O’Brien, Susan

Abstract Introduction: REGN1979 is a hinge-stabilized CD20xCD3bispecific full-length antibody (Ab) based on an IgG4isotype modified to reduce Fc binding. It is designed to bind T cells (via CD3) and CD20-expressing cells. Cross-linking results in specific, local T cell activation and engagement ofcytolytic functions, independent of T cell receptor mediated recognition. This mechanism of action (MOA) is distinct from approved anti-CD20 Abs, and may provide additional therapeutic benefit. This report describes safety and clinical outcomes in 25 patients (pts) treated with REGN1979. Methods: The study uses a 3+3 design to assess safety, pharmacokinetics (PK), pharmacodynamics (PD), and activity of REGN1979 inpts with NHL and CLL, in separate dose escalation cohorts. REGN1979 is administered IV over 1-4 hours, weekly (QW) for 4 doses followed by every 4 weeks (Q4W) for 5 doses. Each dose level (DL) consists of an initial starting dose followed by a higher (step-up) dose.Pts with either progressive disease (PD) after initial response or suboptimal initial response could be retreated. Results: As of clinical cut-off, 25pts had been enrolled and treated with REGN1979 at flat doses ranging from 0.03 - 3.0 mg: 20pts with NHLand 5pts with CLL. NHL subtypes included DLBCL (n=12), FL (n=6), and MCL (n=2). Allpts hada medianof3 (range 1-7) prior regimens, and received a median of 5 (range 2-9) doses of REGN1979. Sixpts remained on initial treatment, 3pts completed treatment, and 16pts discontinued treatment (14 for PD; 2 subject decision). Of 4pts who entered retreatment, 2pts remained ongoing. The most common treatment-related treatment-emergent AEs (TR-TEAEs) were pyrexia (56%), infusionrelated reaction (IRR) (40%), chills (36%), cytokine release syndrome (CRS) (28%), fatigue (24%), tachycardia (24%), hypomagnesaemia (20%) and hypotension (20%). Grade >= 3 TR-TEAEs occurred in 8 pts(32%): IRR (12%), CRS (8%), hypotension (8%), and pyrexia, tachycardia, dyspnea, anemia, hypoxia, hypertension, tachypnea, transaminases increased, and tumor pain each in 1 pt(4%). All were grade 3 with the exception of 1 ptwith grade 4 hypotension. There were no protocol-defined DLTs, nor grade 5 TEAE. No ptsdiscontinued REGN1979 due to TR-TEAE. IRR and CRS events were most commonly reported with the first administration of both initial and step-up dose with incidence and severity decreasing with increasing exposure. Tenptsreported at least one TR-SAE: CRS (24%), IRR (20%), and increased AST and tumor pain, each in 1pt(4%). Threeptswith aggressive lymphoma who discontinued REGN1979 due to PD died of their disease within 30 days of their last dose. Notably, modifications to pre-medication(s) and drug administration instructions have improved tolerability (fewer and less severe IRR/CRS). No clinically significant CNS TEAEs have been observed. CT-based (Cheson, 2007) anti-tumor activity was observed in 11 ptswith NHL: PR [n=4,median duration of 50d];SD [n=7, median duration of >196d]. The overall response rate (ORR) in NHL ptsacross DLs was 20%. In 2 highest dose levels, ORR was 27% (Fig 1). Of the 14pts evaluated by PET, 4pts had a partial metabolic response, withmedian duration of 244d perLugano Criteria. Twopts with CLL attained SD as best overall response. PK: REGN1979 concentrations in serum increased with increasing DL and were variable across pts. Variability was less at higher DLs and also decreased over time during therapy. At DLs tested, REGN1979 concentrations did not notably increase over time during treatment. PD/Cytokines: At the lowest dose tested, 0.03 mg, transient B-cell depletion was observed inpts with measurable circulating B cells.Samples from 12pts were available for cytokine analysis. Interim analysis indicates REGN1979 induces cytokine release as expected based on MOA. An increase in IL-6, IL-10 and to lesser extent IFN-γ was observed. The magnitude of cytokine response generally correlated with symptomatic IRR/CRS. Conclusion: REGN1979 demonstrated an acceptable safety profile at flat doses of 0.03 - 3.0 mg (< 1% of rituximab dose) inpts with NHL and CLL. Most TEAEs were associated with IRR/CRS, and were managed with supportive therapy and modification to REGN1979 administration. No clinically significant neurological toxicity was observed. Preliminary antitumor activity demonstrates increased activity at higher doses. Dose escalation and treatment schedule optimization continue. Disclosures Brown: Acetylon, Gilead: Research Funding; Celgene, Roche/Genentech, Gilead, Infinity, Janssen, Pharmacyclics, ProNai, Sun BioPharma: Consultancy. Arnason:Gilead: Consultancy. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Chavez:Janssen: Speakers Bureau. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Topp:Amgen: Consultancy, Honoraria, Other: travel, Speakers Bureau; Roche: Honoraria, Other: travel; Boehringer: Consultancy, Other: Travel, Research Funding; Jazz: Consultancy; Pfizer: Consultancy, Other: Travel. Adriaens:Regeneron Pharmaceuticals Inc.: Employment, Equity Ownership. Ufkin:Regeneron Pharmaceuticals Inc.: Employment, Equity Ownership. Kostic:Regeneron Pharmaceuticals Inc.: Employment, Equity Ownership. Paccaly:Regeneron Pharmaceuticals Inc.: Employment, Equity Ownership. Gao:Regeneron Pharmaceuticals Inc: Employment, Equity Ownership. Trail:Regeneron Pharmaceuticals Inc: Employment, Equity Ownership. Lowy:Regeneron Pharmaceuticals Inc: Employment, Equity Ownership. Brownstein:Regeneron Pharmaceuticals Inc: Employment, Equity Ownership.

