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Placental growth factor (PlGF), a VEGF-homolog implicated in tumor angiogenesis and adaptation to antiangiogenic therapy, is emerging as candidate target in malignancies. Here, we addressed the expression, function, and prognostic value of PlGF in neuroendocrine tumors (NETs). PlGF was determined in NET patients' sera collected retrospectively (n=88) and prospectively (n=87) using Roche-Elecsys and correlated with clinicopathological data. Tumoral PlGF was evaluated by immunohistochemistry, effects of PlGF on proliferation and migration in vitro were assessed using different NET cell lines and effects on tumor growth in vivo in orthotopic xenografts. Circulating and tumoral PlGF was elevated in patients with pancreatic NETs (pNETs) compared with control sera and respective healthy tissue. De novo PlGF expression occurred primarily in the tumor stroma, suggesting paracrine stimulatory circuits. Indeed, PlGF enhanced NET proliferation and migration in vitro and, conversely, neutralizing antibodies to PlGF reduced tumor growth in vivo. Elevated circulating PlGF levels in NET patients correlated with advanced tumor grading and were associated with reduced tumor-related survival in pNETs. Subsequent determinations confirmed and extended our observation of elevated PlGF levels in a prospective cohort of grade 1 and grade 2 pNETs (n=30) and intestinal NETs (n=57). In low-grade pNETs, normal circulating PlGF levels were associated with better survival. In intestinal NETs, circulating PlGF above median emerged as an independent prognostic factor for shorter time-to-progression in multivariate analyses. These data assign to PlGF a novel function in the pathobiology of NETs and propose PlGF as a prognostic parameter and therapeutic target.

High-dose chemotherapy followed by autologous stem cell transplantation has been shown to be feasible and highly effective in newly diagnosed primary central nervous system lymphoma. In this retrospective multicenter study, we investigated prognosis and baseline risk factors in patients with primary central nervous system lymphoma who underwent this treatment approach. We retrospectively analyzed 105 immunocompetent patients with primary central nervous system lymphoma who underwent high-dose chemotherapy followed by autologous stem cell transplantation with or without whole brain radiotherapy as first-line consolidation treated at 12 German centers between 1997 and 2011. We estimated survival rates and investigated the impact of age, performance status, serum lactate dehydrogenase level, and deep brain involvement on overall and progression-free survival. Patients were additionally categorized into three prognostic groups according to the Memorial Sloan Kettering Cancer Center prognostic model. After a median follow up of 47 months, median progression-free survival and overall survival was reached after 85 and 121 months; 2- and 5-year survival rates were 82% and 79%, respectively. The Memorial Sloan Kettering Cancer Center prognostic model did not predict survival. Only age revealed some evidence of prognostic relevance. Overall response rate was 95%; of those patients with progressive disease before high-dose chemotherapy, 7 of 20 achieved ongoing complete remission after therapy without whole brain radiation therapy. Transplantation-associated mortality was 2.8%. High-dose chemotherapy followed by autologous stem cell transplantation is a highly effective and safe treatment modality for selected primary central nervous system lymphoma patients. Superiority compared to standard chemotherapy still warrants further investigation.

6584 Background: In Study 406, the anti-CD20 monoclonal antibody ofatumumab (ofa), given as monotherapy over 6 months, showed 47% overall response rate (ORR) in patients (pts) with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab (FA-ref), or to fludarabine with bulky (>5cm) lymphadenopathy (BF-ref). The effects of ofa retreatment (retx) and maintenance (mt) are unknown. Methods: Pts who responded to ofa and then progressed or had stable disease (SD) in Study 406, were offered retx in Study 416 (NCT00802737; GSK/Genmab) with ofa 1 x 300 mg + 7 x 2000 mg weekly followed by mt with ofa 2000 mg monthly for up to 2 years (if SD or better). Primary endpoint was ORR (1996 NCI-WG). Safety and time to event outcomes were also assessed. Results: Of 29 pts enrolled, 7 had SD and 22 had partial response (PR) and progressed in Study 406. Pts were defined per Study 406: 17 FA-ref, 11 BF-ref, 1 “other”. Pretreatment characteristics were similar between groups. Pts received a median of 12 doses (range 3-32); 86% had 8 doses, 3% received all 32 doses. 72% of pts had infusion-related adverse events (AEs), 41% at 1st infusion, mostly grade 1-2. The most common grade >3 AE occurring up to 60 days after last tx was infection (38%); the most common was pneumonia (17%). 3 pts (10%) had fatal infections, all bronchopneumonia. Clinical efficacy is shown in Table. Comparative analysis to Study 406 is ongoing. Conclusions: The response to ofatumumab (ofa) as induction retreatment and progression-free survival in this limited number of pts was similar to 1st treatment (Study 406). Ofa maintenance had some clinical benefit for pts with advanced CLL. Ofa was well-tolerated with no unexpected toxicities. [Table: see text]

The chemoimmunotherapy FCR (fludarabine and cyclophosphamide with rituximab) is the standard first-line treatment for physically fit chronic lymphocytic leukemia (CLL) patients. To assess the risks and benefits, we investigated health-related quality of life (HRQOL). 817 untreated CLL patients received either FC or FCR within the GCLLSG CLL8 trial. The European Organization for Research and Treatment of Cancer Quality of life Questionnaire C30 was sent to all patients at baseline, after 3, 6, and 12 months and then yearly as follow-up. A total of 769 (94%) of 817 patients completed at least one questionnaire. Comparing HRQOL of CLL patients with the general German population, CLL patients' health declined in most scales except for global health and pain. No major differences in HRQOL were found during treatment or follow-up between both treatment arms. Females were more likely to have treatment-related symptoms than males. Although FCR was associated with more side effects, this did not influence HRQOL. During follow-up after FCR only minor improvement of HRQOL compared with FC was assessed.

Approximately 1 % of all malignant solid tumours of the head and neck area are metastases from primary tumours beneath the clavicles. The aim of this study was to analyse the distribution of primary tumours since meta-analyses might have been biased due to the usually extraordinary character of case reports. All patient files from 1970 to 2012 from the Oral and Maxillofacial Surgery unit at a University Hospital were analysed regarding the existence of metastases to the head and neck area from distant primaries. Of the seventy-three patients 18 had breast cancers (25 %), 9 melanomas (12 %), 8 tumours of the kidneys and 8 of the lungs (each 12 %), 3 colon cancers (6 %), 2 prostate cancers (3 %), 2 Ewing sarcomas (3 %), and 1 each of liposarcoma, esophagus, rectum, hepatocellular carcinoma, vulva, ovarian and testicular cancer. In 15 cases, a cancer of unknown primary was diagnosed. In 28 cases the metastasis was the initial sign of the malignant disease. Skeletal metastasis occurred in 37 cases and a soft tissue metastasis in 36 patients. The different primaries seem to metastasize in different frequencies to the head and neck area. The relatively common prostate cancer rarely seems to produce metastases in the head and neck area compared to cancers arising in the kidneys. In case of a malignant tumour of unknown primary, osseous metastases most often are caused by breast or lung cancer or renal cell carcinoma. Soft tissue metastases are most often caused by breast cancer.

BACKGROUND: Standard treatment for patients with primary CNS lymphoma remains to be defined. Active therapies are often associated with increased risk of haematological or neurological toxicity. In this trial, we addressed the tolerability and efficacy of adding rituximab with or without thiotepa to methotrexate-cytarabine combination therapy (the MATRix regimen), followed by a second randomisation comparing consolidation with whole-brain radiotherapy or autologous stem cell transplantation in patients with primary CNS lymphoma. We report the results of the first randomisation in this Article.METHODS: For the international randomised phase 2 International Extranodal Lymphoma Study Group-32 (IELSG32) trial, HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and measurable disease were enrolled from 53 cancer centres in five European countries (Denmark, Germany, Italy, Switzerland, and the UK) and randomly assigned (1:1:1) to receive four courses of methotrexate 3·5 g/m(2) on day 1 plus cytarabine 2 g/m(2) twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m(2) on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m(2) on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after the first stage were then randomly allocated between whole-brain radiotherapy and autologous stem cell transplantation. A permuted blocks randomised design (block size four) was used for both randomisations, and a computer-generated randomisation list was used within each stratum to preserve allocation concealment. Randomisation was stratified by IELSG risk score (low vs intermediate vs high). No masking after assignment to intervention was used. The primary endpoint of the first randomisation was the complete remission rate, analysed by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01011920.FINDINGS: Between Feb 19, 2010, and Aug 27, 2014, 227 eligible patients were recruited. 219 of these 227 enrolled patients were assessable. At median follow-up of 30 months (IQR 22-38), patients treated with rituximab and thiotepa had a complete remission rate of 49% (95% CI 38-60), compared with 23% (14-31) of those treated with methotrexate-cytarabine alone (hazard ratio 0·46, 95% CI 0·28-0·74) and 30% (21-42) of those treated with methotrexate-cytarabine plus rituximab (0·61, 0·40-0·94). Grade 4 haematological toxicity was more frequent in patients treated with methotrexate-cytarabine plus rituximab and thiotepa, but infective complications were similar in the three groups. The most common grade 3-4 adverse events in all three groups were neutropenia, thrombocytopenia, anaemia, and febrile neutropenia or infections. 13 (6%) patients died of toxicity.INTERPRETATION: With the limitations of a randomised phase 2 study design, the IELSG32 trial provides a high level of evidence supporting the use of MATRix combination as the new standard chemoimmunotherapy for patients aged up to 70 years with newly diagnosed primary CNS lymphoma and as the control group for future randomised trials.FUNDING: Associazione Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Foundation.

Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma.This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74).Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32-0·58]; median progression-free survival 14·6 months [95% CI 10·4-not estimable] vs 6·2 months [4·2-7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]).Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma.Janssen ResearchDevelopment, LLC.

Relationships between patient characteristics, ofatumumab pharmacokinetics, and treatment outcomes were investigated in this phase 2 trial of ofatumumab plus fludarabine and cyclophosphamide (FC) in untreated chronic lymphocytic leukemia. Patients were randomized 1:1 to receive 500 or 1000 mg ofatumumab (Cycle 1; 300 mg) plus FC every 4 weeks for six cycles. Median C(max) and C(trough) values were similar at Cycle 1 regardless of the ultimate clinical outcome. At later doses, these values were higher for patients with complete response (CR) than for other patients. Higher C(max) and C(trough) values at Cycles 3 and 6 were significantly associated with an increased likelihood of CR, whereas ofatumumab pharmacokinetics were not associated with an objective response (OR) on the basis of univariate analyses. Multivariate analyses indicated that baseline patient/disease factors were predominantly associated with CR (17p status) or OR (bulky lymphadenopathy, gender, and serum thymidine kinase), rather than ofatumumab pharmacokinetics. Trial registration: www.clinicaltrials.gov (NCT00410163).

Purpose Blinatumomab is a CD19/CD3 BiTE (bispecific T-cell engager) antibody construct for the treatment of Philadelphia chromosome–negative acute B-lymphoblastic leukemia. We evaluated blinatumomab in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Patients and Methods This 3 + 3 design, phase I dose-escalation study determined adverse events and the maximum tolerated dose (MTD) of continuous intravenous infusion blinatumomab in patients with relapsed/refractory NHL. Blinatumomab was administered over 4 or 8 weeks at seven different dose levels (0.5 to 90 μg/m2/day). End points were incidence of adverse events, pharmacokinetics, pharmacodynamics, and overall response rate. Results Between 2004 and 2011, 76 heavily pretreated patients with relapsed/refractory NHL, who included 14 with diffuse large B-cell lymphoma, were enrolled; 42 received treatment in the formal dose-escalation phase. Neurologic events were dose limiting, and 60 μg/m2/day was established as the MTD. Thirty-four additional patients were recruited to evaluate antilymphoma activity and strategies for mitigating neurologic events at a prespecified MTD. Stepwise dosing (5 to 60 μg/m2/day) plus pentosan polysulfate SP54 (n = 3) resulted in no treatment discontinuations; single-step (n = 5) and double-step (n = 24) dosing entailed two and seven treatment discontinuations due to neurologic events, respectively. Grade 3 neurologic events occurred in 22% of patients (no grade 4/5). Among patients treated at 60 μg/m2/day (target dose; n = 35), the overall response rate was 69% across NHL subtypes and 55% for diffuse large B-cell lymphoma (n = 11); median response duration was 404 days (95% CI, 207 to 1,129 days). Conclusion In this phase I study of relapsed/refractory NHL, continuous infusion with CD19-targeted immunotherapy blinatumomab at various doses and schedules was feasible, with an MTD of 60 μg/m2/day. Single-agent blinatumomab showed antilymphoma activity.

In most patients, mantle cell lymphoma (MCL) shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. In the current study generation of the European MCL Network, the addition of high-dose Ara-C to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival in younger patients. In elderly patients, rituximab maintenance led to a marked prolongation of remission duration. Emerging strategies include mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, immune modulatory drugs, Bruton's tyrosine kinase inhibitors and others, all based on the dysregulated control of cell cycle machinery and impairment of several apoptotic pathways. Combination strategies are currently being investigated in numerous trials, but their introduction into clinical practice and current treatment algorithms remains a challenge. In the current survey, the application of the molecular targeted compounds were collected and evaluated by a representative national network of 14 haematological institutions. Optimised strategies are recommended for clinical routine. Future studies will apply individualised approaches according to the molecular risk profile of the patient.

High sensitive Troponin (hsTn) assays enable detection of minimal marker elevation in heart failure patients previously deemed Troponin negative. Biovariability, reference change values (RCV), and index of individuality (II) have not been previously described for hsTnT although serial testing is important in interpreting low concentrations. For these values, a difference between ischemic heart disease (IHD) and dilated cardiomyopathy (dCMP) appears conceivable. Change in hsTnT was determined alongside with clinical variables in 41 patients with stable chronic systolic dysfunction at 2-week-, 1-month-, 2-month-, and 3-month-intervals (IHD n = 17; dCMP n = 24). HsTnT was detectable in all patients. Individual hsTnT-variations at 2-week, 1-month, 2-month, and 3-month follow-up were 7.2, 22.6, 28.9, and 15.7%, respectively, corresponding to RCVs of 20.1, 62.5, 80.0, and 43.3%, respectively, for crude values. For log-normalised values, individual variations were 3.2, 2.8, 2.7, and 3.5%, respectively, corresponding to RCVs of 8.8, 7.9, 7.6, and 9.7%, respectively. The II was 0.03 to 0.33 according to interval. Aetiology of heart failure was not a consistent determinant of variation (p = 0.28; p = 0.07; p = 0.98; p = 0.03 for 2-week, 1-month, 2-month, and 3-month follow-up, respectively). While short-term biological variation of hsTnT is low, it becomes relatively more important for intermediate follow-up. It is not related to aetiology of heart failure. The corresponding indices of individuality indicate high individuality of values.

Background: A substantial proportion of patients fail first line treatment of diffuse large B-cell lymphoma. Currently available salvage therapies are often ineffective and cannot be tolerated, especially for elderly patients. Thus, probably less than 25% of patients achieve a long lasting remission. Regimens like gemcitabine/oxaliplatin, or bendamustin, both in combination with rituximab are available for elderly or after failure of HDT, however induce only short lived responses. Obinutuzumab (GA101) is a type II anti-CD20 antibody, with preclinical evidence of superiority over rituximab in xenograft models of MCL and DLBCL. Recently a large phase III trial failed to show a benefit in patients with untreated DLBCL, although a subset analysis showed a potential benefit in a subset GCB DLBCL of patients, its value in relapsed disease is not yet finally determined. Although desirable, cumulative dose-related, progressive cardiotoxicity eliminates anthracyclines from relapse treatments. With pixantrone, a drug related to anthracyclines, a re-exposition against this drug class has been shown to be feasible, a best EOT-ORR of 37% (20% CR/CRu) was observed in a phase III trial. We thus initiated a trial combining both agents for the first time. The trial has opened in Q3/2015 and recruitment of 70 patients is completed as of 7/2018. Primary endpoint is the ORR, secondary endpoints being safety, PFS and OS. We report about available data after enrollment of the last patient. Methods: this is a multicenter, national, prospective trial. Main inclusion criteria: histologically proven DLBCL, FL grade IIIb or transformed iNHL (20% Quorum), no curative option available, relapsed and measurable disease, ECOG < 3, sufficient BM reserve, no severe concomitant diseases and given informed consent. There was no upper limit of prior treatment lines. Treatment consisted of up to 6 cycles of pixantrone 50mg/m² day 1, 8 and 15 of each cycle, obinutuzumab 1000 mg flat dose day 1, 8 and 15 of cycle one and day 1 of each subsequent cycle. Interim staging was scheduled after 3 cycles. Results: Basic data are available of 67 patients, all were caucasian, 37 were female the other 30 male and median age was 75 years. Most of the patients suffered from DLBCL (49 pts, 68%), 68% had advanced stage at diagnosis and the median secondary IPI was 3. Data collection is ongoing, until now data of 32 patients are fully available and updated results will be presented. Median number of prior therapies was 2 (1 to 6). Treatment seemed to be well tolerated, median number of cycles applied was 3, pre-mature stop of treatment was primarily based on progression. Response evaluation: at this time 13/32 (40.6%) evaluable patients responded with 5 patients achieving CR/CRu (15.6%) and 8 a PR. One year after initiation of treatment 54% of patients remained alive. Median follow up is 8.2 months. Median PFS and OS is 82 day and not reached, 1 year PFS and OS are 37% and 54%, respectively, no patient experienced relapse if the patient remained free from relapse at one year. Observed toxicity was predominantly hematologic. The following hematologic grade 3/4 adverse events were observed: leukopenia (9.4%) neutropenia (75%), thrombocytopenia (12.5%). The febrile neutropenia rate was 6.3%. Non-hematologic grade 3/4 adverse events were very rare, no single side effect was observed with a frequency of 5% or more. Summary: the combination of Obinutuzumab and Pixantrone is feasible and safe. Early response rates are interesting. Importantly, although some patients experience progress early, a promising proportion shows long lasting remissions. Molecular analyses are ongoing, as well as a detailed analysis on the impact of factors such as of number of prior treatments, status at inclusion. Figure. Figure. Disclosures Hess: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Marks:BMS: Honoraria; Merck: Honoraria; Servier: Honoraria. Dreyling:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Acerta: Consultancy; Sandoz: Consultancy. Keller:Takeda: Consultancy, Research Funding; MSD: Consultancy; Janssen-Cilag: Consultancy, Equity Ownership; Roche: Consultancy; BMS: Consultancy; Celgene: Research Funding. Ernst:Novartis: Research Funding. Viardot:Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria. Lenz:Novartis: Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Celgene Corp.: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria.

Introduction: In CLL, chemoimmunotherapies (CIT) and combinations with novel agents have proven to be highly effective with regard to eradication of minimal residual disease (MRD), while complete remissions (CR) are frequently not achieved due to residual lymphadenopathy. We have previously reported that minimal residual disease (MRD) negativity after CIT is a prognostic factor irrespective of the clinical response (Kovacs et al., JCO 2016). Because inferior outcome was observed in small subgroups of patients (pts) with residual lymphadenopathy, we analyzed the prognostic value of residual lymphadenopathy after CIT in comparison to MRD detection in a larger pt population. Methods: We included 361 pts receiving frontline CIT within 3 prospective clinical trials of the GCLLSG (CLL2M: 23 pts, CLL8: 113 pts, CLL10: 225 pts) with available CT/MRI scans to assess abdominal lymphadenopathy at the final restaging (FR; 2 months after the end of last treatment cycle). Pts with available data on all classical lymph node regions (N=217) were analyzed separately (Figure 1). Enlarged lymph nodes (LN+) were defined as >1.5 cm in the longest diameter according to iwCLL 2008 guidelines regardless of the investigator-assessed response category. MRD levels in peripheral blood (PB) were assessed at FR. PFS and OS was analyzed from time point of radiological assessment. Kaplan-Meier curves were plotted and compared using the log-rank test. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression modelling. Results: Of the 361 pts included in this analysis, 227 (62.9%) received fludarabine, cyclophosphamide and rituximab (FCR) and 134 (37.1%) pts received bendamustine and R (BR). Median age was 60 years (range, 34-79); median observation time was 55.8 months (mo) (3.2-85.5). 62 (17.2%) pts had residual abdominal LN+, 299 (82.8%) had no residual abdominal lymphadenopathy (LN-) at FR. Of 217 pts with documented CT/MRI of all LN regions at FR, 48 (22.1%) pts had residual LN+ in at least one LN region and 169 (77.9%) showed no residual LN in any of the regions. Baseline characteristics were equally distributed between pts with and without available radiological assessments, between pts with radiological assessments of all regions or only abdominal and between LN+ and LN- pts. MRD in PB was available for 231 (64.0%) pts in this analysis group; of these, 165 pts (71.4%) showed MRD negativity (MRD-) at FR. PFS and OS were analyzed for different LN size categories (≤1 cm; >1 & ≤2 cm; >2 & ≤3 cm; >3 cm). Patient outcome decreased with larger residual abdominal LN size at FR with regard to PFS (median, 52.9 mo vs. 24.6 mo vs. 30.5 mo vs. 10.6 mo; p1.5 cm in any lymph node region, PFS and OS was significantly worse compared to LN- pts (median PFS: 27.3 mo vs. 60.4 mo; HR 2.409; CI=1.622-3.577; p In the MRD- group, PFS was significantly shorter in MRD-/LN+ pts compared to MRD-/LN- pts (abdominal LN: median, 34.7 mo vs. 75.6 mo; HR 2.150; CI=1.190-3.883; p=0.011; any LN: median, 34.7 mo vs. 75.6 mo; HR 2.343; CI=1.221-4.497; p=0.01). This observation was confirmed for OS (abdominal LN: 5-year survival, 52.9% vs. 88.8%; HR 3.153; CI=1.183-8.407; p=0.022; any LN: 5-year survival, 61.9% vs. 94.3%; HR 4.213; CI=1.179-15.016; p=0.027) (Figures 2 & 3). Conclusions: Residual abdominal lymphadenopathy at FR is an independent prognostic factor for PFS and OS regardless of MRD negativity. It remains to be determined whether these findings can be transferred to novel targeted agents such as kinase inhibitors, venetoclax, novel CD20 antibodies or combinations of these. Residual disease in the lymph node compartment may identify a pt population which might benfit from strategies using consolidation therapies. Disclosures Bahlo: Roche: Honoraria, Other: Travel Grants. Fink:Celgene: Consultancy, Research Funding; AbbVie: Consultancy, Other: travel geants; Roche: Other: travel grants; Mundipharma: Other: travel grants. Dreyling:Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Research Funding; Bayer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Sandoz: Consultancy; Acerta: Consultancy; Gilead: Consultancy, Honoraria. Hess:CTI: Research Funding; Janssen: 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; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ritgen:Roche: Honoraria, Research Funding; abbvie: Research Funding. Kneba:AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Döhner:Bristol Myers Squibb: Research Funding; Jazz: Consultancy, Honoraria; Pfizer: Research Funding; Astellas: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Pfizer: Research Funding; Amgen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; AROG Pharmaceuticals: Research Funding; AbbVie: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding. Stilgenbauer:AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding. Wendtner:Mundipharma: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding. Goede:Roche: Consultancy, Honoraria, Other: Travel grants; Janssen: Consultancy, Honoraria, Other: Travel grants; Gilead: Consultancy, Honoraria; AbbVie: Consultancy. Fischer:Roche: Other: Travel support. Böttcher:Genentech: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Research Funding. Hallek:Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding.

Introduction: Advanced follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease. About 20% of patients have early progression of disease (POD) and short overall survival (OS). We have previously shown that integration of lymphoma-specific gene mutations and clinical factors improves pretreatment risk stratification (Pastore, 2015) and prediction of early POD (i.e., within 24 months, POD24; Jurinovic, 2016). Recently, we have shown that high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) is an effective treatment option for eligible patients with high-risk disease as defined by POD24 (Jurinovic, 2018). Here, we aimed to explore whether HDT/ASCT is an effective frontline therapy for patients identified to be high-risk by clinical (i.e., FLIPI) or clinicogenetic risk models (i.e., m7-FLIPI, POD24-PI). Methods: We performed targeted DNA deep-sequencing of >150 genes in available diagnostic FL biopsies from 165 patients ≤60 years with advanced FL from the GLSG2000 trial who uniformly received R-CHOP as frontline treatment. Of these, 87 patients (53%) were randomized to receive consolidative HDT/ASCT, 78 (47%) were randomized to interferon maintenance. We performed intention-to-treat (ITT) survival and regression analyses to explore whether known clinical and clinicogenetic risk factors can be overcome by ASCT. Results: The HDT/ASCT and no-HDT/ASCT cohorts were balanced regarding age (48 vs 50 years), sex (49% vs 64% male patients), high-risk FL International Prognostic Index (FLIPI; 25% vs 29%), Eastern Cooperative Oncology Group Performance Score >1 (6% vs 5%) and mutation status of EZH2 (23% vs 18%) and TP53 (3% vs 3%). The incidence of POD24 was not significantly lower in the HDT/ASCT cohort (8% vs 14%, p=0.32). After a median follow-up of 7.5 years, 5-year failure-free survival (FFS) rates in the HDT/ASCT and no-HDT/ASCT cohorts were 77% and 69% (HR 0.7, p=0.16), 5-year OS rates were 95% and 90% (HR 0.6, p=0.21), respectively. The high-risk cohorts identified by FLIPI, m7-FLIPI, and POD24-PI comprised 27% (n=45), 18% (n=29) and 22% (n=37) of patients, respectively (Fig. A). The m7-FLIPI reclassified 10% (n=16) of patients from high-risk FLIPI to low-risk m7-FLIPI. The POD24-PI reclassified 5% (n=9) of patients from high-risk FLIPI to low-risk POD24-PI; one patient was reclassified from low-risk FLIPI to high-risk POD24-PI. Patients identified to be high-risk by all three indices had shorter FFS (FLIPI: HR 2.8, p=0.0002; m7-FLIPI: HR 3.0, p=0.0003; POD24-PI: HR 2.5, p=0.0013), but OS was not different (FLIPI: HR 1.4, p=0.47; m7-FLIPI: HR 1.5, p=0.45; POD24-PI: HR 1.5, p=0.47). The risk to develop POD24 was increased in high-risk patients (FLIPI: OR 4.4, p=0.007; m7-FLIPI: OR 4.8, p=0.005; POD24-PI: OR 4.3, p=0.008). Consolidative HDT/ASCT did not prolong FFS in high-risk patients as defined by FLIPI (HR 1.2, p=0.67), m7-FLIPI (HR 1.2, p=0.70; Fig. B) and POD24-PI (HR 1.3, p=0.63; Fig. B). Similarly, OS was not significantly improved in all three high-risk cohorts (FLIPI: HR 0.2, p=0.13; m7-FLIPI: HR n/a, p>0.99; and POD24-PI: HR 0.3, p=0.22). In low-risk patients, HDT/ASCT was associated with a non-significant trend towards prolonged FFS (FLIPI: HR 0.5, p=0.061; m7-FLIPI: HR 0.6, p=0.16; POD24-PI: HR 0.5, p=0.068; Fig. B), but again OS was not significantly different (FLIPI: HR 0.8, p=0.69; m7-FLIPI: HR 0.8, p=0.66; and POD24-PI: HR 0.7, p=0.52). Conclusions: Our ITT-analysis confirms that consolidative HDT/ASCT should not be offered to unselected cohorts of patients with previously untreated, advanced FL after R-CHOP. Also, our current clinicogenetic risk models are not optimized to select high-risk patients who may benefit from frontline HDT/ASCT. The fraction of patients identified to be high-risk by FLIPI, m7-FLIPI and POD24-PI is low when applied to younger, medically fit patients. Moreover, the fraction of patients being reclassified by integrating gene mutation data is low in this patient cohort. Therefore, we are developing specific stratification algorithms for younger, medically fit patients who are eligible for dose-intensified approaches. Figure. Figure. Disclosures Klapper: F.Hoffman-La Roche: Honoraria, Research Funding; HTG Molecular Diagnostics, Inc.: Research Funding; Regeneron: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Schmitz:Riemser: Honoraria, Other: Travel grants; Kite/Gilead: Honoraria, Other: Travel grants; Novartis: Honoraria, Other: Travel grants; Celgene: Other: Travel grants; Roche: Honoraria. Hess:CTI: Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Unterhalt:F. Hoffman-La Roche: Other: Travel support. Dreyling:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees. Schmidt:Gilead: Honoraria, Other: Travel Grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Honoraria. Hoster:F. Hoffman-La Roche: Other: Travel support, Research Funding; Roche Pharma AG: Other: Travel support, Research Funding. Hiddemann:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Weigert:Roche: Research Funding; Novartis: Research Funding.

Introduction: Immunochemotherapy is standard of care treatment for previously untreated patients (pts) with advanced stage follicular lymphoma (FL). However, the majority of pts relapse, with around 20% relapsing within 2 years. Obinutuzumab (GA101; G) is a glycoengineered type II anti-CD20 monoclonal antibody (mAb) with increased antibody-dependent cell-mediated phagocytosis and cytotoxicity, and direct B-cell killing, compared with the type I mAb rituximab (R). The randomized Phase III GALLIUM study (NCT01332968) compared the efficacy and safety of G-chemotherapy (G-chemo) vs R-chemotherapy (R-chemo) in previously untreated pts with advanced stage FL. In the primary analysis (PA), a significant improvement in the primary study endpoint of investigator (INV)-assessed progression-free survival (PFS) was demonstrated with G-chemo relative to R-chemo after 34.5 months' median follow-up. Results for other time-to-event outcomes (including time-to-next treatment; TTNT) were supportive, and additional analyses demonstrated a higher rate of minimal residual disease, and a lower risk of disease progression within 24 months, in the G-chemo arm. Here we report the results from an updated analysis of time-to-event endpoints and safety in the GALLIUM study. Methods: In GALLIUM, enrolled pts were aged ≥18 years with previously untreated FL (grades 1-3a), Stage III/IV disease (or Stage II with bulky disease), and ECOG PS 0-2, and requiring treatment according to GELF criteria. Pts were randomized 1:1 to receive G 1000mg IV (days 1, 8 and 15 of cycle 1 and day 1 of subsequent cycles) or R 375mg/m2 IV (day 1 of each cycle) plus chemotherapy for 6 or 8 cycles, depending on the chemotherapy backbone (CHOP, CVP, or bendamustine). Chemotherapy backbone was a stratification factor and was chosen upfront by the participating centers. Pts with a complete or partial response at the end of induction received maintenance with the same antibody every 2 months for 2 years. The data cut-off for the current analysis was February 12, 2018. Results: In total, 1202 pts with FL were enrolled (G-chemo, n=601; R-chemo, n=601), with a median age of 59 years (46.8% male). After 57.3 months' median follow-up, a sustained and clinically meaningful improvement in INV-assessed PFS was observed with G-chemo relative to R-chemo (HR 0.73; 95% CI: 0.59, 0.90; p=0.0034; 4-year PFS rate: G-chemo, 78.1% [95% CI: 74.4%, 81.3%]; R-chemo, 67.2% [95% CI: 63.1%, 71.0%]; Figure 1A). Since the PA, 114 new PFS events (57 in G-chemo and 57 in R-chemo) had occurred. Overall survival (OS) data, which remain immature, were comparable across treatment arms (HR 0.88; 95% CI: 0.61, 1.27; p=0.49; 4-year OS rate: G-chemo, 92.6% [95% CI: 90.1%, 94.4%]; R-chemo, 90.3% [95% CI: 87.6%, 92.5%]; Figure 1B). A sustained benefit in favor of G-chemo was observed in TTNT (HR 0.70; 95% CI: 0.54, 0.90; p=0.0046; 4-year TTNT rate: G-chemo, 84.2% [95% CI: 80.9%, 86.9%]; R-chemo, 76.7% [95% CI: 73.1%, 80.0%]; Figure 1C). Since the PA, 29 and 36 additional pts in the G- and R-chemo arms, respectively, had received new anti-lymphoma treatment. At cut-off, 54 (9.1%) pts in the G-chemo arm and 61 (10.2%) in the R-chemo arm had died. Common causes were disease progression (G-chemo, n=21 [3.5%]; R-chemo, n=28 [4.7%]) and AEs (G-chemo, n=24 [4.0%]; R-chemo, n=24 [4.0%]). The most common fatal AEs were infections (9 vs 4 pts, respectively) and new malignancies (5 vs 6 pts, respectively). Incidences of AEs of any grade were comparable across the G-chemo (99.8%) and R-chemo (99.5%) arms, although grade 3-5 AEs (79.2% vs 71.2%) and serious AEs (48.7% vs 42.2%) were more common in the G-chemo arm. AEs led to discontinuation in 16.3% of G-chemo pts and 14.6% of R-chemo pts. As in the PA, the incidence of grade 3-5 infections (22.2% vs 18.6%), grade 3-5 neutropenia (and associated complications reported as AEs, 48.4% vs 41.4 %), and grade 3-5 second malignancies (6.9% vs 4.4%) was numerically higher in pts receiving G-chemo than R-chemo. Conclusions: In line with the PA, the results from this updated analysis of the GALLIUM study, with a median follow-up of almost 5 years, reinforce that G-chemo provides clinically meaningful improvements in outcomes relative to R-chemo in previously untreated FL pts. OS data remain immature, with additional follow-up needed to draw conclusions. Safety data are consistent with those reported in the PA. Figure 1. Figure 1. Disclosures Townsend: Gilead: Consultancy; Roche: Consultancy. Buske:Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Research Funding. Cartron:Roche: Consultancy, Honoraria; Sanofi: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Celgene: Consultancy, Honoraria. Cunningham:Roche pharmaceuticals: Research Funding. Dyer:Roche: Honoraria, Research Funding. Gribben:Medical Research Council: Research Funding; Acerta Pharma: Honoraria, Research Funding; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; TG Therapeutics: Honoraria; Abbvie: Honoraria; Wellcome Trust: Research Funding; Unum: Equity Ownership; Pharmacyclics: Honoraria; NIH: Research Funding; Cancer Research UK: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Kite: Honoraria. Hess:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, Research Funding; CTI: Research Funding; Janssen: 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; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Keller:BMS: Consultancy; Celgene: Research Funding; MSD: Consultancy; Takeda: Consultancy, Research Funding; Janssen-Cilag: Consultancy, Equity Ownership; Roche: Consultancy. Kneba:Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Malladi:Roche: Membership on an entity's Board of Directors or advisory committees. Neidhart:Gilead: Consultancy; Roche: Consultancy, Other: Travel support and lecture fees. Rusconi:Celgene: Research Funding. Zhu:Beijing Cancer Hospital (Peking University Cancer Hospital): Employment. Catalani:Roche: Employment. Knapp:Roche: Employment. Zeuner:F. Hoffman-La Roche: Employment, Equity Ownership. Hiddemann:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marcus:Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy; F. Hoffman-La Roche: Other: Travel support and lecture fees.

Background Multiple studies have demonstrated the efficacy and safety of ibrutinib for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL). This first-in-class inhibitor of Bruton's tyrosine kinase has become a standard treatment for patients with CLL and MCL. Patients and Methods We conducted an integrated safety analysis to characterize the frequency, severity, natural history, and outcomes of adverse events (AEs) with ibrutinib versus comparators. Data were pooled from 4 completed randomized controlled studies that had included 756 ibrutinib-treated and 749 comparator-treated patients with CLL/SLL or relapsed/refractory MCL. Safety analyses included reporting of AEs using crude and exposure-adjusted incidence rates. Results The median treatment duration was 13.3 months (maximum, 28.2 months) for ibrutinib and 5.8 months (maximum, 27.3 months) for comparators. When adjusted for exposure, diarrhea, atrial fibrillation, and hypertension were the only common grade ≥ 3 AEs more often reported with ibrutinib than with the comparators. Dose reductions (7% vs. 14%) and discontinuation (12% vs. 16%) because of AEs occurred less often with ibrutinib, and deaths due to AEs occurred at similar rates (6% vs. 7%). When adjusted for exposure, the corresponding data were all lower with ibrutinib than with the comparators (0.06 vs. 0.22, 0.11 vs. 0.22, and 0.06 vs. 0.09 patient-exposure-years, respectively). The prevalence of common grade 3/4 AEs with ibrutinib generally decreased over time, with the exception of hypertension. Conclusion These results from an integrated analysis support a favorable benefit/risk profile of ibrutinib in patients with CLL/SLL and MCL.

Background: We sought to determine the diagnostic performance of the new high-sensitivity cardiac troponin T (hs-cTnT) assay for early detection of non–ST-segment myocardial infarction (NSTEMI) in patients with acute coronary syndrome. Methods: We enrolled patients with retrospectively confirmed unstable angina or NSTEMI and an initially negative cTnT concentration and compared the performance of baseline concentrations and serial changes in concentration within 3 and 6 h. Percentage change criteria included ≥20% δ change and ROC-optimized value. Results: Based on the standard fourth-generation cTnT result of ≥0.03 μg/L, an evolving NSTEMI was diagnosed in 26 patients, and 31 patients were classified as having unstable angina. With the use of the hs-cTnT assay at the 99th-percentile cutoff, the percentage of NSTEMI cases detected increased gradually from 61.5% on presentation to 100% within 6 h, and the overall number of MI diagnoses increased by 34.6% (35 vs 26 cases). A δ change ≥20% or ≥ROC-optimized value of >117% within 3 h or ≥243% within 6 h yielded a specificity of 100% at sensitivities between 69% and 76%. The standard cTnT at the 99th percentile was less sensitive than hs-cTnT for early diagnosis of MI on presentation, and follow-up samples obtained within the initial 3 h demonstrated very low specificity of cTnT compared with hs-cTnT. Conclusions: The high-sensitivity cTnT assay increases the number of NSTEMI diagnoses and enables earlier detection of evolving NSTEMI. A doubling of the hs-cTnT concentration within 3 h in the presence of a second concentration ≥99th percentile is associated with a positive predictive value of 100% and a negative predictive value of 88%.

The clinical course of peripheral T-cell lymphoma (PTCL) is usually aggressive and the prognosis unfavorable. Therefore, there is a need for improvement of treatment options. Patients with newly diagnosed (n = 27) or refractory/relapsed (n = 11) PTCL received a combination of alemtuzumab, fludarabine, cyclophosphamide, and doxorubicin. The overall response rate (ORR) was 61%, with a complete response rate of 39%. In newly diagnosed patients the ORR was 63%, the median overall survival 25.9 months, and progression-free survival 11.8 months. In relapsed/refractory patients the median OS was 6.1 months. The most frequent grade 3/4 toxicities were leukopenia (95% of patients) and thrombocytopenia (58%). Cytomegalovirus (CMV) reactivation occurred in 12 patients, but only two had CMV disease. Treatment-related deaths occurred in six newly diagnosed patients and one with relapsed/refractory disease. In conclusion, Campath-FCD is active in PTCL but is associated with significant toxicity and is, therefore, not recommended for use or further study. Further studies are warranted to investigate other approaches to combining alemtuzumab with chemotherapy for the treatment of PTCL.

Purpose Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has shown clinical activity in mantle cell lymphoma (MCL). We evaluated two dose regimens of temsirolimus in comparison with investigator's choice single-agent therapy in relapsed or refractory disease. Patients and Methods In this multicenter, open-label, phase III study, 162 patients with relapsed or refractory MCL were randomly assigned (1:1:1) to receive one of two temsirolimus regimens: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigator's choice therapy from prospectively approved options. The primary end point was progression-free survival (PFS) by independent assessment. Results Median PFS was 4.8, 3.4, and 1.9 months for the temsirolimus 175/75-mg, 175/25-mg, and investigator's choice groups, respectively. Patients treated with temsirolimus 175/75-mg had significantly longer PFS than those treated with investigator's choice therapy (P = .0009; hazard ratio = 0.44); those treated with temsirolimus 175/25-mg showed a trend toward longer PFS (P = .0618; hazard ratio = 0.65). Objective response rate was significantly higher in the 175/75-mg group (22%) compared with the investigator's choice group (2%; P = .0019). Median overall survival for the temsirolimus 175/75-mg group and the investigator's choice group was 12.8 months and 9.7 months, respectively (P = .3519). The most frequent grade 3 or 4 adverse events in the temsirolimus groups were thrombocytopenia, anemia, neutropenia, and asthenia. Conclusion Temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly significantly improved PFS and objective response rate compared with investigator's choice therapy in patients with relapsed or refractory MCL.

The MDM-2 (murine double minute 2) gene codes for a cellular protein that can bind to the p53 tumor suppressor gene product, thereby functioning as a negative regulator of p53. In order to define the role of the MDM-2 gene in the pathogenesis of human acute myeloid leukemia, the expression and the sequence of the MDM-2 gene were examined in samples of bone marrow and/or peripheral mononuclear cells of 38 patients by using immunostaining, polymerase chain reaction (PCR), single strand conformation polymorphism, and sequencing. Immunohistochemical staining detected a weak accumulation of the MDM-2 protein in AML patients of FAB classification M4 and M5. RT-PCR analysis revealed a heterogeneous expression pattern of MDM-2 mRNA in AML samples of different FAB classification. An increased level of MDM-2 mRNA expression was observed in 17 of 38 AML patients when compared to normal controls. No structural changes in a 488 bp region extending from nucleotide 890 to 1378 of the MDM-2 cDNA were detected using RT-SSCP and sequence analysis. In addition, heterogeneous expression of p53 transcripts was found with the highest p53 mRNA levels in AML M4 and M5. Interestingly, there seems to be a correlation between the relative ratios of p53 and MDM-2 mRNA levels in AML M4 and M5: in 15 of 23 cases high p53 mRNA expression was directly associated with high levels of MDM-2 transcripts. An exclusively intranuclear p53 immunostaining pattern was found in 10 of 16 (58%) AML FAB M4 and M5, whereas the remaining AML samples tested were negative for p53 (0/10). Using RT-SSCP analysis and direct sequencing of the RT-PCR amplification products of p53 exon 5-8, we observed that only 1 of 38 AML patients showed a point mutation in the p53 gene. This missense mutation occurred in the evolutionary highly conserved region of p53 at codon 255 (Ile to Phe). These data indicated that structural alterations of the p53 gene do not play an important role in the initiation and progression of AML. However, abrogation of p53 tumor suppressor function due to MDM-2 overexpression may be an alternative molecular mechanism by which a subset of AMLs may escape from p53-regulated growth control.

Serum concentrations of the amino-terminal pro-B-type natriuretic peptide (NT-proBNP) may be used to monitor cardiac function during pregnancy but normal values are not established for this purpose. Therefore, we investigated NT-proBNP in normotensive healthy pregnancies compared to a non-pregnant control group. Serum NT-proBNP was measured in 94 normotensive, healthy pregnant women (32+/-6 years) every five weeks beginning from 12th gestational week (GW) in a longitudinal study and compared to a non-pregnant control group of 521 women (32+/-7 years). Pooled median serum NT-proBNP levels (25th; 75th percentile) were significantly higher in pregnant women compared to non-pregnant women (56 (33; 95) pg/ml vs. 38 (22; 62) pg/ml (p

— Six hundred and sixty-six homosexuals were analysed in respect of hepatitis B virus and delta infections. Evidence of ongoing or recent hepatitis B virus infection was found in 450/666 (67.6%) homosexuals; 44 were HBsAg positive. Anti-delta was found in two HBsAg-positive homosexuals. Both individuals had a non-replicative form of HBV infection and biochemical evidence of liver disease. The study confirms that HBV infection is frequent in homosexuals and indicates that delta-infection is rare in male homosexuals.

— The sera of 15 individuals with transfusion-associated acute or chronic non A, non B hepatitis, which lacked hepatitis B virus markers, were tested for hepatitis B virus DNA by dot blot hybridization test. Three sera of two patients positive in this test, however, also gave positive results when the labeled plasmid was used as probe instead of labeled HBV-DNA, indicating false positive results in the initial test. In conclusion, the data indicated that sera of patients with confirmed non A, non B hepatitis do not contain DNA-sequences in the serum hybridizing with HBV-DNA.

Lymphoplasmacytic lymphoma (LPL) is an indolent lymphoma with moderate sensitivity to conventional chemotherapy. This study investigated whether the addition of rituximab to standard chemotherapy improves treatment outcome in LPL and the subgroup of LPL patients fulfilling the criteria of Waldenstroem's macroglobulinemia (WM). A total of 69 patients with previously untreated LPL were enrolled into the trial; 64 patients were evaluable for treatment outcome. In all, 48 of the 64 LPL patients fulfilled the criteria of WM. Patients were randomly assigned to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, n=34) or CHOP (n=30). R-CHOP resulted in significantly higher overall response (OR) rate (94 vs 67%, P=0.0085) in the LPL patients and in the WM subgroup (91 vs 60%, P=0.0188). With a median observation time of 42 months, R-CHOP induced a significantly longer time to treatment failure (TTF) with a median of 63 months for R-CHOP vs 22 months in the CHOP arm in the LPL patients (P=0.0033) and in the WM subgroup (P=0.0241). There was no major difference of treatment-associated toxicity between both treatment groups. These data indicate that the addition of rituximab to front-line chemotherapy improves treatment outcome in patients with LPL or WM.

Previous attempts have shown the potential of T cells in immunotherapy of cancer. Here, we report on the clinical activity of a bispecific antibody construct called blinatumomab, which has the potential to engage all cytotoxic T cells in patients for lysis of cancer cells. Doses as low as 0.005 milligrams per square meter per day in non–Hodgkin's lymphoma patients led to an elimination of target cells in blood. Partial and complete tumor regressions were first observed at a dose level of 0.015 milligrams, and all seven patients treated at a dose level of 0.06 milligrams experienced a tumor regression. Blinatumomab also led to clearance of tumor cells from bone marrow and liver. T cell–engaging antibodies appear to have therapeutic potential for the treatment of malignant diseases.

SummaryTreatment of relapsed or refractory autoimmune mediated haemolytic syndromes, such as autoimmune haemolytic anaemia (AIHA) and thrombotic thrombocytopenic purpura (TTP), represents a therapeutic challenge. Here we report on our experience with the monoclonal anti-CD20 antibody rituximab (R) compared to standard treatment in these diseases. Patients with non-familialTTP orAIHA and no underlying malignancy were included in our analysis. Safety and efficacy of R-treatment were compared to results obtained in standard treatment approaches. Altogether, 27 patients were analyzed, comprising 15 patients withTTP and 12 patients with AIHA. The patients’ average age at the time of diagnosis was 54 years. Eleven patients received antibody treatment (8 TTP, 3 AIHA). No acute or late WHO grade III/IV toxicity associated with rituximab was noted. With standard therapy, the overall response rate (ORR) was 66.7% for AIHA and 65.8% for TTP, respectively. For the R-containing regimens the ORR was 100%. In patients with TTP, median progression free survival (PFS) with R-treatment was 3.8 years, as compared to 0.1 years in the standard-treatment group. In patients with AIHA median PFS was not reached for R-containing treatment; all patients are in sustained remissions with a median follow up of 12.5 months. In the absence of prospective trials, our data underline the safety and efficacy of rituximab in relapsed and refractory autoimmune anaemias with favourable response rates and promising long-term progressionfree survival. Therefore, prospective clinical trials evaluating rituximab as salvage- and first-line-therapy are clearly warranted.

On the basis of a preceding phase I study, the current trial explored bendamustine in combination with mitoxantrone and rituximab (BMR) in patients with stage III/IV relapsed or refractory indolent lymphomas and mantle cell lymphoma (MCL) with or without prior rituximab containing chemo-immunotherapy (R-chemo) treatment. Therapy consisted of bendamustine 90 mg/m(2) days 1 + 2, mitoxantrone 10 mg/m(2) day 1, rituximab 375 mg/m(2) day 8. Treatment was repeated on day 29 for a total of four cycles. Between 3 April and 04 July, 57 patients were recruited from 24 participating institutions, 39% of whom had received prior R-chemo therapy. Median age was 66 years (40 - 83). Lymphoma subtypes were 29 follicular (FL), 18 MCL, and 10 other indolent lymphomas. The overall response rate (ORR) was 89% with 35% CR and 54% PR. ORR in R-chemo pretreated patients was 76% (38% CR, 38% PR). After a median observation time of 27 months (1 - 43), the estimated median progression free survival is 19 months. The 2 year overall survival is 60% for patients with FL and MCL. Treatment related toxicities of grade 3/4 comprised a reversible myelosuppression (10% anemia, 78% leukocytopenia, 46% granulocytopenia, 16% thrombocytopenia). However, unexpected hospitalisations were necessary after 4% of BMR-application only. BMR is a very effective new outpatient immuno-chemotherapy with low toxicity for patients with relapsed/refractory FL, MCL and other indolent lymphomas.

The mammalian target of rapamycin (mTOR) is a protein kinase involved in the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway. It plays a pivotal role in the control of cell proliferation, survival, and angiogenesis with multiple and frequent dysregulations of this pathway in human tumors. Temsirolimus is an intravenous drug, specifically inhibiting the mTOR pathway. Bendamustine is well known for its clinical activity in indolent non-Hodgkin-lymphoma (NHL) and has lately shown clinical activity in mantle cell lymphoma (MCL). Here, we present a case report of temsirolimus in combination with bendamustine and rituximab leading to a CR in a pretreated male. In addition, our in vitro data underlines the additive and synergistic efficacy in cell growth reduction of temsirolimus combined with bendamustine in MCL cell lines and in DLBCL cell lines. Furthermore, as an underlying mechanism of this additive, effects on cell cycle inhibition and apoptosis induction could be identified.

Presepsin (PSEP) is released during infectious diseases and can be detected in the blood. PSEP has shown promising results as sepsis marker. We examined the diagnostic and prognostic validity of PSEP in patients suspicious of sepsis on admission in the emergency department (ED). Methods One hundred twenty three patients with signs of SIRS and/or sepsis and 123 healthy individuals were enrolled. PSEP was determined on admission, after 8, 24 and 72 h. Results Mean PSEP concentrations of the control group and the patient group were 130 and 1945 pg/ml. PSEP differed between SIRS, sepsis, severe sepsis and septic shock and showed strong association with 30-day mortality ranging from 10.3% in the 1st to 32.1% in the 4th quartile. The ROC curve analyses revealed an AUC value of 0.743. Combined assessment of PSEP and MEDS score increased the AUC up to 0.878 demonstrating the close relationship with outcome. Based on the PSEP values in the different severity degrees, decision thresholds for risk stratification were established. The course of PSEP during the first 72 h was associated with effectiveness of treatment and outcome. Conclusions PSEP allowed outcome prediction already on admission to a similar degree as the clinical scores MEDS and APACHE II. Combination of PSEP with MEDS score improved the discriminatory power for outcome prediction. Our study has been supported by Mitsubishi Chemical Europe through providing the PSEP reagents free of charge. Dr. Carpio has received speaker honoraria from Mitsubishi Chemical Europe. DIAneering – Diagnostics Engineering & Research consulted to Axis Shield Diagnostics, Mitsubishi Chemical Europe, Radiometer, Roche Diagnostics, Shanghai Kehua Bio-engineering. No potential conflict of interest to this paper was reported Peer review

Few patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) achieve prolonged disease-free survival. Blinatumomab, a bispecific T-cell engaging antibody construct, transiently links CD3-positive T cells to CD19-positive B cells. This phase 2 study evaluated stepwise (9-28-112 μg/d with weekly dose increases; n = 23) or flat (112 μg/d; n = 2) dosing of blinatumomab by continuous infusion, with dexamethasone prophylaxis, in patients with relapsed/refractory DLBCL. Patients received a median of 3 prior lines of therapy. Median time since last regimen was 1.5 months. Seventeen patients ended treatment in cycle 1 (induction), 7 in cycle 2 (consolidation), and 1 in retreatment. Among 21 evaluable patients, the overall response rate after 1 blinatumomab cycle was 43%, including complete responses (CRs) in 19%. Three patients had late CR in follow-up without other treatment. The most common adverse events with stepwise dosing were tremor (48%), pyrexia (44%), fatigue (26%), and edema (26%). Grade 3 neurologic events with stepwise dosing were encephalopathy and aphasia (each 9%) and tremor, speech disorder, dizziness, somnolence, and disorientation (each 4%). Of 5 (22%) patients who discontinued stepwise dosing because of adverse events, 4 (17%) had neurologic events. Most neurologic events resolved. The flat-dose cohort was stopped because of grade 3 neurologic events in both patients. Blinatumomab monotherapy appears effective in patients with relapsed/refractory DLBCL, a heavily pretreated patient population with a high unmet medical need. Further studies need to define the optimal approach to achieve the target dose without early dropout. The study was registered at www.clinicaltrials.gov as #NCT01741792.

Background Temsirolimus, a selective inhibitor of the mammalian target of rapamycin, has demonstrated clinical benefit versus investigator’s choice (INV) of therapy in patients with relapsed/refractory mantle cell lymphoma (MCL). Methods This post hoc study retrospectively assigned simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) scores (ie, secondary MIPI) based on parameters at the time of randomization in patients with MCL (N = 162) who received temsirolimus 175 mg once weekly for 3 weeks followed by once-weekly 75 mg or 25 mg or the INV of active therapy. Outcomes were analyzed according to the low-, intermediate- or high-risk category. Results Patient distribution by MIPI risk category was 31%, 39%, and 30% in the low-, intermediate-, and high-risk groups, respectively. Among patients in all categories, objective response rate (complete response + partial response) was higher in patients in the temsirolimus 175/75-mg group versus the INV group, respectively: 42% versus 0% (low-risk); 33% versus 5% (intermediate-risk); 10% versus 0% (high-risk). Median progression-free survival was significantly longer with temsirolimus 175/75 mg versus INV, respectively, in patients with intermediate (4.3 vs 1.9 months; P = 0.035) or high (4.5 vs 1.6 months; P = 0.0025) risk, and a trend toward improvement was observed in patients with low risk (5.3 vs 2.6 months; P = 0.091). Improvement in median overall survival was observed with temsirolimus 175/75 mg versus INV in low-risk patients (18.0 vs 10.5 months, respectively; P = 0.069). Conclusions This analysis suggests that, compared with INV, temsirolimus demonstrated benefit in all MIPI risk categories in patients with MCL. In all treatment groups, patients with high secondary MIPI scores at baseline faced a dismal prognosis. Trial registration ClinicalTrials.gov NCT00117598. Electronic supplementary material The online version of this article (doi:10.1186/s40164-015-0006-1) contains supplementary material, which is available to authorized users.

There is controversy whether new biomarkers are able to identify myocardial ischemia in the absence of myonecrosis.We measured NT-pro BNP, NT-pro ANP, ischemia-modified albumin (IMA) and placental growth factor (PlGF) in patients undergoing nuclear stress testing for suspected ischemic heart disease. A thallium scan was used for detection of reversible myocardial ischemia and cardiac troponin T (cTnT) for exclusion of stress-induced myonecrosis. Of 195 patients, 24 with reversible and 62 with no perfusion defect were included in the analysis. Plasma levels were measured before, 18 min and 4 h after stress testing.Of the 86 patients, 52 received an exercise stress and 34 dipyridamol. New myonecrosis indicated by cTnT could be excluded in all patients. Plasma levels of NT-pro BNP and NT-pro ANP before testing were significantly higher in patients who later developed reversible perfusion defects (NT-pro BNP 139.00 (58.25/367.01) pg/mL vs 327.45 (120.50/972.85) pg/mL, p0.05; NT-pro ANP 732.5 (470.0/1220.0) pg/mL vs 1470.0 (694.0/1910.0) pg/mL, p0.05). Plasma levels of NT-pro BNP, NT-pro ANP and PIGF did not change significantly after stress testing, IMA levels rose significantly after 4 h in patients with and without reversible perfusion defects.The elevation of NTpro BNP and NT-pro ANP at baseline may represent the cumulative effect of repeated bouts of myocardial ischemia. A single brief episode of provoked ischemia does not cause a significant increase of the measured biomarkers beside from IMA after exercise stress test potentially indicating skeletal muscle ischemia.

