Abstract: Background: Despite the recent approval of DNA-hypomethylating agents (HMAs) for treatment of elderly AML patients (pts) ineligible for induction, their prognosis is still poor, and rational, effective HMA-based combination treatments are under study. Histone deacetylase inhibitors (HDACi) show synergism with HMAs in vitro. ATRA - as single agent clinically ineffective in non-M3 AML - in combination with HMAs also shows in vitro synergistic antileukemic activity in non-M3 AML cells. We previously conducted a non-randomized phase II trial in elderly non-fit AML pts with DAC (3-dy schedule), given alone or combined with ATRA (45 mg/m2 dy 4-28, only during course 2), with encouraging results (Lübbert et al., Haematologica 2012). We now expanded this approach to a 4-arm randomized phase II study (2x2 factorial design) asking whether the addition of either VPA (HDACi activity) or ATRA or both to DAC as first-line treatment of elderly AML pts might improve the effect of DAC monotherapy (NCT00867672). Patients and Methods: Inclusion criteria: newly diagnosed pts 〉 60 yr unfit for induction (reasons for treatment decision prospectively captured) with non-M3 AML (WHO, de novo or after antecedent hematologic disorder [AHD], therapy-associated [t] AML), ECOG performance status (PS) 0-2. Pts with 〉 30,000 WBC/µl were to receive a short course of hydroxyurea. Treatment: DAC 20 mg/m2 dy 1-5 (treatment arms A/B/C/D), VPA p.o. continuously (target serum levels: 50-110 mg/l) from dy 6 (arms B/D), ATRA p.o. dy 6-28 (arms C/D) of each 28-dy course (repeated until relapse/progression, prohibitive toxicity, withdrawal or death). Key endpoints: objective response rate (ORR): CR/CRi/PR (ELN criteria), overall survival (OS). Sample size calculation was based on the primary endpoint ORR, assuming an ORR of 25% in arm A (Lübbert et al., Haematologica 2012). For a power of 80% (test in this phase II study at 1-sided alpha=0.1) for an increase of ORR to 40% with VPA or ATRA, 176 pts were necessary, planned sample size 200. Efficacy analyses were performed in the intention-to-treat (ITT) population including all randomized pts for whom treatment was started. VPA was investigated by comparing arms B+D vs arms A+C, ATRA by comparing arms C+D vs arms A+B. ORR was analyzed with logistic regression, OS with Cox regression, without adjustment for prognostic factors. Odds ratios (OR) for the effect on ORR and hazard ratios (HR) for the effect on death with 95% confidence intervals (CI), and two-sided p values of the tests of no treatment effect are presented. Central hematopathological review by an independent morphologist was conducted in a blinded fashion as to treatment arms. Results: Between 12/2011 and 2/2015, 204 pts were randomized (4 were excluded from the analysis because no treatment was administered). Median age: 76 yrs (interquartile range 72-79, range 61-92), ECOG PS 0/1/2-3: 19/61/20%: 52% had an HCT-CI 〉 3, 16.5% WBC 〉 30.000/µl, 31.5% poor cytogenetics (ELN), 51% had an AHD, 13.5% tAML (characteristics overall balanced across all 4 treatment arms). A median of 3 DAC courses were administered (per arm: 2/3/5.5/4), however 53 pts (26.5%), who were older, with reduced PS and a higher HCT-CI compared to the other 147 pts, received only a single course. The ORR (usually achieved only after 〉 3 courses) was 17.5%, median OS 6.2 mths (arm A: 8.5% and 4.8 CI [2.8,7.6] mths, arm B: 17.5% and 6.1 CI [3.7,7.2] mths, arm C: 26.1% and 8.4 CI [4.0,14.0] mths, arm D: 18% and 7.7 CI [4.6,11.2] mths, respectively). Effect on ORR of VPA vs no VPA (17.8 vs 17.2%): OR 1.06, CI [0.51,2.21], p=0.88; of ATRA vs no ATRA (21.9 vs 13.5%): OR 1.80, CI [0.86,3.79] , p=0.12. Effect on OS of VPA vs no VPA (6.2 vs 6.4 mths median OS): HR 0.94, CI [0.70,1.28], p=0.70; of ATRA vs no ATRA (8.2 vs 5.1 months median OS): HR 0.65, CI [0.48,0.88] , p=0.006 (after adjustment for PS, HCT-CI, WBC, LDH: HR 0.59, CI [0.43,0.82], p=0.002). Improved survival with ATRA was also seen in pts with poor cytogenetics. Toxicities (predominantly hematologic) did not show relevant differences between the 4 treatment arms. Conclusions: Based on this ITT analysis of a randomized trial, the addition of ATRA to standard-dose DAC resulted in a higher ORR and in a clinically relevant extension of OS, without additional (hematologic and non-hematologic) toxicity. In contrast, the addition of VPA did not affect ORR or OS. Disclosures Lübbert: Celgene: Other: Travel Funding; Janssen-Cilag: Other: Travel Funding, Research Funding; Ratiopharm: Other: Study drug valproic acid. Schlenk:Pfizer: Honoraria, Research Funding; Amgen: Research Funding. Heuser:Pfizer: Research Funding; Tetralogic: Research Funding; BerGenBio: Research Funding; Karyopharm Therapeutics Inc: Research Funding; Bayer Pharma AG: Research Funding; Celgene: Honoraria; Novartis: Consultancy, Research Funding. Bug:Janssen: Other: Travel Grant; Astellas: Other: Travel Grant; Teva Oncology: Other: Travel Grant; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Grant; Nord Medica: Consultancy. Giagounidis:Celgene Corporation: Consultancy. Brugger:Astrazeneca: Employment. Niederwieser:Amgen: Speakers Bureau; Novartis Oncology Europe: Research Funding, Speakers Bureau.

