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Background: Approximately 40-60% of older patients (pts) with AML achieve complete remission (CR) with IC. Factors influencing the use of consolidation after induction include disease-related considerations, extent of hematopoietic recovery, pt fitness, and physician and pt preference. Most older pts who achieve AML remission will experience disease relapse despite consolidation therapy (Schlenk, Haematologica, 2018). In the phase III, randomized, double-blind QUAZAR AML-001 Maintenance Trial, CC-486, an oral hypomethylating agent, was shown to significantly prolong OS and RFS vs. placebo (PBO) in pts with AML in first remission following induction ± consolidation. Prior to study entry, the use of consolidation chemotherapy and number of consolidation cycles was at the discretion of the treating physician, with study eligibility not contingent on the use of consolidation. Objective: Assess survival outcomes in the QUAZAR AML-001 trial in pt subgroups defined by number of consolidation courses received before study entry. Methods: Eligible pts were aged ≥55 years with newly diagnosed AML, intermediate- or poor-risk cytogenetics, and ECOG PS ≤3. Within 4 months (mo) of attaining first CR or CR with incomplete blood count recovery (CRi), pts were randomized 1:1 to CC-486 300 mg or PBO QD for 14 days per 28-day treatment (Tx) cycle. OS and RFS were compared among pts who received no consolidation ("No Consolidation"), 1 cycle of consolidation ("1 Consolidation"), or ≥2 cycles of consolidation ("≥2 Consolidations"). For these analyses, "induction" and "consolidation" defined regimens received before and after, respectively, the reported date of first CR/CRi. OS was defined as the time from randomization to death, and RFS as time from randomization to relapse or death. Kaplan-Meier OS/RFS estimates were compared for CC-486 vs. PBO using log-rank test. Hazard ratios (HRs) and 95% CIs were generated using a stratified Cox proportional hazards model. These analyses were not powered sufficiently to determine statistical significance. Results: 472 pts were randomized to CC-486 (N=238) or PBO (N=234). Most pts (80%) received consolidation before study entry. The No Consolidation cohort comprised 94 pts (20%; CC-486 52, PBO 42), the 1 Consolidation cohort comprised 212 pts (45%; CC-486 110, PBO 102), and the ≥2 Consolidations cohort comprised 166 pts (35%; CC-486 76, PBO 90), including 19 pts (CC-486 6, PBO 13) who received 3 consolidation cycles. Common agents used for consolidation were cytarabine (377/378 pts), idarubicin (95/378), and daunorubicin (37/378). While most pts received 1 induction, 97 pts received ≥2 induction courses; of them, 21 (CC-486 14, PBO 7) did not receive consolidation and 76 (CC-486 43, PBO 33) received ≥1 consolidation cycle. Baseline characteristics (eg, CR / CRi after IC, ECOG PS, cytogenetic risk at diagnosis) were generally similar among Tx arms and cohorts. Median (range) ages of pts in the 0 / 1 / ≥2 Consolidation cohorts were 71 (58-84), 68 (55-86), and 67 (55-82) years, respectively. In the No Consolidation cohort, median OS from the time of randomization with CC-486 vs. PBO was 23.3 vs. 10.9 mo, respectively (HR 0.55 [95%CI 0.34, 0.89]), and median RFS was 8.4 vs. 3.9 mo (0.55 [0.34, 0.88]) (Figure A). In the 1 Consolidation cohort, median OS was 21.0 vs. 14.3 mo with CC-486 vs. PBO, respectively (HR 0.75 [95%CI 0.55, 1.02]), and median RFS was 10.0 vs. 4.7 mo (0.72 [0.53, 0.99]) (Figure B). In the ≥2 Consolidations cohort, median OS was 28.6 mo with CC-486 vs. 17.6 mo with PBO (HR 0.75 [95%CI 0.50, 1.11]), and median RFS was 13.0 vs. 6.1 mo (0.59 [0.41, 0.87]) (Figure C). Conclusions: CC-486 was associated with consistent survival benefits vs. PBO regardless of number of prior consolidation cycles. Use of consolidation was generally associated with nominal improvements in OS and RFS within each Tx arm; however, in the CC-486 arm, median OS for pts who did not receive consolidation was similar to those who received 1 consolidation cycle (23.3 and 21.0 mo, respectively). Results should be interpreted with caution, as these cohorts were not prospectively defined and the study was not powered to detect significant differences between subgroups. Nevertheless, these data clearly suggest that older pts with AML in first remission after induction can benefit from CC-486, regardless of their fitness to receive consolidation or the number of consolidation cycles received before starting CC-486. Disclosures Wei: AMGEN: Honoraria, Other: Advisory committee, Research Funding; Walter and Eliza Hall Institute: Patents & Royalties; Novartis: Honoraria, Research Funding, Speakers Bureau; Abbvie: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Genentech: Honoraria, Other: Advisory committee; Servier: Consultancy, Honoraria, Other: Advisory committee; Astellas: Honoraria, Other: Advisory committee; Pfizer: Honoraria, Other: Advisory committee; Macrogenics: Honoraria, Other: Advisory committee; Celgene: Honoraria, Other: Advisory committee, Speakers Bureau; Astra-Zeneca: Honoraria, Other: Advisory committee, Research Funding; Janssen: Honoraria, Other. Roboz:Orsenix: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Jazz: Consultancy; Astex: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Array BioPharma: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Jasper Therapeutics: Consultancy; Cellectis: Research Funding; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Eisai: Consultancy; Celltrion: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy; Sandoz: Consultancy; Roche/Genentech: Consultancy; Amphivena: Consultancy. Dombret:Sunesis: Consultancy; Abbvie: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy; Otsuka: Consultancy; Janssen: Consultancy; Menarini: Consultancy; Pfizer: Consultancy, Research Funding; Jazz Pharma: Consultancy, Research Funding; Celgene: Consultancy; Nova: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Astellas: Consultancy; Servier: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Cellectis: Consultancy. Döhner:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; AROG: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Sunesis: Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Pfizer: Research Funding; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; GEMoaB: Consultancy, Honoraria. Selleslag:Amgen: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Belgian College: Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. La Torre:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne:Bristol Myers Squibb: Current Employment. Kumar:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dong:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Beach:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ravandi:Macrogenics: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria.

INTRODUCTION: About 50% of older patients with AML attain remission with intensive induction chemotherapy (IC) but the majority will eventually relapse. Effective, well tolerated maintenance treatments are needed to reduce the risk of relapse and prolong survival for older patients with AML in remission, who are less likely than younger patients to be candidates for hematopoietic stem cell transplant (HSCT). CC-486 is an oral hypomethylating agent that allows for extended dosing schedules to sustain therapeutic activity. In the randomized, phase III QUAZAR AML-001 Maintenance Trial, CC-486 significantly prolonged overall survival (OS) and relapse-free survival (RFS) vs. placebo in patients aged ≥55 years with AML in first remission after IC ± consolidation. Gastrointestinal (GI) events were the most common treatment-emergent adverse events (TEAEs) reported in patients who received CC-486. Here we assess the rates of GI TEAEs and associated management strategies over time with CC-486 treatment in QUAZAR AML-001. METHODS: Eligible patients were aged ≥55 years and had AML with intermediate- or poor-risk cytogenetics and Eastern Cooperative Oncology Group performance status (ECOG PS) scores ≤3. Patients had achieved complete remission (CR) or CR with incomplete blood count recovery (CRi) after IC ± consolidation and were not candidates for HSCT. Within 4 months of achieving CR/CRi, patients were randomized 1:1 to CC-486 300 mg or placebo, administered once-daily on days 1-14 of repeated 28-day treatment cycles. Safety was assessed among patients who received ≥1 dose of study drug, from the date of first dose through 28 days after the last dose. Prophylaxis and treatment of GI TEAEs were allowed but not mandatory. RESULTS: In all, 236 patients received CC-486 and were evaluated for safety. The median age at study entry was 68 years (range 55-86), 202 patients (85.6%) had intermediate-risk cytogenetics at diagnosis, 185 (78.4%) had achieved CR after induction, and 184 (78.0%) received ≥1 course of consolidation before randomization. Overall, nausea, vomiting, and diarrhea (any grade) were reported in 65%, 60%, and 50%, respectively, of patients treated with CC-486. Few patients experienced grade 3 TEAEs (nausea, 3%; vomiting, 3%; diarrhea, 5%) or serious events (0.4%, 0.8%, and 1.3%, respectively), and only 1 grade 4 event (diarrhea) was reported at any time on-study. Rates of GI TEAEs were highest during initial treatment and decreased thereafter. In cycles 1-2, 3-4, and 5-6, respectively, nausea was reported in 53%, 17%, and 15% of patients; vomiting in 49%, 15%, and 10% of patients; and diarrhea in 29%, 16%, and 11% of patients (Figure). The most commonly used concomitant GI medications were 5-HT3 antagonists, metoclopramide, lactulose, and loperamide; use of these agents was also highest during the first 2 treatment cycles and decreased over time (Figure). GI events required CC-486 treatment interruptions for 13% of patients, dose-reductions for 6% of patients, and treatment discontinuation for 5% of patients. DISCUSSION: Most GI-related TEAEs reported by patients treated with CC-486 were low-grade, and events decreased in frequency after initial treatment cycles, indicating these events were well managed. Use of GI medications decreased concurrently, suggesting progressive GI tolerance to CC-486 with continued therapy. Few patients discontinued CC-486 due to GI TEAEs. Prophylaxis and symptomatic intervention of GI events during early CC-486 therapy may facilitate treatment adherence to promote better outcomes. Disclosures Ravandi: Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Selleslag:Alexion: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Belgian College: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Sayar:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Safah:Amgen: Honoraria; Astellas: Speakers Bureau; Verastem: Honoraria; Janssen: Speakers Bureau. Hiwase:Novartis Australia: Research Funding. La Torre:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne:Bristol Myers Squibb: Current Employment. Kumar:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dong:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Beach:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dombret:Otsuka: Consultancy; Abbvie: Consultancy; Servier: Consultancy, Research Funding; Sunesis: Consultancy; Amgen: Consultancy, Research Funding; Jazz Pharma: Consultancy, Research Funding; Celgene: Consultancy; Nova: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Menarini: Consultancy; Janssen: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy.

Background Chronic myelomonocytic leukemia (CMML) is a highly heterogeneous myeloid neoplasm with poor prognosis and limited therapeutic options. Tefinostat (CHR-2845) is a cell permeant ester that is converted to an active acid histone deacetylase (HDAC) inhibitor (CHR-2847) by human carboxylesterase 1 (hCE-1), an enzyme predominantly found in cells of monocyte lineage. Pre-clinical studies confirmed selective activity of tefinostat, correlating with hCE-1 expression and acetylation induction, in monocyte derived cell lines, primary CMML and AML (M4/M5) cells (1). A phase 1 study in refractory haematological malignancies showed tefinostat to be well tolerated, with complete remission reported in 1/2 CMML patients (2). Given the compelling rationale for selective activity in monocytoid malignancies, we conducted a phase 2 study to assess safety and efficacy of tefinostat in CMML. Methods MONOCLE was a single arm phase 2 trial conducted to a Bryant and Day 2-stage design with dual primary endpoints of safety and clinical efficacy. CMML-2 patients were included; additionally CMML-1 patients with symptomatic bone marrow failure or proliferative disease, symptomatic splenomegaly, extramedullary involvement, systemic symptoms or CMML-specific Prognostic Score (CPSS) int-2/high. Tefinostat was administered orally in continuous 28-day cycles starting at 360mg once daily, increasing to 480mg after 4 weeks if well tolerated. Concomitant hydroxycarbamide was permitted only with cycles 1-3. Clinical response was assessed according to International Consortium MDS/MPN Response Criteria (3); responding patients at cycle 6 were permitted to continue therapy. Toxicity was assessed according to CTCAE v4.0. Results In stage 1, 21 patients were enrolled at 9 centers (Jan-Sep 2017). 20 patients received tefinostat (median age 75 years [64-88], M/F 14/6) including 16 with CMML-1 (80%) and 4 CMML-2 (20%), 8 (40%) with myelodysplastic and 12 (60%) myeloproliferative CMML; respective proportions in CPSS low/int-1/int-2/high risk groups were 5/50/40/5%. Myeloid NGS analysis confirmed a molecularly relatively high risk population: 70% ASXL1 mutation frequency and median 4 (2-7) mutations per patient; other most commonly observed mutations being TET2 (65%), SRSF2 (50%), EZH2 (35%) and NRAS (35%). Prior therapy included azacitidine (3 patients) and hydroxycarbamide (7). 17/20 patients had high hCE-1 levels, assessed flow cytometrically at trial entry in monocytoid cells (vs bulk myeloid population). Median number of cycles of tefinostat received was 4 (1-15). Of 13 patients completing ≥3 cycles of tefinostat, 1 patient achieved clinical benefit (partial bone marrow response at cycle 6 with red cell transfusion independence sustained over 15 cycles of treatment), 9 had stable disease (of whom 1 had transient clinical benefit [MPN-SAF symptom reduction] which was not sustained to cycle 6) and 3 had progressive disease. Most frequent non-hematologic adverse events of any grade were raised creatinine (55% patients), fatigue (40%) and nausea/vomiting (30%). Grade ≥3 AEs judged potentially related to tefinostat included thrombocytopenia (3 patients), fatigue (2), raised creatinine (2), anorexia, AV block, nausea and neutropenia (1 each). Creatinine rises were in all cases reversible following tefinostat dose reduction/cessation. Induction of intracellular lysine acetylation in monocytes (a marker of HDAC inhibition) was observed in 50% of patients (including clinical responders), peaking between days 15-28 of cycle 1. While no clear relationship between baseline hCE-1 expression and clinical response was evident, reductions in marrow monocyte and myeloid blast fractions were seen in both clinical responders. Conclusion Following failure to achieve a pre-defined minimum number of clinical responses to tefinostat, patient recruitment was not continued into stage 2 of this phase 2 study. Drug tolerability was encouraging although observed renal effects will likely preclude dose escalation in this challenging, often frail patient group. Despite compelling scientific rationale and pre-clinical data favoring this monocyte targeted treatment approach we were unable to demonstrate a clinically significant single agent disease modifying effect in CMML. (1) Zabkiewicz J. Oncotarget 2016; 7: 16650-62 (2) Ossenkoppele G. Br J Haem 2013; 162: 191-201 (3) Savona M. Blood 2015; 125: 1857-65 Disclosures Knapper: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Meeting and travel support; Jazz: Other: Meeting and travel support; Daiichi Sankyo: Other: Meeting and travel support; Chroma Therapeutics: Research Funding. Hills:Daiichi Sankyo: Consultancy, Honoraria. Dillon:Teva Pharmaceuticals UK: Consultancy, Honoraria; AbbVie UK: Consultancy, Honoraria. Pocock:Kent & Canterbury Hospital: Employment. Culligan:Pfizer: Honoraria; Takeda: Honoraria, Other: Support to attend conferences; JAZZ: Honoraria; Merck Sharp & Dohme (MSD): Honoraria; Abbvie: Other: Support to attend conferences; Celgene: Other: Support to attend conferences; Daiichi-Sankyo: Other: Support to attend conferences.

