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Background: Myeloma causes profound immunodeficiency and recurrent, serious infections. There are approximately 5,500 new UK cases of myeloma per annum; a quarter will have a serious infection within 3 months of diagnosis. Newly diagnosed patients may benefit from antibiotic prophylaxis to prevent infection and early death but this may be associated with healthcare-associated infections (HCAI). Methods: The TEAMM trial was a multicentre randomised, double-blind, placebo-controlled trial in newly-diagnosed myeloma patients randomised to receive Levofloxacin or placebo for 12 weeks at the start of anti-myeloma treatment. Follow-up was 4-weekly to 16 weeks and again at 1 year. The primary outcome was time to first febrile episode or death in the first 12 weeks from start of trial treatment. Secondary outcomes included number of infections, deaths, healthcare-associated organism carriage and invasive infections, and overall survival (OS). Findings: 977 patients were randomised (489 levofloxacin, 488 placebo). Primary events (febrile episodes, deaths, febrile episodes with death) in levofloxacin versus placebo arms were 19% vs 27% (87, 4, 4 vs 112, 15, 7), respectively; HR=0.66 (95% CI 0.51-0.86) p=0.002. There was no difference for new acquisitions of clostridium difficile, Methicillin-resistant Staphylococcus aureus and Extended Spectrum Beta Lactamase-positive (ESBL) Gram-negative coliforms when assessed up to 16 weeks. There was an OS benefit at 12 weeks (p=0.008) but not at one year (p=0.94). Interpretation: The addition of prophylactic levofloxacin to active myeloma treatment during the first 12 weeks of therapy significantly reduced febrile episodes and deaths without increasing healthcare associated infections or carriage. Trial Registration Number: ISRCTN number: ISRCTN51731976 and EudraCT number: 2011-000366-35. Funding Statement: Funded by NIHR Health Technology Assessment Programme. 08/116/69. Declaration of Interests: None. Ethics Approval Statement: Approved by the UK Coventry & Warwickshire Multi-Research Ethics Committee on 29th July 2011. All patients provided written informed consent.

Introduction: With a median age of diagnosis in the late 60s, many patients with Acute Myeloid Leukemia (AML) are deemed unsuitable for conventional curative therapy (typically anthracycline and ara-C). The decision may be based upon a patient's age, cytogenetic profile, fitness, comorbidities, or indeed a preference for less-intensive therapy. Survival in these patients has traditionally been poor with Methods: Within the LI-1 trial, QoL using EORTC, QLQ30C and EQ-5D3L was collected at baseline, 3, 6 and 12 months. Summary scores were calculated according to the scoring manuals for these instruments with QLQ30C summarised using the summary score obtained from the 13 individual dimensions. QLQ30C and EQ5D Visual Analogue Score (VAS) were scored from 0-100; the EQ5D utility score had a maximum of 1 (equating to perfect health). For the purposes of this analysis data from all trial arms were combined. Comparisons at individual timepoints were performed using Student's t-test, with Mixed Models Repeated Measures analysis performed to give overall differences across timepoints. Results: A total of 1653 questionnaires (baseline n=827; 3 month n=402; 6 month n=280, 12 month n=143) were received from 833 patients. On all measures, QoL was lower in patients not surviving to the next assessment point (Figure); using repeated measures analysis, patients who died before the next QoL assessment point had QLQ30C summary score 8.65 (6.68-10.61) points lower, EQ5D utility score 0.11 (0.08-0.14) points lower, and EQ5D VAS 7.73 (5.13-10.34) lower (all p Conclusion: This is the largest study to date of quality of life in this population. Patients who died demonstrated a downturn in QoL, measured either using QLQ30C, EQ5D Utility Score or EQ5D VAS at the assessment immediately prior to their death. In particular, early mortality was associated with lower QoL at baseline, although there was considerable overlap meaning it is unlikely that QoL alone can be used to guide treatment. Additionally, in patients achieving complete remission, both the QLQ30C and EQ5D Utility Score were significantly higher at timepoints when the patient was in remission, although differences were modest. The EQ5D VAS was not however significantly different. These data indicate that even without prolonging survival, an increase in complete remission rates may be associated with patient benefit. Clinical trials in this population should include QoL measures as a matter of course, as treatments which improve remission rates may deliver meaningful benefit in terms of QoL and health utility. Further work is required to determine whether, in light of the lack of benefit on the patient's own summary measure of their QoL, these potential improvements are perceived by patients as being worthwhile. Figure caption: Quality of Life scores at each timepoint - open boxes represent patients who die before the next assessment is due (or 18 months in the case of the 12 month assessment). Disclosures Hills: Daiichi Sankyo: Consultancy, Honoraria. Russell:Jazz Pharma: Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Daiichi Sankyo: Consultancy.