Abstract: Allogeneic hematopoietic cell transplantation (HSCT) is a powerful consolidation option for acute myeloid leukemia (AML) patients (pts) in hematologic complete remission (CR). Disease recurrence after HSCT remains a major clinical problem & early identification of AML pts at risk of relapse is crucial to improve outcomes. High expression of the AML associated gene BAALC (Brain and acute leukemia, cytoplasmic) at diagnosis adversely impacts on outcomes in AML pts. Little is known about its prognostic capacity during disease course & as a marker of residual disease. Here we adopted digital droplet polymerase chain reaction (ddPCR) for absolute quantification of BAALC copy numbers in peripheral blood (PB) prior to HSCT in AML pts in hematologic CR. We identified 82 AML pts with PB in first (60%) or second CR (23%) or CRi (17%) up to 28 days prior to HSCT available. Median age at HSCT was 63.9 (range 50.8-76.2) years (y). All pts received non-myeloablative (NMA) conditioning (fludarabine 3x30 mg & 2 Gy total body irradiation). At diagnosis, mutation status (mut) of the NPM1, CEBPA, IDH1, IDH2, & DNMT3A gene & presence of FLT3-ITD or FLT3-TKD were assessed. In pre-HSCT PB, absolute quantification of BAALC copy numbers was performed by ddPCR & results were normalized to ABL1 copy numbers.Additionally, absolute BAALC copy numbers wereassessedin PB of healthy controls (n=7) with a median age of 62.7 (range 39.6-82.0) y. Pts were grouped according to the European LeukemiaNet (ELN) classification in 21% favorable, 23% intermediate-I, 24% intermediate-II, 23% adverse & 9% unknown. Pts & healthy control were evenly matched in age (P=1) & sex (P=1). BAALC/ABL1 copy numbers did not differ between AML pts at HSCT (median 0.03 [range 0.01-2.48]) & the healthy controls (median 0.04 [range 0.03-0.10], P=.34, Figure 1). A cut-off point of 0.14absolute BAALC/ABL1 copies was determined using the R package 'OptimalCutpoints' & used to define pts with high (26%) & low (74%) pre-HSCT BAALC/ABL1 copy numbers. The copy number at this cut-off point was higher than the two-fold standard deviation over the median of the healthy controls (0.10 BAALC/ABL1). Pts with high & low pre-HSCT BAALC/ABL1 copy numbers did not differ significantly in pre-treatment characteristics (i.e. hemoglobin, white blood count, platelets, blasts in bone marrow or PB, ELN genetic group, FLT3-ITD, FLT3-TKD, NPM1, CEBPA, DNMT3A, IDH1 or IDH2 mut) or remission status at HSCT (CR1 vs. CR2 vs. CRi). However, pts with high pre-HSCT BAALC/ABL1 copy numbers had a significantly higher cumulative incidence of relapse (CIR, P=.02, Figure 2a) & shorter overall survival (OS, P=.02, Figure 2b). High pre-HSCT BAALC/ABL1 copy numbers especially impacted on CIR when we restricted our analysis to pts with normal cytogenetics (P=.003). In multivariate analysis for the entire cohort, high pre-HSCT BAALC/ABL1 copy numbers retained the prognostic impact on CIR (Hazard Ratio [HR] 3.6, Confidence Interval [CI] 1.6-8.2, P=.002) after adjustment for disease status at HSCT (P=.006) & the prognostic impact on OS (HR 2.2, CI 1.1-4.3, P=.02). In conclusion, ddPCR is a feasible method for absolute quantification of BAALC copy numbers in PB, which may indicate residual disease burden in AML pts. High PB BAALC/ABL1 copy numbers ( 〉 0.14) in AML pts in hematologic CR at HSCT associated with higher CIR & shorter OS in univariate & multivariate models. AML pts with high PB BAALC/ABL1 copy numbers at HSCT should be closely monitored for relapse in the post-transplant period. In the future prospective studies will be required to validate the absolute PB BAALC/ABL1 copy number cut-off point & to evaluate whether AML pts with high BAALC/ABL1 copy numbersmight benefit from additional treatment before HSCT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Poenisch: Mundipharma: Research Funding. Niederwieser:Amgen: Speakers Bureau; Novartis Oncology Europe: Research Funding, Speakers Bureau.

Abstract: Loss of physical performance is a universal problem of cancer patients undergoing chemotherapy. We postulated that this impairment can be partially prevented by aerobic exercise. In a randomized study, 33 cancer patients receiving high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (training group, T) performed an exercise program consisting of biking on an ergometer in the supine position after an interval-training pattern for 30 minutes daily during hospitalization. Patients in the control group (C, n = 37) did not train. Maximal physical performance was assessed with a treadmill test by admission and discharge. Physical performance of the two groups was not different on admission. The decrement in performance during hospitalization was 27% greater in the control group than in the training group (P = .05); this resulted in a significantly higher maximal physical performance at discharge in the trained patients (P = .04). Duration of neutropenia (P = .01) and thrombopenia (P = .06), severity of diarrhea (P = .04), severity of pain (P = .01), and duration of hospitalization (P = .03) were reduced in the training group. We conclude that aerobic exercise can be safely carried out immediately after high-dose chemotherapy and can partially prevent loss of physical performance. Based on the potential significance of the observed outcomes, further studies are warranted to confirm our results.

