Citations

Abstract A device that would provide a rapid evaluation of hemostasis would greatly aid physicians in making scientific decisions regarding transfusion therapy; especially with perioperative bleeding. We performed a prospective in-vitro study with reconstituted, recalcified whole blood (n = 6) separated into samples containing specific deficiencies in platelets, plasma, lyophilized platelets and lyophilized plasma such that the concentrations of the specific platelet or plasma were 0%, 10%, 30%, 50%, and 100%. The whole blood was obtained from consenting healthy volunteers. Samples from the various concentrations of the reconstituted blood were subjected to the following point of care coagulation tests: activated clotting time (ACT), thromboelastogram (TEG), laboratory prothrombin time (PT), laboratory activated partial thromboplastin time (APTT) and Signature+ PT. ACT’s were performed for each of four celite doses (1.5 mg, 3.0 mg, 6.0 mg and 12 mg celite). The four dose celite ACT’s were performed in duplicate and the mean recorded. The TEG was performed in duplicate, and the mean was recorded. The signature+ PT was performed in duplicate, and the mean recorded. The laboratory PT, aPTT, Platelet Count and Fibrinogen were performed once each. ACT values were analyzed within each of the three preparations using analysis of variance. This assessed the strength of the relationship between blood constituent concentration and ACT, and determined whether this relationship differed across varying amounts of celite. Other coagulation parameters including TEG (mA), PT and APTT were analyzed using analysis of variance with a single term for blood constituent concentration. This model determined the strength of the relationship between these coagulation parameters and blood constituent concentration. In addition, the kaolin activated TEG and the signature+ PT was evaluated to determine the strength of the relationship between these tests and the variations in platelet and plasma concentrations. There was a significant correlation between the plasma, platelets and lyophilized plasma concentrations and ACT results (all p < 0.001). There was a significant correlation between plasma platelets and lyophilized plasma and the TEG MA and angle (all p < 0.028). There was a significant correlation between laboratory PT and APTT and plasma, platelets, and lyophilized plasma, lyophilized platelets (all p < 0.001). There was a significant correlation between the Signature+ PT and plasma, lyophilized platelets, and lypholized plasma and platelets (all p < 0.005), (figure 1). A better point of care coagulation device that is based on in-vitro additions of various therapies, and comparison of their effects on coagulation tests may provide better treatment of the bleeding patient. The Signature+ PT could provide the endpoint for such a device whereas the ACT was nonspecific and had a small change in results with large changes in plasma concentration. The additional benefit of lypholized plasma to behave similarly to human plasma may allow such a device to be built. Figure Figure

Abstract Abstract 970 The mammalian target of rapamycin, mTOR, is a highly conserved serine/threonine kinase known to play a role in regulating mRNA translation, cell cycle progression, cell proliferation and apoptosis. As a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, mTOR is a component of two distinct complexes, TORC1 and TORC2. While TORC1 facilitates cell cycle progression from G1 into S phase by phosphorylating p70S6 kinase and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), TORC2 catalyzes the activating phosphorylation of Akt on Ser473, providing a feedback loop for further activation of mTOR. Phase II trials have shown activity of the TORC1-selective inhibitor rapamycin and its analogs in a wide range of lymphoma subtypes. The purpose of this study was to evaluate the anti-proliferative and pro-apoptotic effects of the dual TORC1/TORC2 inhibitor OSI-027 in human neoplastic lymphoid cells in vitro. MTS assays demonstrated that OSI-027 inhibited proliferation in a wide range of lymphoid lines, including SeAx (Sezary syndrome), DoHH2 (large cell lymphoma), RL (follicular lymphoma) and Jurkat (T cell ALL), as well as clinical lymphoma and T cell ALL samples, with IC50 values ranging from 0.078 to 10 μM. Propidium iodide staining followed by flow cytometry for subdiploid cells revealed induction of apoptosis within 48 h of treatment with OSI-027 (but not rapamycin) in SeAx, DoHH2, and Jurkat cells. Examination of Jurkat variants with alterations in key proteins involved in the death receptor versus mitochondrial pathway revealed diminished apoptotic responses to OSI-027 when Bcl-2 was overexpressed or caspase 9 was silenced, indicating involvement of the mitochondrial pathway. Immunoblotting for Bcl-2 family members revealed