ALBERT

Description: Background : Ibrutinib is the only once-daily Bruton's tyrosine kinase inhibitor with significant progression-free survival (PFS) benefit demonstrated in 5 randomized phase 3 studies in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) compared with standard-of-care chemotherapy and/or immunotherapy (RESONATE, RESONATE-2, iLLUMINATE, Alliance 041202, and ECOG 1912), and significant overall survival (OS) benefit in 3 of these studies. To understand how treatment with single-agent ibrutinib in earlier lines impacts patient outcomes, we evaluated long-term follow-up data from RESONATE and RESONATE-2 to compare efficacy and safety by number of prior lines of therapy. Methods : This integrated analysis included patients treated with single-agent ibrutinib in the first-line (RESONATE-2, NCT01722487) and relapsed/refractory (R/R; RESONATE, NCT01578707) settings. R/R patients were grouped by number of prior lines of therapy (1-2 vs ≥3). Patients with del(17p) were excluded from this analysis given their exclusion from RESONATE-2. Patients with high-risk prognostic features were defined as having TP53 mutation, del(11q), and/or unmutated IGHV. Outcomes included investigator-assessed PFS and objective response rate (ORR), OS, and safety. Results : This analysis of 271 patients included 136 patients in the first-line and 135 patients in the R/R groups (1-2 prior: n=68; ≥3 prior: n=67). Patients in the first-line group were older (median age [range], 73 years [65-89]) than those with 1-2 prior lines (65 years [30-86]) and ≥3 prior lines (67 years [44-83]). The proportion of patients with high-risk prognostic features was lower in the first-line group (first-line: 54%; 1-2 prior: 81%; ≥3 prior: 76%). Median follow-up was 59.8 months for first-line, 66.2 months for 1-2 prior, and 65.1 for ≥3 prior. Median PFS was not reached (NR) for first-line or 1-2 prior lines and was 40.1 months for ≥3 prior lines (Figure 1A). A greater proportion of patients treated with ibrutinib in earlier lines remained progression-free or alive at 60 months (first-line: 70%; 1-2 prior: 60%; ≥3 prior: 33%). First-line treatment resulted in a 34% reduction in risk of disease progression or death compared to 1-2 prior lines (HR: 0.66 [95% CI, 0.40-1.09]). PFS was significantly prolonged for first-line vs ≥3 prior lines (HR: 0.32 [95% CI, 0.21-0.49]) and 1-2 prior vs ≥3 prior lines (HR: 0.48 [95% CI, 0.30-0.77]). For patients with high-risk prognostic features, median PFS was NR for first-line or 1-2 prior lines and was 42.5 months for ≥3 prior lines (Figure 1B); treatment in earlier lines resulted in better PFS for these patients (first-line vs 1-2 prior, HR: 0.64 [95% CI, 0.35-1.18]; first-line vs ≥3 prior, HR: 0.33 [95% CI, 0.19-0.57]; 1-2 prior vs ≥3 prior HR: 0.51 [95% CI, 0.30-0.87]). Median OS for the overall population was NR (range, 0.10+-66.04+) for first-line, NR (5.98-71.56+) for 1-2 prior, and 67.4 months (1.15-69.78+) for ≥3 prior lines. The ORR was 91%, 94%, and 82% for first-line, 1-2 prior, and ≥3 prior lines, respectively. The CR rate (CR+CR with incomplete marrow recovery) was highest for the first-line group (first-line: 30%; 1-2 prior: 12%; ≥3 prior: 10%). At the time of analysis, 58% of patients remain on ibrutinib treatment in the first-line group. Prior to study closure, 38% of patients with 1-2 prior and 18% of patients with ≥3 prior lines remained on ibrutinib treatment. In the overall population, 8 patients (6%) in the first-line group discontinued due to progressive disease while it was the most common reason for discontinuation for patients with 1-2 (n=15, 22%) and ≥3 prior lines (n=25, 37%). Across all three groups, 52 patients (19%) discontinued due to adverse events (AEs) (first-line: n=29, 21%; 1-2 prior: n=13, 19%; ≥3 prior: n=10, 15%). AEs leading to dose reduction occurred in 20% of first-line, 13% of 1-2 prior, and 22% of ≥3 prior lines. Conclusions : Overall, this integrated analysis of data with up to 6 years of long-term follow-up demonstrates that using single-agent ibrutinib in earlier lines of treatment results in better PFS, OS, and ORR with sustained efficacy for patients with CLL, including patients with high-risk prognostic features. During this extended follow-up, only 6% of patients treated in the first-line setting discontinued due to progressive disease. Ibrutinib was well tolerated with only 19% of patients across all lines of therapy discontinuing due to AEs. Disclosures Barr: Gilead: Consultancy; Verastem: Consultancy; Seattle