Abstract: In acute myeloid leukemia (AML) high expression of the transcription factor ERG (ETS related gene) is associated with dismal outcome. The mechanisms that regulate differential ERG expression remain to be fully elucidated. MicroRNAs (miRs), small RNAs that are able to regulate gene expression, have emerged as important players in AML. We hypothesized that part of the differential expression of ERG is mediated by miRs. In silico prediction tools identified three putative miR-9 binding sites (BS) in the 3'-untranslated region (UTR) of ERG. First, we determined the expression levels of ERG & miR-9 in eight leukemia cell lines (i.e. KG1a, K562, THP-1, MV4-11, EOL1, NB4, OCI-AML3 & ME1) & found an inverse correlation between ERG & miR-9 expression (rank correlation -0.90). The cell line KG1a had the highest ERG & low miR-9 expression, and was therefore used for miR-9 overexpression experiments. In these cells miR-9 overexpression decreased ERG expression at the mRNA level to 82±7% (P=.079) & at the protein level to 72±14% (P=.005) after 12 hours (h) compared to empty vector control transfected cells. Next, we tested the activity of the three putative miR-9 BS in the 3'-UTR of ERG using luciferase assays. 12 h after cotransfection of HEK-293T cells with a miR-9 overexpression vector & an appropriate luciferase vector containing two of the putative BS (BS1 & BS2) from the 3'-UTR of ERG, we found the luciferase activity reduced to 52±4% (P=.023). Mutation experiments showed BS1, but not BS2 to be essential for this activity. The insertion of BS3 into the luciferase vector had no effect on reporter gene expression. Thus miR-9 most likely regulates expression of the transcription factor ERG by directly binding to BS1 in its 3'-UTR. To test if a differential expression of miR-9 is also of functional significance in AML, we first analyzed its impact on cell proliferation. Overexpression of miR-9 led to decreased proliferation rates in KG1a cells compared to control vector treated cells. After 5 days, the relative cell count was 133±21% vs. 241±67% in the miR-9 overexpressing cells compared to empty vector expressing cells, respectively. Next, we determined if this difference was based on a higher apoptosis rate. An Annexin V staining revealed no significant difference between the apoptotic threshold of miR-9 overexpressing (21%) and empty vector cells (21%) after 24 h. However, a subsequent cell cycle analysis demonstrated a higher percentage of miR-9 overexpressing cells in the G2/M phase, (39±2%) compared to the empty vector control treated cells (31±3%) after 24 h (P=.084), indicating that the cell cycle is slowed or stopped during cell division. Since miR-9 targets the poor prognostic marker ERG & higher miR-9 expression led to decreased proliferation & reduced cycling in AML cells in vitro we speculated that the differential miR-9 expression would also impact the outcome of AML patients (pts). Mature miR-9 is derived from three precursor molecules of which pre-miR-9-1 & pre-miR-9-3 are known to be expressed in hematopoietic cells. We assessed the pre-miR-9-1 expression of bone marrow by real-time PCR in 131 AML pts (median age 64 [range 22 – 75] years) with favorable (n=4, 3%), intermediate (n=90, 69%), adverse (n=33, 25%), or unknown (n=4, 3%) cytogenetic risk (according to the Medical Research Council [MRC] Classification) who received a RIC-HCT. The median follow-up was 4 years. The pre-miR-9-1 expression levels were normalized to ABL to define high & low pre-miR-9-1 expressers by the median expression of all AML pts. At diagnosis, high pre-miR-9-1 expresser status associated with a lower white blood count (P=.065) and lower % of peripheral blasts (P=.108) by trend. Furthermore, pts with high pre-miR-9-1 expression were more likely to be NPM1 wild-type (P=.047) & FLT3-ITD negative (P=.020). Pts with high pre-miR-9-1 had a lower probability of relapse (P=.048). In conclusion, miR-9 targets & regulates expression of the poor outcome predictor ERG. Overexpression of miR-9 led to decreased proliferation and a pause in AML cell cycling. Furthermore, high pre-miR-9-1 expression associated with reduced relapse rates in AML. Thus a pharmacologically induced expression of miR-9 in AML blasts may improve outcomes of AML pts. Disclosures No relevant conflicts of interest to declare.