Introduction: Many older patients (pts) with AML respond to intensive induction chemotherapy (IC), but responses are often short-lived and overall survival (OS) is poor. The benefit of post-remission maintenance treatment (Tx) for pts with AML is unclear, as no therapy has shown to significantly improve OS. CC-486 is an oral hypomethylating agent that allows for prolonged drug exposure during each Tx cycle to sustain therapeutic activity. We hypothesized that prolonged Tx with CC-486 could be effective as post-remission maintenance in AML. Herein, we report the primary results of QUAZAR AML-001 (NCT01757535), a phase III international, randomized, double-blind, placebo (PBO)-controlled study evaluating CC-486 as maintenance therapy in pts aged ≥55 years with AML in first remission following IC. Methods: Eligible pts had de novo or secondary AML, intermediate- or poor-risk cytogenetics, and Eastern Cooperative Oncology Group performance status (ECOG PS) scores of ≤3; had achieved first complete remission (CR) or CR with incomplete count recovery (CRi) after IC, with or without consolidation chemotherapy; and were not candidates for hematopoietic stem-cell transplant (HSCT). Within 4 months of attaining CR/CRi, pts were randomized 1:1 to receive CC-486 300 mg or PBO once-daily on days 1-14 of repeated 28-day Tx cycles. A 21-day dosing schedule was permitted for pts who experienced AML relapse with 5-15% blasts in blood or bone marrow while on-study. Tx could continue indefinitely until the presence of >15% blasts, unacceptable toxicity, or HSCT. The primary endpoint was OS. Secondary endpoints included relapse-free survival (RFS), health-related quality of life (HRQoL), and safety. Samples were collected for exploratory translational endpoints, including measurable residual disease (MRD). Kaplan-Meier estimates of OS and RFS were compared for CC-486 vs. PBO by stratified log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were generated using a stratified Cox proportional hazards model. Results: Between May 2013 and October 2017, 472 pts were randomized to receive CC-486 (n=238) or PBO (n=234). Baseline characteristics were balanced between Tx arms. Median age was 68 years (range 55-86), 91% of pts had de novo AML, and 86% and 14% of pts, respectively, had intermediate-risk or poor-risk cytogenetics. Following induction, 81% of pts achieved a CR and 19% achieved CRi; 80% of pts had received consolidation chemotherapy (45% received 1 consolidation cycle and 31% received 2 consolidation cycles). At a median follow-up of 41.2 months, OS was significantly improved with CC-486 vs. PBO: median OS was 24.7 months vs. 14.8 months from time of randomization, respectively (P=0.0009; HR 0.69 [95%CI 0.55, 0.86]) (FigureA). RFS was also significantly prolonged: median RFS was 10.2 months in the CC-486 arm, compared with 4.8 months in the PBO arm (P=0.0001; HR 0.65 [95%CI 0.52, 0.81]) (Figure B). OS and RFS benefits of CC-486 were demonstrated regardless of baseline cytogenetic risk, the number of prior consolidation cycles received, and CR/CRi status. CC-486 did not adversely impact overall HRQoL vs. PBO, as assessed by mean changes from baseline in HRQoL measures during Tx. CC-486 had a manageable safety profile generally consistent with that of injectable azacitidine. Median exposure to CC-486 was 12 cycles (range 1-80) and to PBO was 6 cycles (1-73). The most frequently reported adverse events (AEs) with CC-486 and PBO were grade 1 or 2 gastrointestinal (GI) events, including nausea (64% and 23%, respectively), vomiting (59% and 10%), and diarrhea (49% and 21%). The most common grade 3-4 AEs were neutropenia (CC-486, 41%; PBO, 24%), thrombocytopenia (23% and 22%), and anemia (14% and 13%). Serious AEs were infrequent, mainly infections, which occurred in 17% of pts in the CC-486 arm and 8% of pts in the PBO arm. Few AEs led to Tx discontinuation, most often GI events (CC-486, 5%; PBO, 0.4%). Conclusions: CC-486 is the first therapy used in the maintenance setting to provide statistically significant and clinically meaningful improvements in both OS and RFS in pts with AML in remission following induction chemotherapy, with or without consolidation. Oral CC-486 has a manageable safety profile and represents a new therapeutic standard for pts with AML in remission. Disclosures Wei: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Döhner:AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; AROG, Bristol Myers Squibb, Pfizer: Research Funding; Celgene, Novartis, Sunesis: Honoraria, Research Funding. Montesinos:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. Ravandi:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Orsenix: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenix: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sayar:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Porkka:Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Selleslag:Celyad: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Daichii Sankyo: Consultancy; Janssen-Cilag: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Astex Otsuka: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Sandhu:Takeda: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Bioverativ: Consultancy; Celgene Corporation: Consultancy; Pfizer: Consultancy; Janssen: Consultancy. Giai:BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Beltrami:Ospedale Policlinico San Martino: Employment. Ossenkoppele:Celgene Corporation: Consultancy, Honoraria, Research Funding. La Torre:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene Corporation: Employment, Equity Ownership. Kumar:Celgene Corporation: Employment, Equity Ownership. Dong:Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Introduction: Minimal residual disease (MRD) status reflects depth of response and informs prognosis after first-line therapy in patients (pts) with follicular lymphoma (FL). In the GALLIUM study (NCT01332968), the primary endpoint of investigator (INV)-assessed progression-free survival (PFS) in previously untreated FL pts was significantly improved with obinutuzumab (GA101; G)- versus rituximab (R)-based immunochemotherapy treatment. We previously reported consistently higher MRD response rates with G- versus R-based treatment at the end of induction (EOI) (92% vs 85%, respectively; p=0.0041; Pott et al. ASH 2016). Here we report the correlation of MRD response at EOI with updated PFS data and the results of MRD response assessment during maintenance treatment and follow-up. We also assessed MRD responses and outcome in pts who remained MRD-positive at EOI. Methods: Previously untreated pts aged ≥18 years with FL requiring treatment were randomized 1:1 to receive 6-8 cycles of G (1000mg IV on days [D] 1, 8, and 15 of cycle [C] 1 and D1 of C2-6 or 8) or R (375mg/m2 IV on D1) plus standard chemotherapy (CHOP, CVP, or bendamustine). Responding pts received the same antibody as maintenance every 2 months for up to 2 years. MRD status was assessed by real-time quantitative (RQ)-PCR assays at mid-induction (MI) in peripheral blood (PB), at EOI in PB and bone marrow, at 4-monthly intervals during maintenance in PB, and at 6-monthly intervals during follow-up in PB, and was defined as negative (MRD response) if RQ-PCR and subsequent nested PCR were negative in all samples analyzed at the respective time point. INV-assessed PFS was estimated using Kaplan-Meier methods (data cut-off, February 12, 2018). Pts were included in the various analyses if they had evaluable MRD data and achieved a complete or partial response at EOI. Results: After 57 months' median follow-up, MRD evaluable pts (n=634/1202 randomized FL pts) who had a MRD-negative response at EOI (n=564) continued to have a longer PFS than those who had a MRD-positive response at EOI (n=70; hazard ratio 0.38; 95% confidence interval 0.26, 0.56; p Conclusions: These data confirm the prognostic value of MRD status at EOI in previously untreated FL pts receiving immunochemotherapy. Analysis of MRD kinetics revealed that most of the pts who achieved MRD negativity at EOI sustained their responses during maintenance. The majority of pts who were MRD positive at EOI achieved MRD negativity during the first 4 months of maintenance. While this is likely to be indicative of the efficacy of continued treatment, it also suggests that response kinetics can be slower than in those pts who have an early MRD response at MI, and that responses that are beyond the sensitivity of the MRD assay may be less deep. Importantly, pts who failed to achieve MRD negativity at EOI or during early maintenance had a high chance of experiencing early progression or death. These data demonstrate the prognostic value of MRD response assessments in previously untreated FL pts receiving immunochemotherapy. Disclosures Hoster: F. Hoffman-La Roche: Other: Travel support, Research Funding; Roche Pharma AG: Other: Travel support, Research Funding. Unterhalt:F. Hoffman-La Roche: Other: Travel support. van der Jagt:F. Hoffman-La Roche Ltd: Employment, Honoraria, Research Funding. Janssens:Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Sanofi-Genzyme: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Kneba:Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Mayer:Affimed: Research Funding; Roche: Research Funding; Johnson & Johnson: Research Funding; Eisai: Research Funding; Novartis: Research Funding. Pocock:Kent & Canterbury Hospital: Employment. Knapp:Roche: Employment. Danesi:F. Hoffmann-La Roche Ltd: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Brown:PAREXEL, external business partner with Roche Products Ltd, Welwyn, UK: Employment. Mundt:Roche: Employment, Other: Ownership interests PLC. Marcus:Gilead: Consultancy; F. Hoffman-La Roche: Other: Travel support and lecture fees; Roche: Consultancy, Other: Travel support and lecture fees . Hiddemann:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background Survival rates for older pts with advanced HL (aged ≥60 yrs) were historically poor with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). Reasons may include decreased tolerance of therapy, increased toxicity (particularly with bleomycin), comorbidities, and disease biology. The pivotal phase 3 ECHELON-1 study demonstrated superior 2-yr modified progression-free survival (mPFS) with frontline brentuximab vedotin + doxorubicin, vinblastine and dacarbazine (A+AVD) vs ABVD in pts with stage III/IV cHL (Connors JM et al, NEJM 2018). The study allowed entry of older pts, with no upper age limit. Alternative dosing schedules of the A+AVD regimen have been studied (e.g., sequential brentuximab vedotin before and after AVD; NCT01476410, Evens AM et al, J Clin Oncol 2018). We report efficacy and safety results from ECHELON-1 for older pts with cHL and compare these with those for pts aged Methods mPFS per independent review facility (IRF) for pts ≥60 years was a prespecified subgroup analysis of ECHELON-1. Additional exploratory safety and efficacy analyses were also assessed and compared with younger pts ( Results 14% (186/1334) of pts in the intent-to-treat (ITT) population were aged ≥60 yrs (A+AVD, n=84; ABVD, n=102) and included in the sub analyses. Median age (range) of older pts was: A+AVD, 68.0 yrs (60-82); ABVD, 66.0 yrs (60-83). Baseline pt and disease characteristics in older pts were similar in both arms. ECOG PS scores were 0 (36% vs 36%), 1 (52% vs 54%), and 2 (12% vs 10%) in A+AVD and ABVD arms, respectively. Pts received a median of 6 cycles with mean relative dose intensities for each drug (%) in older pts of: A+AVD, 92.3, 96.6, 93.3, and 97.9; ABVD, 97.3, 88.7, 93.3, and 95.9. With median follow-up of ~25 months, 2-yr mPFS per IRF was similar in both arms for older ITT pts (A+AVD 70.3% [95% CI: 58.4, 79.4] vs ABVD 71.4% [95% CI: 60.5, 79.8]; HR=1.00 [95% CI: 0.58, 1.72]; p=0.993). An exploratory analysis of standard PFS per investigator (INV) showed HR=0.85 ([95% CI: 0.49, 1.48]; p=0.576) (Table 1). For older pts with stage IV cHL (A+AVD n=51; ABVD n=67), there was an increase in 2-yr PFS per INV with A+AVD vs ABVD (74.0% [95% CI: 59.5, 84.0] vs 59.9% [95% CI: 45.6, 71.5]; HR, 0.66 [95% CI: 0.34, 1.26]; p=0.20); mPFS per IRF improvement with A+AVD in older stage IV pts was lower (HR=0.80; [95% CI: 0.42, 1.53]). In younger stage III/IV pts ( Conclusions For older ECHELON-1 pts, mPFS and PFS were similar in both arms. In the larger subgroup of younger pts, mPFS and PFS were improved vs older pts. As expected, incidence of treatment-emergent AEs was higher in older pts, with regimen-specific AEs seen, including fatal pulmonary events in ABVD pts. The high incidence of FN in older A+AVD pts points to the need for G-CSF PP. Disclosures Evens: Acerta: Consultancy; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Tesaro: Research Funding; Novartis: Consultancy. Connors:Merck: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Roche Canada: Research Funding; NanoString Technologies: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Seattle Genetics: Honoraria, Research Funding; Janssen: Research Funding; F Hoffmann-La Roche: Research Funding; Bayer Healthcare: Research Funding; Cephalon: Research Funding; Bristol Myers-Squibb: Research Funding; Lilly: Research Funding; Genentech: Research Funding. Younes:Sanofi: Honoraria; Merck: Honoraria; Astra Zeneca: Research Funding; Celgene: Honoraria; Incyte: Honoraria; Seattle Genetics: Honoraria; Bayer: Honoraria; Novartis: Research Funding; Curis: Research Funding; J&J: Research Funding; Genentech: Research Funding; Takeda: Honoraria; Roche: Honoraria, Research Funding; Abbvie: Honoraria; Janssen: Honoraria, Research Funding; Pharmacyclics: Research Funding; BMS: Honoraria, Research Funding. Ansell:Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Bristol-Myers Squibb: Research Funding. Radford:Takeda: Consultancy, Research Funding, Speakers Bureau; GlaxoSmithKline: Equity Ownership; AstraZeneca: Equity Ownership; Seattle Genetics: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Pfizer: Research Funding; Celgene: Research Funding; BMS: Consultancy, Speakers Bureau. Feldman:Seattle Genetics: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Celgene: Speakers Bureau; Portola: Research Funding; KITE: Speakers Bureau. Tuscano:Takeda: Research Funding; Genentech: Consultancy, Research Funding; Amgen: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding. Oki:Seattle Genetics: Research Funding; Takeda Millenium: Honoraria, Research Funding; Jazz Pharmaceuticals: Employment. Grigg:Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pocock:Kent & Canterbury Hospital: Employment. Dlugosz-Danecka:Roche: Consultancy; Servier: Consultancy. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Engley:Seattle Genetics: Employment. Liu:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Miao:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jolin:Takeda Pharmaceuticals International Co.: Employment. Gautam:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Gallamini:Takeda: Consultancy, Speakers Bureau.

