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Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma.We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed.Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group.Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.).

Background Most older patients with acute myeloid leukemia (AML) who attain morphologic remission with intensive chemotherapy (IC) will eventually relapse and post-relapse prognosis is dismal. In the pivotal QUAZAR AML-001 trial, oral azacitidine maintenance therapy significantly prolonged overall survival by 9.9 months (P P Methods QUAZAR AML-001 is an international, placebo-controlled randomized phase 3 study. Patients aged ≥ 55 years with AML and intermediate- or poor-risk cytogenetics at diagnosis, who had attained first complete remission (CR) or CR with incomplete blood count recovery (CRi) within 4 months before study entry, were randomized 1:1 to receive oral azacitidine 300 mg or placebo once-daily for 14 days in repeated 28-day cycles. Safety was assessed in all patients who received ≥ 1 dose of study drug. Results A total of 469 patients received oral azacitidine (n = 236) or placebo (n = 233). Median age was 68 years. Patients received a median of 12 (range 1–80) oral azacitidine treatment cycles or 6 (1–73) placebo cycles. Gastrointestinal AEs were common and typically low-grade. The most frequent grade 3–4 AEs during oral azacitidine therapy were hematologic events. AEs infrequently required permanent discontinuation of oral azacitidine (13%), suggesting they were effectively managed with use of concomitant medications and oral azacitidine dosing modifications. Conclusion Oral azacitidine maintenance had a generally favorable safety profile. Prophylaxis with antiemetic agents, and blood count monitoring every other week, are recommended for at least the first 2 oral azacitidine treatment cycles, and as needed thereafter. Awareness of the type, onset, and duration of common AEs, and implementation of effective AE management, may maximize treatment adherence and optimize the survival benefits of oral azacitidine AML remission maintenance therapy. Trial registration This trial is registered on clinicaltrials.gov: NCT01757535 as of December 2012.

Effective and tolerable treatments are needed for older patients with classical Hodgkin lymphoma. We report results for older patients with classical Hodgkin lymphoma treated in the large phase III ECHELON-1 study of frontline brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Modified progression-free survival per independent review facility for older versus younger patients (aged ≥60 vs.

We compared the International Prognostic Index (IPI), Revised (R)-IPI and age-adjusted (aa)-IPI as prognostic indices for patients with diffuse large B-cell lymphoma (DLBCL) in the UK National Cancer Research Institute (NCRI) R-CHOP 14 versus 21 trial (N = 1080). The R-IPI and aa-IPI showed no marked improvement compared to the IPI for overall and progression-free survival, in terms of model fit or discrimination. Similar results were observed in exploratory analyses incorporating the Grupo Español de Linfomas/Transplante de Médula Ósea (GELTAMO)-IPI, where baseline β2-microglobulin data were available (N = 655). Although our findings support current use of the IPI, a novel prognostic tool to better delineate a high-risk DLBCL group in the rituximab era is needed.

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.

Kinase domain mutations in BCR-ABL1 are associated with resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukaemia. Next-generation sequencing (NGS) allows detection of low-level kinase domain mutations, but its relevance in clinical practice remains debated. We aimed to examine the clinical effects of low-level kinase domain mutations identified using NGS in patients with chronic myeloid leukaemia.In this population-based study, we included consecutive patients newly diagnosed with chronic myeloid leukaemia treated with first-line tyrosine kinase inhibitors, and patients identified at the time of resistance to first-line treatment with imatinib at six institutions (teaching hospitals and district hospitals) in southeast England. We screened patients for BCR-ABL1 kinase domain mutations using NGS, irrespective of patient response to tyrosine kinase inhibitor therapy. When we detected a mutation with NGS, we retrospectively analysed all previous samples to establish the date of first occurrence and subsequent kinetics of the mutant subclone (or subclones). The primary endpoints of this study were progression-free and event-free survival at 5 years.Between Feb 1, 2007, and Dec 31, 2014, we screened 121 patients with chronic myeloid leukaemia for BCR-ABL1 kinase domain mutation. 99 consecutive patients were newly diagnosed, with available sequential RNA stored. The remaining 22 patients were diagnosed between June 1, 1999, and June 30, 2006, and were screened at the time of resistance to first-line treatment with imatinib. Imatinib was the first-line treatment for 111 patients, nilotinib for seven patients, and dasatinib for three patients. We detected a kinase domain mutation in 25 (21%) of 121 patients. Low-level kinase domain mutations were first identified in 17 (68%) of 25 patients with mutation. For patients with a complete cytogenetic response, 13 (14%) of 93 patients screened had a mutation. Five (71%) of the seven patients with a clinically relevant mutation lost complete cytogenetic response compared with 15 (17%) of 86 patients without a clinically relevant mutation (80 patients without mutation and six patients with a tyrosine kinase inhibitor-sensitive mutation, p=0·0031). Patients harbouring a mutant clone had poorer 5-year progression-free survival (65·3% [95% CI 40·5-81·8] vs 86·9% [75·8-93·2]; p=0·0161) and poorer 5-year event-free survival (22·2% [CI 5·6-45·9] vs 62·0% [50·4-71·6]; p0·0001) than did patients without a mutation. We identified a kinase domain mutation in four (10%) of 41 patients with samples available at 3 months after starting first-line tyrosine kinase inhibitor treatment; all four subsequently progressed to accelerated phase disease compared with only three (8%) of 37 without a mutation (p0·0001).NGS reliably and consistently detected early appearance of kinase domain mutations that would not otherwise be detected by Sanger sequencing. For the first time, to our knowledge, we report the presence of kinase domain mutations after only 3 months of therapy, which could have substantial clinical implications. NGS will allow early clinical intervention and our findings will contribute to the establishment of new recommendations on the frequency of kinase domain mutation analysis to improve patient clinical care.None.