Abstract: Allogeneic hematopoietic cell transplantation (HCT) represents a post-remission therapy offering potential cure for acute myeloid leukemia (AML) patients (pts). Reduced-Intensity Conditioning (RIC) is increasingly used in AML pts undergoing HCT ineligible for conventional conditioning. The ecotropic viral integration site 1 (EVI1) gene maps to chromosome 3q26 and encodes a transcription factor that has an important role during embryogenesis. EVI1 activation, e.g. through chromosome 3 translocations, is found in several human myeloid disorders. The presence of EVI1 expression has been described as a predictor of poor outcome in pts treated with standard cytarabine based chemotherapy. Whether the expression of EVI1 also associates with outcome in AML pts undergoing RIC-HCT, with a therapeutic approach mainly based on a graft-versus-leukemia effect, remains unknown. Here we tested the prognostic impact of EVI1 expression in RIC-HCT treated AML pts. We analyzed 57 AML pts (median age, 61 years [y]; range 27–74y) who received RIC (Fludarabin 30mg/m^2 at day-4 to -2 & 2Gy total body irradiation at day 0)-HCT at the University of Leipzig, with pretreatment bone marrow material available. Donors were human leucocyte antigen (HLA)-matched related (n=6, 10.5%) or HLA-matched (n=41; 72%) or mismatched ( 〉 = 1 antigen; n=10; 17.5%) unrelated. At HCT 82.4% (n=47) of the pts were in complete remission (CR). 28.6% (n=14) had acute graft-versus-host disease (GvHD; 〉 = grade 2) and 80.5% (n=33) (31.7% (n=13) limited; 48.8% (n=20) extensive) chronic GvHD. Median follow-up was 7.0 y for pts alive. Medical research council (MRC) genetic classification was: intermediate (n=39; 73.5%) or adverse (n=14; 26.5%). The pts were also characterized for CEBPA and NPM1 mutations, as well as presence of an FLT3-ITD at diagnosis. EVI1 expression was measured with quantitative reverse transcription polymerase chain reaction and normalized to 18S. 71.9% (n=41) of our pts were EVI1 expressers. The presence of EVI1 expression did not significantly associate with any clinical or biological characteristics. Still, by trend EVI1 expression associated with an adverse karyotype (P=.08) and NPM1 mutations (P=.16). The presence of EVI1 expression significantly associated with shorter overall survival (OS; P=.04) and event-free survival (EFS; P=.03; Figure 1).Figure 1Overall Survival(A) and Event-free Survival (B) in RIC-HCT treated AML pts according to EVI1 expression statusFigure 1. Overall Survival(A) and Event-free Survival (B) in RIC-HCT treated AML pts according to EVI1 expression status In multivariable analysis in our set, none of the analyzed clinical or biological parameters were significantly associated with OS or EFS. However, in multivariable analysis cytogenetics (intermediate vs. adverse) associated with OS by trend (P=.12); while EVI1 expression status (P=.14), cytogenetics (intermediate vs adverse; P=.11) and remission status at the time point of RIC-HCT (CR vs all other; P=.10) associated with EFS by trend. In conclusion, the presence of EVI1 expression associated with worse outcome in RIC-HCT treated AML pts. Pretreatment EVI1 expression may refine the risk stratification for AML pts undergoing RIC-HCT. Disclosures: No relevant conflicts of interest to declare.

Abstract: Introduction Chronic lymphocytic leukemia (CLL) is a disease of the elderly patient with a median age of 72 years at diagnosis. In addition to a generally increased obesity prevalence, higher age is also associated with increased body fat contents, and currently 22.5% of men and 31.8% of women above 65 years in Germany qualify as obese (body mass index [BMI] ≥30 kg/m²). While high BMI values are regarded as a risk factor for certain cancers, the impact of obesity on treatment outcomes is controversial and differs between genders. In aggressive B-cell lymphoma the prognosis of obese elderly women was worse following R-CHOP chemoimmunotherapy (CIT). With this meta-analysis the question whether obesity has an impact in CLL was addressed. Methods We analyzed pooled data from three prospective phase III trials (CLL4, CLL8, CLL10) of the German CLL study group (GCLLSG). With the aim to assess the effect of rituximab, patients treated with fludarabine monotherapy (F) or bendamustine and rituximab (BR) were excluded from this analysis. Underweighted patients (BMI 〈 18.5 kg/m², n=10) were excluded as well. Finally, the total analysis cohort comprised 1237 previously untreated patients receiving fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR). We analyzed progression-free survival (PFS) and overall survival (OS) according to baseline BMI (normal weight (NW) 18.5-24.9 kg/m²; overweight (OW) 25-29.9 kg/m²; obese (OB) ≥ 30 kg/m²), gender and treatment regimen. Kaplan-Meier curves were plotted and compared by non-stratified log-rank test. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression modelling. Results In this combined cohort 560 (45.3%) patients received FC and 677 (54.7%) received FCR. 319 (25.8%) patients were female, 918 (74.2%) were male, median age was 60 years (range 30-81). The cohort comprised 497 (40.2%) NW patients, 521 (42.1%) OW patients and 219 (17.7%) OB patients. Median BMI was 25.1 kg/m² (range 18.6-45.0) in the female and 26.0 kg/m² (range 18.7-45.2) in the male study population. Clinical characteristics, in particular CLL-IPI risk groups and other prognostic factors, were equally distributed between BMI subgroups. Median observation time was 68.4 (range 0.4-151.3) months. OB patients received lower CIT doses compared to NW patients with regard to planned doses based on body surface area (Table 1). Medians of given dose intensities were for fludarabine: NW 95.1% (range 10.8-124.7) vs. OB 84.0% (range 9.2-121.0), for cyclophosphamide: NW 93.5% (range 11.1-105.7) vs. OB 84.0% (range 9.2-102.3), and for rituximab: NW 98.2% (range 0.1-108.7) vs. OB 88.9% (range 26.8-101.3). This difference