Key Points MRD response has value as a prognostic factor for blinatumomab treatment in R/R B-cell precursor ALL. MRD response was associated with better outcomes in terms of OS and RFS in blinatumomab-treated R/R ALL.

Abstract Introduction REGN1979 is an anti-CD20 x anti-CD3 bispecific IgG4 antibody (Ab) modified to reduce Fc binding. Engaging both targets results in CD20-specific, local T-cell activation and cytotoxicity, a mechanism of action distinct from standard anti-CD20 Abs. We report updated promising efficacy results of a Phase 1 trial of REGN1979 in patients (pts) with relapsed/refactory (R/R) B-NHL previously treated with anti-CD20 Abs. Methods The primary objectives of the study are to determine safety, tolerability, and occurrence of dose limiting toxicities (DLTs). Other objectives include assessment of preliminary antitumor activity, pharmacokinetics (PK), and pharmacodynamics. Eligible pts with R/R NHL must have received at least 1 prior CD20-directed therapy. Treatment consists of 12 weekly doses of REGN1979 followed by every 2 week dosing for 12 doses for a total of 36 weeks. Guidelines are provided for management of cytokine release syndrome (CRS) and include steroids and/or tocilizumab at investigator discretion. Results As of June 1, 2018, 54 pts with B-NHL were treated with REGN1979 monotherapy: DLBCL (pt number [n]=30), FL (n=16), MCL (n=5), MZL (n=2), and WM (n=1). The median number of prior regimens was 3 (range, 1-11); 41 pts were refractory to their last prior systemic therapy, 18 had bulky disease, and 6 had prior HSCT. Pts were treated with REGN1979 0.03-27 mg and received a median of 7 (range, 1-24) doses. Eight pts remain on treatment, 13 completed treatment, and 33 discontinued therapy prior to the planned 36 wks (majority [n=22] due to progressive disease [PD]). There have been no DLTs to date. The most common treatment-related treatment-emergent adverse events (TR-TEAEs) included infusion-related reactions (IRR) or CRS; 26 pts experienced CRS (Grade 1-2, n=23; Grade 3, n=3) with a median duration of CRS of 2 (range 1-15) days. Six pts received tocilizumab. The severity of CRS symptoms declined through optimized pre-medication even with REGN1979 dose escalation. Other common Grade ≥3 TR-TEAEs were lymphocytopenia/ decreased lymphocyte count (n=8); neutropenia/ decreased neutrophil count (n=7); and thrombocytopenia/ decreased platelet count, hypotension, hypophosphatemia, and anemia (each n=3). Seventeen pts experienced a nervous system event including headache, dizziness, paraesthesia, dysgeusia, and peripheral neuropathy with no Grade ≥3 events; no neurologic event required termination of study drug. Seven pts died on study: PD (n=5), gastric perforation (n=1), and cardiac arrest (n=1). TEAEs leading to premature discontinuation of REGN1979 were Grade 3 fatigue (n=1), Grade 3 hemolysis (n=1), and Grade 2 pyrexia/Grade 2 tachycardia (n=1). Among 27 pts treated with REGN1979 ≥5 mg (dose associated with tumor killing in pre-clinical data), the overall response rate (ORR) was 55.6% (5 complete response [CR] and 10 partial response [PR]; Table/Figure). Responses were seen in 7/7 FL Grade 1-3a pts (5 CR, 2 PR), 6/15 DLBCL pts (all PR), 2/2 MCL pts (all PR). At 18 mg and 27 mg of REGN1979, 4 of 4 pts with DLBCL had best response of PR. Post data cut-off, 1 pt with a DLBCL best response of PR converted to CR. PK and pharmacodynamic assessments suggest that for pts treated with REGN1979 5-18 mg, best exposures in the first 3 weeks appear to linearly increase with dose. In pts treated with up to REGN1979 18 mg, a maximum mean Ctrough of 1.6 mcg/mL was observed in the first 3 weeks of weekly dosing. Studies of peripheral blood biomarkers demonstrated depletion of peripheral B lymphocytes, transient margination of circulating T-cells, and elevated circulating cytokines following REGN1979 dosing. Increased peak cytokine levels (IL-6, IL-10, and TNF-alpha) were observed in pts with CRS. Immunohistological analysis of malignant lymph node tissue demonstrated a decrease of CD20 expression in responding pts; among the responders, subsequent relapse was associated with either maintenance of CD20 expression or further CD20 loss, suggesting antigen-dependent and independent disease escape mechanisms. Conclusions REGN1979 displays efficacy and an acceptable safety profile in pts with R/R B-NHL. Most TR-TEAEs were IRR/CRS and have been well managed with supportive care. No significant neurological toxicity has been observed. At doses of 5-27 mg of REGN1979, the preliminary ORR was 100% in pts with FL Grade 1-3a and 40.0% in pts with DLBCL. This promising efficacy warrants further clinical investigation. Disclosures Bannerji: Regeneron Pharmaceuticals, Inc.: Consultancy; AbbVie, Inc.: Consultancy. Arnason:Regeneron Pharmaceuticals, Inc.: Consultancy. Advani:Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Janssen Pharmaceutical: Other: Institutional Research Support; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Takeda: Other: Consultancy/Advisory Role; Millenium: Other: Institutional Research Support; Gilead/Kite: Other: Consultancy/Advisory Role; Infinity: Other: Institutional Research Support; Merck: Other: Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Cell Medica: Other: Consultancy/Advisory Role; Agensys: Other: Institutional Research Support; Celgene: Other: Institutional Research Support; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Kura: Other: Institutional Research Support; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Kyowa: Other: Consulting/Advisory Role; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Autolus: Other: Consultancy/Advisory Role; AstraZeneca: Other: Consultancy/Advisory Role. Brown:Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Pharmacyclics: Consultancy; Celgene: Consultancy; Genentech: Consultancy; TG Therapeutics: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Abbvie: Consultancy; Gilead: Consultancy, Research Funding; Sun Pharmaceutical Industries: Research Funding; Sunesis: Consultancy; Loxo: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Invectys: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy; Boehringer: Consultancy. Allan:Genentech: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy. Ansell:Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Celldex: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. O'Brien:Kite Pharma: Research Funding; Aptose Biosciences Inc.: Consultancy; Pharmacyclics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Astellas: Consultancy; Sunesis: Consultancy, Research Funding; Alexion: Consultancy; Amgen: Consultancy; TG Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Regeneron: Research Funding; Janssen: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding. Chavez:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Humanigen: Consultancy. Lowy:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Charnas:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Sternberg:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ambati:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Adriaens:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ufkin:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Yan:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Li:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Navarro:Regeneron Pharmaceuticals, Inc.: Employment. Gasparini:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Jankovic:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Fiaschi:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Zhang:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Hamon:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Thurston:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Topp:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding.

Abstract Background: Patients (pts) with deletion 17p (del17p) CLL follow an aggressive clinical course and experience poor outcomes with chemoimmunotherapy. Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), is approved for pts with CLL with ≥1 prior therapy and for pts with del17p CLL (including first-line). In the phase 2 RESONATE-17 study (PCYC-1117), ibrutinib demonstrated high efficacy with a favorable risk-benefit profile in del17p CLL/SLL (O'Brien, ASH 2014). We evaluate the baseline genetic features and prognostic factors of these pts to determine their impact on outcome. Methods: Pts with del17p CLL or SLL defined by peripheral blood FISH who failed ≥1 therapy received 420 mg oral ibrutinib once daily until progression or unacceptable toxicity. Using the primary analysis data cut, the overall response rate (ORR; iwCLL 2008 criteria by investigators), progression-free survival (PFS), and overall survival (OS) were assessed by subgroup. Results: Among 144 treated pts (137 CLL, 7 SLL), the median age was 64 (range 36-89). At baseline, 63% of pts had Rai stage III or IV disease, and 39% had received ≥3 prior therapies. Baseline cytogenetics included del11q (16%), del13q (74%), and trisomy 12 (17%), in addition to del17p in all pts. Of 116 pts with valid baseline genomic samples, IGHV status was unmutated in 84%; genomic variants that included mutations, rearrangements, insertions, deletions, and copy number variants affecting coding regions were identified as follows: ATM (14%), BIRC3 (3%), BTK (1%), MYC (2%), MYD88 (2%), NOTCH1 (16%), PLCG2 (3%), SF3B1 (27%), and TP53 (92%), which were consistent with previously identified mutations in pts with CLL (Wang, NEJM 2011; Winkelmann, Haematologica 2015). At a median follow-up of 11.5 months, the investigator-assessed ORR including partial response with lymphocytosis (PR-L) for all treated pts was 83% (17% PR-L). Median PFS and OS were not reached, with 12-month PFS and OS rates of 79% and 84%. Any-grade adverse events (≥15%) included diarrhea (36%), fatigue (31%), cough (24%), arthralgia (22%), nausea (19%), hypertension (19%), anemia (19%), pyrexia (17%), decreased appetite (17%), muscle spasms (17%), neutropenia (17%), and peripheral edema (15%). Serious AEs occurred in 40% of pts (38% ≥ grade 3). ORR, 12-month PFS, and 12-month OS are presented by subgroup for baseline characteristics, cytogenetics, and genomic variants (Table). There were no substantial differences in response rates and survival outcomes in the subgroups with and without baseline cytogenetic aberrations or genomic variants (Table). Response rates were similar for pts with and without NOTCH1 or SF3B1 variants. Of 11 pts with del17p CLL who developed Richter transformation, baseline aberrations included ATM (n=2), SF3B1 (n=3), and/or NOTCH1 (n=3); none had BIRC3 variants. Overall at baseline, there were 3 pts with a PLCG2 mutation (L163F, H193Q, P236L), and 1 with a BTK mutation (R236Q); all achieved a best overall response of PR-L or better. None had received prior therapy with a BTK or PI3K inhibitor. Two pts had a baseline MYD88 mutation (L265P, L142F) with a best overall response of PR in 1 pt. Two pts had baseline MYC amplifications with 5 of 5 exons amplified to 6 and 7 copies, respectively; 1 pt achieved a best overall response of PR. Conclusions: These results provide further evidence of ibrutinib's robust clinical activity and encouraging survival outcomes in this high-risk population regardless of baseline cytogenetic aberrations or genomic variants. The prognostic role of these clinical characteristics and genetic anomalies will continue to be elucidated with longer term follow-up of this population. Figure 1. Investigator-assessed efficacy outcomes by subgroups Figure 1. Investigator-assessed efficacy outcomes by subgroups Disclosures Stilgenbauer: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jones:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Coutre:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: 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. Mato:Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; TA Therapeutics: Research Funding; Gilead: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses. Hillmen:AbbVie: Honoraria, Research Funding; Roche Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Tam:Janssen: Consultancy, Honoraria, Research Funding. Osterborg:Gilead: Honoraria; Janssen: Honoraria, Research Funding; GSK: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding. Siddiqi:Pharmacyclics: Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Thirman:Gilead: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding. Furman:Gilead: Consultancy; Acerta Pharma BV: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Li:Pharmacyclics LLC, an AbbVie Company: Employment. Eckert:Pharmacyclics LLC, an AbbVie Company: Employment. Chang:Pharmacyclics LLC, an AbbVie Company: Employment. James:Pharmacyclics LLC, an AbbVie Company: Employment. Chu:Pharmacyclics LLC, an AbbVie Company: Employment. Hallek:Pharmacyclics LLC, an AbbVie Company: Consultancy, Speakers Bureau; Janssen: Speakers Bureau. O'Brien:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.