Genetics: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Merck: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding. Tedeschi:Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; SUNESIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Munir:AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy; Pharmacyclics: Other: TBC; Acerta: Membership on an entity's Board of Directors or advisory committees. Hillmen:Acerta: Membership on an entity's Board of Directors or advisory committees; Apellis: Research Funding; Gilead: Research Funding; Roche: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Byrd:Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Genentech: Research Funding; BeiGene: Research Funding. Ghia:ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Juno/Celgene: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy. Mulligan:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Participant, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Participant, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Clinical Trial participant, Research Funding, Speakers Bureau; Commonwealth Serum Laboratories (CSL): Other: Clinical Trial participant; Sanofi-Aventis: Other: Clinical Trial participant; Acerta: Other: Clinical Trial participant. Dai:AbbVie: Equity Ownership; Celgene: Equity Ownership; Exelixis: Equity Ownership; Gilead: Equity Ownership; GSK: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. Amaya-Chanaga:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. Dean:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. o'Brien:Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy; Astellas: Consultancy; Celgene: Consultancy; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Kite: Research Funding; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Regeneron: Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy.

Description: Abstract 5138 INTRODUCTION: The population of Australians aged 90–99 years has increased by 204% (42,234 to 128,654) [0.25% to 0.59%] between 1990 and 2010 compared to a 30% increase in the general population (17.06 million to 21.99 million) highlighting the trend to aging of the population. At this age bracket the M:F ratio is ~1:3. One third of the Australian population lives in the state of New South Wales (NSW) (www.abs.gov.au). The Australian heathcare system of federally funded pathology has resulted in marked consolidation of pathology providers servicing all non-hospital healthcare settings. Symbion Pathology account for ~35% of all pathology services in NSW and hence closely reflects the community incidence for laboratory diagnosed disorders. Community-based pathology laboratories now see large numbers of patients in this 90–99 year old age range. METHODS: We assessed all individual patients aged between 90 and 99 years with anaemia over the 5 year period 2005–2009. Patients were included in the analysis if they had at least one full blood count (FBC/CBC) showing a hemoglobin below the laboratory reference range (RR) of 130g/L for males and 115g/L for females. All duplicate individuals and full blood counts (FBC) were excluded. RESULTS: There were 4,369 (33.8%) of 12,921 individuals with anaemia. Classification by red cell size showed the majority were normochromic (80.6%), while 5.8% were microcytic and 13.6% were macrocytic. In microcytic anaemias, 136 (53%) had a ferritin level performed and 63 (46% of this 136 patients) were iron deficient. In macrocytic anaemias, only 149 (25%) had B12 assays and 13 were deficient. In normocytic anaemias, 2910 (82.7%) had urea performed with 1413 patients had urea 〉10 mmol/L (48%) and 976 patients had urea 〉12 mmol/L (33%) (RR 3.5–9.0 mmol/L). Pancytopenia was present in 44 (1%) patients. In most patients, anaemia was mild but 25% of females and 50% of males had Hb 〉15g/L below the lower limit of the RR. CONCLUSION: Anaemia is very common in individuals aged 90–99 years occurring in one-third of the population at this age. Half the males and a quarter of females have a Hb 〉15g/L below the RR making this a significant comorbidity in the very elderly. As might be expected the aetiology is heterogeneous but appears to be frequently under investigated. In particular, simple haematinic assays appear to be under-utilised to better define the aetiology despite being inexpensive and readily available. The study highlights the substantial social, economic and healthcare implications in this era of significant ageing of the population. Disclosures: No relevant conflicts of interest to declare.