Background: Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor.\ud \ud Methods: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bioequivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life.\ud \ud Results: A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P

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.

Context In the phase III QUAZAR AML-001 Maintenance Trial, CC-486, an oral hypomethylating agent significantly prolonged overall and relapse-free survival vs. placebo among patients with AML in first remission after induction chemotherapy (IC). Gastrointestinal (GI) events were the most frequent adverse events (AEs) with CC-486. Objective Assess GI AE rates with CC-486 over time and associated management strategies. Methods Eligible patients were aged ≥55 years and had AML with intermediate- or poor-risk cytogenetics, and ECOG-PS scores ≤ 3. Patients achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi) after IC ± consolidation and were not transplant candidates. Within 4 months of CR/CRi, patients were randomized 1:1 to once-daily CC-486 300-mg or placebo on days 1-14 of repeated 28-day cycles. Safety was assessed in patients who received ≥1 dose, through 28 days after the last dose. Prophylaxis and treatment of GI AEs was allowed but not mandatory. Results 236 patients received CC-486 and were evaluated for safety. Median age was 68 years (range, 55-86). Rates of any-grade nausea, vomiting, and diarrhea were 65%, 60%, and 50%, respectively; few patients experienced grade 3 (3%, 3%, and 5%) or serious (0.4%, 0.8%, and 1.3%) events, and only 1 grade 4 event (diarrhea) was reported. Rates were highest during initial treatment and decreased thereafter: in cycles 1-2, 3-4, and 5-6, nausea was reported in 53%, 17%, and 15% of patients, respectively; vomiting in 49%, 15%, and 10%; and diarrhea in 29%, 16%, and 11%. 5-HT3-antagonists, metoclopramide, lactulose, and loperamide were the most common concomitant medications; use of these agents also decreased over time. GI events required CC-486 dose-reductions for 6% of patients, treatment interruptions for 13%, and discontinuation for 5%. Conclusions Most GI AEs with CC-486 were low-grade, and events decreased in frequency after initial cycles. Use of GI medications decreased concurrently, suggesting progressive GI tolerance to CC-486. Few patients discontinued CC-486 due to GI AEs, indicating these events were easily managed. Clinicians and patients should be aware of possible GI events during early CC-486 treatment; prophylaxis and symptomatic intervention may facilitate treatment adherence to promote better outcomes.

Background:\ud All studies of treatment-free remission (TFR) in patients with chronic myeloid leukaemia have discontinued tyrosine kinase inhibitor (TKI) treatment abruptly and have focussed on patients with stable MR4 (BCR-ABL to ABL ratio ≤0·01%). We aimed to examine the effects of gradual treatment withdrawal and whether TFR is feasible for patients with less deep but stable remission.\ud \ud Methods:\ud The De-Escalation and Stopping Treatment with Imatinib, Nilotinib, or sprYcel (DESTINY) study is a non-randomised, phase 2 trial undertaken at 20 UK hospitals. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase, who had received TKI therapy for 3 years or more, with three or more BCR-ABL quantitative PCR transcript measurements (BCR-ABL to ABL1 ratio) less than 0·1% (major molecular response [MMR]) in the 12 months before entry. Patients with all PCR measurements less than 0·01% were assigned to the MR4 group. Patients with results between 0·1% and 0·01% were allocated to the MMR group. TKI treatment was de-escalated to half the standard dose for 12 months, then stopped for a further 24 months, with frequent PCR monitoring. Recurrence was defined as the first of two consecutive samples with PCR measurement greater than 0·1%, which required treatment recommencement at full dose. The primary endpoint was the proportion of patients who could first de-escalate their treatment for 12 months, and then stop treatment completely for a further 2 years, without losing MMR. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985.\ud \ud Findings:\ud Treatment at entry was imatinib (n=148), nilotinib (n=16), or dasatinib (n=10), for a median of 6·9 years (IQR 4·8–10·2). Between Dec 16, 2013, and May 6, 2015, we enrolled 49 patients into the MMR group and 125 into the MR4 group. In the MR4 group, 84 (67%) patients reached the 36-month trial completion point and recurrence-free survival was 72% (95% CI 64–80). In the MMR group, 16 (33%) entrants completed the study and recurrence-free survival was 36% (25–53). No disease progression was seen and two deaths occurred due to unrelated causes. All recurrences regained MMR within 5 months of treatment resumption.\ud \ud Interpretation:\ud Initial de-escalation before discontinuation might improve the success of TFR protocols, although the mechanism of its benefit is not yet clear. The findings also suggest that TFR merits further study in patients with stable MMR.\ud \ud Funding:\ud Newcastle University and Bloodwise.