Abstract Background: Blinatumomab is an investigational bispecific T-cell engager (BiTE®) antibody construct designed to direct cytotoxic T cells to CD19-expressing B cells. In a study in minimal residual disease (MRD)-positive ALL, 80% of pts achieved MRD-negative status after receiving one treatment cycle of blinatumomab (Topp MS, et al. J Clin Oncol. 2011;29:2493-8). For pts with newly diagnosed ALL, persistence of MRD after first-line treatment predicts disease recurrence. However, only limited data are available about the relationship between MRD and outcome in adult pts with r/r ALL. Therefore, the aim of this secondary analysis was to evaluate MRD responses and their relationships to other efficacy indices in adult pts with r/r ALL receiving blinatumomab in this phase 2 study. Methods: Eligibility criteria included adult pts ≥18 years, with Philadelphia chromosome negative B-cell r/r ALL who were primary refractory or refractory to first salvage, had their first relapse within 12 months of first remission or allogeneic hematologic stem cell transplantation (HSCT), or received second or later salvage. Blinatumomab was dosed via continuous IV infusion at 28 μg/d (cycle 1 only: 9 μg/d on days 1-7, 28 μg/d on days 8-28) for up to five cycles (one cycle: 4 weeks on, 2 weeks off). The primary endpoint was complete remission (CR: ≤5% blasts with platelets >100,000/µL, absolute neutrophil count >1000/µL) or CR with partial hematologic recovery (CRh*: platelets >50,000/µL, absolute neutrophil count >500/µL) within the first two treatment cycles. MRD in bone marrow was assessed at a central laboratory using allele-specific real-time quantitative PCR. Two MRD-based exploratory endpoints were analyzed: MRD response (no PCR amplification at a minimum sensitivity of 10-4 or <10-4 leukemic cells by PCR) and complete MRD response (no PCR amplification at a minimum sensitivity of 10-4) within the first two treatment cycles. Results: Of 189 treated pts (median [range] age = 39 [18–79] years), 81 (43%) pts had a CR (n = 63, 33%) or a CRh* (n = 18, 10%) during the first two treatment cycles. In the subgroup of pts with a CR/CRh* and evaluable MRD data (n = 73), 60 (82%) pts had an MRD response. Of those, 51 (70%) pts had a complete MRD response. The majority of those who achieved a CR/CRh* also achieved a complete MRD response regardless of the number of prior lines of salvage therapy (Table 1). Of all treated pts, 64 (34%) pts had prior HSCT. In pts who achieved CR/CRh*, the rate of MRD response was 81% in pts without and 85% in pts with prior HSCT. In pts who achieved CR/CRh*, the median (95% CI) duration of overall survival was 11.4 (8.5, not estimable) months for those with a MRD response and 6.7 (2.0, not estimable) months for those with no MRD response. The median (95% CI) duration of relapse-free survival was 6.9 (5.5, 10.1) months in patients with a MRD response and 2.3 (1.2, not estimable) months in patients with no MRD response. The HSCT realization rate did not differ significantly between pts with CR/CRh* and a MRD response and those with CR/CRh* and no MRD response (31% and 43%, respectively). Seventeen pts classified as nonresponders per protocol had ≤5% blasts and no evidence of disease, but recovery of peripheral counts did not meet criteria for CRh*. Ten of these 17 pts had evaluable MRD assessments; 50% (5/10) had MRD response and 20% (2/10) had complete MRD response. The clinical significance of this finding remains open. Grade ≥3 adverse events regardless of causality and occurring in >10% of all treated pts during treatment until 30 days after treatment were febrile neutropenia (25%), neutropenia (16%), and anemia (14%). Grade 3 cytokine release syndrome (CRS) was reported in three (1.6%) patients. Three (1.6%) patients had grade 4 neurologic events, all resolved. Twenty-one (11%) patients had grade 3 neurologic events, 17 were resolved, with 4 events unresolved at death or unknown. Conclusion: In this largest study to date of adult pts with r/r ALL with PCR-based central assessment of MRD, pts who achieved CR/CRh* during single-agent treatment with blinatumomab had high MRD response rates. The exploratory analyses suggested that within pts with a CR/CRh*, those who did not achieve MRD responses tended to have shorter durations of overall and relapse-free survival. These results are consistent with prior reports highlighting the importance of achieving an MRD response in first-line therapy. Disclosures Goekbuget: Amgen Inc.: Consultancy, Honoraria, Research Funding. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities. Kantarjian:Amgen Inc.: Research Funding. Brüggemann:Amgen Inc.: Consultancy, Research Funding. Stein:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees. Bargou:Amgen Inc.: Consultancy, Honoraria. Dombret:Amgen Inc.: Research Funding. Heffner:Amgen Inc.: Honoraria, Research Funding; Biotest: Research Funding; Dana Farber CI: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Idera: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Pharmacyclics: Honoraria, Research Funding; Onyx: Research Funding; Spectrum: Research Funding; Talon Therapeutics: Research Funding. Rigal-Huguet:Amgen, Inc.: Consultancy; Ariad: Consultancy; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Litzow:Amgen Inc.: Honoraria, Research Funding. Zugmaier:Amgen Reseach (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Jia:Amgen Inc.: Employment, Equity Ownership. Maniar:Amgen Inc.: Employment, Equity Ownership. Huber:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Nagorsen:Amgen