upregulation of Bim and Puma after a 48-hour exposure to OSI-027 but not rapamycin. This upregulation was also seen at the mRNA level, with a 12- to 20-fold increase in Puma mRNA and 4- to 12-fold induction of Bim mRNA. Small interfering RNA (siRNA)-mediated knockdown of Bim and Puma significantly diminished the apoptotic response to OSI-027. Because the Foxo3a transcription factor has been implicated in Bim and Puma expression and is known to be activated when Akt is inhibited, we next examined whether Bim and Puma induction was Foxo3a-dependent. Luciferase reporter assays showed that OSI-027 activated the full-length Puma and Bim promoters and that this activation was diminished when the Foxo3a binding sites were deleted or mutated. In addition, OSI-027 induced nuclear translocation of Foxo3a, while Foxo3a siRNA diminished OSI-027-induced apoptosis in Jurkat cells. Collectively, these results indicate that OSI-027 inhibits proliferation and induces apoptosis in a wide range of neoplastic lymphoid cells through a process that involves Foxo3a-mediated upregulation of Bim and Puma. These results also suggest that dual inhibition of TORC1 and TORC2 may be an effective treatment strategy in lymphoid malignancy. Disclosures: Barr: OSI Pharmaceuticals: Employment. Witzig:Novartis and Celgene: Patents & Royalties, Research Funding, Served on advisory boards with Novartis and Celgene – both uncompensated with compensation to Mayo Clinic.

Abstract Primary central nervous system lymphoma (PCNSL) is an aggressive and incurable variant of non-Hodgkin lymphoma (NHL) that is confined to the central nervous system. Most PCNSL (90%) are part of the immune-privileged site-associated diffuse large B-cell lymphomas (DLBCL). Unlike nodal DLBCL, only a limited number of genetic studies have been performed in PCNSL, partly due to lack of available tissue specimens. Because of the fragmented knowledge of the genomic basis, it is still a matter of debate whether they differ from systemic DLBCL with respect to their molecular features and pathogenesis and also if there is a CNS specific signature. We performed a comprehensive genomic study in a cohort of 22 immunocompetent (HIV- and EBV-) PCNSL. DNA was extracted from FFPE tissues (N=15) and frozen tissue (N=7). Samples were analyzed using a combination of aCGH (N=18), exome sequencing (N=10), mate-pair genome sequencing (N=2) and targeted sequencing (N=8). We found a complex karyotype with a median of 21 copy-number abnormalities (range 10–47), 6 structural abnormalities, 6 frameshift indels and 67 nonsynonymous mutations. By integrating mutation and copy number data we found a group of genes recurrently mutated and/or deleted in PNCSL. Remarkable findings were the high prevalence of MYD88 activating mutations (L265P/M232T/V217F), found in 69% of cases and the biallelic loss of CDKN2A (60%). A subset of recurrent abnormalities was exclusively found in PCNSL, and not being previously identified in systemic DLBCL. Thus, 11% of PCNSL have biallelic inactivation of TOX (a regulator of T-cell development) and PRKCD (protein kinase C delta), while another 17% of cases show focal monoallelic deletions/mutations in these genes. Finally, recurrent mutations have been identified in ATM, which have not been found in nodal DLBCL. Several other genes affected have been previously identified in nodal DLBCL, such as biallelic loss of TNFAIP3 (16%), PRDM1 (16%), GNA13, TMEM30A, B2M and CD58 (11% each), activating mutations of CD79B (28%) and CARD11 (19%) and translocations of BCL6 (22%). Components of the NF-kB pathways were altered in >90% of PNCSL. Pathway analysis also showed an enrichment of networks associated with immune response, proliferation, regulation of apoptosis and lymphocyte differentiation and activation. Finally, we searched for associations between genetic alterations and clinical outcome. We showed that deletions of 6q21 (PRDM1) and 6q23 (TNFAIP3) were both associated with shorter overall survival (p=0.007 and p=0.03, respectively). In summary, we report a genomic background in PCNSL similar to post-GC DLBCL but reinforcing the existence of a subset of abnormalities specific to PCNSL, suggesting their potential relevance in the disease pathogenesis. Additionally, the results obtained from FFPE samples are encouraging and larger archival tissue collections can now be analyzed in order to complement the still fragmented knowledge we have of the genetic basis of the disease. Disclosures: Stewart: Onyx: Consultancy, Research Funding; Millenium: Honoraria, Research Funding; Celgene: Honoraria; BMS: Honoraria. Fonseca:Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy, Research Funding; Binding Site: Consultancy; Millennium: Consultancy; AMGEN: Consultancy; Cylene: Research Funding; Prognostication of MM based on genetic categorization of the disease: Patents & Royalties.