Background: The International Prognostic Index (IPI) was first described in 1993 and is the most widely used prognostication tool in diffuse large B-cell lymphoma (DLBCL). Five independent risk factors for OS: age (≤60 yrs versus >60 yrs), stage (I/II versus III/IV), number of extranodal (EN) sites (≤1 versus >1), performance status (PS) (0-1 versus ≥2) and serum lactate dehydrogenase (LDH) (normal versus elevated) were used to design a prognostic model which stratified patients into 4 prognostic groups according to the number of risk factors present: low (0-1), low-intermediate (2), high-intermediate (3), and high-risk (4-5); predicting 5-yr OS rates of 73%, 51%, 43% and 26% and 5-yr relapse-free survival (RFS) rates of 70%, 50%, 49%, 40% respectively. For patients aged ≤60 yrs 3 risk factors (stage, PS and LDH level) remained independently significant for OS, and an age-adjusted (aa) model (the aa-IPI) was proposed which predicted 5-yr OS for the low (0), low-intermediate (1), high-intermediate (2) or high-risk (3) groups of 83%, 69%, 46% and 32% respectively (Shipp et al, 1993). The British Columbia Cancer Agency re-evaluated the role of IPI in the rituximab era in their registry-based cohort of 365 patients in 2007. Although the IPI remained predictive, only 2 (rather than 4) prognostic groups were identified and the authors recommended use of the Revised-IPI (R-IPI) where redistribution of the absolute number of IPI risk factors better stratified patients into 3 prognostic groups: very good (0) good (1,2) and poor (3-5) (Savage et al, 2007). However, a subsequent analysis of pooled data from 3 prospective trials (Ziepert et al, 2010) confirmed that the IPI remained highly predictive of outcomes in the rituximab era. Here we report an evaluation of prognostic indices within the UK NCRI R-CHOP 14 vs 21 prospective trial cohort (Cunningham et al, 2013). Methods: The IPI and R-IPI were applied to the R-CHOP 14 versus 21 trial cohort (n=1,080) and for the subgroup of patients aged ≤60 yrs (n=515) and correlated with OS and progression-free survival (PFS). For patients aged ≤60 yrs the aa-IPI was applied in addition. It was not possible to evaluate the NCCN-IPI in our cohort as absolute LDH values were not collected at enrolment. The association between baseline clinical factors (age, gender, PS, stage, presence of >1 EN site of disease, presence of an elevated LDH, disease bulk and B symptoms) and patient outcomes were investigated in univariable and multivariable analysis (MVA). Performance of the prognostic indices was compared using the Concordance Probability Estimate (CPE) and Akaike's Information Criterion (AIC): CPE evaluates discriminatory power to assess the strength of statistical models (higher values indicate better discrimination); AIC estimates the quality of statistical models relative to each other in terms of fitting the data (lower values indicate a better model fit). Results: After a median follow-up of 6.5 years, both the IPI and R-IPI were significantly associated with OS (Figure 1) and PFS; the IPI performed better than the R-IPI for OS and PFS in terms of discrimination and model fit (Table 1). All IPI factors were significantly associated with OS, and remained in MVA with the exception of disease stage. For patients aged ≤60 yrs, the IPI, R-IPI and aa-IPI were all strongly associated with OS and PFS; the IPI performed best overall of the 3 prognostic indices in terms of discrimination and model fit (Table 2). All individual IPI risk factors, excepting stage, were again found to be significantly associated with OS in MVA for patients aged ≤60 yrs. Conclusion: For the entire DLBCL cohort both the IPI and R-IPI identified meaningful prognostic groups for OS and PFS. Although the IPI outperformed the R-IPI, neither index identified a patient subgroup with an OS of Disclosures Cunningham: Roche pharmaceuticals: Research Funding. Hawkes:Bristol Myers Squibb: Other: Speaker fee, Research Funding; Merck KGA: Research Funding; Astra Zeneca: Research Funding; Merck Sharpe Dohme: Research Funding; Celgene: Other: Advisory board, Research Funding; Takeda: Other: Speaker fee; Merck: Other: Advisory board; Roche: Other: Speaker fee; advisory board. Pocock:Kent & Canterbury Hospital: Employment. Ardeshna:Celgene: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference expenses, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Radford:Celgene: Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Speakers Bureau; GlaxoSmithKline: Equity Ownership; Novartis: Consultancy, Speakers Bureau; AstraZeneca: Equity Ownership; BMS: Consultancy, Speakers Bureau; Pfizer: Research Funding. McMillan:Celgene: Honoraria, Other: travel support; BMS: Honoraria; Amgen: Honoraria; Takeda: Other: travel support; Roche: Consultancy, Honoraria, Other: travel support; Pfizer: Research Funding; MSD: Honoraria. Johnson:Janssen: Consultancy, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; Boeringher Ingelheim: Consultancy; Kite: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria, Travel, accommodations, expenses; Novartis: Honoraria; Celgene: Honoraria; Eisai: Research Funding; Zenyaku Kogyo: Other: Travel, accommodations, expenses; Genmab: Consultancy.

Objective. SPIRIT 2 is the largest phase 3 prospective randomized open-label trial comparing imatinib (I) 400mg with dasatinib (D) 100mg daily in newly diagnosed chronic phase CML. The primary endpoint was 5 year event-free survival. Methods. 812 (406 in each arm) of 814 patients recruited started study medication (median age 53.2, 275/812 (33.8%) were over 60 years old). Patients were recruited at 144 hospitals between August 2008 and March 2013 and randomized to receive either imatinib 400mg or dasatinib 100mg daily. Secondary endpoints included overall survival, rates of treatment failure, cytogenetic/molecular response - RT-PCR BCR-ABL/ABL ratio of Disclosures O'Brien: Bristol Myers Squibb: Research Funding; CTI: Other: Chair of Independent Data Monitoring Committee; National Institute for Health and Care Excellence (NICE): Other: Chair of Technology Appraisal Committee. Osborne:Servier: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; MSD: Honoraria; Roche: Honoraria; Novartis: Honoraria. Bell-Gorrod:Bristol-Myers Squibb: Consultancy; Merck EDM Serono: Consultancy; PharmaMar: Consultancy; Novartis: Consultancy; GlaxoSmithKline: Consultancy. Latimer:Pfizer: Consultancy; BMS: Consultancy; Merck: Consultancy; Astra Zeneca: Consultancy; Bluebirdbio: Consultancy; Janssen: Consultancy. Apperley:Incyte: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Byrne:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Pocock:Kent & Canterbury Hospital: Employment. Copland:Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Clark:Ariad/Incyte: Consultancy; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

The reverse transcriptase–polymerase chain reaction (RT-PCR) has become widely used for monitoring minimal residual disease after allogeneic stem cell transplantation (SCT) for chronic myeloid leukemia (CML). However, most of these studies were performed using qualitative RT-PCR, and the interpretation of the results obtained has been conflicting. The correlation of a quantitative RT-PCR test performed early after SCT (at 3 to 5 months) and long-term outcome of CML patients surviving for more than 6 months was studied. Between January 1991 and June 1999, data from 138 CML patients who received allografts were evaluated. Early RT-PCR results were classified as (1) negative if there were no BCR-ABLtranscripts detected (n = 61), (2) positive at low level if the total number of BCR-ABL transcripts was less than 100 per μg RNA and/or the BCR-ABL/ABL ratio was less than 0.02% (n = 14), or (3) positive at high level if transcript levels exceeded the thresholds defined above (n = 63). Three years after SCT the cumulative incidence of relapse was 16.7%, 42.9%, and 86.4%, respectively (P = .0001). The relationship betweenBCR-ABL transcript level and probability of relapse was apparent whether patients had received sibling or unrelated donor SCT and also whether or not the transplantation was T cell depleted. The results suggest that quantitative RT-PCR performed early after SCT is useful for predicting outcome and may help to define the need for further treatment.

Several studies have established that some chronic myeloid leukaemia (CML) patients with enduring deep molecular responses to tyrosine kinase inhibitor (TKI) therapy can discontinue treatment. However, these studies are confined to patients in stable MR4, i.e. whose BCR-ABL/ABL ratio is consistently below 0.01% (molecular response 4 logs below an arbitrary baseline). Although there are anecdotal reports of successful treatment cessation for a few months in patients in stable MR3 (i.e. BCR-ABL In the British De-Escalation and Stopping Therapy with Imatinib, Nilotinib or sprYcel (DESTINY) study, patients in at least stable MR3 (on the International Standard) initially decreased their TKI to half the standard dose for 12 months, followed by complete cessation. Key entry requirements included first chronic phase of CML; receiving the same TKI since original diagnosis (except that one switch was permissible if for intolerance to the initial drug); on TKI for at least 3 years; all PCR tests in the past 12 months were in at least MR3 (minimum of 3 tests, each with >10,000 ABL control transcripts). Central monitoring was carried out monthly. Molecular recurrence was defined as loss of MR3 (>0.1%) on two consecutive samples; this prompted resumption of full dose of their entry TKI. Between December 2013 and April 2015, 174 patients (male 98; female 76) were recruited after giving informed consent from 20 UK centres. At entry, 148 patients were receiving imatinib, 16 nilotinib and 10 dasatinib. After 12 months of half-dose therapy (imatinib 200mg daily, nilotinib 200mg twice daily or dasatinib 50mg daily), molecular recurrence was lower in patients with stable MR4 at entry (3 of 125 patients; 2.4%) than in those in MR3 but not MR4 (9 of 49 patients; 18.4%) (p < 0.001). The median time to relapse was shorter in the sustained MR3 group than in those in sustained MR4 at entry (4.4 months vs 8.7 months). The probability of molecular recurrence on de-escalation was not related to age, gender, performance status, prior TKI (imatinib vs second generation) or the duration of TKI therapy (median 7.0 years overall). No progression to advanced phase or loss of cytogenetic response was seen; one death and 15 serious adverse events occurred which were all unrelated to CML or TKI treatment. All 12 patients with molecular recurrence regained MR3 within 4 months of resumption of full dose TKI. During the first 3 months of de-escalation but not thereafter, the number of patient-reported common TKI side effects decreased, though interestingly 53 new musculoskeletal symptoms were reported by 36 patients (21%) which were typically mild and transient. In CML patients with stable MR3 or better, decreasing TKI treatment to half the standard dose appears safe, and is associated with improvement in TKI related side effects, implying that many patients with stable responses are being overtreated. Studies of more ambitious de-escalation are warranted. Disclosures Clark: Ariad: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Apperley:Novartis: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Ariad: Honoraria, Speakers Bureau. Pocock:Gilead Sciences: Other: Sponsorship to attend the EHA 2016 Meeting; Janssen: Speakers Bureau; Takeda: Honoraria. Smith:Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Byrne:Bristol Myers Squibb: Consultancy, Speakers Bureau. O'Brien:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Copland:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction: The discovery of 3 distinct molecular subgroups of diffuse large B-cell lymphoma (DLBCL) according to cell-of-origin (COO): germinal centre B-cell (GCB), activated B-cell (ABC) and type III/unclassifiable by gene expression profiling (GEP) (Alizadeh et al, Nature 2000; Rosenwald et al, NEJM 2002) was a key advance in understanding the disease biology. The ABC subtype is associated with inferior survival which has persisted in the rituximab era (Lenz et al, NEJM 2008). Determination of COO by GEP has not been incorporated into routine practice however due to a lack of accessibility and requirement for fresh frozen tissue. Barrans et al (BJH 2012) recently demonstrated that COO could be accurately classified by the Illumina DASL® platform, using RNA extracted from routinely processed FFPE tissue from a population-based cohort of 172 R-CHOP-treated patients, and predicted clinical outcome. The aim of this analysis was to determine GEP-based DLBCL COO using the Illumina DASL® platform, to correlate results with outcome, and to validate this methodology using FFPE tissue samples from patients enrolled in the prospective phase III R-CHOP 14 v 21 trial. Methods: The UK NCRI R-CHOP-14 v 21 trial assessed R-CHOP given 2-weekly versus 3-weekly in 1080 previously untreated DLBCL patients aged ≥18 years and enrolled from 2005-2008. We previously reported that R-CHOP-14 was not superior to R-CHOP-21 for overall survival (OS), progression-free survival (PFS), response rate or safety. COO as determined by the Hans classifier (n=560) was not prognostic for OS (Cunningham et al, Lancet 2013). All patients with sufficient FFPE material remaining were included in this analysis. RNA was extracted and GEP was performed using the Illumina DASL® platform. Cases were classified as ABC, GCB or type III according to the DAC classifier (Care et al, Plos One 2013). Response was assessed using IWG 1999 criteria. PFS and OS were calculated from date of randomisation and analysed using Kaplan-Meier and Cox regression methods. Results: 369 patients had sufficient FFPE material remaining for analysis. COO classification was as follows: ABC 15.2% (n=56), GCB 46.3% (n=171), type III 38.5% (n=142). Baseline characteristics are shown in Table 1. Patients with GCB subtype had a significantly higher incidence of BCL-2 (p1 extranodal site of disease, elevated LDH), sex, bulky disease, B symptoms and trial arm; patients classified as GCB or type III had superior OS versus ABC subtype (HR 0.53, 95% CI: 0.31-0.89; p=0.02) and (HR 0.56, 95% CI: 0.33-0.96; p=0.03) respectively. GCB subtype was also independently associated with superior PFS versus ABC subtype (HR=0.59, 95% CI: 0.37-0.96; p=0.03). The difference in PFS between type III and ABC subtypes did not reach statistical significance, but followed a similar trend (HR=0.65, 95% CI: 0.40-1.07; p=0.09). Results of univariate and multivariate analyses of individual factors and OS are shown in Table 2. Conclusion: Our results demonstrate that the ABC subtype of DLBCL as determined by GEP is independently associated with inferior PFS and OS. Our findings confirm those of Barrans et al (BJH 2012) and serve as a validation cohort for this methodology in the setting of a prospective trial where patients were exclusively R-CHOP-treated. Of note our patient cohort included a high proportion of type III/unclassifiable patients (38.5%) which are being further investigated currently and updated results will be presented at the meeting. Our analysis confirms that GEP-based COO is a significant prognostic biomarker for DLBCL in the rituximab era which can be accurately determined using routinely processed FFPE tissue samples. Table 1 Baseline characteristics Table 1. Baseline characteristics Figure 1. Overall survival by cell-of-origin determined by gene expression profiling group Figure 1. Overall survival by cell-of-origin determined by gene expression profiling group Table 2 Overall survival: univariate and multivariate analyses Table 2. Overall survival: univariate and multivariate analyses Disclosures Cunningham: Medimmune: Research Funding; Merrimack: Research Funding; Celgene: Research Funding; Bayer: Research Funding; Astra-Zeneca: Research Funding; Amgen: Research Funding. Hawkes:Merck Serono: Research Funding; Takeda: Other: travel expenses; BMS: Other: travel expenses, Research Funding. Pocock:Gilead Sciences: Other: Sponsorship to attend the EHA 2016 Meeting; Janssen: Speakers Bureau; Takeda: Honoraria. Ardeshna:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses, Research Funding. Radford:Astra Zeneca: Equity Ownership; GlaxoSmithKline: Equity Ownership; Novartis: Honoraria; Seattle Genetics: Honoraria; Takeda: Honoraria, Research Funding.

Introduction: Therapies able to improve overall survival in patients with relapsed/refractory (RR) CLL are needed. We have previously reported that idelalisib (IDELA), a selective PI3K delta inhibitor, administered in combination withbendamustine/rituximab (BR) improves progression-free survival compared with BR alone after a medianfollowup of 12 months. This study (NCT01569295) was unblinded by the independent data monitoring committee at first interim analysis for efficacy. We now present updated data on overall survival (OS). Methods: Between June 2012 and August 2014, 416 patients (pts) with RR CLL were enrolled in the study across 19 countries. The current analysis data cutoff date of May 2016 represents a median follow-up of 21 months. Progression-free survival based on independent review committee assessment was the primary endpoint of this study, with OS as a secondary endpoint. All pts had completed study treatment with BR. Key eligibility criteria included pts with RR CLL requiring therapy, having received previous purine analog or bendamustine (ineligible if refractory to bendamustine); and anti-CD20 antibody; relapsing or progressing within 36 months of the completion of the last therapy. Patients were randomized to BR for 6 cycles Q 28 days (B = 70 mg/m2 D1, D2 of each cycle; R = 375 mg/m2 C1 and 500 mg/m2 C2-6) and IDELA 150 mg BID or placebo (administered until IRC-confirmed PD), death, intolerable toxicity, or withdrawal of consent. Stratification was based on presence/absence ofdel(17p) and/or p53 mutation (mut), immunoglobulin heavy chain variable region (IGHV) mutated/unmutated (analysis performed by a central lab), and disease status refractory (CLL progression Results: The ITT population reflects 207/209 pts in the IDELA + BR/BR + placebo arm: 76% male; 42% ≥65 years; Rai stage III/IV 46%; median time since completion of last prior therapy 16 months; pts with high-risk features (del[17p]/p53mut 32.9%, unmutated IGHV 83.2%, refractory 29.8%); median number of prior therapies: 2 (range 1-13); and median follow-up 21 months. All pts have completed study treatment with BR. A total of 65 pts remain on study treatment: 64 on IDELA monotherapy and 1 pt on placebo. Overall by ITT and IRC, 260/416 pts (IDELA/placebo 95/165) have met the primary endpoint of PD or death. Median OS (mo) of IDELA + BR vs BR + placebo was not reached vs 41 (HR = 0.67; p value 0.036; 95% CI 0.47, 0.96) (Figure 1). The safety findings were similar to what we previously reported: Serious AEs occurred in 147 (71%)/94 (5%) IDELA/placebo arms, respectively. The commonly occurring SAEs by system organ class were infections and infestations (41%/23%) and by MEDRA-preferred terms febrile neutropenia 43 (21%)/10 (5%) and pneumonia 35 (17%)/16 (8%) in the IDELA/placebo arms respectively. The total number of pts with opportunistic infections (Pneumocystis jirovecii pneumonia [PJP]/cytomegalovirus [CMV]) in the IDELA arm was 5/13 vs 0/3 in the placebo arm. Conclusion: IDELA in combination with BR is superior to BR alone with regard to OS in RR CLL. The improvement in OS was observed across risk categories. Opportunistic infections (PJP, CMV) and SAEs were more frequent in the IDELA vs placebo arm. Results of IDELA-containing regimens may be further improved with implementation of adequate PJP prophylaxis and CMV monitoring measures. This regimen represents an important new option for pts with RR CLL. Figure 1. Kaplan-MeierCurve: Overall Survival. Figure 1. Kaplan-MeierCurve: Overall Survival. Disclosures Zelenetz: Gilead Sciences: Research Funding. Brown:Celgene: Consultancy; Sun BioPharma: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Gilead Sciences: Consultancy; Janssen: Consultancy; Infinity: Consultancy; Abbvie: Consultancy. Delgado:Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; GSK/Novartis: Honoraria; Abbvie: Consultancy. Eradat:Genentech: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria. Ghia:Adaptive: Consultancy; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Jurczak:Celltrion, Inc: Research Funding; Acerta: Research Funding; Gilead Sciences: Research Funding; Bayer: Research Funding; Janssen: Research Funding. Loscertales:Roche: Honoraria, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees. MacDonald:Gilead Sciences: Speakers Bureau. Morschhauser:Celgene: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Honoraria. De la Serna:Abbvie: Consultancy; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Speakers Bureau. Shadman:Pharmacyclics: Honoraria, Research Funding. Pocock:Gilead Sciences: Other: Sponsorship to attend the EHA 2016 Meeting; Janssen: Speakers Bureau; Takeda: Honoraria. Adewoye:Gilead Sciences: Employment, Equity Ownership. Kim:Gilead Sciences: Employment, Equity Ownership. Simpson:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Stilgenbauer:Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding.

A significant number of patients who relapse after allogeneic stem cell transplantation (SCT) for chronic myeloid leukemia (CML) will achieve sustained remissions after treatment with interferon-, second transplants, or donor lymphocyte infusions (DLI) from the original stem cell donor. Because leukemia-free survival (LFS) is at present defined as survival without evidence of relapse at any time posttransplant, patients who relapse but are then restored to complete remission are treated as failures when estimating LFS. We have established a new category of LFS, termed current LFS (CLFS), which we define as survival without evidence of leukemia at the time of most recent assessment. To gauge the contribution of treatment for relapse to the efficacy of allogeneic SCT in the management of CML in chronic phase, we compared conventional LFS and CLFS in 189 consecutive patients who underwent SCT over a 7-year period with a minimum follow-up of 3 years. Patients with sibling donors (n = 111) received cyclosporine and methotrexate as prophylaxis for graft versus host disease; patients with unrelated donors (n = 78) also received Campath-1G or 1H as intravenous T-cell depletion. The 5-year LFS defined conventionally was 36% (CI: 29% to 43%) versus a 5-year CLFS of 49% (CI: 36% to 62%). This new method of defining LFS confirms the view that appropriate “salvage” therapy, principally DLI, makes a major contribution to the capacity of allogeneic SCT to produce long-term LFS in patients who receive SCT for CML and emphasizes the importance of redefining LFS to take account of successful treatment of relapse.

Introduction: DLBCL subtypes may be classified by gene expression corresponding to germinal centre (GCB) or activated peripheral blood (ABC) B-cells. Treatment outcomes with R-CHOP therapy were inferior for ABCs in retrospective series, and this study investigated whether adding bortezomib could reverse the adverse prognosis. The trial used gene expression profiling (GEP) to stratify cases, with adaptive design to analyse the outcome by subtypes at predefined timepoints. Methods: Newly diagnosed patients with DLBCL underwent staging and commenced standard R-CHOP. During cycle 1, formalin-fixed paraffin-embedded (FFPE) tissue was used to extract messenger RNA for GEP using the Illumina DASL array platform. Cases were allocated to GCB, ABC or Unclassifiable (Unc) type before starting cycle 2, using an established algorithm based upon 20 genes. Patients with successful GEP were randomised 1:1 to receive R-CHOP +/- bortezomib 1.6 mg/m2 s/c on days 1+8 in cycles 2-6. The study was powered to detect a difference in progression-free survival (PFS) of 10% with bortezomib, with a 2-sided significance, 5% and 90% power. The adaptive design allowed for closure of randomization for GCB cases if 1-year PFS was Results: Between 6/2011 and 5/2015 1132 patients were enrolled from 109 sites, with 1078 samples analysed. Of these, 157 (15%) biopsies had inadequate material for GEP, but the remaining 921 were classified as 246 (27%) ABC, 476 (52%) GCB and 199 (22%) Unc. Successful classification was possible from both surgical and needle core biopsies. Median laboratory turnaround time was 12 working days and all results were available prior to the scheduled administration of cycle 2. Characteristics of the patients of different subtypes are shown in the table. Following both interim analyses the DMEC recommended continued recruitment of patients with a GCB phenotype. Table. ABC GCB Unc Age (years): median 67 63 63 Age (years) : range 23 to 86 20 to 82 20 to 85 % performance status 0-1 88 88 90 % at least one extranodal site 53 54 62 % bone marrow involved 15 14 23 % LDH>ULN 69 76 79 % IPI score 0/1 29 27 26 % IPI score 2/3 57 55 55 % IPI score 4/5 15 19 19 % B symptoms 46 43 49 % Bulk>10cm 17 26 21 Conclusions: This study has demonstrated the feasibility of GEP at diagnosis to subsequently guide therapy in a large multicentre trial. Although patients with ABC type lymphoma were in general slightly older, they did not appear to have other adverse prognostic features at diagnosis vs GCB. All patients will have completed therapy by the time of the meeting, allowing the initial response and toxicity data to be available for presentation. Disclosures Davies: GIlead: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; CTI: Honoraria; Takeda: Honoraria, Research Funding; Bayer: Research Funding; GSK: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Pfizer: Honoraria; Celgene: Honoraria, Research Funding. Off Label Use: The addition of bortezomib to R-CHOP chemotherapy in diffuse large B-cell lymphoma. Pocock:Janssen: Honoraria. Jack:Jannsen: Research Funding. Johnson:Takeda: Honoraria; Pfizer: Honoraria; Janssen: Research Funding.