Description: BACKGROUND The prior Australasian Leukaemia and Lymphoma Group (ALLG) CLL5 Study showed dose-reduced oral fludarabine and cyclophosphamide plus rituximab (FCR3) was safe, tolerable and effective in fit elderly patients for front-line therapy for CLL. The German CLL11 Study showed chlorambucil plus obinutuzumab (Cbl+G) was superior to chlorambucil alone or with rituximab in unfit patients requiring initial therapy. We conducted a randomized study to assess the safety, tolerability, and efficacy of dose-reduced FC + obinutuzumab (G) (FC+G) versus Cbl+G in unfit (i.e. with comorbidity), elderly patients with CLL. METHODS Patients aged ≥65 years and considered "unfit" defined by co-morbidities using the Cumulative Illness Rating Scale [CIRS] ≥6 were eligible for the ALLG CLL7 study. Patients with any single organ system score ≥4 were excluded. Previously untreated patients with progressive CLL aged ≥65 and CIRS ≥6 were randomised to one of 2 therapy arms: (i) Chlorambucil 0.5mg/kg D1+15 p.o. + obinutuzumab ("G") (i.v. 1000mg/m2 cycle 1, Day 1, 8, 15, and 1000mg/m2 D1 cycles 2-6), or (ii) FC(rd)+G: F-24mg/m2 p.o. and C-150mg/m2 p.o. D1-3 + G (same schedule above) at 4 weekly intervals for planned 6 cycles. Early stopping for toxicity was mandated: treatment could be delayed for 2 weeks for grade 3+ toxicity, but if unresolved by 2 weeks, patients were taken off study. The primary end-point was grade 3+ non-hematological, and grade 4 hematological adverse events. Secondary objectives were overall response rate (ORR), complete remission (CR), partial remission (PR), progression-free survival (PFS) and overall survival (OS) and minimal residual disease (MRD) negativity. Final staging was performed between 2-3 months following final treatment cycle. RESULTS Patient characteristics Patient recruitment was terminated early due to poor recruitment. At the time of study closure, there were 32 patients, with 15 on Cbl+G and 17 on FC(rd)+G. The mean age was 74.2 years (range 66-85 years) with 23 females (71.9%) and 9 males (28.1%). The CIRS score was 6 in 4 patients (12.5%), 6-8 in 14 (43.8%), 8-10 in 11 (34.4%) and 〉10 in 3 (9.4%). Binet stage at registration was stage A 18.2%, B 27.3% and C 54.5%. Tolerability Both therapies were tolerable with 15/17 (88.2%) completing all 6 cycles of FC(rd)+G and 12/15 (92.3%) completing six cycles of Cbl+G. Toxicity Most toxicity was hematological and manageable. Grade 3/4 hematological toxicity was more common with FC(rd)+G than Cbl+G occurring in 60% with FC(rd)+G and 38.5% with Cbl+G (Table 1). There was one death due to progressive CLL on the FC(rd)+G arm. Response rate A complete remission (CR), confirmed by bone marrow (BM) trephine, was achieved in 86.6% of patients on FC(rd)+G versus (vs) 53.9% on Cbl+G, partial response (PR/nPR) in 1 (6.7%) on FC(rd)+G, and 6 (46.2%) on Cbl+G, and either stable or progressive disease (SD or PD) on 1 on FC(rd)+G, and nil on Cbl+G. BM MRD-negativity rates were 3/17 (20.0%) FC(rd)+G vs 1/15 (7.7%) Cbl+G (Table 2). CONCLUSION This randomized trial of dose-reduced FC(rd)+G vs Cbl+G in elderly patients aged ≥65 and with co-morbidities (CIRS ≥6) was terminated early due to poor recruitment. Due to the dose-reduced FC, and early stopping rule, treatment was safe and tolerable and most patients completed all 6 cycles of planned therapy. Grade 3/4 toxicity was mainly hematological and manageable, with higher rates of neutropenia with the FC (60%) vs Cbl (35.7%) backbone. FC(rd)+G compared to Cbl+G resulted a higher CR rate of 86.6%% versus 53.9%, and higher MRD-negativity (20% vs 7.7%). Progression-free and overall survival are being evaluated. Disclosures Badoux: Roche: Research Funding. Cull:Takeda Australia: Other: Travel Expenses; Amgen Australia: Other: Travel Expenses; AbbVie (Australia): Membership on an entity's Board of Directors or advisory committees. Tam:Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: BACKGROUND: The WHO and iwCLL diagnostic criteria for CLL rely on morphology and immunophenotype based on the co-expression of CD19/CD5/CD23 on B-cells with weak CD20 and monoclonal sIg expression. These diagnostic criteria are likely to persist in the near future because there is no specific diagnostic molecular abnormality for CLL. The current criteria have some limitations affecting reproducibility, particularly flexibility in marker expression with many centres using a scoring system that permits absence of CD5 or CD23. Potentially informative new markers have been identified but there is no consensus yet on which should be routinely assessed. AIM: To identify reproducible criteria and to achieve a consensus on markers recommended for the diagnosis of CLL METHODS: ERIC/ESCCA members were invited to classify 35 flow-cytometry markers as being required or recommended for the diagnosis of CLL. Consensus was considered to be achieved if 〉75% of participants agreed on the marker classification. A diagnostic panel was identified by the steering committee and characteristics of component markers that could be reproducibly validated within an individual laboratory were identified. The proposed panel was assessed in 13 different centres. RESULTS: Responses were received from 154 members (100 laboratory staff, 14 clinicians and 36 from both laboratory and clinic) with a diagnostic workload 〉20 cases per week in 23/154 (15%), 5-20 in 82/154 (53%) and