Inc.: Employment, Equity Ownership, Related to blinatumomab Patents & Royalties. Topp:Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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 Sequencing studies have significantly improved our understanding of the CLL genetic landscape and allowed the identification of the first associations between specific mutations and clinical outcome. Hence, mutations in TP53, NOTCH1, SF3B1, BIRC3 and MYD88 are known to be associated with differential prognosis and have been incorporated in CLL risk stratification models. Despite the work performed on these 5 genes, several additional putative tumor-driver genes are recurrently mutated in CLL, but their clinical impact remains unclear. In order to gain further understanding, we performed targeted sequencing in baseline samples of 308 CLL patients (pts) participating in the North American Intergroup study (NAIG) designated as E1912 and led by ECOG. This trial is a randomized Phase III of Ibrutinib (Ibr) and Rituximab (R) vs FCR in previously untreated CLL. Besides the 5 genes aforementioned, we screened another 19 genes recurrently mutated in CLL, and 2 genes (BTK and PLCy2) recently associated with Ibr resistance. The CD5+/CD19+ B lymphocyte population of these pts was flow-sorted. All coding regions were amplified using customized oligos. Libraries were templated and enriched using IonOneTouch2 and IonOneTouch ES systems, respectively. Samples were run on an IonTorrent sequencer using 318TM chips. Variants were called using IonTorrent Somatic VariantCaller. VCF files were annotated using BioR, which provides annotation from NCBI/Ensembl, UCSC, dbSNP, HapMap, 1000Genomes, COSMIC, SIFT, and PolyPhen-2. Somatic variants with a Mapping Quality <20 or read depth <5X were removed. Variants of interest were inspected using Integrative Genomics Viewer. The mutational status of genes and pathways was analyzed for association with chromosomal abnormalities detected by FISH, expression of CD38, CD49d and ZAP70, Rai stage, age and gender. We were not able to evaluate associations to clinical responses for the different arms as this trial is still underway and remains blinded for clinical outcome. We found 511 SNVs (442 missense, 45 nonsense and 24 splice sites) and 115 indels. An average coverage of 770X depth was obtained, allowing the detection of minor subclonal mutations (<10% of reads) in almost 35% (218/626 mutations). Overall, 215 pts (70%) carried at least one mutated gene, 102 (33%) carried 2 or more and 32 (10%) 3 or more mutated genes. The most commonly mutated gene was SF3B1 (22%), followed by NOTCH1 (19%), ATM (12%), XPO1 (11%), BIRC3 (9%), KRAS (7%), BRAF, DDX3X, EGR2, POT1 and TP53 (6% each). No BTK or PLCy2 mutations were found in progressive but untreated CLLs. In contrast to a recent report (Nature 2015;526:525-30), we found BRAF mutations located in the canonical hotspot p.V600E (25% of total mutations). Another 13% were located in amino acid K601 (p.K601E/N) and the remaining in the kinase domain (p.G469A, p.D594G, p.F595L, p.G596R, p.L597Q).Nearly 27% of cases with activating mutations in the RAS pathway (BRAF, KRAS, NRAS), showed >1 mutation affecting one or more genes of the pathway. Similar observations were found in mutational hotspots of BIRC3 (30% of mutated cases showed >1 mutation), MED12 (18%), SF3B1 (7%), XPO1 (6%), and NOTCH1 (5%), suggesting the existence of genetic subclones showing convergent evolution in a substantial number of CLL. We found multiple associations between mutations and known prognostic and clinical parameters. These included mutations in NOTCH1 associated with +12 (p=0.005), and expression of ZAP70 (p=0.01), CD38 (p=0.001) and CD49d (p=0.004). Mutant BIRC3 was associated with +12 (p<0.001) and CD38 expression (p=0.01). Mutations in RAS pathway, with +12 (<0.001), and expression of CD38 (p=0.002) and CD49d (p=0.05). ATM (p=0.007) and EGR2 (p=0.002) with -11q; POT1 with CD49d expression (p=0.01), and MYD88 with -13q (p=0.04) and lack of CD38 (p=0.01) and CD49d (p=0.01) expression. This study, performed on a large cohort of untreated but progressive CLLs, provides novel data about the mutation status of driver genes and their associations with clinical and prognostic parameters. Our data indicate that convergent evolution is a common event in CLL, affecting several driver genes. Furthermore, it reinforces that BTK and PLCy2 mutations are not found in Ibr-naive pts. Finally, this study provides the genetic groundwork for subsequent prospective comparative analyses of the clinical outcome for CLL cohorts treated with Ibr-R vs FCR in this phase 3 NAIG trial. Disclosures O'Brien: Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Fonseca:Novartis: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Novartis: Consultancy; Janssen: Consultancy; BMS: Consultancy; AMGEN: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; AMGEN: Consultancy; Millennium, a Takeda Company: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Sanofi: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Millennium, a Takeda Company: Consultancy; Millennium, a Takeda Company: Consultancy; AMGEN: Consultancy; AMGEN: Consultancy; Bayer: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Millennium, a Takeda Company: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms. Shanafelt:Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; GlaxoSmithkKine: Research Funding; Janssen: Research Funding; Cephalon: Research Funding; Hospira: Research Funding.