Background: Imatinib and dasatinib are established drugs in the first-line treatment of chronic myeloid leukemia (CML). Several studies, including SPIRIT2 have shown that first-line dasatinib (100mg once daily) has a superior complete cytogenetic and major molecular response rate compared to imatinib (400mg once daily), but no significant differences in progression-free or overall survival have been shown in any study. To date, there has been no direct comparison of quality of life (QoL) using generic and cancer-specific instruments for first-line treatment of chronic-phase CML with imatinib and dasatinib. SPIRIT2 (STI571 Prospective International Randomised Trial 2) is the first randomized clinical trial to incorporates generic and cancer-specific QoL measurement for first-line therapy. Methods: Quality of life is a secondary endpoint in the SPIRIT2 trial and has been assessed at baseline, and at 1, 2, 3, 6 and 12 months post trial entry and thereafter annually. The EQ-5D, FACT-G, FACT-BRM and the FACT-TOI have been used as QoL measures in this trial. The FACT-G covers cancer-specific QoL measure dimensions such as physical well-being, functional well-being, social and family well-being, emotional well-being and the FACT-BRM and the FACT-TOI different subsets of them. The QoL scores (EQ-5D, FACT-G, FACT-BRM, FACT-TOI) were calculated at different time points and comparison of the mean scores for both treatment groups was made. Results: A comparison between imatinib and dasatinib shows no significant difference in QoL in generic instruments and also in cancer-specific instruments. EQ-5D was 0.77 and 0.79 at baseline and 0.80 and 0.82 at one year for dasatinib and imatinib, respectively (2-3 basis points increase over 1 year). Similar results were obtained for the FACT-G, FACT-BRM and the FACT-TOI. There was a slight increase for the FACT-G (4-5 basis points), FACT-TOI (3-4 basis points) and FACT-BRM (8-10 basis points) after 1 year for both treatments, but this difference was not significant. The effects on the well-being and the emotional dimensions have been analysed for both drugs and there was no change over time, demonstrating results similar to the imatinib arm of the IRIS trial. Conclusions: Standard dose imatinib and dasatinib are both used as first-line treatments for CML and, despite different side effect profiles, there is no significant difference in QoL using the instruments described here between these two drugs over time. These data will allow the derivation of utility values to contribute to future health economic/technology appraisals. Additional analyses of how generic and cancer-specific measures of different QoL instruments change in CML patients over time in those patients that develop side effects, e.g. fluid retention with imatinib or pleural effusion with dasatinib will be presented. Disclosures Copland: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cork:BMS: Research Funding; Novartis: Research Funding; Roche: Research Funding; Ariad: Research Funding. Hedgley:Ariad: Research Funding; Roche: Research Funding; BMS: Research Funding; Novartis: Research Funding. Gills:Novartis: Research Funding; Ariad: Research Funding; BMS: Research Funding; Roche: Research Funding. Holyoake:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Bescoby:Roche: Research Funding; Ariad: Research Funding; BMS: Research Funding; Novartis: Research Funding. Pocock:Janssen: Honoraria. Clark:Novartis: Honoraria, Research Funding, Speakers Bureau; Pzifer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding. O'Brien:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Pzifer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding.

Background: Elderly patients with diffuse large B-cell lymphoma (DLBCL) have an inferior prognosis compared to younger patients. Dose intense administration of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP14) is superior to 3-weekly CHOP in elderly DLBCL patients (Pfreundschuh, Blood 2004), but this benefit has not been demonstrated with addition of rituximab (Delarue, Lancet Oncol 2013). We have previously shown that R-CHOP14 did not improve outcome compared to standard R-CHOP21 in newly diagnosed DLBCL patients aged 19-88 years across all subgroups (Cunningham, Lancet 2013). Here, we provide a detailed subgroup analysis of elderly patients (over 60 years) from the UK NCRI R-CHOP14 vs 21 randomised phase 3 trial. Methods: Between 2005 and 2008, 1080 patients were randomly assigned to receive 8 cycles R-CHOP21 or 6 cycles R-CHOP14 (+ G-CSF) with two additional rituximab applications. Of these, 604 patients were over 60 years and included in the current analysis (301 in the R-CHOP21 arm, 303 in the R-CHOP14 arm), with a median follow-up of 45 months. Results: Baseline characteristics were well balanced between treatment arms. 36% of patients were over 70 years, 15% had a WHO performance status (PS) of 2, 65% stage III/IV disease, 44% bulky disease and 42% B symptoms. There was a trend towards a higher rate of BCL6 rearrangements (26% vs. 16%; P=0.10) and concurrent MYC - and BCL2 rearrangements (double hit lymphoma as determined by FISH, 8% vs. 2%; P=0.06) in the R-CHOP14 arm compared to the R-CHOP21 arm. 85% (257/303) of patients received 8 cycles of R-CHOP14, whereas only 76% (230/301) completed all 8 cycles R-CHOP21. However, percentage of patients receiving at least 6 cycles of therapy was similar (88% and 89%, respectively). Dose delays of myelosuppressive drugs occurred more frequently in patients receiving R-CHOP21 vs. R-CHOP14 (51% vs. 39%; P=0.03) due to a higher incidence of haematological toxicities likely related to the reduced use of G-CSF. G-CSF was mandatory for patients on R-CHOP14 and was given to 57% of patients on R-CHOP21 as secondary prophylaxis. The frequency of dose reductions was similar in the R-CHOP21 and R-CHOP14 arms (15% vs. 16%; P=0.73). Toxicities of grade III+ were seen in 72% and 60% of patients in the R-CHOP14 and R-CHOP21 arms, respectively. There was evidence of a higher incidence of grade III+ neutropenia (62% vs. 36%) and a lower rate of thrombocytopenia (7% vs. 12%) in the R-CHOP21 arm compared to R-CHOP14. The incidence of fever and infections was similar in both arms. There was no evidence of a difference in response rates between the R-CHOP14 and R-CHOP21 arms [complete response (CR)/unconfirmed CR (CRu) rates: 62% vs. 67%, respectively; overall response rate both 91%]. CR/CRu rates after 4 cycles of therapy were 33% and 39% respectively (P=0.15). There was no difference regarding progression-free survival (PFS) and overall survival (OS) between arms, neither in the total cohort of elderly patients, nor in the subgroup of patients over 70 years [OS (all elderly): hazard ratio (HR) 0.91 (95% CI: 0.67-1.24); P=0.55; PFS (all elderly): HR 0.98 (95% CI: 0.74-1.29); P=0.86]. 3-year PFS was 71% (95% CI: 67-74) in all patients over 60 years and 64% (95% CI: 58-71) in patients over 70 years. 3-year OS was 75% (95% CI: 72-79) and 67% (95% CI: 61-74) in patients over 60 years and over 70 years, respectively. In multivariate analysis including individual factors of the International Prognostic Index (IPI), as well as age as continuous variable, gender, presence of B symptoms, bulky disease, b2-microglobulin higher than 3mg/l and albumin higher than 35 g/l, only age was of independent prognostic significance for OS (P=0.01). Besides the standard IPI and the NCCN-IPI, an elderly IPI (E-IPI; Advani, BJH 2010) and the ABE4 score (Prochazka, PLoS One 2014) have been proposed for better prognostication of elderly DLBCL patients. A detailed comparison of these different prognostic models in our dataset will be presented at the meeting. Conclusion: Outcome and toxicities in DLBCL patients over 60 years treated within the NCRI R-CHOP14 vs 21 trial are comparable to results from other randomised studies investigating R-CHOP14 or R-CHOP21 in elderly DLBCL patients. Our data further support the similar efficacy and tolerability of both R-CHOP variants for first-line treatment of this patient group. Disclosures Cunningham: Amgen: Research Funding; Medimmune: Research Funding; Astra Zeneca: Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding; Merrimack: Research Funding; Merck Serono: Research Funding; Celgene: Research Funding; Sanofi: Research Funding. Pocock:Janssen: Honoraria. Ardeshna:Roche: Honoraria.

Kinase domain (KD) mutations in the BCR-ABL1 gene are associated with resistance to tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML). Next-generation Sequencing (NGS) allows detection of low-level KD mutations but its relevance in clinical practice remains debated, and the incidence and prognostic significance of finding of low-level KD mutation in chronic phase (CP) patients is unknown. We analyzed the outcome for 121 newly diagnosed CP-CML patients treated with TKIs (imatinib 111, nilotinib 7 and dasatinib 3) who we routinely screened for KD mutations using ultra-deep NGS regardless of response to TKI. When a mutation was found by ultra-deep NGS (using Illumina NexteraXT and MiSeq platform) all available previous cDNA samples were analyzed to establish the date of its first occurrence and subsequent kinetics. ABL1 transcripts from 27 healthy donors were sequenced and used as a control. Sequencing for both single and nested PCR products were compared, and samples were re-sequenced in two independent runs in order to analyze reproducibility of variants detection. Median age of patients was 56 years and the Sokal risk score was 'low' in 38% patients, 'intermediate' in 15.5% and 'high' in 46.5%. A mutation was detected in 25 of the 121 patients (20.6%) at a median time of 14 months from starting TKI. 19 different mutations were identified, the most frequents being F317L (n=17), Y253H (n=15), M244V (n=14) and T315I (n=10). All mutations previously detected by Sanger sequencing were also found using ultra-deep NGS. In addition low-level mutations ( Eighteen patients discontinued imatinib while still in CP and received dasatinib, nilotinib or an allogeneic stem cell transplantation. The overall progression-free survival (absence of advanced phase) at 5 years was 85%. Complete cytogenetic responses (CCyR) and major molecular responses (MMR) with front-line TKI therapy were achieved in 74 (61%) and 52 (43%) patients respectively. We stratified patients according to response to TKI therapy as per 2009 ELN guidelines (Baccarani et al., 2009): patients with optimal response ('responders', R), failure at any time ('non-responders', NR) and sub-optimal response (SR). Patients with known TKI dose-interruption were analyzed separately. Mutations were classified and analyzed according to clinical relevance (clinically relevant versus clinically non relevant mutations, Branford et al., 2009). Among non-responders (NR), 37% of patients developed a mutation (29% among patients who lost CCyR), compared to only 5% among responders (2 patients, both with KD mutations sensitive to imatinib). Among patients with suboptimal response (SR), 19% developed a mutation while being in CCyR but not in MMR with all clinically relevant mutated clone percentages increasing in patients being treated with a TKI to which the KD mutation was conferring resistance. Similarly in all NR patients the mutated clone percentage rose in sequential samples if a clinically relevant mutation was detected. Patients harboring a mutant clone had a poorer PFS at 5 years compared to patients without mutation (67% versus 92%, p We next evaluated the incidence and impact of finding of KD mutations at the early molecular response time point (3-months BCR-ABL1 transcript level). Samples from 41 patients were analyzed at 3 months of which 20 with a BCR-ABL1 transcript level > 10%. A KD mutation was found at 3 months in 4/41 patients (9.7%) all of whom progressed subsequently to advanced phase compared to only 3/37 in patients without mutation (p10%, while only one patient had a 3-months BCR-ABL transcript level In conclusion, ultra-deep NGS can reliably and consistently detect early appearance of KD mutation in patients who fail to achieve early molecular response at 3 months as well as in non responder patients or patients who are in CCyR but not in MMR, thus allowing potential early clinical intervention. Disclosures Best: Onconova Therapeutics Inc: Research Funding. Pocock:Janssen: Honoraria. McLornan:Novartis: Research Funding, Speakers Bureau. Mufti:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: 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; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de Lavallade:Ariad: Research Funding; Novartis: Consultancy.

