi ciency virus (HIV)-negative man with relapsed stage IIIB mixed cellularity Hodgkin lymphoma (HL) presented with progressive neurologic defi cits while undergoing treatment with the CD30 directed antibody – drug conjugate, brentuximab vedotin (Adcetris). His prior therapies included eight cycles of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) in 2004, three cycles of ESHAP (etoposide, solumedrol, cytarabine, cisplatin) in 2007 followed by a BEAM (busulfan, etoposide, cytarabine, melphalan) autologous stem cell transplant, involved fi eld radiotherapy to the neck and mediastinum in 2008, and GVD (gemcitabine, vinorelbine, doxil) in 2009. He relapsed in 2011 and started treatment with brentuximab vedotin 1.8 mg/kg every 3 weeks. Th ree weeks following treatment initiation, the patient complained of impaired coordination and exhibited mild left-greater-than-right dysdiadokinesis. Prior to receiving the third dose of treatment (6 weeks after treatment initiation), the patient reported that his coordination had improved, yet his Eastern Cooperative Oncology Group (ECOG) performance status declined considerably from 0 at baseline evaluation to 3. Th e patient had lost signifi cant

Introduction Recent results from the HELIOS phase 3 study in relapsed/refractory CLL/SLL demonstrated that the addition of ibrutinib to chemoimmunotherapy with bendamustine/rituximab (BR) leads to an 80% reduction in risk of progression or death compared with placebo + BR (Chanan-Khan et al. ASCO 2015). In addition to prolongation of progression-free survival (PFS; median not reached vs 13.3 months; hazard ratio: 0.203, 95% confidence interval: 0.150-0.276, p Methods In total, 578 patients (pts) with relapsed/refractory CLL/SLL requiring treatment were randomized 1:1 (289 per arm) to receive BR (≤ 6 cycles) with either ibrutinib (420 mg daily) or placebo. Purine analog refractoriness (yes vs no) and number of prior therapies (1 vs > 1) were stratification factors. Pts with deletion 17p (del17p; > 20% of cells) were excluded. All pts were required to have ≥ 1 abnormal lymph node (LN; defined as a measurable lesion > 1.5 cm). The primary end point was independent review committee (IRC)-assessed PFS. In this analysis, individual parameters of response (LN, spleen, overall radiology, absolute lymphocyte count [ALC], complete blood count [CBC], and bone marrow [BM]) were evaluated. Minimal residual disease (MRD) was assessed by flow cytometry using an 8-color panel (Rawstron AC, et al. Leukemia. 2007;21:956-964); MRD samples were collected at confirmation of suspected CR (bone marrow) and every 3 months thereafter (peripheral blood). Rate of MRD-negative response was defined as the proportion of pts who reached negative disease status (< 0.01%, ie, < 1 CLL cell/10,000 leukocytes) in any sample. Reported MRD rates are based on the intent-to-treat (ITT) population. Results The ORR assessed by the IRC was 82.7% with ibrutinib + BR vs 67.8% with placebo + BR (p < 0.0001), and was consistent with ORR reported by the treating physician (investigator assessed) (ORR: 86.2% vs 68.9%, p < 0.0001). However, rates of CR/CRi were higher by investigator assessment (21.4%, ibrutinib + BR vs 5.9%, placebo + BR) than IRC (10.4% vs 2.8%). The IRC employed an independent evaluation of radiological scans including stringent evaluation of LN and volumetric assessment of spleen size-the main reasons for the difference in CR/CRi rates between investigator and IRC assessment. At baseline, similar proportions of pts in each arm had bulky disease defined as LN > 5 cm (54%-58%) or abnormal spleen (~40%) as assessed by IRC. Complete resolution of previous CLL/SLL manifestations as assessed by the IRC was achieved more often in the ibrutinib + BR arm in comparison with placebo + BR for LN (34.6% vs 15.2%), spleen (56.7% vs 37.0%), overall radiology (21.1% vs 9.0%), and BM (19.7% vs 5.9%). Rates of normalization of ALC (> 90%) and CBC (> 70%) were high and similar in the 2 arms. MRD was assessed in 120 pts treated with ibrutinib + BR and 57 pts treated with placebo + BR and was negative in 37 pts and 14 pts, respectively, which corresponds with an MRD-negative response rate of 12.8% vs 4.8% for ibrutinib + BR vs placebo + BR (p = 0.0011). Investigator-determined responses by different levels of MRD are shown in Table 1. The percentage of pts with an MRD level < 1% was higher with ibrutinib + BR vs placebo + BR (32.2% vs 11.8%). Moreover, the percentage of pts with an MRD level < 0.1% was higher for ibrutinib + BR vs placebo + BR (24.6% vs 7.6%) suggesting that the depth of response with ibrutinib + BR was superior. Kaplan-Meier plots by MRD level (Figure 1) show that a lower MRD level was associated with a longer PFS. However, pts in the ibrutinib + BR arm had a more sustained response at every MRD level compared with pts in the placebo + BR arm. Conclusions Pts treated with ibrutinib + BR showed not only a higher ORR, but also a greater depth of response, with more CRs and a higher rate of resolution of LN, spleen, and BM involvement. Furthermore, the rate and depth of MRD negativity was improved, and appeared to last longer in pts treated with ibrutinib + BR compared with pts receiving placebo + BR. With a median follow up of 17 months in the ibrutinib + BR arm, no MRD-negative pts and few MRD-positive pts had progressed, thus evaluating a trend in PFS with MRD negativity is currently limited in this arm. Disclosures Cramer: Gilead: Other: Travel grant, Research Funding; Glaxo Smith Klein/Novartis: Research Funding; Astellas: Other: Travel grant; Mundipharma: Other: Travel grant; Janssen: Other: Travel grant, Research Funding, Speakers Bureau; Hoffman LaRoche: Other: Travel grant, Research Funding, Speakers Bureau. Off Label Use: Combination of bendamustine, obinutuzumab and ibrutinib for treatment of CLL. Fraser:Hoffman LaRoche: Consultancy, Honoraria; Janssen: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding. Demirkan:Amgen: Consultancy; Celgene: Other: Travel reimbursement. Santucci Silva:Merck: Research Funding; Celgene: Research Funding; GSK: Research Funding; Janssen: Other: Travel reimbursement, Research Funding; Hoffman LaRoche: Other: Travel reimbursement, Research Funding; Novartis: Other: Travel reimbursement. Janssens:Mundipharma: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy. Goy:Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Mayer:Janssen: Research Funding. Dilhuydy:Roche: Honoraria, Other: Travel reimbursement; Janssen: Honoraria, Other: Travel reimbursement; Mundipharma: Honoraria. Bartlett:Millenium: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; ImaginAB: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Gilead: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celgene: Research Funding. Rule:Roche: Consultancy, Other: Travel reimbursement; J&J: Consultancy, Other: Travel reimbursement, Research Funding; Celgene: Consultancy, Other: Travel reimbursement; Gilead: Research Funding. Sun:Janssen/J&J: Employment, Equity Ownership. Phelps:Janssen/J&J: Employment, Equity Ownership. Mahler:Janssen: Employment, Other: Travel reimbursement. Salman:Janssen/J&J: Employment, Equity Ownership. Schaffer:Janssen: Employment. Balasubramanian:Pharmacyclics LLC, an AbbVie Company: Equity Ownership; Janssen: Employment, Equity Ownership. Howes:Janssen/J&J: Employment, Equity Ownership. Hallek:AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding.