Rule, Simon

Abstract Despite the effectiveness of immuno-chemotherapy, 40% of patients with diffuse large B-cell lymphoma (DLBCL) experience relapse or refractory disease. Longitudinal studies have previously focused on the mutational landscape of relapse but fell short of providing a consistent relapse-specific genetic signature. In our study, we have focused attention on the changes in GEP accompanying DLBCL relapse using archival paired diagnostic/relapse specimens from 38 de novo patients with DLBCL. COO remained stable from diagnosis to relapse in 80% of patients, with only a single patient showing COO switching from activated B-cell–like (ABC) to germinal center B-cell–like (GCB). Analysis of the transcriptomic changes that occur following relapse suggest ABC and GCB relapses are mediated via different mechanisms. We developed a 30-gene discriminator for ABC–DLBCLs derived from relapse-associated genes that defined clinically distinct high- and low-risk subgroups in ABC–DLBCLs at diagnosis in datasets comprising both population-based and clinical trial cohorts. This signature also identified a population of <60-year–old patients with superior PFS and OS treated with ibrutinib–R-CHOP as part of the PHOENIX trial. Altogether this new signature adds to the existing toolkit of putative genetic predictors now available in DLBCL that can be readily assessed as part of prospective clinical trials.

AbstractBackgroundStudies suggest that immune checkpoint inhibitors may represent a promising strategy for boosting immune responses and improving the antitumor activity of standard therapies in patients with relapsed/refractory hematologic malignancies.AimsPhase 1/2 FUSION NHL 001 was designed to determine the safety and efficacy of durvalumab, an anti‐programmed death ligand 1 (PD‐L1) antibody, combined with standard‐of‐care therapies for lymphoma or chronic lymphocytic leukemia (CLL).Methods and ResultsThe primary endpoints were to determine the recommended phase 2 dose of the drugs used in combination with durvalumab (durvalumab was administered at the previously recommended dose of 1500 mg every 4 weeks) and to assess safety and tolerability. Patients were enrolled into one of four arms: durvalumab monotherapy (Arm D) or durvalumab in combination with lenalidomide ± rituximab (Arm A), ibrutinib (Arm B), or rituximab ± bendamustine (Arm C). A total of 106 patients with relapsed/refractory lymphoma were enrolled. All but two patients experienced at least one treatment‐emergent adverse event (TEAE); those not experiencing a TEAE were in Arm C (diffuse large B‐cell lymphoma [DLBCL]) and Arm D (DLBCL during the durvalumab monotherapy treatment period). No new safety signals were identified, and TEAEs were consistent with the respective safety profiles for each study treatment. Across the study, patients with follicular lymphoma (FL; n = 23) had an overall response rate (ORR) of 59%; ORR among DLBCL patients (n = 37) was 18%. Exploratory biomarker analysis showed that response to durvalumab monotherapy or combination therapy was associated with higher interferon‐γ signature scores in patients with FL (p = .02).ConclusionDurvalumab as monotherapy or in combination is tolerable but requires close monitoring. The high rate of TEAEs during this study may reflect on the difficulty in combining durvalumab with full doses of other agents. Durvalumab alone or in combination appeared to add limited benefit to therapy.