Abstract Background: Patients (pts) with CLL/SLL that have del11q tend to have relatively short remission durations and shorter overall survival (OS) with standard chemotherapy regimens. Ibrutinib (ibr), a first-in-class, oral, once-daily inhibitor of Bruton's tyrosine kinase (BTK) is indicated by the US FDA for the treatment of pts with CLL/SLL and allows for treatment without chemotherapy. In phase 3 studies, treatment with single-agent ibr was superior to treatment with ofatumumab (ofa) in relapsed/refractory (R/R) CLL/SLL (RESONATE; Byrd, N Engl J Med 2013) or chlorambucil (clb) in treatment-naïve (TN) CLL/SLL (RESONATE-2; Burger, N Engl J Med 2015); treatment with ibr + bendamustine/rituximab (BR) was also superior to treatment with BR in R/R CLL/SLL (HELIOS; Chanan-Khan, Lancet Oncol 2016). We examined the outcome of pts in these 3 studies who did or did not have del11q to determine the impact of del11q on clinical outcomes. Methods: In RESONATE, pts with R/R CLL/SLL received ibr 420 mg/day until progressive disease (PD) or unacceptable toxicity (tox) vs ofa for up to 24 weeks (300 mg week 1, 2000 mg weekly for 7 weeks, 2000 mg every 4 weeks for 16 weeks). In RESONATE-2, pts ≥65 years of age with TN CLL/SLL (excluding del17p) received ibr 420 mg/day until PD or tox vs clb 0.5 mg/kg (up to max of 0.8 mg/kg) on days 1 and 15 of each 28-day cycle (≤12 cycles). In HELIOS, pts with R/R CLL/SLL (excluding del17p) received BR (≤6 cycles) with or without ibr 420 mg/day (starting on day 2 of cycle 1) followed by single-agent ibr or placebo continued until PD or tox. Data from pts in the 3 studies were pooled (ibr pool, comparator pool) and analyzed based on whether or not their CLL/SLL had del11q. We performed a multivariate analysis to examine for risk factors prognostic for survival (del11q del17p, age, sex, race, current Rai stage, baseline ECOG PS, number of prior therapies, cytopenias; no multiplicity adjustment). Results: A total of 1210 pts with del11q data were included in the analysis: 609 in the ibr pool (179 with del11q, 430 without del11q) vs 601 in the comparator pool (149 with del11q, 452 without del11q). Demographics and baseline characteristics were generally similar in pts regardless of del11q status; differences of more than 10% included proportions with bulky disease ≥5 cm (63% vs 49%) and unmutated IGHV (88% vs 72%) in pts with or without del11q, respectively. Median lymphadenopathy and absolute lymphocyte counts were also higher in pts with del11q. At the time of the primary analysis, median treatment durations in the ibr pool were 20.0 mo with del11q and 18.7 mo without del11q; in the comparator pool 5.3 mo with del11q and 8.5 mo without del11q. Overall, ibr-treated pts had higher overall response rate (ORR) and complete response (CR) rates and longer progression-free survival (PFS, Figure) and OS than comparator-treated pts regardless of del11q status. In the ibr pool, the presence of del11q was associated with a trend of longer PFS and OS while in the comparator pool, pts with del11q had shorter PFS (Figure, Table), as compared to pts without del11q. Results were similar when excluding pts with del17p (10% of ibr pool [6%/11% with/without del11q] and 9% of comparator pool [8%/10% with/without del11q]; Table). By multivariate analysis, in the comparator pool, del11q, male sex, >1 prior therapy, presence of cytopenias, and unmutated IGHV (in R/R only) were associated with shorter PFS. However, these differences were not found in the ibr pool. The presence of del11q did not unfavorably impact the tempo of reductions in lymphadenopathy for ibr-treated pts, but did for comparator-treated pts. Adverse events leading to discontinuation were similar in ibr- and comparator-treated pts (12% [9% vs 13% with/without del11q] vs 13% [12% vs 13% with/without del11q]). Deaths within 30 days of last dose occurred in 31 pts (5% [3% vs 6% with/without del11q]) in the ibr pool and 28 pts (5% [6% vs 4% with/without del11q]) in the comparator pool. Conclusions: Treatment with ibr was superior to comparator regardless of del11q status; the benefit of ibr was most marked for pts with CLL/SLL with del11q. Presence of del11q was associated with a trend of longer PFS and OS in ibr-treated pts and shorter PFS and lower ORR in comparator-treated pts. By multivariate analysis, presence of del11q was a prognostic factor for shorter PFS for comparator-treated pts, but not for ibr-treated pts. Disclosures Kipps: Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Demirkan:Amgen: Consultancy. Coutre:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding. Barrientos:Gilead: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy, Research Funding. Barr:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Fraser:Celgene: Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau. Jaeger:Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Cramer:Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Mundipharma: Other: Travel, Accommodations, Expenses; Astellas: Other: Travel, Accommodations, Expenses; Roche: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Other: Travel, Accommodations, Expenses, Research Funding. Stilgenbauer:Novartis: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Hoffman La-Roche: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding. Salman:Janssen Research & Development: Employment, Equity Ownership, Other: Travel, Accommodations, Expenses. Solman:Pharmacyclics LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses; AbbVie: Equity Ownership. Cheng:Johnson & Johnson: Equity Ownership; AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. Phelps:Johnson & Johnson: Employment, Equity Ownership. Ninomoto:Pharmacyclics LLC, an AbbVie Company: Employment; Amgen, Inc.: Equity Ownership; AbbVie: Equity Ownership. Howes:Janssen: Employment, Other: Leadership; Johnson & Johnson: Equity Ownership. James:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Hallek:Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau.