Abstract Abstract 4219 Background: Clinical characteristics associated with abdominal vein thrombosis (including hepatic, portal, and mesenteric veins; renal veins; and inferior vena cava [IVC]) overlap with characteristics associated with deep vein thrombosis (DVT) in the legs and pulmonary embolism (PE) but also possess unique attributes. These characteristics may differ between adult and pediatric patient groups. Methods: Using a standardized data-collection form, demographic and baseline characteristics were prospectively collected from consecutive consenting patients enrolled within one of seven Thrombosis and Hemostasis Centers over a seven-year period, August 2003 to June 2010. Patients with intra-abdominal venous thrombosis (defined as abdominal and renal veins, and IVC) were divided into pediatric (age <18 years) and adult (age ≥18 years) groups and compared to patients in the same age ranges with lower extremity DVT and/or PE. RESULTS: As of June 2010, the Patient Registry contained a total of 3105 patients with venous thromboembolism (VTE). A total of 270 patients had intra-abdominal thrombosis (9%) compared to 2276 with lower extremity DVT and/or PE (73%). Of the intra-abdominal clots, pediatric patients were more likely to have IVC thrombus (22 of 42; 52%) than adults (38 of 228; 17%; p<0.0001); conversely, pediatric patients were less likely to have hepatic, portal, and mesenteric thrombosis (n=25; 60%) than adults (n=195; 86%, p<.0001). For adult patients, proportionately more women had abdominal thrombosis (157 of 228; 68.9%) than DVT/PE (1306 of 2140; 61%; p=0.02); in contrast, comparable numbers of female pediatric patients had abdominal thrombosis (20 of 42; 47.6%) and DVT/PE (68 of 136; 50%). The mean age for patients having abdominal thrombosis was lower than patients having DVT/PE for both adults (38.3 vs 43.0 yrs; p<0.0001) and pediatric patients (9.0 vs 11.9 yrs; p=0.014). Similarly, the mean body mass index was lower for patients having abdominal thrombosis than patients having DVT/PE for both adults (28.1 vs 30.8; p<0.0001) and pediatric patients (21.5 vs. 24.7; p=0.05). There were no relationships with race, ethnicity, or inherited thrombophilic disorders. In adults, autoimmune conditions (21.9 vs 13.6; p=0.0007) and recent surgery (14.0 vs 9.2; p=0.02) were more common in patients with abdominal thrombosis, whereas, hyperlipidemia was more frequent in patients with DVT/PE (8.3 vs 13.2; p=0.04). None of these relationships were seen in the pediatric patients, but trauma was more frequently seen in pediatric patients with DVT/PE than abdominal thrombosis. Sixty-one adult (26.8%) and 6 pediatric patients (14.3%) had another VTE elsewhere, with most occurring after the initial event (21 DVT and 7 PE). Similar proportions of adult and pediatric patients had arterial thromboembolic events for both abdominal thrombosis and DVT/PE. CONCLUSIONS: Adult patients with abdominal thrombosis are more likely female, have hepatic, portal and/or mesenteric vein thrombosis, and common co-morbid conditions include recent surgery and autoimmune disorders. Pediatric patients are evenly divided between male and female, more commonly have IVC thrombosis, and co-morbid conditions include recent trauma. Both adult and pediatric patients with abdominal thrombosis tend to be younger and have a lower BMI than patients with DVT and/or PE. We also found a high rate of concurrent thrombosis in both adult and pediatric patients with abdominal thrombosis. In summary, patients with abdominal thrombosis display different clinical characteristics when compared to those with DVT/PE, specifically in terms of gender, location of thrombosis, and associated co-morbidities. Some of these differences, such as higher rates of IVC thrombosis in pediatric patients with abdominal thrombosis, might be caused by variance between genetic and anatomic factors. Further studies are warranted to explain these differences. Disclosures: Kulkarni: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Participate in clinical trials. Philipp:Baxter: Research Funding; Wyeth: Research Funding; Octapharma: Research Funding. Ortel:Sanofi-Aventis: Consultancy, Research Funding; Ortho-McNeil: Consultancy; GlaxoSmithKline: Research Funding; Eisai: Research Funding; Pfizer: Research Funding.