was observed in male and female patients. We found significantly increased creatinine clearance rates in OB patients of both genders calculated by three different methods including the Salazar/Corcoran method that adjusts for obesity. PFS and OS according to the three BMI groups were not different in the entire cohort comprising both genders or males only. However, obese females had significantly worse outcomes following FCR treatment compared to NW females: median PFS was 44.6 in OB vs. 73.0 months in NW females (HR 1.743 [1.022-2.973]; p=0.041) and the median OS was 83.7 months compared to not reached in the female NW group (HR 3.013 [1.345-6.752] ; p=0.007) (Figure 1). These survival differences could not be detected in FC treated females (Figure 2). Conclusions Our data suggest that obesity is associated with significantly shorter PFS and OS in female CLL patients undergoing FCR chemoimmunotherapy but not conventional FC chemotherapy without rituximab. Therefore we assume that lower relative chemotherapy dose exposition that OB females received was not the major contributing factor to this survival difference. In contrast, we assume lower rituximab exposure in OB females treated with FCR due to obesity-associated increased clearance rates as described before. The significantly increased creatinine clearance rates in OB female patients might have additionally contributed to this effect, however the detailed mechanisms remain to be characterized. Our results are in line with recently published data on obesity as a survival risk factor in female patients with aggressive B-cell lymphoma undergoing R-CHOP CIT. Taken together, this warrants closer metabolic and anthropometric status evaluation in future immunotherapeutic studies. Disclosures Hopfinger: Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria; Janssen: Honoraria; Gilead: Honoraria, Research Funding. Fink:Celgene: Consultancy, Research Funding; AbbVie: Consultancy, Other: travel geants; Roche: Other: travel grants; Mundipharma: Other: travel grants. Al-Sawaf:Roche: Honoraria; Gilead: Honoraria; Abbvie: Honoraria. Langerbeins:Sunesis: Consultancy; AbbVie: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Mundipharma: Consultancy, Other: Travel grants; Roche: Consultancy, Other: Travel grants, Research Funding. Cramer:Mundipharma: Other: Travel grants; Roche: Honoraria, Other: Travel grants, Research Funding; Acerta: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Gilead: Other: Travel grants, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grants, Research Funding; AstraZeneca: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel grants, Research Funding. Von Tresckow:Celgene: Consultancy, Other: Travel grants; Roche: Consultancy, Honoraria, Other: Travel grants, Research Funding; Janssen-Cliag: Consultancy, Honoraria, Other: Travel grants, Research Funding; AbbVie: Consultancy, Honoraria. Kutsch:Janssen: Other: Travel support; AbbVie: Other: Travel support; Mundipharma: Other: Travel support; Gilead: Research Funding. Hoechstetter:Hexal: Other: Travel Grants; Abbvie: Other: Travel Grants; Gilead Sciences: Consultancy, Other: Travel Grants. Dreyling:Gilead: Consultancy, Honoraria; Mundipharma: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Acerta: Consultancy; Sandoz: Consultancy. Kneba:AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Stilgenbauer:Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding. Döhner:AbbVie: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Amgen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Agios: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding. Hensel:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jaeger:Amgen: 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, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria. Wendtner:Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding. Goede:Janssen: Honoraria, Other: Travel grants; Abbvie: Consultancy; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel grants. Fischer:Roche: Other: Travel support. Hallek:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding.

Abstract: Introduction FCR is the current standard first line treatment regimen in advanced CLL (Hallek et al., Lancet, 2010), but is associated with significant side effects. The GCCLSG initiated an international phase III study in order to test the non-inferiority regarding efficacy and potentially better tolerability of BR compared to FCR in first-line therapy of physically fit pts without del(17p). Methods and Patients 688 CLL pts from 158 sites in five countries (Germany, Austria, Switzerland, Denmark and Czech Republic) were screened centrally for immunophenotype, genomic aberrations by FISH, IGHV sequenzing, comorbidity burden and renal function. 564 CLL pts with CIRS score ≤ 6, creatinine clearance 〉 70 ml/min and without del(17p) were enrolled between October 2008 and June 2011. Pts were randomly assigned to receive 6 courses of either FCR (N= 284; F 25mg/m2 i.v. d1–3, C 250 mg/m2 i.v. d1–3, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent courses; q 28 days) or BR (N=280; B 90mg/m2 i.v. d1+2, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent courses; q 28 days). The intent-to-treat population consisted of 561 pts, because three patients were excluded due to deferred treatment (1 pt decision, 1 treatment before randomization, 1 misdiagnosis). 22 % were Binet A, 38 % Binet B and 40 % Binet C. The median age was 62 years (yrs) (range 33 to 82), median CIRS score 2 (range 0-6). There were significantly more pts with unmutated IGVH in the BR arm (68%) in comparison to the FCR arm (55%; p=0.003). All other characteristics including median age were well balanced. A mean number of 5.27 courses was given in the FCR arm versus 5.41 courses in the BR arm (p=0.022). 