Background: Although diffuse large B cell lymphoma (DLBCL) can be cured using immuno-chemotherapy, 40% of patients experience relapse or refractory disease. Large-scale profiling studies have mainly focused on DLBCL at diagnosis, resolving different outcome groups based on gene expression (e.g. cell-of-origin (COO) or molecular high grade), MYC/BCL2 translocations (double-hit lymphoma) or gene mutations and copy number aberrations (Schmitz et al, NEJM 2018; Chapuy et al, NatureMedicine 2018). In comparison, longitudinal studies have been hindered by the limited availability of sequential biopsy samples. To date, the relapse-specific gene mutations identified are limited and inconsistent across studies. In our study, we have focussed attention on the changes in gene expression profile (GEP) accompanying DLBCL relapse. Methods: We retrospectively collected archival paired diagnostic/relapse formalin fixed paraffin embedded tumor biopsies from 38 de novo DLBCL patients collected from multiple UK sites treated with rituximab-based immuno-chemotherapy, where partial or complete remission was reported following treatment. COO classification was performed by the Lymph2Cx assay on NanoString to distinguish activated B-cell-like (ABC) and germinal center B-cell-like (GCB) subtypes. The Ion AmpliSeq™ Transcriptome Human Gene Expression Kit was used to measure the expression levels of > 20,000 genes on the paired samples. Results: COO remained stable from diagnosis to relapse in 17 ABC-ABC pairs, 11 GCB-GCB pairs and 4 unclassified (UNC)-UNC pairs. Frank COO switching was observed in 6 cases (1 ABC-GCB, 2 ABC-UNC, 2 GCB-UNC, 1 UNC-ABC). Pairs with stable COO were taken forward for further analysis. Gene expression analysis using the limma R package identified 163 and 136 genes as differentially expressed (DE) (p <= 0.01 and absolute log2FC > 1) between the diagnostic and relapse biopsies in ABC and GCB tumors respectively, with only a one gene overlap. Gene Set Enrichment Analysis further suggested that ABC and GCB relapses are mediated via different mechanisms, with tumor growth and proliferation signatures enriched in ABC relapses, whilst adaptive immunity-related signatures accompanied GCB relapses. Next, we aimed to utilise our relapse-specific genes to identify outcome predictors at diagnosis using publicly available GEP datasets. In order to increase our discovery power and accuracy, a larger set of DE genes from the paired differential analysis (796 genes in ABC pairs and 387 from GCB pairs) were selected (p <= 0.05) and subsequently used in a training cohort (GEP from Reddy et al, Cell 2017). The Prediction Analysis for Microarrays R (PAMR) algorithm identified a 30-gene signature within DE genes from ABC pairs (Fig1.A), capable of separating the 249 ABC cases into 136 low and 113 high-risk cases with significantly inferior overall survival (Hazard Ratio (HR)=1.89, log-rank p=0.0017, measure of goodness-of-fit C-index=0.71; Fig1.B). No equivalent signature was found in the GCB cases using this approach. The prognostic significance of this 30-gene discriminator was successfully validated using a linear predictor in two independent GEP datasets: 1) a population-based cohort (Lenz et al, NEJM 2008) with 93 R-CHOP-treated ABC cases identifying 47 low and 46 high-risk cases (HR=1.92, p=0.046, C-index=0.77; Fig1.C) and 2) a clinical trial dataset (REMoDL-B, Davies et al, Lancet Oncol 2019) with 255 ABC cases identifying 110 low and 145 high-risk ABC cases (HR=1.95, p=0.0051, C-index=0.70; Fig1.D). Conclusions: Here we describe a 30-gene discriminator in ABC-DLBCL, derived from genes differentially expressed between diagnosis and relapse, that allowed the definition of clinically distinct high and low risk subgroups in ABC-DLBCLs at diagnosis. The clinical translation of such a tool may be useful to guide therapy for this unfavourable subgroup of ABC-DLBCLs. Validation of this signature is currently underway in additional datasets and further study is required to understand the contribution of these genes in DLBCL pathology. Disclosures Korfi: Roche: Consultancy. Burton:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rule:TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Crosbie:Janssen: Honoraria. Scott:Celgene: Consultancy; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding; Roche/Genentech: Research Funding. Rimsza:NanoSting: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution]. Davies:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: 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; Pfizer: Honoraria, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Acerta Pharma: Honoraria, Research Funding; ADCT Therapeutics: Honoraria, Research Funding; BioInvent: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gribben:Abbvie: Consultancy, Honoraria, Research Funding; Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Okosun:Gilead Sciences: Honoraria, Research Funding. Johnson:Epizyme: Honoraria, Research Funding; Novartis: Honoraria; Kite: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Boehringer Ingelheim: Honoraria; Takeda: Honoraria; Genmab: Honoraria; Celgene: Honoraria; Incyte: Honoraria. Fitzgibbon:Epizyme: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Speakers Bureau.