Introduction: Primary Mediastinal B-cell Lymphoma (PMBL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL) comprising approximately 10% of cases. Studies in the pre-rituximab (R) era suggested a benefit for dose intensified regimens such as V/MACOP-B over cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP). However no prospective studies comparing dose intensified regimens with R-CHOP have been performed in the rituximab era and controversy exists regarding the current optimal induction chemotherapy. R-CHOP +/- involved field radiotherapy (IFRT) is the most commonly used regimen worldwide with reported 5-yr relapse free and overall survival rates of 68-81% and 79-91% respectively; but with the exception of the MInT trial (which evaluated young patients with PMBL aged ≤60 years with an age-adjusted International Prognostic Index of 0-1), the evidence for R-CHOP in PMBL comes from retrospective studies. The aim of this analysis was to evaluate the outcomes for R-CHOP treated PMBL patients within the UK NCRI R-CHOP 14 v 21 prospective trial. Methods: The phase III randomised UK R-CHOP-14 vs 21 trial assessed R-CHOP given 2 weekly versus 3 weekly in 1080 DLBCL patients aged ≥ 18years who were enrolled from 2005-2008. We previously reported that R-CHOP-14 was not superior to R-CHOP-21 for overall survival (OS), progression free survival (PFS), response rate or safety (Cunningham D et al, Lancet May 2013). Patients with PMBL were not excluded from participation and we identified cases by searching the trial database for patients with a mediastinal mass (≥5cm) who also fulfilled the WHO 2008 clinical criteria for sites of involvement (absence of disease involvement outside of the thorax +/- cervical / supraclavicular lymph node involvement). Response was assessed according to the IWG 1999 criteria. PFS and OS were calculated from date of randomisation and analysed using Kaplan-Meier methods. Results: 50/1,080 (4.6%) patients from the R-CHOP 14 v 21 study database met the WHO 2008 criteria for PMBL and were included in this analysis, with a median follow-up of 7.3 years. The median age at diagnosis was 38.5 years (range 22-78 years). 50% (n=25) of the patients were female. All patients had stage I (n=18, 36%) or II (n=32, 64%) disease. The median mediastinal mass diameter was 11.1cm (range 6-23cm) and 70% (n=35) of patients had a mediastinal mass ≥10cm. 28 (56%) and 22 (44%) patients were treated with R-CHOP-21 and R-CHOP-14 respectively. On completion of R-CHOP chemotherapy CT response was complete (CR) in 43% (n=21), partial (PR) in 49% (n=24), stable disease (SD) in 2% (n=1) and progressive disease (PD) in 6% (n=3), one patient was non-evaluable. IFRT was administered to 58% of patients (n=29). For all patients (n=50) the 5-year PFS was 80.0% (95% CI 68.7-91.1) and 5-year OS was 84.0% (95% CI 73.8-94.2), as shown in Figures 1 and 2 respectively. 5/10 PFS and 4/9 OS events occurred in patients who had received consolidation IFRT post R-CHOP. Where disease progression occurred 9/10 events occurred within the first-year of follow-up. Conclusion: Our data confirms the efficacy of R-CHOP in the management of PMBL and is a benchmark for future studies in PMBL. This is to our knowledge, the largest reported cohort of R-CHOP treated PMBL patients from a prospective trial. The strength of this analysis lies in the long duration of follow-up, the strict selection of patients according to the WHO 2008 criteria and the inclusion of all patients ≥ 18 years without an upper age limit. In line with previous studies we found that disease progression in PMBL occurs early and late relapses are rare. Over half of the patients in our analysis (58%) received consolidation IFRT following R-CHOP. Response assessment by FDG-PET-CT on completion of R-CHOP was not mandated by the study protocol and whether IFRT could have been avoided for PET negative patients in our cohort is unknown. The currently accruing IELSG 37 prospective trial will help to address this important clinical question in PMBL. Excellent results have recently been reported with the combination of DA-EPOCH-R in PMBL, but the efficacy of such dose-intensified regimens in comparison to R-CHOP needs to be evaluated in prospective randomised studies. Figure 1. Progression Free Survival (n=50) Figure 1. Progression Free Survival (n=50) Figure 2. Overall Survival (n=50) Figure 2. Overall Survival (n=50) Disclosures Cunningham: Amgen: Research Funding; Astra Zeneca: Research Funding; Merck Serono: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Merrimack: Research Funding; Medimmune: Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding. Pocock:Janssen: Honoraria.

Objective. SPIRIT 2 is the largest phase 3 prospective randomized open-label trial comparing imatinib 400mg with dasatinib 100mg daily: this is the first presentation of data comparing the two arms. Methods. 814 patients were recruited at 144 hospitals between August 2008 and March 2013. 812 started study medication (406 in each arm). The primary endpoint is event-free survival at 5 years. A key secondary endpoint is the rate of achievement of a BCR-ABL/ABL ratio of Results. Discontinuations. With a median follow up of 34 months a total of 289/812 (35.6%) patients have discontinued study medication. 118/812 (14.5%) patients have discontinued due to non-haematological toxicity: imatinib 47/406 (11.6%); dasatinib 71/406 (17.5%). 40 patients discontinued due to sub optimal response as assessed by the treating physician: imatinib 37/406 (9.1%); dasatinib 3/406 (0.7%). Side effects. Patients receiving imatinib experienced GI toxicity more often than patients receiving dasatinib; fatigue, rash and headache were more common with dasatinib. A higher rate of grade 3/4 thrombocytopenia was observed in the dasatinib arm: imatinib 17/406 (4.2%); dasatinib 52/406 (12.8%). Pleural effusions occurred in 78/406 (19.2%) patients on dasatinib; 13 of 78 (16.7%) patients required drainage. Arterial cardiovascular events (excluding hypertension) were experienced by 10/812 (1.2%) patients: imatinib 2/406 (0.5%; myocardial infarction (MI) x2); dasatinib 8/406 (2.0%; MI x1; angina/acute coronary syndrome x5; peripheral arterial disease x2). Hypertension was observed in 10/812 (1.2%) patients: imatinib 3/406 (0.7%); dasatinib 7/406 (1.7%). Venous CV events occurred in 7/812 (0.9%) patients: imatinib 3/406 (0.7%); dasatinib 4/406 (1.0%).Efficacy.For both PCR and cytogenetic analyses patients that had discontinued their allocated therapy or that did not have a 12 month sample were analysed as not having achieved MR3/CCR. The MR3 (PCR Conclusions. Dasatinib-treated patients have a higher rate of molecular response at 1 year but, with a median of 34 months follow up, there is no significant difference in rates of disease progression or overall survival. More patients abandoned imatinib than dasatinib due to investigator concerns about sub optimal responses. Further follow up is required to evaluate whether there will be differences in event free survival at five years. Disclosures O'Brien: Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Hedgley:BMS: Research Funding; ARIAD: Research Funding. Adams:BMS: Research Funding. Apperley:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Holyoake:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Byrne:BMS: Honoraria; Novartis: Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy. Osborne:ARIAD: Research Funding. Copland:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria. Clark:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Honoraria, Research Funding.

Background: Central Nervous System (CNS) relapse of Diffuse Large B-cell Lymphoma (DLBCL) is associated with a poor prognosis. Prior to the advent of rituximab the incidence of CNS relapse without CNS prophylaxis was around 5% in most unselected series. The risk in the rituximab era appears to be decreased in some but not all reported series (2.2-6.4%). CNS prophylaxis may be administered to patients deemed to be at high-risk but indications are not standardised. Methods: The randomised phase III UK R-CHOP-14 vs 21 trial assessed rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone given 2 weekly versus 3 weekly in 1080 DLBCL patients. We previously reported that R-CHOP-14 was not superior to R-CHOP-21 for OS, response rate, PFS or safety. Administration of CNS prophylaxis was at the discretion of investigators but recommended for patients with involvement of bone marrow, peripheral blood, nasal/paranasal sinuses, orbit and testis (12.5mg intrathecal methotrexate (IT MTX) for the first 3 cycles of treatment or according to local guidelines).We assessed the incidence of CNS relapse in the R-CHOP 14 vs 21 cohort and performed a retrospective analysis of risk factors for CNS relapse. The Chi-Squared Test was used to compare demographics between the groups: CNS relapse (n=16) vs no relapse (n=815) vs systemic (without CNS) relapse (n=249). Demographics assessed were sex, age ( 1 site of extranodal disease (p=0.0056), stage IV disease (p=0.0063), IPI group (p=0.005) and high-risk IPI group (p=0.0015). Raised LDH was not significant (p=0.12). No histopathological feature including COO (p=0.43), C-MYC (p=0.45) or “double-hit” rearrangement (p=0.63) was associated with an increased risk of CNS relapse. Stage IV disease and B symptoms did not differentiate between the risk of developing a CNS vs systemic relapse. No difference in incidence was seen by treatment arm. No risk factor was significant on multivariate analysis. Conclusion: The incidence of CNS relapse in our total study population is very low (1.48%). Risk factors for CNS relapse versus no relapse after R-CHOP were PS 2, >1 site of extranodal disease, high-risk IPI group, B symptoms and stage IV disease by univariate analysis. None of these risk factors were significant on multivariate analysis however and we concluded that this may have been due to the low numbers of patients (n=16) in the CNS relapse group. The incidence of CNS relapse in selected patients identified to be at increased risk of CNS relapse was 3.8% which may suggest some benefit of this therapy. | PT | G | Age | Stage | PS | ↑LDH | B symptoms | >1 ENS | IPI Group | ENS | CNS Prophylaxis | | --- | - | --- | ----- | ----------- | ---- | ---------- | ------ | -------------------------- | ----------------------------------------- | --------------- | | 1 | F | 65 | IV | | Y | Y | Y | 4 | Bone marrow | N | | 2* | M | 58 | IV | 2 | Y | Y | Y | 4 | Bone | Y-IT MTX | | 3 | M | 65 | II | 1 | N | Y | N | 1 | N | Y-Unknown | | 4 | M | 38 | III | | Y | Y | Y | 3 | N | N | | 5 | M | 66 | IV | 1 | N | N | N | 2 | N | Y-IT MTX | | 6 | F | 59 | IV | 2 | Y | Y | Y | 4 | Bone marrow Kidney Bone | Y-IT MTX | | 7 | M | 78 | II | 2 | Y | Y | N | 3 | N | N | | 8* | F | 54 | IV | | Y | N | Y | 3 | Kidney | N | | 9 | F | 59 | III | 2 | Y | Y | Y | 4 | N | Unknown | | 10* | F | 66 | IV | 1 | Y | N | N | 3 | N | N | | 11* | F | 53 | IV | 2 | Y | Y | N | 3 | Bone marrow | Y-Unknown | | 12* | F | 69 | IV | | Y | N | Y | 4 | Bone | N | | 13 | F | 77 | III | 2 | Y | Y | N | 4 | N | Y-IT MTX | | 14* | M | 59 | III | | Y | Y | N | 2 | N | N | | 15* | F | 65 | IV | 1 | N | N | Y | 2 | Breast Bone marrow | N | | 16* | F | 68 | IV | 1 | Y | Y | Y | 4 | Kidney | N | Table 1: Demographic Features of Patients with CNS Relapse Key: *Isolated CNS Relapse Disclosures Cunningham: Roche: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Merck Serono: Research Funding; Novartis: Research Funding; Astra Zeneca: Research Funding. Hawkes: Roche: Travel grant Other. Ardeshna: Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Travel expenses for conferences, Travel expenses for conferences Other; Roche: Membership on an entity's Board of Directors or advisory committees. McMillan: Roche: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Roche: Travel expenses for international meetings, Travel expenses for international meetings Other.

Introduction : Ibrutinib (Imbruvica®), an oral, first-in-class covalent BTK inhibitor, is a new treatment option approved by FDA for chronic lymphocytic leukemia (CLL) patients (pts) with ≥1 prior therapy. We previously reported results from the phase III trial, in which ibrutinib (ibr) significantly improved progression-free and overall survival vs ofatumumab (ofa) in pts with relapsed/refractory CLL or small lymphocytic lymphoma (SLL) (Byrd et al. NEJM, 2014). Here, we report measures of patient well-being, including hematologic, immunologic, and quality of-life parameters, at interim analysis (IA). Methods : Pts with CLL/SLL after ≥1 prior therapy were randomized 1:1 to ibr 420 mg/day until progression or unacceptable toxicity, or to ofa for up to 24 weeks. At IA, secondary efficacy endpoints of hematologic improvement (sustained improvement ≥56 days without transfusions or growth factors) and FACiT-Fatigue (FACiT-F) outcomes were analyzed, along with exploratory endpoints assessing disease-related symptoms (DRS), serum immunoglobulin, patient-reported outcomes (PROs) by EORTC QLQ-C30, and medical resource utilization (MRU). Results : Of 391 enrolled pts (ibr n=195; ofa n=196), 63% had cytopenia(s) at baseline: 45% had anemia (hemoglobin ≤11 g/dL), 35% thrombocytopenia (platelets ≤100×109/L), and 20% neutropenia (absolute neutrophil counts [ANC] ≤1.5×109/L). On the ibr arm, 69% of pts with baseline cytopenias experienced sustained improvement in blood counts compared to 43% on ofa ( P