70.6% (FCR) and 80.3% (BR) of pts received 6 courses (p=0.008). Dose was reduced by more than 10% in 27.3% (FCR) and 31.6% (BR) of all courses given (p = 0.012). Results The median observation time was 27.9 months (mo) in all pts alive. While response evaluation was missing in 14 pts, 547 pts (274 FCR; BR 273) were evaluable for response and all 561 pts (282 FCR; 279 BR) for progression-free survival (PFS), event-free survival (EFS) and OS. The overall response rate was identical in both arms with 97.8% (p=1.0). The complete response rate (CRR) (confirmed by central immunhistology) with FCR was 47.4% as compared to 38.1% with BR (p=0.031). MRD data were available at interim analysis from 192 pts (99 FCR; 93 BR) of the first 300pts. 71.7% of pts in the FCR and 66.7% in the BR arms achieved MRD-levels below 10-4 in peripheral blood at final staging (p=0.448). The complete MRD data set will be available by November. PFS was 85.0% at 2 yrs in the FCR arm and 78.2% in the BR arm (p=0.041). EFS was 82.6% at 2 yrs in the FCR arm and 75.7% in the BR arm (p=0.037).There was no difference in OS rate for the FCR vs BR arm (94.2% vs 95.8% at 2 years p=0.593). Hazard Ratio for PFS, EFS and OS was 1.385, 1.375 and 0.842 respectively. PFS was assessed in pts 〈 65 yrs and ≥ 65 yrs. While there was a significant difference in pts 〈 65 yrs between both treatment arm (median PFS for BR 36.5 mo vs not reached for FCR; p=0.016), the difference disappeared in elderly pts (not reached vs. 45.6 mo; p=0.757). A multivariate analysis including treatment arm, Binet stage, age, sex, comorbidity, serum TK, serum beta2-microglobulin (Beta2M), del(11q) and IGHV status identified treatment arm, Beta2M, del(11q) and IGHV as independent prognostic factors for PFS and EFS. FCR treated pts had significantly more frequent severe, CTC grade 3 to 5, adverse events during the whole observation period (90.8% vs 78.5%; p 〈 0.001). Especially severe hematotoxicity was more frequent in the FCR arm (90.0% vs 66.9%, p 〈 0.001). The higher rate of severe neutropenia (81.7% vs 56.8%, p 〈 0.001) resulted in a significantly higher rate of severe infections (39.0% vs 25.4%, p=0.001) in the FCR arm, especially in the elderly (FCR: 47.4% vs BR: 26.5%; p=0.002). Treatment related mortality occurred in 3.9% (n=11) in the FCR and 2.1% (n=6) in the BR arm. Conclusion The results of this planned interim analysis show that FCR seems more efficient than BR in the first-line treatment of fit CLL pts with regard to higher CRR, as well as longer PFS and EFS. These advantages might be balanced by a higher rate of severe adverse events, in particular neutropenia and infections, associated with FCR. In light of these results, no firm recommendation of one regimen over the other can be given at the present time regarding the first-line use in CLL pts with good physical fitness. Disclosures: Eichhorst: Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding. Gregor:Roche: Consultancy, Honoraria, Travel Support Other; Mundipharma: Travel Support, Travel Support Other. Plesner:Mundipharma: Research Funding. Trneny:Roche: Honoraria, Research Funding. Fischer:Roche: Travel grants Other; Mundipharma: Travel grants, Travel grants Other. Kneba:Roche: Consultancy, Research Funding. Wendtner:Roche: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding. Kreuzer:Roche: Honoraria; Mundipharma: Honoraria. Stilgenbauer:Roche: Consultancy, Research Funding, Travel grants Other; Mundipharma: Consultancy, Research Funding. Böttcher:Roche: Honoraria, Research Funding. Hallek:Janssen: Research Funding; Gilead: Research Funding; Roche: Research Funding.

Abstract: Abstract 1067 Elderly patients with acute myeloid leukemia are heterogenous group with poor outcome. All age, biological status and co-morbidities limit applicability of intensive chemotherapy. The PALG elaborated original system allowing stratification of patients aged 〉 60 years to three groups with different therapeutic approach. Altogether 537 patients with newly diagnosed AML and median age 70 years (range 60–93) were classified as 1) ‘fit’ (n=163): age 60–79y, ECOG 0–2, proper liver and kidney function, without comorbidities, 2) ‘unfit’ (n=210): age 〉 60 years, ECOG 0–2, normal liver and kidney function, comorbidities allowed, 3) ‘frail’ (n=164): ECOG 3–4. According to PALG 1/2005 protocol ‘fit’ patients were treated similarly as younger adults with daunorubicin (DNR, 3 days) + cytarabine (AraC, 7 days) +/ & minus; cladribine, followed by DNR + AraC consolidation and maintenance. ‘Unfit’ patients received either two courses of AraC+DNR (2+5) or AraC (5 days) + thioguanine + methotrexate, followed by manitenance. ‘Frail’ patients were considered for palliative cytoreduction and supportive care. Results: Complete remission (CR) rate was 35% for ‘fit’, 22% for ‘unfit’ and 0% for ‘frail’ patients. Median survival in the respective groups equaled 39 weeks, 26 w., and 14 w., while the probability of survival at 1 year was 39%, 27% and 10%. The rate of early (up to 8 weeks) mortality was 31%, 24% and 31%, respectively. In the Cox model the only factor independently affecting the risk of overall mortality in both ‘fit’ and x‘unfit’ group was serum LDH above upper quartile (HR=2, p=0.005 for ‘fit’, HR=1.65, p=0.006 for ‘unfit’). Among ‘frail’ patients the risk of mortality was increased in patients with performance status ECOG 〉 2 (HR=1.85, p=0.0008), initial WBC 〉 8.5×10e9/L (HR=1.65, p=0.006), and bone marrow blasts 〉 58% (HR=1.8, p=0.001). We conclude that the proposed stratification system is feasible for elderly AML patients and represets a model for further developments of individualized therapeutic approaches. Survival of patients in whom remission induction therapy may be applied depends on initial tumor burden as reflected by high serum LDH level. The outcome of patients referred for palliative treatment depends additionally on initial performance status. In contrast, neither age nor karyotype were found to independently affect outcome in this study. Disclosures: No relevant conflicts of interest to declare.

