Abstract: This is a 5‐year real‐world study of 65 patients treated with ibrutinib for relapsed/refractory mantle cell lymphoma across the UK and Ireland. Ibrutinib was well tolerated with no fatal adverse events. The median progression‐free survival and overall survival (OS) was 12 and 18·5 months, respectively. Overall, 80% of patients discontinued treatment, predominantly for progressive disease. On discontinuation, 20% received alternative immunochemotherapy with a median OS of 24 months. Ibrutinib was used as a bridge to transplant in 8% (median OS not reached). These observations are comparable with trial outcomes with encouraging responses to immunochemotherapy at relapse.

Abstract: Introduction In the phase 3, double-blind, placebo (pbo)-controlled PHOENIX trial (NCT01855750), 838 patients (pts) with non-germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL) were randomized 1:1 to ibrutinib (IBR; 560 mg/day orally) + rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or pbo + R-CHOP. IBR + R-CHOP did not improve event-free survival (EFS) in the intent-to-treat (ITT) non-GCB population (hazard ratio [HR] 0.934; 95% confidence interval [CI] , 0.726-1.200). However, in an exploratory analysis, pts & lt; 60 years benefited from the addition of IBR (HR 0.579; 95% CI, 0.380-0.881 for EFS), whereas pts ≥ 60 years did not (HR 1.228; 95% CI, 0.887-1.699 for EFS) due to increased toxicity and reduced R-CHOP exposure. Based on evidence that co-expression of BCL2 and MYC by immunohistochemistry (IHC) have a worse outcome with R-CHOP, we examined their clinical prognostic effect in the 2 arms of the PHOENIX trial. Methods Pretreatment formalin-fixed paraffin-embedded biopsy samples were collected. RNA was extracted and profiled with Illumina RNAseq. Raw sequence reads were aligned to the hs37d5 genome build with STAR v2.5.1b, and gene-level quantification was conducted using RSEM v1.2.23. The median transcript per million mapped reads (TPM) values for BCL2 and MYC gene expression across all pts with RNAseq data (n = 766) were used as the cutoffs between high and low expression for each gene. BCL2 IHC data were available from 184 pts, and based on these, the threshold expression value from RNAseq data that could best approximate positive calls from IHC (≥ 50% lymphoma cells positive) was determined. This threshold value was very close to the median level calculated above and therefore supported the use of the median expression levels as the cutoffs to define high and low expressors in the subsequent analyses. The relationship between expression by RNAseq and survival (EFS, overall survival [OS] ) in the 2 study arms was analyzed by Kaplan-Meier estimate with Cox regression to determine HRs and log-rank testing to assess significance. Results Based on a cutoff at the median TPM value, the percentage of non-GCB pts with BCL2-high + MYC-high (n = 234, 30.5%) was consistent with previous literature. In the IBR + R-CHOP (n = 386) and pbo + R-CHOP (n = 380) arms, respectively, 123 (31.9%) and 111 (29.2%) pts were MYC-high + BCL2-high by RNAseq. In the pbo + R-CHOP arm, pts with MYC-high + BCL-2-high had worse EFS (HR 1.820; 95% CI, 1.264-2.620; p = 0.0011) and OS (HR 1.662; 95% CI, 1.014-2.724; p = 0.0415) versus those with low expression of 1 or both markers in the ITT population (Figure), consistent with known poor outcomes associated with these genes. However, there was no difference in outcome for high versus low expression of these genes in the IBR + R-CHOP arm in the ITT population. In the ITT population, pts with MYC-high + BCL2-high had better EFS (HR 0.648; 95% CI, 0.423-0.993; p = 0.045) with IBR + R-CHOP versus pbo + R-CHOP, but there was no significant difference in OS (HR 0.783; 95% CI, 0.446-1.372; p = 0.39; Figure). We also examined the outcome of the 97 (30.6%) pts & lt; 60 years of age (n = 317) with MYC-high + BCL2-high and observed an improved EFS and OS with IBR + R-CHOP versus pbo + R-CHOP (HR 0.393; 95% CI, 0.198-0.780; p = 0.0056 for EFS; HR 0.191; 95% CI, 0.055-0.666; p = 0.0037 for OS; Figure). There was no significant difference in EFS or OS in pts & lt; 60 years with MYC-low + BCL2-low or in pts ≥ 60 years with MYC-high + BCL2-high in the 2 arms. Conclusions In this exploratory analysis, IBR was associated with improved EFS in combination with R-CHOP compared with pbo + R-CHOP in pts with MYC-high + BCL2-high expression in the ITT (non-GCB) population, without a significant improvement in OS. In pts aged & lt; 60 years, both EFS and OS were significantly better with IBR, while there was no significant difference in older pts. These data suggest that IBR + R-CHOP may particularly benefit pts with MYC-high + BCL2-high-expressing lymphomas, a hypothesis warranting further testing in other DLBCL cohorts. Disclosures Johnson: Novartis: Honoraria; Genmab: Honoraria; Kite: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; Incyte: Honoraria; Boehringer Ingelheim: Honoraria. Balasubramanian:Janssen: Employment; Johnson & Johnson: Equity Ownership; Gilead Sciences: Equity Ownership; Celgene: Equity Ownership; Vertex: Equity Ownership; AbbVie: Equity Ownership. Hodkinson:Janssen: Employment. Schaffer:Johnson & Johnson: Equity Ownership; Janssen: Employment. Parisi:Janssen: Employment. Shreeve:Johnson & Johnson: Equity Ownership; Janssen: Employment. Sun:Janssen: Employment; Johnson & Johnson: Equity Ownership. Vermeulen:Johnson & Johnson: Equity Ownership; Janssen: Employment. Sehn:Abbvie: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Janssen-Ortho: Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Lundbeck: Consultancy, Honoraria. Staudt:Nanostring: Patents & Royalties. Younes:AstraZeneca: Research Funding; Biopath: Consultancy; Genentech: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding; BMS: Research Funding; HCM: Consultancy; Epizyme: Consultancy, Honoraria; Xynomics: Consultancy; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria.

Abstract: Introduction Mantle cell lymphoma (MCL) is a rare and aggressive form of Non-Hodgkin's lymphoma (NHL) with poor survival outcomes. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is recommended as first-line therapy in younger patients. However the comparative efficacy of such regimens, and of alternative therapy options (for patients unable to tolerate chemotherapy + ASCT), remain unclear. A comprehensive understanding of the current evidence is therefore required. Methods Two systematic reviews (SRs) were developed to identify efficacy and safety data for therapies used in the first-line treatment of MCL. One review identified randomised controlled trials (RCTs) and the other non-randomised studies (NRSs). Searches were carried out in EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Clinical Trials electronic databases. Additionally, conference materials were screened from ASH, EHA, ESMO and ASCO proceedings from the last 2 years. All review methodologies were performed according to Cochrane best practice guidelines Results The RCT SR was run in August 2017 and updated in April 2018. Overall, 2,787 abstracts were screened. The SR included 9 full-text articles and data from 2 conference proceedings, together reporting a total of 7 independent studies. Across the RCTs, the most commonly investigated treatment regimens were rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone (R-CHOP), and bendamustine + rituximab (BR). Frequently reported primary endpoints were response rates and progression-free survival (PFS). Table 1 presents the PFS and overall survival (OS) data reported in the included RCTs. Data from the RCT reporting on intensive induction chemotherapy followed by ASCT are separated from regimens that did not include ASCT. There were notable differences in median PFS rates, between both patients receiving ASCT versus patients not receiving ASCT and also between the two ASCT treatment arms. In pharmacotherapy studies, PFS ranged from 14.4 to 35.4 months, whereas the two arms of the ASCT RCT reported 51.6 and 109.2 months, respectively. Similar trends were observed in OS: the only result for patients undergoing ASCT (117.6 months) was higher than any result reported in patients not receiving transplant (range 40 - 60 months). However, study heterogeneity may affect the appropriateness of directly comparing these results. Frequently reported grade 3-4 adverse events included anemia, infusion-related reactions, nausea, neutropenia and thrombocytopenia (four of seven RCTs reported each event). The NRS SR was run in April 2018. A total of 3,290 abstracts were screened and 75 full papers were assessed. The SR included 25 full-text articles and 6 conference proceedings, together reporting a total of 18 independent single-arm studies. Several of the NRSs investigated treatment regimens that have not been described in RCT studies, including: R-CHOP with alternating or sequential rituximab + cytarabine (maxiCHOP), and cyclophosphamide + vincristine + doxorubicin + dexamethasone alternating with high dose methotrexate or cytarabine + rituximab (hyperCVAD + R). Across the NRSs, the longest median PFS was 8.5 years (102 months), in patients treated with maxiCHOP (who were young/ASCT-eligible patients). This outcome was reported in a patient population who had responded to induction therapy and were treated with consolidative ASCT. Across all studies there was heterogeneity in the eligible patient population, with some studies focusing on unfit patients and others focusing on high-dose-therapy-eligible patient populations. Many studies also reported maintenance or consolidation treatments, which would influence the long-term outcomes of the patients. Conclusions These SRs highlight the paucity of directly comparable evidence on the efficacy and safety of therapies for patients with MCL. Although there are some marked differences in patient outcomes according to therapy regimen, considerable heterogeneity in study design and patient populations make direct comparison difficult. Despite this, these SRs highlight that MCL remains a difficult subtype of NHL to treat, with short survival highlighting the high unmet need. With new and emerging therapies, additional research is essential to understand optimal regimens for first-line MCL. Table 1. Table 1. Disclosures Monga: Janssen Pharmaceutica NV: Employment. Garside:Janssen Pharmaceutica NV: Employment. Davids:Merck: Consultancy; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; BMS: Research Funding; Surface Oncology: Research Funding; Celgene: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: 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; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tam:BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ward:Janssen Pharmaceutica NV: Consultancy. Quigley:Janssen Pharmaceutica NV: Consultancy. Parisi:Janssen: Employment. Tapprich:Janssen Pharmaceutica NV: Employment.

Abstract: In GLOW, fixed-duration ibrutinib + venetoclax showed superior progression-free survival (PFS) versus chlorambucil + obinutuzumab in older/comorbid patients with previously untreated chronic lymphocytic leukemia (CLL). The current analysis describes minimal residual disease (MRD) kinetics and any potential predictive value for PFS, as it has not yet been evaluated for ibrutinib + venetoclax treatment. METHODS Undetectable MRD (uMRD) was assessed by next-generation sequencing at 〈 1 CLL cell per 10,000 ( 〈 10 −4 ) and 〈 1 CLL cell per 100,000 ( 〈 10 −5 ) leukocytes. PFS was analyzed by MRD status at 3 months after treatment (EOT+3). RESULTS Ibrutinib + venetoclax achieved deeper uMRD ( 〈 10 −5 ) rates in bone marrow (BM) and peripheral blood (PB), respectively, in 40.6% and 43.4% of patients at EOT+3 versus 7.6% and 18.1% of patients receiving chlorambucil + obinutuzumab. Of these patients, uMRD ( 〈 10 −5 ) in PB was sustained during the first year post-treatment (EOT+12) in 80.4% of patients receiving ibrutinib + venetoclax and 26.3% receiving chlorambucil + obinutuzumab. Patients with detectable MRD (dMRD; ≥10 −4 ) in PB at EOT+3 were more likely to sustain MRD levels through EOT+12 with ibrutinib + venetoclax versus chlorambucil + obinutuzumab. PFS rates at EOT+12 were high among patients treated with ibrutinib + venetoclax regardless of MRD status at EOT+3: 96.3% and 93.3% in patients with uMRD ( 〈 10 −4 ) and dMRD (≥10 −4 ) in BM, respectively, versus 83.3% and 58.7% for patients receiving chlorambucil + obinutuzumab. PFS rates at EOT+12 also remained high in patients with unmutated immunoglobulin heavy-chain variable region (IGHV) receiving ibrutinib + venetoclax, independent of MRD status in BM. CONCLUSION Molecular and clinical relapses were less frequent during the first year post-treatment with ibrutinib + venetoclax versus chlorambucil + obinutuzumab regardless of MRD status at EOT+3 and IGHV status. Even for patients not achieving uMRD ( 〈 10 −4 ), PFS rates remained high with ibrutinib + venetoclax; this is a novel finding and requires additional follow-up to confirm its persistence over time.