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.

In the phase III study RESONATE, ibrutinib reduced the risk of progression and improved overall survival versus ofatumumab in previously treated patients with CLL/SLL. In this novel analysis of patient well-being including patient-reported outcomes, ibrutinib reduced disease burden while preserving parameters of hematologic and immunologic function in RESONATE. These results suggest that ibrutinib can improve quality of life while prolonging survival. Background: Ibrutinib compared with ofatumumab significantly improves progression-free and overall survival in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients and Methods: Measures of well-being were assessed in RESONATE, where previously treated patients with CLL/SLL were randomized to receive ibrutinib 420 mg/day (n = 195) or ofatumumab (n = 196) for up to 24 weeks. Endpoints included hematologic function, Functional Assessment of Chronic Illness TherapyeFatigue (FACIT-F), disease-related symptoms, European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 (EORTC QLQ-C30), and medical resource utilization. Results: With up to 24 months' follow-up (median, 16.4 months), 79% of cytopenic patients showed sustained hematologic improvement (82% with improved platelet count, 69% with improved hemoglobin) on ibrutinib versus 43% on ofatumumab (P = 3 hypertension occurred in 6%, grade >= 3 atrial fibrillation in 4%, major hemorrhage in 2%, and tumor lysis syndrome in 1% of patients. Conclusion: Ibrutinib led to significant improvements in hematologic function and disease symptomatology versus ofatumumab, and can restore quality of life while prolonging survival in relapsed/refractory CLL/SLL. (C) 2018 The Authors. Published by Elsevier Inc.

7014 Background: Demographic and disease factors influence outcomes for patients (pts) with AML. In the phase 3 QUAZAR AML-001 trial, Oral-AZA significantly prolonged OS and RFS vs. placebo (PBO) for pts with AML in first remission after IC (Wei, NEJM, 2020). Univariate analyses showed OS and RFS benefits with Oral-AZA vs. PBO across pt subgroups defined by baseline (BL) characteristics. MV analyses were performed to identify BL characteristics independently predictive of OS/RFS in QUAZAR AML-001, and to assess Tx effects of Oral-AZA vs. PBO on survival when adjusted for BL factors. Methods: Pts were aged ≥55 yrs with AML in complete remission (CR) or CR with incomplete count recovery (CRi) after induction ± consolidation. Within 4 months of CR/CRi, pts were randomized 1:1 to receive Oral-AZA 300 mg or PBO for 14d/28d cycle. Cox proportional hazards models were used to estimate Tx effects of Oral-AZA vs. PBO on OS and RFS, adjusting for BL age, sex, ECOG PS score, cytogenetic risk at diagnosis (Dx), prior MDS, geographic region, CR/CRi after induction (per investigator) and at BL (per sponsor), MRD status, receipt of consolidation, number of consolidation cycles, platelet count, and ANC. In a stepwise procedure, randomized Tx and BL variables were selected incrementally into a Cox model if P ≤ 0.25. After each addition, the contribution of the covariate adjusted for other covariates in the model was evaluated and retained in the model if P ≤ 0.15. Results : Oral-AZA Tx remained a significant independent predictor of improved OS (HR 0.70) and RFS (HR 0.57) vs. PBO after controlling for BL characteristics (Table). MRD status, cytogenetic risk, and pt age were each also independently predictive of OS and RFS. Response after induction (CR vs. CRi) and BL ANC were predictive of OS but not RFS, whereas prior MDS, CR/CRi at BL, and number of consolidation cycles were only predictive of RFS. Conclusions: Tx with Oral-AZA reduced the risk of death by 30% and risk of relapse by 43% vs. PBO independent of BL characteristics. Cytogenetic risk at Dx, MRD status, and pt age also independently predicted survival outcomes. Clinical trial information: NCT01757535. [Table: see text]