Abstract: In recent years expression levels of several genes & microRNAs (miR) were identified as strong prognostic markers, capable to refine AML risk stratification. So far technical difficulties, including the limitations of established methods for comparable, absolute quantification & the lack of defined cut points prevented translation of these findings into clinical practice. Innovative digital droplet PCR (ddPCR) is a novel technique with high sensitivity, specificity that allows absolute quantification - without the need for standard curves - & promises better inter-laboratory comparability. In AML pts, high miR-155 expression levels associate with the presence of FLT3-ITD & independently predict inferior outcome. Here, for the first time we applied ddPCR for absolute quantification of pre-miR-155 to define an absolute cut point to discriminate between high & lowexpressers, which was then validated in a second set of AML pts. We analyzed a homogeneous test set of 71 AML pts treated between January 2000 & June 2012 in our institution. All pts received cytarabinebased induction therapies & were consolidated with allogeneic hematopoietic stem cell transplantation (HCT) after non-myeloablativeconditioning (NMA; consisting of fludarabine[30mg / m² at days -4 to -2] & 2Gy total body irradiation [day 0]). At NMA-HCT ptswere in first (n=43; 60.6%) or second complete remission (CR; n=16; 22.5%) or CR with incomplete recovery (n=12; 16.9%). At diagnosis, cytogenetics & mutation status of the NPM1, CEBPA, IDH1, IDH2 & DNMT3A gene & presence of FLT3-ITD or FLT3-TKD mutation were assessed. The expression of the pre-miR-155 stem loop was measured using an EvaGreen-based ddPCR assay & normalized to the absolute copy numbers of ABL1. The R Package OptimalCutpointswas used to determine a cut point of 1.104 copies pre-miR-155 per 100 ABL1 copies to discriminate between high (n =29; 40.8%) & low (n =42; 59.2 %) miR-155 expressers. High miR-155 expressers, more often had a FLT3-ITD (p=.039) & less frequently a mutation in the FLT3-TKD (p=.010). No significant association was found for other clinical or biological markers at diagnosis. In the test set, pts with more than 1.104 copies pre-miR-155 per 100 ABL1 copies at diagnosis had a significant shorter event-free survival (EFS; p=.03, figure 1A) & overall survival (OS; p=.009, figure 1B). To validate these findings, we used a second set of 71 pts (median age 63.4y [range 37.1 to 74.7]) with a median follow-up of 3.7y for pts alive that all received cytarabinebased induction therapies & NMA-HCT as consolidation. The ptsin the validation set also did not differ significantly in the analyzed clinical or molecular characteristics (i.e. white blood count, hemoglobin, platelets, blasts in bone marrow or peripheral blood at diagnosis, remission status at HCT [CR1 vs. CR2 vs. CRi], ELN genetic group, mutational status of FLT3-TKD, NPM1, CEBPA, DNMT3A, IDH1 or IDH2 & presence of FLT3-ITD). Using the determined cut point of 1.104 copies pre-miR-155 / 100 ABL1 copies in the test set, patients in the validation set were divided in 39 patients (54.9%) with a high miR-155 expression & 32 (45.1%) with a low miR-155 expression. Pts with high miR-155 expression in the validation set had shorter EFS (p=.11, figure 2A) by trend & a significant shorter OS (p=.05, figure 2B). In conclusion, ddPCRis a novel, feasible method that allows absolute quantification of miRexpression. We defined an absolute cut point of 1.104 copies pre-miR-155 per 100 ABL1 copies for the prognosticator miR-155 in AML without the need for standard curves. Pts with pre-miR-155 expression above the cut point had a significant shorter EFS & OS. Remarkably, using a second clinically comparable set, we were able to validate our test set findings. Future studies are planned to confirm the clinical impact of pre-miR-155 expression levels at diagnosis, as well as the identified absolute pre-miR-155 / ABL1 copy number cut point to distinguish high from low miR-155 expressers. Figure 1 Test Set Figure 1. Test Set Figure 2 Validation Test Figure 2. Validation Test Disclosures Poenisch: Mundipharma: Research Funding.