A large number of prognostic factors are available to help predict the outcome of patients who present with B-cell chronic lymphocytic leukemia (B-CLL). These include clinical stage, leukemic cell morphology, lymphocyte doubling time, the pattern of infiltration in bone marrow trephine biopsies, cytogenetic abnormalities, p53 function and serum factors such as beta-2 microglobulin. Two recently described major prognostic factors are immunoglobulin heavy chain variable region (IgVH) mutation status and cell membrane expression of CD38. These are both highly significant independent prognostic factors, but are not closely correlated. Whereas IgVH mutational status is a time consuming and demanding technique, only available in a limited number of centres, CD38 expression by flow cytometry is relatively simple and rapidly obtained in most diagnostic laboratories. The predictive value of CD38 expression is enhanced by measurement of antigen density in terms of antibody binding capacity (ABC) rather than as the percentage of cells expressing the antigen. ABC correlates closely with relative median fluorescence (RMF), a parameter which is even more simply and cheaply obtained by flow cytometry. One of these methods of determining CD38 expression should be employed routinely. Recent work suggests that membrane ZAP-70 expression determined by flow cytometry will prove to be an accurate proxy for IgVH mutational status and this assay will be within the reach of any laboratory skilled in flow cytometry. The combination of ZAP-70 expression, CD38 antigen density, p53 function and the concentration of serum factors such as soluble CD23, is likely to provide extremely accurate prognostic information in future studies. This will assist in identifying Stage A patients who may benfit from early and/or more intensive treatment, as well as Stage B and C patients who may require alternative treatment strategies at the outset.

Summary. Recent studies have shown that CD38 expressed as a percentage of the antigen positivity can predict prognosis and disease progression in patients with B-cell chronic lymphocytic leukaemia (B-CLL). The present study showed that quantification of CD38 expressed as antibody-binding capacity (ABC) improves the prognostic value of the percentage of CD38 positivity in B-CLL. In a cohort of 81 patients with B-CLL, a level of CD38 expression of ≥ 30% and an ABC value of 250 proved statistically valid cut-off points to predict disease progression (% CD38: P=0·0027; ABC: P

The development of new treatments for older patients with acute myeloid leukemia is an active area, but has met with limited success. Vosaroxin, a quinolone-derived intercalating agent has several properties that could prove beneficial. Initial clinical studies showed it to be well-tolerated in older patients with relapsed/refractory disease. In vitro data suggested synergy with cytarabine (Ara-C). To evaluate vosaroxin, we performed 2 randomized comparisons within the “Pick a Winner” program. A total of 104 patients were randomized to vosaroxin vs low-dose Ara-C (LDAC) and 104 to vosaroxin + LDAC vs LDAC. When comparing vosaroxin with LDAC, neither response rate (complete recovery [CR]/complete recovery with incomplete count recovery [CRi], 26% vs 30%; odds ratio [OR], 1.16 (0.49-2.72); P = .7) nor 12-month survival (12% vs 31%; hazard ratio [HR], 1.94 [1.26-3.00]; P = .003) showed benefit for vosaroxin. Likewise, in the vosaroxin + LDAC vs LDAC comparison, neither response rate (CR/CRi, 38% vs 34%; OR, 0.83 [0.37-1.84]; P = .6) nor survival (33% vs 37%; HR, 1.30 [0.81-2.07]; P = .3) was improved. A major reason for this lack of benefit was excess early mortality in the vosaroxin + LDAC arm, most obviously in the second month following randomization. At its first interim analysis, the Data Monitoring and Ethics Committee recommended closure of the vosaroxin-containing trial arms because a clinically relevant benefit was unlikely.

The treatment of older patients with acute myeloid leukaemia, who are not considered suitable for conventional intensive therapy, is unsatisfactory. Low-dose Ara-C(LDAC) has been established as superior to best supportive care, but only benefits the few patients who enter complete remission. Alternative or additional treatments are required to improve the situation. This randomised trial compared the addition of the immunoconjugate, gemtuzumab ozogamicin (GO), at a dose of 5 mg on day 1 of each course of LDAC, with the intention of improving the remission rate and consequently survival. Between June 2004 and June 2010, 495 patients entered the randomisation. The addition of GO significantly improved the remission rate (30% vs 17%; odds ratio(OR) 0.48 (0.32-0.73); P=0.006), but not the 12 month overall survival (25% vs 27%). The reason for the induction benefit failing to improve OS was two-fold: survival of patients in the LDAC arm who did not enter remission and survival after relapse were both superior in the LDAC arm. Although the addition of GO to LDAC doubled the remission rate it did not improve overall survival. Maintaining remission in older patients remains elusive.