We performed a subgroup analysis of the phase III UK National Cancer Research Institute R-CHOP-14 versus R-CHOP-21 (two- versus three-weekly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) trial to evaluate the outcomes for 50 patients with World Health Organization 2008 classified primary mediastinal B-cell lymphoma identified from the trial database. At a median follow-up of 7·2 years the 5-year progression-free survival and overall survival was 79·8% and 83·8%, respectively. An exploratory analysis raised the possibility of a better outcome in those who received R-CHOP-14 and time intensification may still, in the rituximab era, merit testing in a randomised trial in this subgroup of patients.

7533 Background: Effective AML maintenance treatment (Tx) should decrease the risk of relapse and prolong survival without compromising HRQoL. In the placebo (PBO)-controlled phase III QUAZAR AML-001 trial (NCT01757535), CC-486, an oral hypomethylating agent, provided significant improvements in overall (OS) and relapse-free survival (RFS) in patients (pts) with AML in first remission following IC. Here we present pt-reported HRQoL outcomes from that study. Methods: Eligible pts were ≥ 55 yrs of age with intermediate- or poor-risk cytogenetics and ECOG PS ≤ 3, and in CR/CRi after IC ± consolidation. Pts were randomized 1:1 to CC-486 300 mg or PBO QD on days (d) 1–14 of 28d Tx cycles. HRQoL was assessed by FACIT-Fatigue scale and EQ-5D-3L health utility index, completed on d1 of each cycle and at end of Tx (EOT). Endpoints include Tx differences in mean changes from baseline (BL), and proportions of pts with clinically meaningful change from BL (improvement, no change, deterioration). Evaluable pts had an HRQoL assessment at BL and ≥ 1 post-BL visit. Stratified ANCOVA models included Tx and BL scores as covariates. Results: In all, 225/238 pts (95%) in the CC-486 arm were evaluable for FACIT-Fatigue and EQ-5D-3L, and 219/234 pts (94%) in the PBO arm were evaluable for FACIT-Fatigue and 217 (93%) for EQ-5D-3L. Pt characteristics were comparable between Tx arms. Most pts (61%) were 65-74 yrs of age. Median number of CC-486 Tx cycles was 12 and PBO cycles was 7. Compliance rates were > 95% at BL and remained high ( > 85%) at all post-BL visits except for EOT. At BL, pts in both Tx arms had comparable low levels of fatigue and generally good HRQoL relative to an age-matched general population. There were no meaningful differences between CC-486 and PBO in mean changes from BL in FACIT-Fatigue or EQ-5D-3L scores at any post-BL visit. There was no statistically significant difference between Tx arms in proportion of pts with a clinically meaningful deterioration in FACIT-Fatigue score at any post-BL visit except at cycle 29 (likely due to chance; no adjustment made for multiple testing), or in EQ-5D-3L at any visit. Median time to deterioration was not significantly different between CC-486 and PBO on the FACIT-Fatigue scale (41 vs 44 weeks, respectively; P = 0.70) or the EQ-5D-3L (200 vs 164 weeks; P = 0.63). Conclusions: HRQoL and low levels of fatigue were preserved with CC-486 maintenance Tx. CC-486 significantly improved OS and RFS while maintaining HRQoL comparable to PBO. Clinical trial information: NCT01757535 .

Mantle cell lymphoma is an incurable and generally aggressive lymphoma that is more common in elderly patients. Whilst a number of different chemotherapeutic regimens are active in this disease, there is no established gold standard therapy. Rituximab has been used widely to good effect in B-cell malignancies but there is no evidence that it improves outcomes when added to chemotherapy in this disease. We performed a randomized, open-label, multicenter study looking at the addition of rituximab to the standard chemotherapy regimen of fludarabine and cyclophosphamide in patients with newly diagnosed mantle cell lymphoma. A total of 370 patients were randomized. With a median follow up of six years, rituximab improved the median progression-free survival from 14.9 to 29.8 months (P