Abstract Background: Mantle cell lymphoma (MCL) remains challenging particularly in the relapsed/refractory setting, where patients often show chemoresistance. Novel molecular-based therapies have shown impressive and durable activity in that setting, although primary and acquired resistance remains problematic. A recent retrospective series of 114 patients who had failed ibrutinib (median of 4.7 month exposure) showed very short median overall survival of 2.9 months after ibrutinib cessation (Martin et al. Blood 2015). Here we report the results from the observationalMCL-004 study investigating outcomes of patients treated with lenalidomide (an IMiD® immunomodulatory agent) after failing ibrutinib; patients were either relapsed, progressed, refractory, or intolerant to ibrutinib. The objective here is to evaluate the clinical effectiveness of lenalidomide monotherapy or a lenalidomide-containing regimen in relapsed/refractory MCL after ibrutinib failure or intolerance. Methods: MCL-004 is a multicenter study in patients with MCL who relapsed/progressed after or were refractory/intolerant to ibrutinib, and were subsequently treated with lenalidomide. With patient informed consent, data were collected retrospectively from patients who, after their disease failed to respond to ibrutinib, received lenalidomide-based therapy from March 1, 2009 to June 9, 2015. The primary endpoint was investigator-assessed overall response rate (ORR) based on 2007 International Working Group criteria, with required patient monitoring and routine imaging. Results: Thirty patients were enrolled at 7 US sites and 1 EU site, including patients receiving lenalidomide monotherapy (n=8), lenalidomide + rituximab (n=8), and lenalidomide + other treatment (n=14). Lenalidomide + other treatment included combination with rituximab, carfilzomib, and dexamethasone (n=3); other combinations were given in ≤2 patients. Patients had a median age of 69 years (range, 50-84), and median time from last dose of ibrutinib to first dose of lenalidomide was 1.3 weeks (range, 0.1-21.7). All patients received ≥2 prior lines of therapy, and 83% received ≥3 prior therapies (median prior therapies, 3.5; range, 2-8). With prior ibrutinib, the best responses achieved were 10% complete response (CR), 43% partial response (PR), 3% stable disease, 40% relapse/progressive disease (PD), and 3% unknown. Primary reasons for ibrutinib discontinuation were 50% relapse/PD, 40% refractory, and 10% intolerance. Patients received a median of 2 cycles (range, 1-11) of lenalidomide-based treatment. Eight patients' disease responded (4 CR, 4 PR), resulting in an ORR of 27% (95% CI, 12%-46%). Five of 8 maintained their response at data cut-off (3 CR, 2 PR). ORR was similar for patients with relapse/PD vs. those refractory to ibrutinib (29% vs. 33%, respectively). Median duration of response (DOR) was 18 weeks (95% CI, 2.9-25+) for all patients. Median DOR was not reached in patients who previously relapsed/progressed with ibrutinib compared with a median of 11 weeks for those whose disease was refractory to ibrutinib. Most common treatment-emergent adverse events (TEAEs) were 33% fatigue; 27% nausea; and 23% each dyspnea, neutropenia, dizziness, or rash. In general, TEAEs were less common with lenalidomide monotherapy. The most frequently reported serious AEs were pneumonia, dyspnea, deep vein thrombosis, hypotension, and acute kidney injury (7% each). At data cutoff, 15 patients (50%) had died, mostly due to MCL and none due to second primary malignancy. Conclusions: Most patients received ≥3 prior lines of treatment, and median time from last dose of ibrutinib to first dose of lenalidomide was short. Lenalidomide-based treatment showed clinical activity in this difficult-to-treat patient population, including 27% ORR and 13% CR. No new safety signals for lenalidomide were identified. Overall, our results show that lenalidomide is active in a selected group of patients with relapsed/refractory MCL that previously failed ibrutinib. Disclosures Wang: BeiGene: Research Funding; Asana BioSciences: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Kite Pharma: Research Funding; Juno Therapeutics: Research Funding; Onyx: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Martin:Acerta: Consultancy; Teva: Research Funding; Novartis: Consultancy; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses. Goy:Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Writing support, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Johnson & Johnson: 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; Genentech: Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hamadani:Takeda: Research Funding. Ghosh:Gilead: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; SGN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Research Funding. Reeder:Millennium: Research Funding; BMS: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Barnett:Celgene Corporation: Employment, Equity Ownership. Casadebaig Bravo:Celgene: Employment, Equity Ownership. Schuster:Pharmacyclics: Consultancy, Research Funding; Novartis: Research Funding; Gilead: Research Funding; Janssen Research & Development: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Hoffman-LaRoche: Research Funding.