Description: Background The diagnosis and treatment of CLL may have a great impact on the quality of life (QoL) due to a variety of reasons including disease-related symptoms, infection, effects of therapy and the emotional, socio-economic, and functional effects of living with an 'incurable' illness. The main aim of any treatment is to maximize QoL by inducing remission with minimal short- and long-term toxicity. Balancing disease and symptom control with QoL in elderly patients receiving CLL therapy regimens can be challenging. There is little published QoL data in elderly CLL patients receiving the FCR (fludarabine, cyclophosphamide, rituximab) immunochemotherapy regimen. Our prior study showed no significant difference in health related QoL for first-line therapy of CLL with monotherapy between chlorambucil, fludarabine and cladribine (Mulligan, SP et al. Leuk Lymphoma, 2014). Aim We report the QoL assessments of CLL patients enrolled in the ALLG clinical trial CLL5, a randomised, 3-arm, dose de-escalation study of the FCR regimen. Methods The treatment schedule has been described with fit elderly patients randomly assigned to one of three treatment regimens: FR5, FCR3, and FCR5 (Mulligan SP et al. iwCLL Abstract, 2015). Treatment was repeated every 28 days for a planned total of 6 cycles. Importantly, an early stopping rule mandating cessation of therapy was included for any patient having grade 3 or 4 toxicity lasting 〉2 weeks. QoL assessments using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) were measured at 8 time points: before commencement of therapy, at the end of the 3rd and 6th cycles of treatment, at the final staging and thereafter every 3 months for 12 months. Results Of the 116 evaluable in the study, 2 patients had no QoL data, 6 patients had only baseline QoL data, and 4 patients had no baseline QoL data, therefore the number of patients included in the QoL analysis was 104. There appeared to be a trend towards improved global health (figure 1), physical functioning (figure 2) and role functioning with full dose (FCR5) towards the end of the follow-up period compared to commencement of therapy. Comparison of cognitive functioning (figure 3) between the three arms showed a statistically significant improvement with FCR5. However, on multivariate analysis there was no statistical significant difference. Conclusions Despite a trend favouring full-dose FCR, there were no definitively significant differences in the QoL domains following treatment with FCR-based immunochemotherapy between the three different groups. QoL continues to be a neglected issue, particularly for the typical elderly CLL patient. This study highlights the need for objective QoL assessment as part of all CLL trials, especially those targeted in the typical elderly patient. Figure 1. Mean change from baseline global health status scores with 95% confidence intervals Figure 1. Mean change from baseline global health status scores with 95% confidence intervals Figure 2. Mean change from baseline physical functioning scores with 95% confidence intervals Figure 2. Mean change from baseline physical functioning scores with 95% confidence intervals Figure 3. Mean change from baseline cognitive functioning scores with 95% confidence intervals Figure 3. Mean change from baseline cognitive functioning scores with 95% confidence intervals Disclosures Gill: Roche: Research Funding; Sanofi Aventis: Research Funding; AbbVie: Honoraria; Roche: Honoraria. Turner:Roche: Research Funding; Sanofi Aventis: Research Funding. Renwick:Sanofi Aventis: Research Funding; Roche: Research Funding. Latimer:Sanofi Aventis: Research Funding; Roche: Research Funding. Mackinlay:Sanofi Aventis: Research Funding; Roche: Research Funding. Berkahn:Sanofi Aventis: Research Funding; Roche: Research Funding. Simpson:Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx Pharmaceuticals: Research Funding; Roche: Honoraria. Forsyth:Sanofi Aventis: Research Funding; Roche: Research Funding. Cull:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel. Harrup:Roche: Research Funding; Sanofi Aventis: Research Funding. Kuss:Sanofi Aventis: Research Funding; Roche: Research Funding. Mulligan:Sanofi Aventis: Research Funding; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Description: Background: The ALLG CLL5 randomised dose de-escalation study examined the tolerability, safety and efficacy of oral FCR therapy as first-line treatment in fit elderly CLL patients (Mulligan, SP et al. iwCLL Abstract, 2015). The study incorporated an early stopping rule for prolonged