Background Rituximab is part of the standard induction and maintenance therapy for most patients with first-line or relapsing indolent non-Hodgkin's lymphoma (iNHL). However, the optimal duration of maintenance is still to be defined. The MABCUTE trial is designed to evaluate the efficacy and safety of maintenance therapy with subcutaneous (SC) rituximab until disease progression (PD). Patients with relapsed or refractory iNHL, who respond to induction and an initial 2 years' maintenance therapy, are randomized to receive additional maintenance therapy or observation. Here we report the findings of a planned interim safety analysis in the first 231 patients enrolled in the trial. Methods MABCUTE (NCT01461928) is an ongoing multicenter, randomized, parallel-group, phase IIIb study that started in December 2011. Eligible patients were aged ≥18 years with relapsed or refractory CD20+ iNHL (histologically confirmed) following ≥1 line of immunotherapy and/or chemotherapy and/or radiotherapy. Patients were scheduled to receive induction therapy consisting of rituximab every 3–4 weeks for 8 cycles (intravenous [IV] 375 mg/m2 in cycle 1 then SC 1400 mg in cycles 2–8) and 6–8 cycles of standard chemotherapy. Patients who achieved a complete or partial response (CR/PR) continued into standard maintenance (rituximab SC 1400 mg every 8 weeks for 24 months). Upon completion of standard maintenance, patients in sustained CR/PR will be randomized to receive additional maintenance (rituximab SC 1400 mg every 8 weeks) until PD, or observation. Results At data cut-off (January 16, 2013), the safety population consisted of 216 patients who had received ≥1 dose of rituximab SC: 70 (32%) had completed induction therapy, 122 (57%) were receiving induction therapy, and 24 (11%) had discontinued induction therapy. A total of 58 (27%) patients had continued into standard maintenance, with 2 patients having subsequently discontinued maintenance therapy. Patients had a median age of 64.5 years (range, 20–90). At screening, the most common types of iNHL were follicular NHL (n=131, 61%), marginal zone lymphoma (n=41, 19%), and Waldenström's macroglobulinemia (n=31, 14%). The most commonly used chemotherapy regimens were bendamustine (n=137, 63%), CHOP (n=31, 14%) and CVP (n=21, 9.7%). During therapy, AEs occurred in 174 (81%) patients (Table), grade 3 or higher AEs in 70 (32%) patients and serious AEs (SAEs) in 44 (20%) patients. Administration-related reactions (ARRs) were reported by 61 (28%) patients after 1 dose of rituximab IV and by 89 (41%) patients after a median (range) of 5 (1–11) doses of rituximab SC. The majority of ARRs were mild to moderate and transient, and expected with the change in the route of administration. Overall, 25 patients had grade 4 hematological events, most commonly neutropenia (22 patients). Only 4 cases of neutropenia lasted >14 days and these resolved without interruption to treatment. One patient had a grade 4 non-hematological event (thrombosis and pulmonary embolism that resolved after 12 days). Among the 26 patients who discontinued study treatment, reasons given were AEs (n=8; skin reactions [3], neutropenia [2], general health problems [2], and oseophagitis [1]), patient or investigator request (n=6), PD (n=5), death (n=2), and other (n=5). One patient died of bronchopneumonia and sepsis due to leucopenia and 1 died of myocarditis; neither was considered by the investigator to be related to the study drug. Conclusions Rituximab SC is associated with ARRs that are transient and mainly mild to moderate in severity. The incidence and intensity of other hematological and non-hematological toxicities are within the expected range for rituximab SC or IV administration. No new safety signals or concerns associated with rituximab SC were identified during induction and maintenance therapy in this interim safety analysis, as confirmed by the Independent Data Monitoring Committee. Rituximab SC appears to be well tolerated and the study continues. Disclosures: Rule: Pharmacyclics, Inc: Consultancy; J&J: Consultancy; F. Hoffmann-La Roche: Consultancy. Off Label Use: Rituximab, administered as an IV infusion, is approved for use in a number of hematologic indications. The data presented here assess a subcutaneous approach to rituximab administration in patients with indolent Non-Hodgkin’s Lymphoma. Briones:Celgene: Membership on an entity’s Board of Directors or advisory committees; Takeda: Membership on an entity’s Board of Directors or advisory committees; Novartris: Membership on an entity’s Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria. Casasnovas:F. Hoffmann-La Roche: Consultancy, Research Funding. Pocock:F. Hoffmann-La Roche: Honoraria. Osborne:F. Hoffmann-La Roche: Employment. Smith:F. Hoffmann-La Roche: Employment. Zaja:F. Hoffmann-La Roche: Consultancy.

Abstract 785 We assessed the correlation between molecular response at 3 and 6 months of dasatinib 100mg daily treatment and subsequent cytogenetic and molecular responses in 150 newly-diagnosed chronic phase CML patients treated with front line dasatinib in the UK SPIRIT 2 study (imatinib vs dasatinib). The median age was 54 years (range 18.4–82.1); 90 patients were male. The Sokal risk distribution was: 39 low, 65 intermediate and 46 high. At diagnosis 26 patients had splenomegaly >10cm below the costal margin; median WBC and platelet count were 65.7 (2.2-428) and 404 (101-2,433). The median hemoglobin level was 11.0 g/dl (4.17-15.8). The median percentage of blasts and basophils in peripheral blood was 0.4% (0-13.5) and 3.6% (0-19.2) respectively. The dose of dasatinib was adjusted according to tolerance. BCR-ABL1 transcripts in the peripheral blood were analyzed at 12 week intervals using RQ-PCR. Results were expressed as percentage ratios relative to an ABL1 internal control and expressed on the international scale. Complete molecular response (CMR) was defined as two consecutive samples with no detectable transcripts (RQ-PCR negative) and ABL1 control >40,000 (the median ABL1 control in the CMR samples was 96,000). In addition, we also explored a less stringent definition of CMR, namely CMR4.5 which was recently defined by the EUTOS group as BCR-ABL1 ratio of 0.0032 on the international scale, consistent with a 4.5 log reduction in the transcript level, without necessarily being RQ-PCR negative. With a median follow up of 15 months (range 6–29) the 2 year cumulative incidences (CI) of CCyR, MMR, CMR4.5 and CMR were 84.5, 72.1, 24.1 and 5.6% respectively. The median BCR-ABL/ABL ratios at 3, 6, 12 and 24 months were 0.830%, 0.093%, 0.040% and 0.034% respectively. We investigated the predictive value of the BCR-ABL1 transcript levels at 3 (>10% vs ≤10% and >1% vs ≤1%) and 6 months (>1% vs ≤1%) of dasatinib therapy on the 2 years CI of cytogenetic and molecular responses. The 135 patients who at 3 months had a BCR-ABL1/ABL1 ratio ≤10% and the 81 patients who had a ratio ≤1% had a significantly better 2 year CI of CCyR (89.1% vs 50.2%, p=0.02 and 100% vs 84.7%, p=0.01), MMR (83.7% vs 14.2%, p=0.004 and 85.2% vs 54.3 p We used a receiver operating characteristic (ROC) curve to identify the optimal cut-off in the transcript level at 3 and 6 months that would predict the probability of each outcome with maximal sensitivity and specificity. Table 1 shows the results of applying the optimal cutoffs for each outcome in the 3-month analysis. Then we investigated whether the various outcomes could be better predicted using the cut-offs defined at 3 or at 6 months (including both the 1 and 10% cut-offs and the newly identified cut-offs) by using a multivariate model. For each outcome the cut-off defined at 3 months shown in Table 1 was superior. No pre-therapy patient characteristics were an independent predictor for cytogenetic or molecular response.Table 1.CI of the various responses according to cut-offs identified in the ROC analysis.3 month BCR-ABL1/ABL1 ratio (%)n2 year CI (%)pCCyR10493.3p2.72MMR7987.6p0.387CMR4220.1p=0.01≤0.241080>0.24 The key finding from this analysis is that patients who achieve a transcript level ≤10% after 3 months of dasatinib (135 of 150) have an 89.1% probability of eventually achieving CCyR, compared to 50.2% for patients with higher transcript levels (p=0.02). This preliminary observation may allow the identification of around 10% of dasatinib-treated patients for whom other forms of treatment might be considered although our conclusions require verification in further studies. The predictive power of RQ-PCR assessment can be greatly improved by identifying the optimal cut-offs for the specific outcomes, which is particularly important when predicting for the achievement of CMR. It remains uncertain whether these differences in response will translate into differences in survival and the SPIRIT 2 study continues to address this question. Disclosures: No relevant conflicts of interest to declare.

Abstract 1634FN2 Introduction: The treatment of patients with DLBCL who are unsuitable for anthracycline containing chemotherapy remains a clinical challenge. Gemcitabine is a nucleoside analogue which has proven efficacy in the relapse setting in both non Hodgkin's and Hodgkin's lymphoma. We therefore developed a protocol incorporating Gemcitabine in a first line approach combined with CVP-R chemo-immunotherapy in DLBCL patients considered unfit for anthracycline containing chemotherapy. Methods: We performed a prospective, multicentre phase II trial in patients with DLCBL who were considered unfit for anthracycline containing chemo-immunotherapy. Eligibility criteria included ejection fraction < 50%, or ejection fraction ≥ 50% but with the presence of attendant significant co-morbidities (including: ischaemic heart disease, hypertension, diabetes mellitus), and ECOG PS 0–3. Patients received 6 cycles of Rituximab (375 mg/m2 IV D1), Cyclophosphamide (750mg/m2 IV D1), Vincristine (1.4 mg /m2 IV D1), Prednisolone (100mg, orally D1–5) and Gemcitabine IV D1 and D8. The Gemcitabine dose, if tolerated was sequentially escalated from 750mg/m2 in cycle 1 to 875mg/m2 in cycle 2 to 1000mg/m2 in cycle 3 with the dose maintained at 1000mg/m2 for cycles 4–6. Cycles were repeated every 21 days with growth factor support administered on day 9 of each cycle (pegfilgrastrim 6mg s/c).The primary endpoint was to achieve an overall response rate of > 40% assessed by CT scan at the end of treatment according to the Cheson criteria. Secondary endpoints were progression free survival and overall survival. Results: 62 patients were recruited from 32 UK sites over a 28 month period from April 2008 to July 2010. 66% were male. Median age was 76 years (range 52–90), 48 (77%) were > 70 years. 43 (69%) had stage III/IV disease and 46 (72%) had high – intermediate or high IPI (3–5) disease. ECOG performance status was ≥ 2 in 50% patients. Left ventricular ejection fraction (LVEF) was < 50% in 28 patients (45%). The 34 patients with LVEF ≥ 50% had significant co-morbidities, 22 (65%) had multiple co-morbidities. 44 (70%) received ≥ 3 cycles of treatment, reasons for early termination of treatment in the remaining 18 patients were progression (n=2), toxicity (n=5), death (n=6) patient choice (n=1) and other (n=4). 29 patients (47%) received the full 6 cycles. A total of 250 treatment cycles were delivered. Of the 44 patients who received ≥ 3 cycles of treatment, the dose of Gemcitabine was escalated to the full dose (1000mg/m2) in 67%. Day 8 Gemcitabine was delivered in 215/250 (86%) cycles of treatment. The overall response rate (CR/CRu/PR) at end of treatment for all 62 patients was 60%. For patients who received ≥ 3 cycles of treatment (n =44) the ORR was 79.5% at the end of treatment. There was no significant difference in ORR between those with LVEF Conclusion: This multicentre trial demonstrates that the R-GCVP regimen delivers excellent overall response rates with durable remissions in a group of patients where anthracycline use was precluded. The efficacy attained in this difficult group of patients provides a platform for testing the regimen in subsequent randomised phase II and phase III studies to confirm its efficacy. Disclosures: No relevant conflicts of interest to declare.