Abstract Introduction In 2 large phase 3 trials of patients (pts) with relapsed or refractory (R/R) CLL/SLL, single-agent ibrutinib (ibr) was superior to ofatumumab (ofa) (RESONATE; Byrd. NEJM 2013) and ibr + BR was superior to placebo + BR (HELIOS; Chanan-Khan. ASCO 2015). Both studies evaluated ibr in different pt populations with different relevant comparators (eg, ofa in pts who had relapsed following prior anti-CD20-based chemoimmunotherapy [CIT] and/or with del17p, and BR in pts eligible for CIT). In the absence of head-to-head evaluations of single-agent ibr vs BR or single-agent ibr vs ibr + BR, indirect comparisons can be used for hypothesis testing by potentially providing insights on the relative efficacy of treatments. As such, an indirect comparative analysis of data from RESONATE and HELIOS was performed. Recognizing biases inherent in cross-trial comparisons, including lack of randomization across trials and consequent differences in distributions of important confounding variables (eg, pt characteristics, prognostic factors), we used pt-level data from both studies to risk adjust for confounders using accepted multivariate statistical approaches. Methods In RESONATE, pts received 420 mg oral ibr daily until disease progression or unacceptable toxicity or intravenous ofa for up to 24 weeks. The primary end point was IRC-assessed PFS, with secondary end points of OS and ORR. In HELIOS, pts received BR (≤ 6 cycles) with either 420 mg oral ibr daily or placebo until disease progression or unacceptable toxicity. Pts with del17p were excluded. The primary end point was IRC-assessed PFS, with secondary end points of ORR and OS. Per protocol amendment in both studies, pts in comparator arms could switch to ibr upon IRC-confirmed progression. The current exploratory analysis was based on the latest available data from each trial (median time on study: RESONATE, 19 months; HELIOS, 17 months) using investigator assessments, but excluding del17p pts from RESONATE. Analyses were performed using data from both the overall CLL/SLL population and only the CLL pts. Separate multivariate Cox proportional hazards models were constructed for PFS and OS, including treatment and clinically relevant prognostic variables as covariates (age, gender, Rai staging, ECOG score, del11q status, refractory status, number of prior lines of therapy, bulky disease, IgVH status). Adjusted HRs and 95% CIs are presented vs single-agent ibr, along with predicted survival curves derived from the multivariate Cox regressions. Results RESONATE and HELIOS enrolled populations with notable differences making naïve comparison flawed. Because HELIOS enrolled only CIT-eligible pts, the trial included younger pts who had received fewer lines of therapy, as well as lower proportions of pts with purine analog refractory disease, del11q, or Rai stage 4 disease. These factors have been previously reported to influence outcomes in pts with R/R CLL/SLL and thus were included as covariates in the statistical models. Other baseline factors (gender, ECOG score, bulky disease, and IgVH status) were not notably different between the trials, but were found to impact PFS and OS and thus were included as additional covariates. In the overall CLL/SLL population, PFS and OS were comparable for single-agent ibr vs ibr + BR, and were significantly improved for single-agent ibr vs BR (Figure 1). Results for only the CLL pts were similar to those shown in Figure 1 for both PFS (ibr + BR vs single-agent ibr: 1.03 [0.61-1.75], p = 0.9042; BR vs single-agent ibr: 7.52 [4.72-11.99], p < 0.0001; single-agent ibr reduced the risk of progression/death by 87% vs BR) and OS (ibr + BR vs single-agent ibr: 1.20 [0.59-2.43], p = 0.6197; BR vs single-agent ibr: 2.24 [1.14-4.40], p = 0.0197; single-agent ibr reduced the risk of death by 55% vs BR). Conclusions The adjusted indirect comparisons reported here suggest superiority of