grade 3/4 toxicity and documented the regimen to be safe, generally well tolerated, and highly effective. There is a relative paucity of published data on the long term outcomes of such patients, particularly in relation to the development of second malignancies as well as disease relapse rates, with its associated potential long-term complications. We aimed to review the long term outcomes in fit elderly patients that were recruited to ALLG CLL5 trial from Royal North Shore Hospital (RNSH) where 17 of the total cohort of 116 evaluable patients (15%) were recruited, treated and managed. Methods: The treatment schedule for the open-label, multi-centre, phase 2 ALLG CLL5 study has been described elsewhere, whereby fit (Cumulative Illness Rating Scale, CIRS ≤6) elderly (≥65 years) old patients, with previously untreated CLL were randomly assigned to receive one of three different chemoimmunotherapies: FR5, FCR3, FCR5 (Mulligan, SP et al. iwCLL Abstract, 2015). Treatment was repeated every 28 days with a planned total of 6 courses. A total of 116 eligible patients were recruited during the period of November 2008 and July 2012. After the completion of treatment, patients were followed every 3 months for 15 months. Ongoing review was subsequently at the treating physician's discretion. We reviewed the clinical progress from the hospital medical records of the 17 patients that were recruited from RNSH for this study. Results: Long-term follow up clinical data to cut-off date 3/7/2015 are described in the table below. Of this elderly CLL patient cohort of 17 patients, 5 have died (30%), the remainder (70%) are alive 4 to 7 years from therapy. About half (n=8) the cohort at this single hospital remain very well up to 7 years following FCR-based treatment, 2 with documented MRD-negativity, and 2 with a tiny small clone of 〉0.05x109/L. CIRS Cumulative illness rating scale, CR complete remission, SD stable disease, nPR nodular partial remission, MRD minimal residual disease, IVIG intravenous immunoglobulin, C3 cycle3, C5D1 cycle 5 day1, C5D2 cycle 5 day2, IV intravenous, MDS myelodysplastic syndrome, NSCLC non-small cell lung cancer, AIHA autoimmune haemolytic anaemia, G-CSF granulocyte colony stimulating factors, ALL acute lymphoblastic leukemia, CRi complete remission with incomplete count recovery, BCC basal cell carcinoma, SCC squamous cell carcinoma, JC virus John Cunningham virus. Conclusions: Long-term outcome monitoring of patients on CLL trials, particularly the elderly, is becoming increasingly important as we attempt to understand the course of treating this disease with full dose or reduced-intensity chemoimmunotherapy, together with the development of other medical conditions that subsequently contribute to morbidity and mortality. Such monitoring has key implications in directing future management options in such an elderly cohort who are at increased risk of relapse, development of secondary cancers and cognitive decline. In this elderly patient cohort, half remain very well 4-7 years after therapy. Table 1 Table 1. Table 2 Table 2. Disclosures Mackinlay: Sanofi Aventis: Research Funding; Roche: Research Funding. Mulligan:Janssen: Consultancy, Honoraria, Speakers Bureau; Sanofi Aventis: Research Funding; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Description: Background Though the majority of patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) are curable with R-CHOP chemotherapy, a significant proportion will relapse or have refractory disease. The most commonly used clinical tool is the international prognostic index (IPI), though this cannot fully capture the heterogeneity of cases seen in practice. In recent years biomarkers such as MYC are entering clinical use. Pts with lymphomas demonstrating dual abnormalities of MYC in association with BCL2 and/or BCL6-known as 'double-hit' lymphomas are consistently shown to have poorer disease free and overall survival. While Fluorescence in-situ hybridization (FISH) for MYC translocation is the gold-standard, immunohistochemistry (IHC) is faster and significantly cheaper. Studies in recent years have confirmed the prognostic significance of increased MYC expression by IHC. Due to significant inter-laboratory variability however, internal validation is required. Methods Tissue samples of pts treated at Royal North Shore Hospital in Sydney, Australia between 2003-2012 were retrospectively assessed. Pts were included if they were transplant eligible (age 70%. This was seen in 23% of samples. From the 13 cases with MYC FISH results, the positive and negative predictive values of positive MYC IHC were 50% and 92% respectively. There was no significant difference between the MYC positive and negative groups with respect to demographics or IPI score (Table 1). Significantly more patients with MYC positivity received intensive treatment (37% versus 16%, p=0.047). Despite this, 5 year OS was significantly poorer at 51% versus 87% at median follow-up of 40 months (P=0.0025, Figure 3). There was a trend towards worse EFS at 61% versus 75% though this did not reach statistical significance (P=0.242). On multivariate analysis, MYC IHC and IPI score were the only independent prognostic factors. Based on the relative odds ratio, a combined scoring system was designed, attributing 1 point for positive MYC IHC and/ or IPI intermediate-high risk, and 2 points for IPI high risk. This resulted in 4 risk groups with significantly different 5 year OS of 94%, 78%, 45% and 0% (P