Diffuse large B-cell lymphoma (DLBCL) forms a heterogeneous collection of aggressive non-Hodgkin's Lymphoma in which three principle classes of neoplasia have been defined according to gene expression and immunophenotyping studies. The present investigation sought to examine the immunophenotype of proposed subgroups and relate these to patient survival. A series of 155 DLBCL treated uniformly with anthracycline therapy in clinical trials, were stratified upon the basis of common biomarker expression with combination immunophenotype being related to patient overall survival. Stratification of tumours with respect to combined expression profiles of the three biological markers (CD10, Bcl-6 and MUM-1) revealed six groups showing significant differences in survival (p=0.014). The greatest difference resided between distinct populations of germinal centre (GC) cell tumours; the first being CD10-, Bcl-6+, MUM-1- and the second CD10+ Bcl-6+ MUM-1+ (p=0.002). The former group displayed median survival time of 143 months, the latter only 11 months. A third population of GC tumours (CD10+ Bcl-6+ and MUM-1-) also displayed a relative short median survival (32 months). Of the three groups presenting a non-GC or activated B cell (NGC/ABC) phenotype, only one (CD10-, Bcl-6+ and MUM-1+) presented short-term median survival (27 months) comparable with poor prognosis GC sub-populations. Within the remaining ABC tumour groups (CD10- Bcl-6- MUM-1- and CD10- Bcl-6- MUM-1+) patients presented intermediate median survival times of 54 and 58 months, respectively. Thus, the GC phenotype did not act as a universal indicator of good clinical prognosis, but rather multiple groups of GC tumours were associated with distinct overall survival profiles. Ultimately, the data allowed definition of a predictive algorithm defining three groups predicting poor, intermediate and good clinical prognosis. The first of these comprised two patient sub-populations with GC-like tumours together with one sub-population of NGC/ABC, the second two sub-populations of ABC-like tumours, and the final a single group of GC-like tumours associated with optimal long-term survival.

Anti-apoptotic factors including IAP-survivin and bcl-2 are involved in carcinogenesis and predict for disease outcome for patients with cancer. We used RT-PCR and specific primers to generate two recombinant IAP-survivin proteins; one encoding for the full-length protein and the second comprising the survivin sequence incorporating amino acids 98 to 142. Both proteins were used to immunize mice and as capture antigens to screen NS1/immune splenocyte hybridoma supernatants for anti-survivin antibody in ELISA assays. The antibody designated F2-9C3 was most effective and reacted with both recombinant proteins and with the native protein present in lysates of A549 (lung carcinoma) and Jurkat cells in Western blots, immunoprecipitation and formalin-fixed tissue sections. Immunohistochemical staining of normal and neoplastic tissues showed association of the F2-9C3 antibody with the mitotic spindles. Expression of survivin was not detected elsewhere in sections of normal tissue while all neoplastic tissues examined, including those from patients with diffuse large B-cell lymphoma (DLBCL), showed significant expression of survivin. The intensity and localization of staining in these tumours varied and was observed in cytoplasm and/or nuclei. High nuclear expression of survivin predicted the disease outcome in patients with DLBCL. This association was evident when relating intensity to patient survival (p=0.0321) and strengthened when a score was calculated based on both staining intensity and the proportion of the reactive tumour cells (p=0.0128; reduction in the mean survival times: 35% and 46%, respectively). Elevated expression of bcl-2 protein also identified the high-risk patients (p=0.0095; reduction in mean survival time: 37%). Over-expression of both factors was a more powerful indicator of poor prognosis than either marker alone (p=0.0054, 70% reduction in mean survival time). In conclusion, our novel F2-9C3 monoclonal antibody is effective in determination of expression of IAP-survivin in neoplastic tissue. Nuclear overexpression of IAP-survivin using this antibody predicts the disease outcome in patients with DLBCL and significantly improves the predictive power of bcl-2 in these patients.

Recent studies have shown that CD38 expressed as a percentage of the antigen positivity can predict prognosis and disease progression in patients with B-cell chronic lymphocytic leukaemia (B-CLL). The present study showed that quantification of CD38 expressed as antibody-binding capacity (ABC) improves the prognostic value of the percentage of CD38 positivity in B-CLL. In a cohort of 81 patients with B-CLL, a level of CD38 expression ofor = 30% and an ABC value of 250 proved statistically valid cut-off points to predict disease progression (% CD38: P=0.0027; ABC: P0.0001). There was a positive and significant correlation between the percentage of CD38 expression and ABC (r=0.7; P0.0001). There was a better discrimination of survival using ABC rather than percentage CD38 positivity (P0.0001 compared with P=0.0027). Only ABC predicted for survival in patients under 60 years of age (P=0.0076) or with stage A disease (P=0.0195). Both percentage CD38 and ABC discriminated between time to first treatment for all patients but only ABC predicted time to treatment for stage A patients (P=0.0004). In conclusion, CD38 positivity is an important prognostic factor in B-CLL. However, quantification of CD38 is superior to the percentage positivity and should be used clinically in conjunction with other variables of predictive value to identify B-CLL patients that are likely to progress.