single-agent ibr over BR for PFS and OS in patients with R/R CLL/SLL. The comparisons also suggest that the addition of BR to ibr did not improve PFS or OS compared with single-agent ibr. However, as median PFS has not been reached for either ibr arm, it is too early to draw firm conclusions. Longer follow-up in the ibr arms of these studies will be required to give an indication of whether CIT adds any benefit to ibrutinib for PFS and OS. Overall, these findings provide support for single-agent ibr as an appropriate choice for all pts with previously treated CLL/SLL. Disclosures Hillmen: Roche Pharmaceuticals: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding. Fraser:Janssen: Honoraria, Research Funding, Speakers Bureau; Hoffman LaRoche: Consultancy, Honoraria; Celgene: Honoraria, Research Funding. Jones:Acerta Pharma BV: Research Funding. Rule:Roche: Consultancy, Other: Travel reimbursement; J&J: Consultancy, Other: Travel reimbursement, Research Funding; Celgene: Consultancy, Other: Travel reimbursement; Gilead: Research Funding. Dilhuydy:Roche: Honoraria, Other: Travel reimbursement; Janssen: Honoraria, Other: Travel reimbursement; Mundipharma: Honoraria. Jaeger:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cymbalista:Karyopharm: Honoraria; Roche: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Research Funding. Sun:Janssen/J&J: Employment, Equity Ownership. Ninomoto:Pharmacyclics LLC, an AbbVie Company: Employment. Mahler:Janssen: Employment, Other: Travel reimbursement. Cheng:Pharmacyclics LLC, an AbbVie Company: Employment. Diels:Janssen: Employment. Clow:Pharmacyclics LLC, an AbbVie Company: Employment. Salman:Janssen/J&J: Employment, Equity Ownership. James:Pharmacyclics LLC, an AbbVie Company: Employment. Howes:Janssen/J&J: Employment, Equity Ownership.

Abstract Introduction Ibrutinib has become a new standard of care in patients with previously treated CLL/SLL based on the phase 3 RESONATE study (Byrd, et al. NEJM 2014) and other trials evaluating ibrutinib mainly as a single agent in CLL. The first randomized, double-blind, placebo-controlled phase 3 study (HELIOS) investigating ibrutinib in combination with bendamustine and rituximab (BR) was recently reported (Chanan-Khan, et al. ASCO 2015), with ibrutinib significantly extending progression-free survival and reducing the risk of progression/death by 80%. The study design provides an opportunity to examine the overall safety and management of adverse events (AEs) with ibrutinib and placebo in a blinded manner that previously has not been possible. Here we examine the safety and management of AEs with ibrutinib + BR vs placebo + BR in HELIOS. Methods Patients with active CLL/SLL following ≥ 1 prior line of systemic therapy were randomized 1:1 to receive BR (≤ 6 cycles) with either ibrutinib 420 mg daily or placebo (n = 289 in each group). Safety was a secondary end point. Results Median exposure to ibrutinib and placebo was 14.7 and 12.8 months, respectively. Rates of infection in the ibrutinib + BR and placebo + BR arms were similar (all-grade, 70.4%; grade ≥ 3, 26.8% vs all-grade, 70.0%; grade ≥ 3, 22.6%, respectively) but exposure-adjusted analysis reveals an overall lower rate of infections with ibrutinib + BR vs placebo + BR (10.3/100 vs 11.2/100 patient-months), with similar rates of grade ≥ 3 infections (2.4/100 patient-months each arm). Rates of all-grade (grade 3/4) anemia were 22.3% (3.5%) with ibrutinib + BR and 28.9% (8.0%) with placebo + BR. Patients also required fewer transfusions with ibrutinib + BR (23%) vs placebo + BR (29%), the majority of which were red blood cell transfusions. Similar proportions of patients used growth factors in both arms (54% vs 52%, respectively). Grade 3/4 neutropenia was reported at similar rates in both arms (53.7% vs 50.5%, respectively); however, fewer patients discontinued due to treatment-related neutropenia with ibrutinib + BR (1.0%) vs