Abstract: Low-density lipoprotein (LDL) contributes to atherogenesis and cardiovascular disease through interactions with peripheral blood cells, especially platelets. However, mechanisms by which LDL affects platelet activation and atherothrombosis, and how to best therapeutically target and safely prevent such responses remain unclear. Here, we investigate how oxidized low-density lipoprotein (oxLDL) enhances glycoprotein VI (GPVI)-mediated platelet hemostatic and procoagulant responses, and how traditional and emerging antiplatelet therapies affect oxLDL-enhanced platelet procoagulant activity ex vivo. Human platelets were treated with oxLDL and the GPVI-specific agonist, crosslinked collagen-related peptide, and assayed for hemostatic and procoagulant responses in the presence of inhibitors of purinergic receptors (P2YR), cyclooxygenase (COX), and tyrosine kinases. Ex vivo, oxLDL enhanced GPVI-mediated platelet dense granule secretion, α-granule secretion, integrin activation, thromboxane generation and aggregation, as well as procoagulant phosphatidylserine exposure and fibrin generation. Studies of washed human platelets, as well as platelets from mouse and nonhuman primate models of hyperlipidemia, further determined that P2YR antagonists (eg, ticagrelor) and Bruton tyrosine kinase inhibitors (eg, ibrutinib) reduced oxLDL-mediated platelet responses and procoagulant activity, whereas COX inhibitors (eg, aspirin) had no significant effect. Together, our results demonstrate that oxLDL enhances GPVI-mediated platelet procoagulant activity in a manner that may be more effectively reduced by P2YR antagonists and tyrosine kinase inhibitors compared with COX inhibitors.

Abstract: Abstract 4110 Background: The ACT trial (ACT-1 and −2) tests the addition of alemtuzumab (ALZ) to 6 courses of bi-weekly CHOP (A-CHOP-14) followed, in younger patients (ACT-1), by high-dose therapy with autologous stem cell transplant (HDT/ASCT) in newly diagnosed primary systemic peripheral T-cell lymphoma (PTCL). To date, the trial has accrued a total of 131 patients (ACT-1 n=72; ACT-2 n=59). Here, we present the first planned interim safety analysis of the ACT-1 trial based on the first 51 randomized patients. Aims: The aim of the present analysis is to report on the feasibility of a dose-dense chemo-immunotherapy schedule combining ALZ and bi-weekly CHOP followed by HDT/ASCT in ‘de novo' PTCL patients. Results: Results contain two data subsets corresponding to ALZ dose levels prior and subsequent to a dose-reduction amendment tapering ALZ dose from 360 mg (30 mg on days 1 and 2 of each CHOP course) to 120 mg (30 mg on day 1 of CHOP courses 1–4), respectively. Of the 51 randomized patients, 43 had a complete set of evaluable data and represent the background for the present set of results. Of these, 5 received the higher ALZ dose, 17 the lower and 21 belonged to the antibody-void control arm. Treatment arms were well balanced with regard to histological subtypes, IPI sub-groups, and single prognostic factors. Neither of the two treatment cohorts, and for the experimental one irrespective of ALZ dose level, showed significant treatment delay. The median duration of chemotherapy (calculated for 5 bi-weekly cycles of an expected cumulative duration of 70 days) for non-ALZ vs. ALZ-treated patients was 73 vs. 81 days, respectively. No suspected unexpected serious adverse reactions (SUSARs) were reported. Grade 3–4 leucopenia and anemia were more frequent in ALZ-treated patients (71% vs 29% and 47% vs 14%, respectively), whereas no difference was seen in terms of thrombocytopenia (17% vs 18%). Non-hematological toxicity unrelated to infectious complications was similar in the two groups. At the higher ALZ dose level, two cases of systemic fungal infection were reported, of which one (verified as being aspergillosis) with fatal outcome in a patient with pre-existing type II diabetes and steroid-requiring chronic obstructive pulmonary disease. These two events prompted the ALZ dose-reduction amendment, which led to a significant drop in the number of serious adverse events (SAEs) for ALZ-treated patients (SAE/patient pre-amendment: 2.6, post-amendment: 0.76) to a level comparable with the control arm (SAE/patient pre-amendment: 0.67, post-amendment: 0.44). With regard to the types of infection (≥grade 2), there was a similar frequency in reported fungal infections between the two treatment cohorts, bacterial infections were more often reported in the standard treatment arm (55% vs 46%), while the opposite was observed for viral infections (29% vs. 35%). Among the latter, there were 8 cases of cytomegalovirus reactivation among ALZ-treated patients, of which only two were clinically symptomatic and regressed upon specific treatment. Conclusion: In conclusion, the early-on impression of a SAE decrease subsequent to the ALZ dose-reduction amendment (applied on both ACT-1 and ACT-2) has been further confirmed by a larger cohort of patients treated at the lower ALZ dose level. The number of adverse events in the two study arms is now fairly comparable and adds further useful information to the previous reports on feasibility of stem cell harvest (Blood 2010;116: 2395) and hematopoietic recovery (Ann Oncol 2011;22(s4): 476) in ‘de novo' PTCL patients treated with a dose-dense ALZ-CHOP regimen followed by HDT/ASCT. Disclosures: Walewski: 4SC AG: Consultancy. Jantunen:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) primarily affects older patients (pts) who often have medical comorbidities along with disease-related immunosuppression and myelosuppression. Although alkylating agents such as chlorambucil (clb) have been commonly used in these pts, novel therapies are needed. Ibrutinib (ibr) is a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase FDA-approved for pts with CLL who received ≥1 prior therapy and for del17p CLL (including first-line). Ibr showed high activity in treatment-naïve pts age ≥65 years, with an overall response rate (ORR) of 84% (complete response [CR] in 23%) and 30-month progression-free survival (PFS) of 96% (Byrd et al. Blood 2015). We conducted a randomized, open-label phase 3 trial to evaluate efficacy and safety of single-agent ibr vs clb in treatment-naïve older pts with CLL/SLL. Methods: Pts aged ≥65 years with treatment-naïve CLL/SLL were randomized 1:1 to receive 420 mg ibr daily until progression or clb 0.5 mg/kg (up to maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Pts with del17p were excluded. Primary endpoint was independent review committee (IRC)-assessed PFS per iwCLL 2008 criteria, with 2012 clarification for treatment-related lymphocytosis. Secondary endpoints included overall survival (OS), ORR, event-free survival (EFS), rate of hematologic improvement, and safety. Pts with IRC-confirmed progression could transfer to an extension study where next-line therapy (including ibr) could be initiated if they had an iwCLL indication for treatment. Results: Among 269 pts enrolled, median age was 73 years (70% ≥70 years). Baseline characteristics were balanced between arms; 45% had advanced Rai stage, 20% had del11q, and 69% had comorbidities at baseline including CIRS score 〉 6, reduced creatinine clearance, or ECOG status of 2. For pts treated with clb, 40% completed 12 cycles of therapy (mean dose 0.6 mg/kg). At a median follow-up of 18.4 months (mos), ibr significantly prolonged IRC-assessed PFS vs clb (median not reached [NR] vs 18.9 mos; HR 0.16, 95% CI 0.09-0.28, P 〈 0.0001); this was consistent within subgroups including age ≥70 years, del11q, and unmutated IGHV. As assessed by investigator, ibr reduced the risk of progression or death by 91% (HR 0.09; 95% CI, 0.04-0.17; P 〈 0.0001; Figure 1A), with an 18-mo PFS of 93.9% vs 44.8%. Ibr significantly prolonged OS vs clb (median NR for either arm; HR 0.16, 95% CI 0.05-0.56, P=0.0010; Figure 1B); 24-mo OS was 97.8% vs 85.3%, respectively. Three deaths occurred on the ibr arm vs 17 deaths on clb arm. The IRC-assessed ORR was 86.0% with ibr (4.4% CR/CRi) vs 35.3% with clb (1.5% CR/CRi). ORR with ibr was higher than clb at all evaluated time points; at 8 mos, ORR was 84% and 31%, respectively. Investigator-assessed ORR was 90.4% (9.6% CR/CRi) vs 35.3% (4.5% CR/CRi), respectively. Median EFS was also prolonged with ibr (NR vs 12 mos; HR 0.17, 95% CI 0.10-0.26; P 〈 0.0001). A ≥50% reduction in lymph node burden was observed in 91.2% vs 36.8% (P 〈 0.0001), and reduction in spleen enlargement in 75.7% vs 39.1% (P 〈 0.0001), for ibr and clb, respectively. Rates of sustained hematologic improvements were significantly higher with ibr vs clb, including in pts with baseline anemia (84% vs 45%; P 〈 0.0001) or thrombocytopenia (77% vs 43%; P=0.0054). Median duration of treatment was 17.4 mos with ibr and 7.1 mos with clb. Most frequent (≥20% of pts) adverse events (AEs) with ibr included diarrhea, fatigue, cough and nausea. Most frequent AEs with clb included nausea, fatigue, neutropenia, anemia and vomiting. AEs leading to treatment discontinuation were less frequent with ibr (9% vs 23%). Atrial fibrillation occurred in 6% (6 pts grade 2 and 2 pts grade 3) with ibr and 1% with clb. Hypertension was noted more frequently on ibr, but was limited to grade 1-3 and managed without ibr dose modification or discontinuation. Major hemorrhage occurred in 4% (1 pt grade 2, 4 pts grade 3, 1 pt grade 4) with ibr over median follow-up of approximately 1.5 years, and in 2% with clb. At the time of study closure, 87% of pts randomized to ibr continue to receive ibr. Conclusions: Treatment with single-agent ibr was superior to clb in terms of PFS, OS, ORR, EFS and hematologic improvement in treatment-naïve older CLL/SLL patients, with an 84% reduction in risk of death, and an acceptable safety profile. Disclosures Off Label Use: ibrutinib in first-line CLL (including non-del17p CLL). Barr:Gilead: Consultancy; Abbvie: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Robak:Janssen: Consultancy, Research Funding; MorphoSys AG: Consultancy, Honoraria, Research Funding. Owen:Janssen: Honoraria; Lundbeck: Honoraria; Gilead: Honoraria; Roche: Honoraria. Ghia:Adaptive: Consultancy; Pharmacyclics: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; GSK: Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Roche: Consultancy, Research Funding; Acerta Pharma BV: Research Funding. Hillmen:Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Bartlett:Novartis: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Gilead: Consultancy, Research Funding; Genentech: Research Funding; MERC: Research Funding; Insight: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Kite: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Coutre:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding. Quach:Celgene Corp, ONYX, Janssen, Takeda, Novartis, BMS: Honoraria, Research Funding. Janssens:Mundipharma: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy. O'Dwyer:Celgene: Honoraria, Research Funding. Hellmann:BMS: Consultancy, Other: funding of travel, accomodations or expenses, Speakers Bureau; Novartis: Consultancy, Other: funding of travel, accomodations or expenses, Research Funding, Speakers Bureau. Schuh:Acerta Pharma BV: Research Funding. Siddiqi:Seattle Genetics: Speakers Bureau; Pharmacyclics/Jannsen: Speakers Bureau; Kite pharma: Other: attended advisory board meeting. Tam:AbbVie: Honoraria; Roche: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Keating:Glaxo-Smith-Kline Inc.: Other: Advisory board; Celgene Corp.: Consultancy. Suri:Pharmacyclics LLC, an AbbVie Company: Employment. Zhou:Pharmacyclics LLC, an AbbVie Company: Employment. Clow:Pharmacyclics LLC, an AbbVie Company: Employment. Styles:Pharmacyclics LLC, an AbbVie Company: Employment. James:Pharmacyclics LLC, an AbbVie Company: Employment. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor; Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor. Burger:Pharmacyclics LLC, an AbbVie Company: Research Funding.