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.

Abstract Introduction Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of BTK that has excellent single-agent activity in patients with previously treated CLL/SLL, based on results of published clinical studies. In the HELIOS trial, addition of ibrutinib to BR resulted in an 80% reduction in disease progression or death and confirmed for the first time, in a randomized setting, the benefit of ibrutinib-based therapy compared with standard chemoimmunotherapy (CIT) in previously treated patients (Chanan-Khan et al. ASCO 2015). In patients with CLL or SLL, deletion 17p (del17p) and 11q (del11q), complex karyotype, unmutated IgVH, and elevated ZAP70 are known high-risk prognostic factors. The current analysis reports on the efficacy of ibrutinib + BR vs placebo + BR in patients in the HELIOS trial with relevant high-risk biomarkers. Methods HELIOS is a randomized, double-blind, placebo-controlled, phase 3 study. Patients with active CLL/SLL following ≥ 1 prior therapy were randomized 1:1 to receive BR (≤ 6 cycles) with either ibrutinib (420 mg daily) (n = 289) or placebo (n = 289). Patients with del17p (> 20% of cells) were excluded. Ninety patients in the placebo arm with independent review committee (IRC)-confirmed progressive disease crossed over to ibrutinib, per protocol amendment. The primary end point was IRC-assessed progression-free survival (PFS), and overall survival (OS) was a secondary end point. A total of 287 patients in each arm had data available for at least 1 biomarker, and this population was used for the biomarker analyses. Correlation of biological risk factors at baseline with PFS and OS was analyzed using Kaplan-Meier analysis and curves compared using log-rank tests. Hazard ratios (HRs) were estimated using univariate Cox proportional hazards models. Results At a median follow-up of 17 months, IRC-assessed PFS was significantly longer with ibrutinib + BR vs placebo + BR in the overall study population (median not reached vs 13.3 months, respectively; HR: 0.203; 95% CI: 0.150-0.276; p < 0.0001). All subgroups of patients, including those with adverse prognostic parameters, e.g., del11q, complex karyotype, unmutated IgVH and elevated ZAP70 levels, had a significantly longer PFS with the addition of ibrutinib to BR as compared with placebo + BR (Table 1). As expected, each of these adverse prognostic parameters had a negative impact on PFS in the placebo + BR arm, e.g., the median PFS was shortest in patients with complex karyotype [8.5 months vs 13.8 months in patients without complex karyotype] and in patients with unmutated IgVH (11.3 months vs 22.1 months in patients with mutated IgVH). Interestingly, in the ibrutinib + BR arm, the adverse impact of these risk factors could not be detected (median PFS not reached irrespective of presence of risk factors). For example, in Figure 1 showing the PFS curves stratified by both del11q status and treatment, the outcome for patients in the ibrutinib + BR arm with del11q was similar to those without, with a trend toward better outcome in the del11q patients (e.g., longer PFS - not reached vs 24.9 months), unlike for patients in the placebo + BR arm (11.01 months vs 13.86 months). In patients with del11q, unmutated IgVH, or elevated ZAP70, there were also statistically significant benefits in OS for those receiving ibrutinib + BR vs placebo + BR (del11q: HR: 0.326, 95% confidence interval [CI], 0.122-0.870; p = 0.025; unmutated IgVH: HR: 0.515, 95% CI, 0.298-0.890: p = 0.017; elevated ZAP70, HR 0.536, 95% CI, 0.289-0.994: p = 0.048). Addition of ibrutinib also increased PFS in patient subgroups with other cytogenetic or clinical prognostic markers (such as del13q or bulky disease) compared with placebo. Conclusions All subgroups of patients, irrespective of adverse risk factors, such as del11q, complex karyotype, elevated ZAP70, and unmutated IgVH, benefit from the addition of ibrutinib to BR compared with placebo + BR. The negative impact of these known risk factors is apparent in patients in the placebo + BR arm, but is not seen in patients in the ibrutinib + BR arm. These results suggest that ibrutinib + BR is a suitable treatment regimen for all patients with previously treated CLL/SLL, including those with high-risk prognostic markers. Disclosures Cramer: Janssen: Other: Travel grant, Research Funding, Speakers Bureau; Hoffman LaRoche: Other: Travel grant, Research Funding, Speakers Bureau; Mundipharma: Other: Travel grant; Glaxo Smith Klein/Novartis: Research