placebo + BR (2.8%). Rates of thrombocytopenia were slightly higher with ibrutinib + BR (30.7%) than placebo + BR (24.0%), but rates of grade 3/4 events were similar between arms (15.0% each arm). Atrial fibrillation (AF) was observed more frequently in patients on ibrutinib + BR than placebo + BR (7.3% vs 2.8% overall and 2.8% vs 0.7% grade 3/4, respectively). However, only 4 patients with grade 3/4 AF discontinued therapy in the ibrutinib arm. No patients with grade 1/2 AF discontinued treatment. One-third of patients held ibrutinib treatment to manage AF, with all restarting at the same dose (420 mg). Median (range) time to onset was 3.0 (0.3-17.5) months with ibrutinib + BR and 2.4 (0.6-18.9) months with placebo + BR. Importantly, in those with a prior history of AF or abnormal heart rhythm, only 7/25 receiving ibrutinib + BR and 2/22 receiving placebo + BR developed AF/atrial flutter on study. The rates of any-grade bleeding were 31.0% and 14.6%, respectively, with the majority being grade 1 (77.5% and 69.0%, respectively). Low rates of grade 3/4 major bleeding were observed in the ibrutinib + BR (2.1%) and placebo + BR (1.7%) arms. Many patients (41.8% ibrutinib + BR, 41.1% placebo + BR) were receiving concomitant anticoagulant/antiplatelet medication. A low rate of treatment-related lymphocytosis was observed in both arms (7.0% ibrutinib + BR, 5.9% placebo + BR). The majority of cases resolved within 2 weeks. Conclusions In this randomized, double-blind, placebo-controlled trial, the addition of ibrutinib to BR was well tolerated and did not significantly impact the safety profile of BR. In addition, ibrutinib was associated with reduced rates of anemia and transfusional support. Consistent with its known toxicity profile, patients in the ibrutinib + BR arm had higher rates of bleeding (mostly grade 1 or 2) and AF; however, few patients discontinued therapy as a result of these AEs. A prior history of AF or abnormal heart rhythm did not lead to recurrent episodes in the majority of cases. Taken together, the results from HELIOS establish the significant efficacy of ibrutinib and also the overall positive risk-benefit profile of ibrutinib + BR. Disclosures Cramer: Janssen: Other: Travel grant, Research Funding, Speakers Bureau; Hoffman LaRoche: Other: Travel grant, Research Funding, Speakers Bureau; Astellas: Other: Travel grant; Glaxo Smith Klein/Novartis: Research Funding; Gilead: Other: Travel grant, Research Funding; Mundipharma: Other: Travel grant. Demirkan:Celgene: Other: Travel reimbursement; Amgen: Consultancy. Fraser:Hoffman LaRoche: Consultancy, Honoraria; Janssen: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding. Santucci Silva:Janssen: Other: Travel reimbursement, Research Funding; GSK: Research Funding; Celgene: Research Funding; Merck: Research Funding; Novartis: Other: Travel reimbursement; Hoffman LaRoche: Other: Travel reimbursement, Research Funding. Janssens:Roche: Consultancy, Speakers Bureau; Mundipharma: 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: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; Millenium: Research Funding; Celgene: Research Funding. Rule:Roche: Consultancy, Other: Travel reimbursement; Gilead: Research Funding; Celgene: Consultancy, Other: Travel reimbursement; J&J: Consultancy, Other: Travel reimbursement, 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. Howes:Janssen/J&J: Employment, Equity Ownership. Hallek:AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding.

Abstract 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<0.0001), overall response rate (ORR) and rates of complete response (CR) or CR with incomplete marrow recovery (CRi) were significantly improved with ibrutinib + BR (ORR: 82.7% vs 67.8%; CR/CRi: 10.4% vs 2.8%). Here we report additional analyses on the quality of response with ibrutinib combined with BR. 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.