Abstract Background: Chronic lymphocytic leukemia (CLL) is primarily a disease of the elderly, with the majority of patients (pts) older than 65 y at diagnosis (US SEER). Historically, younger, more fit pts were eligible for aggressive chemoimmunotherapy treatments, but older age and comorbid conditions can limit options due to tolerability concerns. Ibrutinib (ibr), a first-in-class, oral, once-daily inhibitor of Bruton's tyrosine kinase, is indicated by the US FDA for the treatment of pts with CLL/small lymphocytic lymphoma (SLL) and allows for treatment without chemotherapy. Results from the phase 3 RESONATE (PCYC-1112) and RESONATE-2 (PCYC-1115) trials established ibr as a standard option in relapsed/refractory (R/R) and treatment-naïve (TN) CLL/SLL. This analysis examines safety and efficacy from these studies by age. Methods: RESONATE randomized 391 pts with R/R CLL/SLL to receive ibr (n=195; 420 mg once daily) until progressive disease (PD) or unacceptable toxicity or intravenous ofatumumab (n=196; 300 mg at week 1, 2000 mg weekly for 7 w and then every 4 w for 16 w). RESONATE-2 randomized TN pts aged ≥65 y to receive ibr (n=136; 420 mg once daily) until PD or chlorambucil (clb; n=133; 0.5 mg/kg to a maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Pt data from both studies were grouped by age (ibr and comparators [comp]) and analyzed for effect of age on outcome. Results: Ibr group included 136 TN pts: 65 to <75 y (termed mid, n=90) and ≥75 y (termed old, n=46), and 195 R/R pts: <65 y (termed young, n=77), 65 to <75 y (mid, n=75), and ≥75 y (old, n=43). Table 1 lists key baseline pt characteristics. For ibr, median follow-up was 28.6 mo for TN and 36.1 mo for R/R pts. PFS is shown in Figure 1. For TN ibr pts, the 24-mo PFS rates were 88% (mid) and 89% (old), whereas clb pts aged ≥75 y did worse than those aged 65 to <75 y (23% vs 40%). For R/R pts, the 24-mo PFS was 75% (young), 77% (mid), and 62% (old). For ibr, median OS was not reached for any age subgroup (R/R or TN). The CR+CRi rates for TN ibr pts were 19% (mid) and 17% (old) and for R/R pts were 6% (young), 9% (mid), and 9% (old). Median treatment duration and the most common grade ≥3 AEs are listed in Table 2. The most frequent any-grade adverse events (AEs) were diarrhea, fatigue, cough, upper respiratory tract infection, nausea, pyrexia, and anemia for all pts and age subgroups. For ibr, grade ≥3 AEs occurred in 64% (mid) and 83% (old) of TN pts, and 70% (young), 84% (mid), and 84% (old) of R/R pts. The prevalence of common grade ≥3 AEs was typically highest in the first 12 mo of ibr therapy, and decreased thereafter for all age groups. Pts ≥75 y had a higher rate of grade ≥3 neutropenia and urinary tract infection in both TN and R/R populations. R/R ibr pts <65 y experienced a lower frequency of grade ≥3 pneumonia and atrial fibrillation (AF) than older subgroups. Any grade AF occurred in 11% (mid) and 9% (old) of TN ibr pts, and 1% (young), 20% (mid), and 14% (old) of R/R ibr pts. For ibr, dose reduction due to AE occurred in 9% (mid) and 22% (old) of TN pts and 6% (young), 20% (mid), and 12% (old) of R/R pts. 107 (79%) TN ibr pts remain on treatment: 81% (mid) and 74% (old); 99 (51%) R/R pts remain on treatment: 49% (young), 59% (mid), and 40% (old). For ibr, discontinuation due to AE occurred in 11% (mid) and 13% (old) of TN pts, and 6% (young), 11% (mid), and 19% (old) of R/R pts. The most common AE leading to discontinuation of ibr was infection(TN: n=4, RR: n=5). Conclusions: The PFS rate for TN ibr pts was similar regardless of age subgroup, whereas it was shorter for clb-treated pts ≥75 y compared with those 65 to <75 y. In the R/R population, ibr pts ≥75 y tended to have shorter PFS compared to those <75 y. There was no perceivable difference in CR rate by age within the TN and R/R ibr populations. The rates of grade ≥3 AEs tended to be higher in pts ≥75 y for both ibr and comp arms. Age did not impact discontinuation rates due to AE for TN pts treated with ibr, but increased with age for R/R pts. This study is limited by the number of pts ≤65 y who were only eligible for the R/R trial. This analysis supports single-agent ibrutinib as a treatment option regardless of pt age, but reinforces the need for close toxicity monitoring, especially in older pts. Disclosures Woyach: Karyopharm: Research Funding; Morphosys: Research Funding; Acerta: Research Funding. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Brown:Pfizer: Consultancy, Honoraria, Other: travel, accommodations, expenses; Genentech: Consultancy, Honoraria; Roche: Honoraria; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Sun Biopharma: Honoraria, Other: travel, accommodations, or other expenses. Coutre:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding. Barr:AbbVie: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Devereux:Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; GSK: Consultancy; Roche: Consultancy, Other: Travel, Accommodations, Expenses ; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Reddy:KITE: Membership on an entity's Board of Directors or advisory committees; celgene: 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. Mulligan:GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Zhou:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. Ninomoto:AbbVie: Equity Ownership; Amgen: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. James:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Burger:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Portola: Consultancy; Gilead: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Roche: Other: Travel, Accommodations, Expenses.