Background Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial. Patients and methods The R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients aged ≥18 years with bulky stage I–IV DLBCL (n = 1080). Details of CNS prophylaxis were retrospectively collected from participating sites. The incidence and risk factors for CNS relapse including application of the CNS-IPI were evaluated. Results 177/984 patients (18.0%) received prophylaxis (intrathecal (IT) methotrexate (MTX) n = 163, intravenous (IV) MTX n = 2, prophylaxis type unknown n = 11 and IT MTX and cytarabine n = 1). At a median follow-up of 6.5 years, 21 cases of CNS relapse (isolated n = 11, with systemic relapse n = 10) were observed, with a cumulative incidence of 1.9%. For patients selected to receive prophylaxis, the incidence was 2.8%. Relapses predominantly involved the brain parenchyma (81.0%) and isolated leptomeningeal involvement was rare (14.3%). Univariable analysis demonstrated the following risk factors for CNS relapse: performance status 2, elevated lactate dehydrogenase, IPI, >1 extranodal site of disease and presence of a ‘high-risk’ extranodal site. Due to the low number of events no factor remained significant in multivariate analysis. Application of the CNS-IPI revealed a high-risk group (4-6 risk factors) with a 2- and 5-year incidence of CNS relapse of 5.2% and 6.8%, respectively. Conclusion Despite very limited use of IV MTX as prophylaxis, the incidence of CNS relapse following R-CHOP was very low (1.9%) confirming the reduced incidence in the rituximab era. The CNS-IPI identified patients at highest risk for CNS recurrence. ClinicalTrials.gov ISCRTN number 16017947 (R-CHOP14v21); EudraCT number 2004-002197-34.

Background:\ud \ud Discontinuation of tyrosine kinase inhibitor (TKI) therapy is feasible for some patients with chronic myeloid leukaemia with deep molecular responses; however, patients with stable major molecular response (MMR), but not MR4, have not been studied, nor has the effect of treatment de-escalation rather than outright cessation. We aimed to examine the effects of treatment de-escalation as a prelude to complete cessation, not only in patients with MR4 or greater, but also in those with MMR but not MR4.\ud Methods:\ud \ud We did this interim analysis of a non-randomised, phase 2 trial at 20 hospitals in the UK. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase who had received TKI for 3 years or more and were either in stable MR4 (BCR-ABL1:ABL1 ratio 0·1%) on two consecutive samples. The primary endpoint of this interim analysis was the proportion of patients who lost MMR on de-escalation and regained MMR on TKI resumption. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985.\ud Findings:\ud \ud Between Dec 16, 2013 and April 10, 2015, we enrolled 174 patients into the MMR cohort (n=49) or the MR4 cohort (n=125). During the 12 months of half-dose therapy, 12 patients (7%) had molecular recurrence, all of whom regained MMR within 4 months of full-dose TKI resumption (median time to recovery 77 days). Recurrence was significantly lower in the MR4 cohort (three [2%; 90% CI 0·2–4·8] of 121 evaluable patients) than in the MMR cohort (nine [19%; 90% CI 9·5–28·0] of 48 evaluable patients; hazard ratio 0·12, 90% CI 0·04–0·37; p=0·0007), but was unrelated to previous TKI or TKI therapy duration. Adverse events (eg, lethargy, diarrhoea, rash, and nausea) improved during the first 3 months of de-escalation, though not thereafter. 16 serious adverse events were reported, including one fatality due to worsening pre-existing peripheral arterial occlusive disease in a patient who had received only imatinib.\ud Interpretation:\ud \ud TKI de-escalation is safe for most patients with excellent responses to TKI therapy, and is associated with improvement in symptoms. These findings show that lower TKI doses might maintain responses in these patients, implying that such patients could be unnecessarily overtreated. Studies of more ambitious de-escalation are warranted.

Purpose Most patients with chronic lymphocytic leukemia (CLL) are elderly and/or have comorbidities that may make them ineligible for fludarabine-based treatment. For this population, chlorambucil monotherapy is an appropriate therapeutic option; however, response rates with chlorambucil are low, and more effective treatments are needed. This trial was designed to assess how the addition of rituximab to chlorambucil (R-chlorambucil) would affect safety and efficacy in patients with CLL. Patients and Methods Patients with first-line CLL were treated with rituximab (375 mg/m2 on day 1, cycle one, and 500 mg/m2 thereafter) plus chlorambucil (10 mg/m2/d all cycles; day 1 through 7) for six 28-day cycles. For patients not achieving complete response (CR), six additional cycles of chlorambucil alone could be administered. The primary end point of the study was safety. Results A total of 100 patients were treated with R-chlorambucil, with a median follow-up of 30 months. Median age of patients was 70 years (range, 43 to 86 years), with patients having a median of seven comorbidities. Hematologic toxicities accounted for most grade 3/4 adverse events reported, with neutropenia and lymphopenia both occurring in 41% of patients and leukopenia in 23%. Overall response rates were 84%, with CR achieved in 10% of patients. Median progression-free survival was 23.5 months; median overall survival was not reached. Conclusion These results compare favorably with previously published results for chlorambucil monotherapy, suggesting that the addition of rituximab to chlorambucil may improve efficacy with no unexpected adverse events. R-chlorambucil may improve outcome for patients who are ineligible for fludarabine-based treatments.