Abstract: INTRODUCTION Chronic lymphocytic leukemia (CLL) is frequently associated with an impaired humoral and cellular immunity. On a global scale chemoimmunotherapy (CIT) has remained one of the most frequently used treatment option. Thus, patients (pts) may experience further cytopenia, particularly treatment-related neutropenia, increasing the risk of infections. In order to better characterize incidence, characteristics and outcomes of infections during and after therapy, a pooled analysis of phase II and III German CLL Study Group trials was performed. METHODS Data of first line pts from 5 clinical trials (CLL7, pts treated with fludarabine, cyclophosphamide, rituximab [FCR]; CLL8, FC vs FCR; CLL10, FCR vs bendamustine-rituximab [BR] ; CLL11, chlorambucil [CLB] vs CLB-R vs CLB-Obinutuzumab [CLB-Ob] and CLL2M, BR) were analyzed. Clinical, laboratory, genetic and event-related data were pooled. Infections defined as severe (CTC grade 3-5) from initiation of therapy until 4 weeks after completion of study treatment were considered related. Due to varying reporting periods for infections of the respective trials later events of infections were not included. Kaplan-Meier curves for landmark overall survival (OS) from completion of study treatment plus 4 weeks were plotted and compared by non-stratified log-rank test. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional-hazard regression modelling. RESULTS Data from 2,291 pts receiving at least one dose of CIT were pooled. Median observation time was 71.7 months, ranging between 43.7 months (CLL2M) and 81.0 months (CLL10). Seven-hundred and twenty-seven pts received FCR, 396 pts FC, 395 pts BR, 116 pts CLB, 326 pts CLB-R and 331 pts CLB-Ob. Overall, 274 severe grad 3/4/5 infections were reported in 229 pts (10.0% of 2,291 pts). Of those 189 pts (82.5%) had max. grade 3 infections, 22 (9.6%) pts had grade 4 infections and 18 (7.9%) pts died due to infectious complications. Median time to severe infection from start of treatment was 1.8 months (IQR 0.9-3.6), with a median number of infectious episodes per patient of 1 (range 1-4). Thirty-one (13.5%) of 229 pts had bacterial infections, 35 (15.3%) viral infections, 5 (2.2%) fungal infections and 172 (75.1%) unspecified infections. Higher grade (i.e. ≥ CTC grade 3) leukopenia and/or neutropenia was reported in 121 (52.8%) pts with severe infections. Eighty-eight (12.1%) of FCR treated pts had severe infections, followed by BR 45 (11.4%), CLB 12 (10.3%), FC 35 (8.8%), CLB-Ob 25 (7.6%) and CLB-R 24 (7.4%). Median age was 64 years in the entire cohort; no differences between pts with and without infections were observed with regards to age, sex, ECOG or creatinine clearance. Molecular and cytogenetic characteristics (deletion 17p, deletion 11q, trisomy 12) and IGHV status were similarly distributed between both groups. Median neutrophil count at enrolment was 4.4x10-9/l in both groups, respectively. Prior to therapy, levels of immunoglobulin were comparable between pts with and without infections (median IgG 7.0 vs 7.5 g/L, IgM 0.3 g/L vs 0.3 g/L). Also, pts with at least one episode of ≥ CTC grade 3 leukopenia/neutropenia had comparable rates of severe infections to pts without higher grade leukopenia/neutropenia (147 [53.6%] vs 127 [46.4%] pts). No differences were observed between pts with or without infections regarding the response to first line treatment (183 pts [79.9%] with complete response or partial response to treatment vs 1715 pts [83.2%] ) as well as the rate of undetectable minimal residual disease levels (50 [21.8%] vs 477 [23.1%] ). Overall survival from 4 weeks after completion of study treatment was significantly shorter in pts with severe infections compared to pts without severe infections (median 73.7 months vs 97.3 months, HR 1.503, 95% CI 1.217-1.856, p & lt; 0.001). CONCLUSION This analysis confirms that prognosis of CLL pts who received first line treatment with (immuno)chemotherapy is influenced by severe infections. This risk does not correlate with the explored cyto- or molecular genetic risk factors, nor with response to treatment, pre-therapeutic levels of immunoglobulins or occurrence of higher grade neutropenia. Pts who experience severe infections have a significantly shorter overall survival compared to pts without severe infections. Due to their vulnerability, careful management of infectious complications in CLL pts is warranted. Figure 1 Disclosures Al-Sawaf: AbbVie: Consultancy, Honoraria, Other: personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: personal fees, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: personal fees; BeiGene: Research Funding; Roche: Consultancy, Honoraria, Other: personal fees, Research Funding; Gilead: Consultancy, Honoraria, Other: personal fees. Fink:Janssen: Honoraria; Celgene: Research Funding; AbbVie: Other: travel grants. Cramer:F. Hoffmann-LaRoche: Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Acerta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Beigene: Research Funding; Novartis: Consultancy, Research Funding; Gilead: Other: travel support, Research Funding; AbbVie: Honoraria, Other: travel support. Herling:Roche: Other: Travel support, Research Funding. Von Tresckow:Janssen-Cilag: Honoraria, Other: travel grants, Research Funding; Celgene: Other: travel grants; F. Hoffmann-LaRoche: Honoraria, Other: travel grants, Research Funding; AbbVie: Honoraria. Böttcher:Novartis: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Research Funding; Janssen: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Dreyling:Astra Zeneca: Consultancy; Abbvie: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Beigene: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau. Jaeger:F. Hoffmann-La Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Infinity: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria; True North: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Gregor:Roche: Honoraria; Mundipharma: Honoraria; AbbVie: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Pfizer: Honoraria. Ritgen:Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel grants; F. Hoffman-La Roche: Consultancy, Honoraria, Other: travel grants, Research Funding; Gilead: Other: travel grants. Dürig:Janssen: Consultancy; AbbVie: Consultancy; Celgene: Consultancy. Tausch:AbbVie: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Stilgenbauer:GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Genzyme: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other, Research Funding; Genentech: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding. Wendtner:Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Other: travel support, Research Funding; Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding. Fischer:F. Hoffmann-La Roche: Honoraria, Other: travel grants; AbbVie: Honoraria. Goede:AbbVie: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-LaRoche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hallek:F. Hoffmann-LaRoche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Eichhorst:Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding. Langerbeins:AbbVie: Honoraria, Other: travel grants, Research Funding; F. Hoffmann-LaRoche: Honoraria, Other: travel grants, Research Funding; Janssen-Cilag: Honoraria, Other: travel grants, Research Funding; Mundipharma: Honoraria, Other: travel grants, Research Funding.