Mouse eosinophils have been shown in 2011 to be required for the maintenance of long lasting plasma cells in the bone marrow and in maintaining the bone marrow plasma cell microenvironment. Human eosinophils have been shown by Wong et al to support multiple myeloma cell proliferation via a mechanism independent of IL6. We looked at bone marrow biopsies taken from patients who had a paraprotein and in whom a diagnosis of multiple myeloma was suspected. These samples were taken solely for the purposes of diagnosisng multiple myeloma and were retrospectively reviewed from the point of view of degree of eosinophil infiltration and its correlation with tumour load, bone lytic lesions, plasma cell morphology, whether blastic, crystalline inclusions, Mott cells, flame cells and or lymphoplasmacytoid. There were no cases of IGD or E myeloma or osteosclerotic myeloma.Nonsecretory myeloma and cases of light chain myeloma with or without amyloid were included in the series. Biopsies were not performed from osteolytic lesion unless biopsy was necessary to make a diagnosis of myeloma. Myeloma was diagnosed when plasma cell infiltrate was greater than 10% on bone marrow aspirate with a paraprotein and or lytic lesions. Eosinophil infiltration did not correlate with any of the tumour clinicopathological markers but showed an inverse correlation with degree of plasmacytosis. Eosinophils were hardly ever found in marrow aspirates that had over 70% plasma cells. They were usually found in trephine sections of bone marrow in areas where there was Grade I/II fibrosis and were often found in close proximity to focal areas of plasma cell infiltration. Whether eosinophils play a role in preventing or maintaining malignant plasma cell recurrence is currently being studied. Disclosures: No relevant conflicts of interest to declare.

Abstract 18 In a significant proportion of older patients with AML intensive chemotherapy is not considered a viable option[1]. Such patients may receive low-dose Ara-C (LDAC), best supportive care (BSC) with hydroxyurea or an experimental agent but outcomes are poor. We have shown that LDAC is superior to BSC [2], but only in patients who enter CR (fewer than 20%).[2]. There is therefore scope to improve outcomes in these patients, and a number of possible treatments have been evaluated in the randomised UK NCRI AML16 trial, one of which is gemtuzumab ozogamicin (GO), which we have shown to benefit the majority of younger patients when given in conjunction with standard chemotherapy[3]. In AML16 novel agents or combinations are tested in untreated older patients with AML or high risk MDS (marrow blasts >10%) using a “pick a winner” design. The design allows unpromising treatments to be identified early (typically after 50 or 100 patients per arm): only those arms which show promise will continue to a trial with OS and DFS as endpoints. The aim is to at least double the remission rate from 15% to 30%, and thus improve overall survival. We now report the results of LD Ara-C (20mg bd days 1–10 for 4 courses) versus LDAC combined with GO (at a fixed dose of 5mg on day 1 of each course for 4 courses at 6–8 week intervals). Patient Details: The comparison opened as part of the UK LRF AML14 trial and was carried forward to AML16 unchanged. Between June 2004 and June 2010, 495 patients were randomised, 249 to LDAC plus ATO, 246 to LDAC. The median age was 75 years (range 54–90); 83% of patients were aged over 70 years, and 61% were male. To be eligible patients’ LFTs had to be less than twice ULN. Treatment arms were balanced for age, gender, performance status, de novo/secondary AML/high risk MDS, presenting WBC and cytogenetic risk group. Follow-up is complete to 1st January 2010, with median follow up of 21 months. Survival and remission data is available on 412, 404 patients respectively. Treatment Results: The trial passed through both stopping hurdles based on CR/CRi rates and therefore continued to full accrual, with overall survival as primary outcome measure. The table shows the distribution of outcomes: there was no heterogeneity by recruitment period (AML14 vs AML16). The causes of death (316) were:- There were no significant interactions between treatment and any of the baseline variables on either remission or survival outcomes. Likewise there were no major toxicity implications, although resource usage tended to be higher in patients given GO. Discussion: While the addition of GO significantly improves CR rate, achieving the 30% response originally sought, this does not translate into survival. This is predominantly due to an increase in relapse, indicating that if GO is to have a role in this setting, it will require effective treatment to maintain remission. [1] Juliusson G et al. Blood 2009; 113: 4179 – 4187 [2] Burnett et al. Cancer 2007 109: 1114–1124 [3] Burnett et al. JCO 2010 to appear. Disclosures: Off Label Use: Mylotarg (gemtuzumab ozogamicin).