Purpose The treatment of patients with diffuse large B-cell lymphoma (DLBCL) with cardiac comorbidity is problematic, because this group may not be able to receive anthracycline-containing chemoimmunotherapy. We designed a single-arm phase II multicenter trial of rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone (R-GCVP) in patients considered unfit for anthracycline-containing chemoimmunotherapy because of cardiac comorbidity. Patients and Methods Sixty-one of 62 patients received R-GCVP, administered on day 1 with gemcitabine repeated on day 8 of a 21-day cycle. Median age was 76.5 years. All patients had advanced disease; 27 (43.5%) had left ventricular ejection fraction of ≤ 50%, and 35 (56.5%) had borderline ejection fraction of > 50% and comorbid cardiac risk factors such as ischemic heart disease, diabetes mellitus, or hypertension. Primary end point was overall response rate at the end of treatment. Results Thirty-eight patients (61.3%; 95% CI, 49.2 to 73.4) achieved disease response (complete response [CR], n = 18; undocumented/unconfirmed CR, n = 6; partial response, n = 14). Two-year progression-free survival for all patients was 49.8% (95% CI, 37.3 to 62.3), and 2-year overall survival was 55.8% (95% CI, 43.3 to 68.4). Thirty-four patients experienced grade ≥ 3 hematologic toxicity. There were 15 cardiac events, of which seven were grade 1 to 2, five were grade 3 to 4, and three were fatal, reflecting the poor cardiac status of the study population. Conclusion Our phase II multicenter trial showed that the R-GCVP regimen is an active, reasonably well-tolerated treatment for patients with DLBCL for whom anthracycline-containing immunochemotherapy was considered unsuitable because of coexisting cardiac disease.

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.

ADMIRE was a multicenter, randomized-controlled, open, phase IIB superiority trial in previously untreated chronic lymphocytic leukemia. Conventional front-line therapy in fit patients is fludarabine, cyclophosphamide and rituximab (FCR). Initial evidence from non-randomized phase II trials suggested that the addition of mitoxantrone to FCR (FCM-R) improved remission rates. Two hundred and fifteen patients were recruited to assess the primary end point of complete remission (CR) rates according to International Workshop on Chronic Lymphocytic Leukemia criteria. Secondary end points were progression-free survival (PFS), overall survival (OS), overall response rate, minimal residual disease (MRD) negativity and safety. At final analysis, CR rates were 69.8 FCR vs 69.3% FCM-R (adjusted odds ratio (OR): 0.97; 95% confidence interval (CI): (0.53-1.79), P=0.932). MRD-negativity rates were 59.3 FCR vs 50.5% FCM-R (adjusted OR: 0.70; 95% CI: (0.39-1.26), P=0.231). During treatment, 60.0% (n=129) of participants received granulocyte colony-stimulating factor as secondary prophylaxis for neutropenia, a lower proportion on FCR compared with FCM-R (56.1 vs 63.9%). The toxicity of both regimens was acceptable. There are no significant differences between the treatment groups for PFS and OS. The trial demonstrated that the addition of mitoxantrone to FCR did not increase the depth of response. Oral FCR was well tolerated and resulted in impressive responses in terms of CR rates and MRD negativity compared with historical series with intravenous chemotherapy.

With immunochemotherapy, remission duration and survival in patients with chronic lymphocytic leukaemia is dependent on the level of minimal residual disease (MRD) after treatment. This phase II trial assessed alemtuzumab consolidation post-chemotherapy in patients who responded with persistent low levels of detectable disease. Blood was screened for MRD using multi-parameter flow cytometry, 6-24 months post-chemotherapy. MRD-positive participants received alemtuzumab 30 mg subcutaneously 3 times weekly for 6 weeks. Following a marrow assessment, MRD-negative participants or non-responders stopped therapy and MRD-positive participants with 1 + log reduction had 6 more weeks of alemtuzumab. Alemtuzumab consolidation was received by 47 participants. One death and 19 of 22 serious adverse events reported from 17 (36%) participants were alemtuzumab-related. MRD eradication from blood and bone marrow was achieved in 39 (83%) participants at the end of consolidation, with 18 (38%) remaining MRD-negative in the blood 6 months later. Of the 18 participants who were MRD-negative at 6 months, the median time to MRD relapse was 46 months, which was similar to patients who were MRD-negative at baseline and were followed up. The 5-year progression-free survival (PFS) and overall survival (OS) of participants who were MRD-negative at 6 months was significantly better than MRD-positive participants [PFS: 78% vs. 39% (P = 0·010), OS: 89% vs. 64% (P = 0·029)].