Funding; Astellas: Other: Travel grant; Gilead: Other: Travel grant, Research Funding. Fraser:Janssen: Honoraria, Research Funding, Speakers Bureau; Hoffman LaRoche: Consultancy, Honoraria; 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. Dilhuydy:Roche: Honoraria, Other: Travel reimbursement; Janssen: Honoraria, Other: Travel reimbursement; Mundipharma: Honoraria. Goy:Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Mato:Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses; TA Therapeutics: Research Funding. Damle:Janssen: Employment. Phelps:Janssen/J&J: Employment, Equity Ownership. Mahler:Janssen: Employment, Other: Travel reimbursement. Salman:Janssen/J&J: Employment, Equity Ownership. Schaffer:Janssen: Employment. Howes:Janssen/J&J: Employment, Equity Ownership. Balasubramanian:Pharmacyclics LLC, an AbbVie Company: Equity Ownership; Janssen: Employment, Equity Ownership.

Abstract Abstract 287 Purpose: Farnesyltransferases are key cellular enzymes involved in the prenylation of proteins. Prenylated proteins are important for malignant cell growth. The purpose of this phase II study (NCT00082888) was to assess tumor response and toxicity associated with the oral farnesyltransferase inhibitor tipifarnib (R115777, Johnson and Johnson) in patients with relapsed aggressive, indolent, or uncommon lymphoma. The uncommon group included low incidence lymphoma types such as Hodgkin lymphoma (HL) and T-cell non-Hodgkin lymphoma- cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). Patients and Methods: Patients with relapsed or refractory non-Hodgkin (NHL) or Hodgkin (HL) were eligible if they had measurable disease, performance status ≤2, platelet count ≥75,000 × 10(6)/L, an absolute neutrophil count ≥1000 × 10(6)/L and a creatinine ≤2 × upper limit of normal. Patients initially received tipifarnib 300 mg twice daily, days 1–21 every 28 days. The trial was conducted by the University of Iowa/Mayo Clinic Lymphoma SPORE. Results: Ninety-three patients with lymphoma (42 aggressive, 15 indolent, and 36 uncommon) enrolled in the trial between March 2004 and November 2008. The median age was 62 years (range, 18–91). The median number of prior therapies was 5 (range, 1–17). The overall response rate (ORR) was 20% (19/93) with 6% (6/93) complete responses (CR) and 14% (13/93) partial responses (PR). The ORR was 17%, 7%, and 31% for the aggressive, indolent, and uncommon groups, respectively (Table). Among the 19 responders were 7 diffuse large B-cell lymphoma (DLBCL), 7 T-cell NHL, 1 follicular grade II, and 4 HL. The overall median response duration for the 19 responders was 7.5 months (mean, 12.8; range, 1.8 – 48.1 months). The median response duration was 11.3 months (mean, 10.1; range, 1.8 – 18.5 months), 2 months, and 7.5 months (mean, 15.5; range, 1.9 – 48.1 months) for the aggressive (7), indolent (1), and uncommon (11) groups, respectively. Five patients in the uncommon group are still receiving treatment with a range of treatment duration between 25 – 60+ months. Among the 5 still receiving treatment 4 responded and 1 is stable. The range of response duration is 15.4, 17.7, 43.1, and 48.1 months. These five patients (2 with HL, 1 anaplastic large cell cutaneous, and 2 PTCL) are currently receiving doses of 400 (1), 200 (2), and 100 (2) mg twice daily. The median time to progression for all patients was 3.6 months (95% CI: 2.1 – 4.5 months). The grade 3,4 toxicities observed were primarily fatigue (10%) and reversible myelosuppression with 11% anemia, 37% neutropenia, and 32% thrombocytopenia. Correlative studies demonstrated tipifarnib-induced upregulation of Bim, a marker of tipifarnib action in lymphoma cell lines, in 7 of 9 paired lymphoma biopsies. Conclusions: Tipifarnib has activity in lymphoma, with responses in patients with heavily pretreated DLBCL, HL and T-cell types, but little activity in follicular NHL. This agent has an excellent toxicity profile and targets a novel pathway. Further studies in combination with other agents are warranted for patients with DLBCL, HL or T-cell NHL. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Treatment of multiple myeloma has evolved considerably in the past few years with availability of several news drugs as well as increasing use of multidrug combinations. These changes have no doubt led to the improved survival seen among patients with MM. We have previously shown that outcomes of patients intolerant or refractory to one of the IMiDs and bortezomib had a poor outcome. Since that time, other drugs of the same class as well as new classes of drugs have been introduced for the treatment of MM. We designed this retrospective study to estimate the outcomes in patients with relapsed myeloma, who have become refractory to the current generation IMiDs and proteasome inhibitors. Patients and Methods: Patients with relapsed multiple myeloma who have received at least 3 prior lines of therapy, is refractory to both an IMiD (lenalidomide or pomalidomide) AND a proteasome inhibitor (bortezomib or carfilzomib), and has been exposed to an alkylating agent were identified from multiple centers. The time patients met the above criteria was defined as T0, and details of all treatment regimens before and after T0 were collected using electronic CRFs. The study was approved by the IRB at the respective centers. Results: 543 patients were enrolled in this study; median age was 62 years (31-87) and 61% were males. Patients were enrolled from centers in North America (n=181), Europe (n=318), and Asia Pacific (n=44). Patients were diagnosed between 2006 and 2014, the median duration between diagnosis of myeloma and study entry (T0) was 3.1 years (0.3 to 9). The median (95% CI) estimated follow up from diagnosis and from T0 were 61 (57, 66) months and 13 (11, 15) months respectively. The median number of lines of therapy prior to T0 was 4 (3-13), 48% had a prior transplant. The median OS from T0 for the entire cohort was 13 (11, 15) months. For these 462 patients, the median number of recorded regimens was 2 (1-9). The overall response and the depth of response to each line of treatment following T0 are as shown in the table. The median (95% CI) PFS and OS from T0 was 5 (4, 6), and 15.2 (13, 17), respectively. The overall survival for the 81 patients with no treatment post T0 was only 2.1 months. In a multivariate analysis, duration from diagnosis to T0, ISS stage III and number of lines of therapy were all associated with inferior PFS, as well as OS, and in addition, serum creatinine>2 mg/dL at T0 also predicted inferior OS. Conclusions: The study provides the expected outcome following development of myeloma that is refractory to a PI and an IMiD. The outcomes of these patients appear to be better than we had seen historically in patients refractory/ intolerant to bortezomib and IMiDs, highlighting the increased treatment options available for these patients. However, there is decreasing response rate to sequential regimens highlighting the development of drug resistance. The data provides a bench mark for comparison of new therapies that are being evaluated in this disease. Table Table. Disclosures Dimopoulos: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kastritis:Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Terpos:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria. Hillengass:Sanofi: Research Funding; Novartis: Research Funding; Amgen: Consultancy, Honoraria; BMS: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. Leleu:TEVA: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; LeoPharma: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Pierre Fabre: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Honoraria. Oriol:Janssen: Honoraria, Other: Expert board committee; Amgen: Honoraria, Other: Expert board committee. Cavo:Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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. Vij:Shire: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy; Karyopharma: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding. Lokhorst:Genmab: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. van de Donk:Amgen: Research Funding; Janssen: Research Funding; BMS: Research Funding; Celgene: Research Funding. Mark:Onyx: Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ludwig:Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; BMS: Speakers Bureau; Janssen: Speakers Bureau. Jagannath:Novartis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Merck: Consultancy. Usmani:Array: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Dytfeld:Janssen Poland: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Moreau:Novartis: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau. Lee:Amgen: Membership on an entity's Board of Directors or advisory committees. Shustik:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. de la Rubia:Celgene: Consultancy; Bristol Myers: Consultancy; Amgen,: Consultancy; Janssen: Consultancy. Durie:Takeda: Consultancy; Amgen: Consultancy; Janssen: Consultancy.

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.