Abstract Background: Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less than 2 years in the relapsed/refractory (R/R) setting. Ibrutinib (ImbruvicaTM), a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for previously treated patients with CLL and for patients with del 17p CLL. We report results from the primary analysis of the Phase II RESONATETM-17 (PCYC-1117-CA) study, designed to evaluate the efficacy and safety of single-agent ibrutinib for treatment of patients with R/R del 17p CLL or small lymphocytic leukemia (SLL). Methods: Patients with del 17p CLL or SLL who failed at least one therapy were enrolled to receive 420 mg oral ibrutinib once daily until progression. All patients receiving at least one dose of ibrutinib were included in the analysis. The primary endpoint was overall response rate (ORR) per an independent review committee (IRC). Other endpoints included duration of response (DOR), progression-free survival (PFS), and safety of ibrutinib. Results: Among 144 treated patients (137 with CLL, 7 with SLL), the median age was 64 (48% 65 years or older) and all had del 17p. Baseline characteristics included 63% of patients with Rai Stage III or IV disease, 49% with bulky lymphadenopathy of at least 5 cm, and 10% with lymphadenopathy of least 10 cm. The median baseline absolute lymphocyte count (ALC) was 32.9 x 109/L with 57% of patients with a baseline ALC at least 25.0 x 109/L. Baseline beta-2 microglobulin levels were at least 3.5 mg/L in 78% of patients (range 1.8-19.8 mg/L), and lactate dehydrogenase levels were at least 350 U/L in 24% of patients (range 127-1979 U/L). A median of 2 prior therapies (range 1-7) was reported. Investigator-assessed ORR was 82.6% including 17.4% partial response with lymphocytosis (PR-L). Complete response (CR)/complete response with incomplete bone marrow recovery (CRi) were reported in 3 patients. IRC-assessed ORR is pending. At a median follow up of 13.0 months (range 0.5-16.7 months), the median PFS (Figure 1) and DOR by investigator determination had not been reached. At 12 months, 79.3% were alive and progression-free, and 88.3% of responders were progression-free. Progressive disease was reported in 20 patients (13.9%). Richter transformation was reported in 11 of these patients (7.6%), 7 of the cases occurring within the first 24 weeks of treatment. Prolymphocytic leukemia was reported in 1 patient. The most frequently reported adverse events (AE) of any grade were diarrhea (36%; 2% Grade 3-4), fatigue (30%; 1% Grade 3-4), cough (24%; 1% Grade 3-4), and arthralgia (22%; 1% Grade 3-4). Atrial fibrillation of any grade was reported in 11 patients (7.6%; 3.5% Grade 3-4). Seven patients reported basal or squamous cell skin cancer and 1 patient had plasma cell myeloma. Most frequently reported Grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%). Major hemorrhage was reported in 7 patients (4.9%, all Grade 2 or 3). Study treatment was discontinued in 16 patients (11.1%) due to AEs with 8 eventually having fatal events (pneumonia, sepsis, myocardial or renal infarction, health deterioration). At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib. Conclusions: In the largest prospective trial dedicated to the study of del 17p CLL/SLL, ibrutinib demonstrated marked efficacy in terms of ORR, DOR, and PFS, with a favorable risk-benefit profile. At a median follow up of 13 months, the median DOR had not yet been reached; 79.3% of patients remained progression-free at 12 months, consistent with efficacy observed in earlier studies (Byrd, NEJM 2013;369:32-42). The PFS in this previously treated population compares favorably to that of treatment-naïve del 17p CLL patients receiving fludarabine, cyclophosphamide, and rituximab (FCR) (Hallek, Lancet 2010;376:1164-74) or alemtuzumab (Hillmen, J Clin Oncol 2007;10:5616-23) with median PFS of 11 months. The AEs are consistent with those previously reported for ibrutinib (Byrd, NEJM 2014;371:213-23). These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL. Figure 1 Figure 1. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Jones:Pharmacyclics: Consultancy, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siddiqi:Janssen: Speakers Bureau. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Stevens-Brogan:Pharmacyclics: Employment. Li:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Clow:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Chu:Pharmacyclics: Employment, Equity Ownership. Hallek:Janssen, Pharmacyclics: Consultancy, Research Funding. Stilgenbauer:Pharmacyclics, Janssen Cilag: Consultancy, Honoraria, Research Funding.