DLBL subtypes identified by patterns of gene expression correspond to germinal center (GCB) or activated (ABC) B‐cells like. The latter demonstrate dysregulation of the NF‐KB pathway. Outcomes of treatment with R‐CHOP are inferior for ABC DLBL in retrospective series. This study investigated whether adding bortezomib (B), a putative NF‐KB inhibitor, can reverse this phenotype.

P>Combination fludarabine (F), cyclophosphamide (C) and rituximab (R) is the standard front-line therapy in chronic lymphocytic leukaemia (CLL), but appropriate treatment of relapsed/refractory CLL is less clear. Combined FC and mitoxantrone (M) has been reported to be effective in a single arm study, and rituximab when added to chemotherapy in CLL is synergistic. A randomized, two-stage, Phase II trial of FCM and FCM-R was conducted in relapsed CLL. The primary endpoint was response rate 2 months after therapy, assessed according to the 2008 International Workshop CLL criteria. In addition, minimal residual disease (MRD) in the marrow was studied 2 months after therapy, with MRD negativity defined as < 0 center dot 01% CLL cells. Fifty-two patients were entered, 26 in each arm. The overall response rates to FCM and FCM-R were 58% and 65% respectively. Combined complete response (CR) and CR with incomplete marrow recovery [CR(i)] was 15% (95% confidence interval [CI]:4-35%) for FCM and 42% (95%CI:23-63%) for FCM-R, with eight patients achieving MRD negativity (3 FCM; 5 FCM-R). The toxicity of both regimens was acceptable. In conclusion, the addition of rituximab to FCM improves the response rates in relapsed CLL, resulting in more complete remissions and without additional safety concerns. Efficacy and safety should be fully tested in a randomized Phase III trial.

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 BCR-ABL-negative chronic myeloproliferative disorders (CMPD) and myelodysplastic/myeloproliferative diseases (MDS/MPD) are a spectrum of related conditions for which the molecular pathogenesis is poorly understood. Translocations that disrupt and constitutively activate the platelet-derived growth factor receptor beta(PDGFRB) gene at chromosome band 5q33 have been described in some patients, the most common being the t(5;12)(q33;p13). An accurate molecular diagnosis of PDGFRB-rearranged patients has become increasingly important since recent data have indicated that they respond very well to imatinib mesylate therapy. In this study, we have tested nine patients with a CMPD or MDS/MPD and a translocation involving 5q31-33 for disruption of PDGFRB by two-colour fluorescence in situ hybridization (FISH) using differentially labelled, closely flanking probes. Normal control interphase cells gave a false positive rate of 3% (signals more than one signal width apart). Six patients showed a pattern of one fused signal (from the normal allele) and one pair of signals separated by more than one signal width in > 85% of interphase cells, indicating that PDGFRB was disrupted. These individuals had a t(1;5)(q21;q33), t(1;5)(q22;q31), t(1;3;5)(p36;p21;q33), t(2;12;5)(q37;q22;q33), t(3;5) (p21;q31) and t(5;14)(q33;q24) respectively. The remaining three patients with a t(1;5)(q21;q31), t(2;5)(p21;q33) and t(5;6)(q33;q24-25) showed a normal pattern of hybridization, with > or = 97% interphase cells with two fusion signals. We conclude that two-colour FISH is useful to determine the presence of a PDGFRB rearrangement, although, as we have shown previously, this technique may not detect subtle complex translocations at this locus. Our data indicate that several PDGFRB partner genes remain to be characterized.