Description: Background Clostridium difficile infection (CDI) is an important and increasingly prevalent healthcare-associated infection. Strongly associated with antibiotic exposure, CDI may result in diarrhea, colitis and death-particularly in at-risk patients. While the incidence of both CDI and CDI-associated complications appears more common in hematology patients - the economic impact of CDI in this patient population has not been assessed. We report the results of a hospital-wide audit and case-control study of CDI incidence to assess length-of-stay (LOS). Methods Hospital wide CDI incidence was reviewed for the period 2010-2013. Medical records were assessed to determine total patient days per specialty and the incidence of CDI as reported on discharge coding data. Hematology cases had CDI confirmed by reviewing diagnostic samples for PCR or toxin. Clinical data was collected including basic demographics, risk factors and outcomes. Controls drawn from departmental database were matched for age, sex, malignancy and admission reason. Statistical analysis was performed with the primary outcome being length of stay (LOS). Results During the period of study hematology patients consistently had the highest incidence of CDI across the hospital. (Cumulative incidence per 10,000 patient days are shown in graph 1.) A case-control study of 79 patients was performed with no significant differences in baseline demographics between groups. The primary outcome of LOS was statistically significant with a mean of 25 days for CDI affected patients compared with 15 days (p = 0.02). Risk factors analysis revealed a trend towards statistical significance for those prescribed a H2 Blocker (RR 1.66 95% CI 1.12-2.45, p = 0.01) but no difference was seen for proton pump inhibitor (PPI) use or antibiotic presence or duration. Analysis of morbidity and mortality demonstrated an increased relative risk of pseudomembranous colitis for those exposed to CDI (RR 2.01, 95% CI 1.72-2.36, p

Description: Abstract 1804 Background Despite the high response rates of patients with Chronic Lymphocytic Leukemia (CLL) to the fludarabine (F), cyclophosphamide (C), rituximab (R) regimen, relapsed or refractory disease is common. Novel therapeutic approaches are required that are effective in this setting. Targeting specific signaling molecules is proving an effective strategy for treating patients who are refractory to FCR. Given that the mitogen-activated protein kinase pathway (MAPK) pathway is constitutively active in CLL cells and that inhibitors of mitogen-activated protein kinase kinase (MEK1) in this pathway are in clinical trials for solid tumors, we sought to investigate the potential of MEK1 as a therapeutic target in CLL. Results Inhibition of MEK1/2 using MEK inhibitor I (MEKi; Calbiochem/Merck) induced apoptosis in the MEC1 cell line and in 18 patient samples. Importantly, sensitivity of the patient samples occurred irrespective of ATM/TP53 functional status, of poor prognostic features or of treatment history. MEKi was also effective against 4 CLL patient samples cultured in an in vitro model of the tumor microenvironment, albeit with a significantly higher IC50 than observed against CLL cells cultured in media alone. As fludarabine-based therapies have become the mainstay of CLL treatment, we investigated the effect of combining the MEK inhibitor with this purine analogue. Synergy between MEKi and fludarabine was apparent against the MEC-1 cell line and 10 patient samples. Dose reduction indices (DRI) calculated from the drug combination indicate this synergy was predominantly due to an increase in fludarabine sensitivity. Investigation of the mechanisms of the synergy between MEKi and fludarabine suggests decreased levels of reactive oxygen species (ROS) and expression of the pro-survival protein, MCL-1, may be contributing factors (see figure). Summary These data suggest for the first time that inhibition of MEK1/2 may represent a potential therapeutic option for CLL patients. The efficacy of the MEK inhibitor against CLL cells cultured in the supportive in vitro environment suggest that this approach may also be effective at targeting the proliferative fraction of CLL cells in the tumor microenvironment. As clinical trials of MEK1/2 inhibitors are currently underway in solid tissue malignancies, our data suggest that trials of these agents may also be warranted for high risk CLL. Disclosures: No relevant conflicts of interest to declare.