Abstract 697 Introduction: Despite the increasing use of combination therapy with rituximab, fludarabine and cyclophosphamide (R-FC) for chronic lymphocytic leukemia (CLL), a significant proportion of patients (pts) are not suitable or eligible for such intensive chemotherapy due to co-morbidity and/or age. In those pts considered unfit for R-FC, chlorambucil (Chl) remains a widely used first-line therapy. However, overall responses rates with Chl are relatively modest with very few complete remissions and therefore more effective treatment options are required for this patient group. In this multi-centre Phase II study we evaluate the feasibility of adding R to Chl and assess response rate compared to single agent Chl. Methods: One hundred previously untreated CLL pts requiring therapy according to iwCLL criteria received R (day 1; 375 mg/m2 i.v. cycle 1, 500 mg/m2 cycles 2–6) plus Chl (days 1–7; 10mg/m2/day p.o.) every 28 days for 6 cycles. A further 6 cycles of Chl alone was permitted in pts with continuing clinical response at 6 cycles. Efficacy data were compared to matched historic data from the UK LRF CLL4 trial, which treated pts between 1999 and 2004 with Chl-monotherapy at the same dose as used in this study. Each patient of this study was matched to 2 pts treated with Chl in the LRF CLL4 study according to Binet Stage (B or C), VH Mutation (mutated or unmutated), 11q FISH (deleted or not) and age. It should be noted that the CLL4 data was from 1999–2005, while the Chl-R responses were from 2008. Over this time, any improvements in patient response may be due to better care, improved knowledge, different concomitant medications, etc, rather than treatment used. In addition the median age of patients in LRF CLL4 was significantly lower than those treated with Chl-R (66.5 compared with 70 yrs). Results: A total of 100 pts from 12 centres, who had completed the treatment were included in this analysis; median age was 70 years (range 43–86) and 65% were male. To date, 88 pts remain alive and 12 pts have died. Ninety-two pts (92%) had reported an AE by the end of treatment. The most common AEs were: nausea (47 pts), neutropenia (39 pts), lymphopenia (38 pts), fatigue (26 pts), pyrexia (26 pts), leukopenia (21 pts), diarrhoea (20 pts), vomiting (19 pts), anaemia (18 pts) and thrombocytopenia (18 pts). Most AEs reported were Grade 1–2; Grade 3–4 neutropenia occurred in 39% of pts. Infusion-related reactions occurred in 7 pts. Overall, 37% of pts reported a total of 53 serious AEs (SAEs). The most common SAEs were febrile neutropenia (5 pts) and neutropenic sepsis (4 pts). Overall response rate (ORR) on an intent-to-treat analysis was 82% (95% CI, 73.1–89.0), with 9 pts achieving a complete response (CR), 58 pts showing partial response (PR), 15 pts showing nodular PR (nPR) and 11 pts with stable disease (SD). Median PFS to date is 23.5 months. ORR in this study was 16% higher than in the matched subset of Chl pts from the CLL4 study (95% CI, 6.0–26.0%), suggesting improved responses for Chl-R compared with Chl-alone. Conclusions: With a median age of 70 years, the population in this study was noticeably older than that of pts in CLL4 and other large trials in CLL. This study represents a more typical CLL patient population, as often seen in the clinic. These data confirm that in previously untreated CLL pts who are unable to tolerate a more intensive chemotherapy regimen, the combination of R and Chl is an efficacious therapy with an acceptable tolerability profile resulting in a better ORR than Chl monotherapy. Further evaluation of R-Chl in a randomized Phase III study is warranted. Disclosures: Hillmen: F.Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glaxo Smith Kline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Rituximab is used broadly in this indication at some specific lines of therapy/chemotherapy combinations may be off label in some countries. Dearden:Roche Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kennedy:Roche Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pettitt:Glaxo Smith Kline: Research Funding. Rawstron:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BD Bioscience: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Genzyme: Honoraria. Pocock:F.Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract 60 Background: The length of remission in patients with chronic lymphocytic leukemia (CLL) is dependent on the level of minimal residual disease (MRD) at the end of therapy, regardless of the therapy received. The conversion of remissions from MRD positive to negative should prolong remissions and survival. Several small studies have used alemtuzumab as consolidation therapy following conventional chemotherapy but with concerns over toxicity; primarily due to immune suppression and infections. The dose and timing (i.e. interval between prior chemotherapy and alemtuzumab) seem to be critical. Trial Design: The Phase II NCRN CLL207 Trial assessed alemtuzumab consolidation post-chemotherapy. Between 6 and 24 months from completing treatment (1 to 3 prior therapies) blood was screened for MRD using multi-parameter flow cytometry with a sensitivity of less than a single CLL cell in 10,000 leucocytes (0.01%). The marrow of MRD positive patients was assessed to quantify the CLL before treatment with alemtuzumab at a dose of 30mg given subcutaneously 3 times a week for 6 weeks, at which time the marrow was repeated. MRD negative patients and non-responders stopped therapy; MRD positive patients with at least one log reduction in MRD continued therapy for a further 6 weeks. All patients received prophylaxis with co-trimoxazole and aciclovir as well as weekly cytomegalovirus (CMV) monitoring by PCR. It was pre-determined that at least 14 of up to 54 (26%) patients would need to be converted from MRD positivity to negativity to justify further studies of this treatment strategy. Results: 47 patients received alemtuzumab in NCRN CLL207 with median age of 58 yrs (40-77) and 35 (74.5%) males. There was a median of 2 prior therapies (range 1 to 4) with 46 pts receiving fludarabine combinations as the latest therapy and 9 receiving rituximab-containing combinations. There were a total of 21 SAE's in 17 (36.2%) pts with 2 (4.3%) treatment related deaths (EBV-LPD and a parainfluenza infection). Alemtuzumab was stopped in 6 patients before week 6 mainly due to toxicity, 32 patients received 6–8 weeks of treatment and 9 patients received a 12-week course. G-CSF was given when the neutrophil count fell below 1 × 10^9/l and 14 (30%) patients required G-CSF during alemtuzumab with an additional 13 (28%) receiving G-CSF after completion of alemtuzumab. Positive CMV PCRs were detected in 21 (45%) patients, all of whom were successfully treated with pre-emptive antiviral therapy. Prior to alemtuzumab 24 patients were in complete remission (CR) and 23 were in partial remission (PR). Three months after alemtuzumab 13/23 (56%) PR converted to CR. 39/47 (83%) patients had MRD negative marrows at the end of alemtuzumab, 7 (15%) remained MRD positive and 1 (2%) was not evaluable. Blood MRD assessment 6 months after completing alemtuzumab showed that 15/31 (48%) MRD negative patients became MRD positive, although all except 2 had low CLL levels (below 0.1×10^9/l) at this time-point. Therefore overall 16/39 (41%) patients were MRD negative 6 months after completing alemtuzumab and of these 8/9 (89%) remained MRD negative in the blood at 12 months. Therefore MRD negativity in the blood at 6 months seems to better predict for persistent MRD negativity than the marrow at the end of therapy and appears to be the most appropriate assessment for the outcome of consolidation. Patients who are MRD negative at this time-point usually have durable remissions. 6 of the 9 patients receiving 12 weeks of alemtuzumab were MRD negative at the end of treatment but only 1 (11%) remained MRD negative in the blood at 6 months. In contrast 33/38 patients receiving up to 8 weeks of alemtuzumab were MRD negative at the end of treatment and 15 (39%) remained MRD negative at 6 months suggesting that the patients who benefit most from alemtuzumab consolidation are those who are MRD negative at 6 weeks. Conclusion: Alemtuzumab consolidation results in the eradication of detectable MRD in 83% of patients and 41% remain MRD negative 6 months later. Consolidation with alemtuzumab is associated with mainly infective toxicities, which are largely manageable with prophylaxis and close monitoring. These results justify the continued investigation of this approach in CLL within a clinical trial setting and with appropriate monitoring of patients. To this end we are now commencing a randomized Phase III trial of consolidation with alemtuzumab compared to observation (the CLARET study). Disclosures: Pocock: F.Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rawstron:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BD Bioscience: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Genzyme: Honoraria. Dearden:Roche Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hillmen:Genzyme: Honoraria, Research Funding, Speakers Bureau; Roche Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Glaxo Smith Kline: Honoraria, Research Funding.

Abstract 6 Patients with asymptomatic, advanced stage, follicular lymphoma have shown no benefit of immediate chemotherapy when compared with a watchful-waiting approach, whereby chemotherapy is deferred until disease progression. Deferring chemotherapy may spare the patient the side effects of the chemotherapy in the short term and historically this has been the preferred approach. With the advent of rituximab and its relatively favourable side effect profile we designed this study to compare a watchful waiting approach with immediate treatment with rituximab. Adult patients with asymptomatic stage 2, 3 or 4 follicular lymphoma (grades 1–2 & 3a) and adequate bone marrow reserve were randomly assigned with a ratio 1:1:1 to watchful waiting (arm A) or rituximab 375mg/m2 weekly for 4 weeks (arm B) or rituximab 375mg/m2 weekly for 4 weeks followed by rituximab maintenance every 2 months for 2 years (starting at month 3 until month 25)(arm C). The primary endpoints were a) time to initiation of new therapy (chemotherapy or radiotherapy) and b) effect on quality of life. The study was designed to detect an improvement in the median time to initiation of therapy in each of the rituximab arms of 18 months (from 30 months to 48 months) with 2.5% significance level and 90% power. A total of 230 events were required and 600 patients were planned. In September 2007, a decision was made to discontinue arm B as evidence of the efficacy of maintenance rituximab became clear. With the two arms comparison, using a significance level of 5%, a total of 360 patients in Arm A and Arm C were planned. Between September 2004 and May 2009 462 patients were randomised (186 Arm A, 84 Arm B, and 192 Arm C). 95% of patients had low tumour burden (GELF criteria) the other 5% had raised LDH but fulfilled the remaining GELF criteria. 98% were entered into the study within 4 months of diagnostic biopsy. Median age 60yr (range27-87). 54% female. ECOG performance status 0=91% & 1=9%. Grade 1–2=89%. Stage 2(21%), stage 3(40%), stage 4 (39%). 42% had bone marrow involvement. FLIPI score: 0=9%, 1=26%, 2=41%, 3=22%, 4=2%. In March 2010 the Data Monitoring committee concluded that the data regarding time to initiation of new therapy was mature and recommended full analysis of data to be performed and presented in the knowledge that rituximab maintenance was still ongoing in 20 patients. To date 45 SAEs have been reported (Arms A=14, B=6, C=25), 14 SAE were considered possibly, probably or definitely related to the study drug (Arm B=4, C=10). 5 allergic reactions (two grade 3), 6 infections, 3 episodes of grade 4 neutropenia. Responses were assessed at month 7, 13 and 25. CT was compulsory at months 7 and 25. Bone marrow was only required if CR on clinical and CT criteria. An interim analysis was performed on 9 Feb 2010. At month 7: Arm A: spontaneous remission was seen in 3%, PR=6%, NC (no change) =74%, PD=17%. Arm B: CR+CRu=45%, PR=33%, NC=19%, PD=3%. Arm C: CR+CRu=49%, PR=36%, NC=11%, PD=3%. At the time of the interim analysis 93 (20%) patients had initiated new treatment. Of these 93 patients 84 (90%) had clinically reported progression. New treatment was chemotherapy in 78 (84%), radiotherapy in 10 (11%), rituximab monotherapy in 2 (2%), surgery in 1(1%),currently not known in 2 (2%). The estimated median time to initiation of new therapy in arm A was 33 months, similar to our previous trial of watchful waiting (Ardeshna et al Lancet 2003). The time to initiation of new therapy was significantly longer in the rituximab arms (fig 1, p value of log-rank test 0.5). These data indicate that initial treatment with rituximab significantly delays the need for new therapy and this finding may change the management of patients with newly diagnosed asymptomatic follicular lymphoma. Disclosures: Ardeshna: Roche: Funding data manager, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Rituximab is currently not licensed for use as a single agent in previously untreated patients with with asymptomatic advanced stage follicular lymphoma. Pocock:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cunningham:Roche: Research Funding. Davies:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; chugai: Honoraria, Research Funding. Walewski:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Linch:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Standard front-line therapy for chronic lymphocytic leukemia (CLL) is fludarabine plus cyclophosphamide. Adding mitoxantrone (FCM) or rituximab (FCR) appears to improve responses although no large randomized trials have been reported. We report a randomized Phase II trial of FCM and FCM-R in relapsed CLL. FCM was oral fludarabine (24mg/m2 for 5 days) and cyclophosphamide (150mg/m2 for 5 days) plus i.v. mitoxantrone (6mg/m2) on Day 1 of each cycle. FCM-R was identical with rituximab on Day 1 of each cycle (375mg/m2 cycle 1; 500mg/m2 cycles 2 to 6). Prophylaxis with aciclovir and co-trimoxazole was given. The primary end-point was response by NCI Criteria 2 months after therapy. Complete remission with incomplete marrow recovery (CR(i)) was defined according to the 2007 CLL Guidelines - clinical CR with a morphologically normal marrow but persistent cytopenias (i.e. platelets 4. The median number of prior therapies was 2 (1–6), 31 had prior fludarabine and 6 (12%) were refractory to or relapsed 20% 17p deleted cells (FCM-R). 36/52 (69%) received 4 or more cycles of therapy with no difference between FCM and FCM-R (18/26). Responses are shown in the Table. 35 SAE’s were reported in 23 patients. There was no difference in the number of patients with SAE’s between the arms (FCM 11, FCM-R 12). 6/7 patients (86%) who had 4 or more prior therapies reported an SAE, compared to 17/45 patients (38%) who had less than 4. 16 SAE’s were suspected to be related to FCM-R and 10 related to FCM. In summary, FCM-R is an effective therapy for relapsed CLL with over two-thirds of patients responding. The study design does not allow a statistical comparison between FCM and FCM-R but the results suggest that adding rituximab to FCM results in a higher complete response rate (CR + CR i = 43% for FCM-R and 13% for FCM) with more patients achieving MRD negativity (5 after FCM-R; 2 after FCM). The results of this randomised Phase II trial justify the study of FC with mitoxantrone and/or rituximab in larger randomized Phase III trials. Responses in 46 evaluable patients (remaining 6 not yet evaluable) All patients FCM FCM-R Number of patients 46 23 23 Overall response rate 29 (63%) 13 (57%) 16 (70%) CR 5 (11%) 1 (4%) 4 (17%) CR(i) 8 (17%) 2 (9%) 6 (26%) PR 16 (35%) 10 (43%) 6 (26%) SD/PD 12 (26%) 7 (30%) 5 (22%) Early Death (before assessment) 4 (9%) 2 (9%) 2 (9%) Withdrew consent (before assessment) 1 (2%) 1 (4%) 0 (0%) MRD negative 7 (15%) 2 (9%) 5 (22%)

Background: In most centres in the United Kingdom, systemic antifungal therapy (AFT) is used as third-line therapy for fever complicating profound, prolonged neutropenia (PPN) during the treatment of acute leukemia. Voriconazole has been recommended as first-line AFT at the Kent and Canterbury Hospital (KCH) since October 2002; liposomal amphotericin B was the previous treatment of choice. The aim of the audit was to identify numbers of episodes of PPN and the numbers of suspected fungal infections in a 2-year period following the policy change. Subsequently the clinical and financial outcomes were examined. In addition, the impact on cost of AFT following centralisation of leukemia treatment from two district hospitals onto one site was examined. Methods: A retrospective audit was conducted on data from hematology inpatients undergoing remission induction or consolidation therapy for acute leukemia at KCH between January 2003 and December 2004. The costs of voriconazole and liposomal amphotericin B treatment from 2002 to 2004, and 8 months prior and post centralisation of inpatient care (April 2004, which increased the population from 400,000 to 600,000), were examined. Results: 84 episodes of PPN were identified in 41 patients undergoing treatment for acute leukemia; mostly acute myeloid leukemia (AML). Itraconazole prophylaxis from d1 of therapy and GCSF from d+5 was used in the majority of cases. 18 cases of suspected or radiologically proven fungal infection were identified. High-resolution computed tomography of the chest was performed in 10 cases and suspicious lesions identified in three. Voriconazole was used as first-line therapy in 17/18 cases. In 7 cases, treatment was switched to liposomal amphotericin B. Reasons for switching were rising C-reactive protein (1 patient), persistent fever (2 patients), radiological progression (1 patient) and side effects (3 patients). Of the 3 patients with radiological evidence of fungal infection, two had a complete resolution (1 voriconazole, 1 voriconazole/liposomal amphotericin B) and 1 patient died of refractory leukemia. There was a fall in total antifungal spend from £263K in 2002/3 to £229K in 2003 and a further 68% fall to £73K in 2004. We suspect this was due to increasing adherence to the new antifungal protocol and to improved practices following centralisation: in the 8 months pre-centralisation the antifungal spend across all hospitals was £102K falling by 74% to £26K in the 8 months on the single site. Conclusion: Since introducing voriconazole as first-line AFT, centralising inpatient services, and adopting common policies for antimicrobial prophylaxis, there has been considerable financial benefit with no increase in morbidity and/or mortality.