Patients with advanced-stage, low-tumour-burden follicular lymphoma have conventionally undergone watchful waiting until disease progression. We assessed whether rituximab use could delay the need for chemotherapy or radiotherapy compared with watchful waiting and the effect of this strategy on quality of life (QoL).Asymptomatic patients (aged ≥18 years) with low-tumour-burden follicular lymphoma (grades 1, 2, and 3a) were randomly assigned centrally (1:1:1), by the minimisation approach stratified by institution, grade, stage, and age, to watchful waiting, rituximab 375 mg/m(2) weekly for 4 weeks (rituximab induction), or rituximab induction followed by a maintenance schedule of 12 further infusions given at 2-monthly intervals for 2 years (maintenance rituximab). On Sept 30, 2007, recruitment into the rituximab induction group was closed and the study was amended to a two-arm study. The primary endpoints were time to start of new treatment and QoL at month 7 (ie, 6 months after completion of rituximab induction). All randomly assigned patients were included in the analysis of time to start of new treatment on an intention-to-treat basis. The main study is now completed and is in long-term follow-up. The study is registered with ClinicalTrials.gov, NCT00112931.Between Oct 15, 2004, and March 25, 2009, 379 patients from 118 centres in the UK, Australia, New Zealand, Turkey, and Poland were randomly assigned to watchful waiting or maintenance rituximab. 84 patients were recruited to the rituximab induction group before it was closed early. There was a significant difference in the time to start of new treatment, with 46% (95% CI 39-53) of patients in the watchful waiting group not needing treatment at 3 years compared with 88% (83-92) in the maintenance rituximab group (hazard ratio [HR] 0·21, 95% CI 0·14-0·31; p0·0001). 78% (95% CI 69-87) of patients in the rituximab induction group did not need treatment at 3 years, which was significantly more than in the watchful waiting group (HR 0·35, 95% CI 0·22-0·56; p0·0001), but no different compared with the maintenance rituximab group (0·75, 0·41-1·34; p=0·33). Compared with the watchful waiting group, patients in the maintenance rituximab group had significant improvements in the Mental Adjustment to Cancer scale score (p=0·0004), and Illness Coping Style score (p=0·0012) between baseline and month 7. Patients in the rituximab induction group did not show improvements in their QoL compared with the watchful waiting group. There were 18 serious adverse events reported in the rituximab groups (four in the rituximab induction group and 14 in the maintenance rituximab group), 12 of which were grade 3 or 4 (five infections, three allergic reactions, and four cases of neutropenia), all of which fully resolved.Rituximab monotherapy should be considered as a treatment option for patients with asymptomatic, advanced-stage, low-tumour-burden follicular lymphoma.Cancer Research UK, Lymphoma Research Trust, Lymphoma Association, and Roche.

Defects in stromal cell function have been demonstrated in a number of aplastic anaemia (AA) patients. Here we have studied a patient with severe AA and abnormal stromal cell function who underwent bone marrow transplantation (BMT). The objective of this study was to investigate the timing and the mechanism of correction of the stromal defect after transplantation. The patient, a 25-year-old woman with severe AA, underwent BMT from her brother. BM was obtained from the patient on five occasions: 2 weeks pre BMT, and 3, 8, 16 and 21 months post BMT. Stromal cells were grown to confluence and recharged with purified CD34+ cells from normal donors. The support of such cells, as assessed by weekly colony-forming assay (CFU) of non-adherent cells, was compared with that of stromal layers grown from normal BM. A novel technique of combined fluorescence in situ hybridization (FISH) and immunocytochemistry was used to determine the origin of specific stromal cell types on cytospins of stroma post BMT. Stromal function was defective at 2 weeks pre BMT and at 3 months post BMT, but returned to normal at 8 and 16 months post BMT. At 21 months post BMT, stromal fibroblasts and endothelial cells were shown to be of recipient origin, and macrophages and T cells were of donor origin. We present here evidence in a case of severe AA for defective stromal function before BMT and delayed normalization of function after BMT. This correlated with engraftment of donor macrophages and T cells, but not fibroblasts and endothelial cells.

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.

Introduction: Allogeneic stem cell transplantation is a potentially curative option for patients with CML. The optimal donor is an HLA-identical sibling but transplants using unrelated volunteers can also be successful. The factors influencing survival after allogeneic SCT for CML are reasonably well defined. Recently however, the Seattle group have emphasised the influence of a high marrow cell dose on outcome following volunteer unrelated donor SCT for high risk acute leukaemia. Materials and methods: We have sought to define factors impacting on transplant related mortality (TRM) in a population of CML patients after allografting with matched sibling or alternative stem cell donors at a single centre over a 20-year period, with emphasis on infused marrow cell dose. Factors entered into a multivariate analysis were: recipient age, recipient CMV serostatus, disease phase, donor sex, cell dose and frequency of CTLP reactivity. Results: In multivariate analysis four factors had an adverse eAect on TRM when using a VUD: low marrow cell dose (53.65610 8 TNC/kg, relative risk 2.05, CI 1.08‐3.90, P=0.029), late disease phase (relative risk 1.68, CI 1.03‐2.74, P=0.038), patient CMV seropositivity (relative risk 1.98, CI 1.25‐3.13, P=0.004) and high frequency of CTLP (relative risk 1.93, CI 1.18‐3.13, P=0.008). For HLA-identical sibling donor transplants the only factor that adversely impacted on TRM was late disease phase (P=0.0004 in univariate analysis). Conclusion: High infused cell dose is a new modifiable factor associated with reduced TRM following allogeneic SCT using an unrelated donor for the treatment of CML. The data support the recommendation that bone marrow harvest teams should aim to collect the highest possible number of nucleated cells for recipients of unrelated donor transplants. The Hematology Journal (2001) 2, 265‐271