GB virus type C (GBV-C) is a human flavivirus that may cause persistent infection, although most infected individuals clear viremia and develop antibodies to the envelope glycoprotein E2. To study GBV-C E2 antigenicity and cell binding, murine anti-E2 monoclonal antibodies (MAbs) were evaluated to topologically map immunogenic sites on GBV-C E2 and for the ability to detect or block recombinant E2 binding to various cell lines. Five competition groups of MAbs were identified. Groups I and II did not compete with each other. Group III competed with both groups I and II. Group IV did not compete with group I, II, or III. One MAb competed with all of the other MAbs, suggesting that the epitopes bound by these MAbs are intimately related. Individually, none of the MAbs competed extensively with polyclonal human convalescent antibody (PcAb); however, combinations of all five MAb groups completely blocked PcAb binding to E2, suggesting that the epitopes bound by these MAbs form a single, immunodominant antigenic site. Only group I and III MAbs detected purified recombinant E2 bound to cells in binding assays. In contrast, group II MAbs neutralized the binding of E2 to cells. Both PcAb and MAbs were conformation dependent, with the exception of one group II MAb (M6). M6 bound to a five-amino-acid sequence on E2 if the peptide included four C-terminal or eight N-terminal residues, suggesting that the GBV-C E2 protein contains a single immunodominant antigenic site which includes a complex epitope that is involved in specific cellular binding.

GB virus C (GBV-C; also called hepatitis G virus) is a common cause of infection associated with prolonged survival among HIV-infected individuals. the prevalences of GBV-C viremia vary widely in different studies, and there has been poor agreement among different laboratories performing GBV-C RNA detection in quality control studies. To determine the optimal method of measuring GBV-C RNA in clinical samples, samples obtained from 939 HIV-infected subjects were studied using reverse transcription (RT)-PCR methods amplifying four separate regions of the GBV-C genome. Primers amplifying the E2 coding region were 100% specific; however, their sensitivity was only 76.6%. in contrast, primers amplifying three additional conserved regions of the GBV-C genome (the 5' nontranslated region and the nonstructural protein-coding regions 3 and 5A) were more sensitive but produced higher rates of false-positive results. Using low-specificity primer sets influenced the significance of association between GBV-C viremia and response to antiretroviral therapy. Using a quantitative GBV-C RNA method, the GBV-C RNA concentration did not correlate with baseline or set point HIV RNA levels; however, a correlation between negative, low, and high GBV-C RNA levels and increasing reduction in HIV RNA following antiretroviral therapy was observed. Subjects with both GBV-C E2 antibody and viremia had significantly lower GBV-C RNA levels than did viremic subjects without E2 antibody. These studies demonstrate that accurate detection of GBV-C RNA by nested RT-PCR requires the use of primers representing multiple genome regions. Analyses based on testing with single primers do not lead to reliable conclusions about the association between GBV-C infection and clinical outcomes. Univ Iowa, Roy & Lucille Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA Iowa City Vet Adm Med Ctr, Iowa City, IA USA Universidade Federal de São Paulo, Paulista Sch Med, Div Infect Dis, São Paulo, Brazil Univ Iowa, Coll Publ Hlth, Dept Biostat, Iowa City, IA USA Roche Diagnost GmbH, Penzberg, Germany Roche Diagnost GmbH, Mannheim, Germany NIAID, Epidemiol Branch, Div AIDS, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA Universidade Federal de São Paulo, Paulista Sch Med, Div Infect Dis, São Paulo, Brazil Web of Science

Allogeneic hematopoietic stem cell transplantation (SCT) regimens incorporating the lymphocytotoxic CD52 antibody alemtuzumab demonstrate efficient engraftment and reduced graft-versus-host disease (GVHD). However, these protocols substantially impair posttransplantation antiviral and antitumor immunity. To accelerate immune reconstitution after alemtuzumab-based reduced-intensity SCT, we administered prophylactic CD8-depleted donor lymphocyte infusions (DLIs) starting on days 60 and 120 after transplantation. DLIs were processed in an immunomagnetic good manufacturing practice depletion procedure resulting in a 2.5- to 6-log reduction in CD8 T cells. Of 23 high-risk patients with hematologic malignancies, 11 received a total of 21 CD8-depleted DLIs. Five patients developed transient grade I acute GVHD following transfer. Only 2 patients with HLA-C–mismatched donors showed grade II and III acute GVHD and subsequently progressed to limited chronic GVHD. Following DLIs, 4 patients with declining hematopoietic donor chimerism converted to full chimeras. A 2.1-fold median increase of circulating CD4 T cells was observed within 2 weeks after infusion. Non-DLI patients did not show a comparable rise in CD4 counts. Four patients demonstrated enhanced frequencies of cytomegalovirus-specific CD4 and CD8 T cells following transfer. Our results suggest that prophylactic CD8-depleted DLIs accelerate immune reconstitution after lymphodepleted HLA-matched SCT and carry a low risk of inducing severe GVHD.

To better define the role of rituximab in salvage and high-dose therapy (HDT) for relapsed or refractory non-Hodgkin's lymphoma (NHL), patients treated before the implementation of rituximab in salvage and HDT (n = 57, control group) were compared with patients with rituximab included in this procedure (n = 36, study group). All patients had been antibody-naive at this point, and analyses were performed separately for 22 and 31 patients with aggressive, and 14 and 26 patients with indolent NHL, respectively. All patients received two courses of salvage therapy, predominantly dexamethasone, BCNU, etoposide, cytosine arabinoside, melphalan. Conditioning regimens included BCNU, etoposide, cytosine arabinoside, melphalan; BCNU, etoposide, cytosine arabinoside, cyclophosphamide or total body irradiation and cyclophosphamide, with rituximab added for patients in the study group. Despite the absence of differences in stem cell collection, haematopoietic recovery was delayed in patients with aggressive NHL treated in the study group: median days to absolute neutrophil count more than 0.5 x 10(9)/l, 11 vs 10 (p = 0.01), and platelets more than 20 x 10(9)/l, 14 vs 11 (p = 0.0005), with an increased requirement for platelet transfusions. No similar observations were made in indolent lymphoma patients. Remission rates were superior for patients with aggressive NHL in the study group. With a median follow-up of 7.25 and 4.5 years, this resulted in an improvement in OS at 4.5 years: 67 vs 45% (95% confidence interval, 47-87% vs 28-64%; p = 0.0468). For patients with indolent lymphoma, no comparable benefit was detectable. Our data support the use of rituximab in HDT for patients with aggressive NHL. For patients with indolent NHL, only longer follow-up and/or randomized trials may help to fully determine the impact of rituximab on the outcome after HDT.

Purpose In the era of molecular therapy of chronic myelogenous leukemia (CML) applying BCR-ABL tyrosine kinase inhibitors, the usefulness of molecular end points, in particular, quantitative polymerase chain reaction (PCR) for BCR-ABL in monitoring responses has been broadly accepted. Therefore, we have designed a prospective phase II trial in CML, which, for the first time, evaluated the feasibility and safety of molecular end points as surrogate markers to guide through a stratified treatment algorithm within a multicenter trial. Patients and Methods As a clinical model, we adopted minimal residual disease (MRD) found in relapse after allogeneic stem cell transplantation (SCT) in CML. Forty-four patients were enrolled and received the BCR-ABL tyrosine kinase inhibitor imatinib (IM) at a starting dose of 400 mg/d. The quality of molecular responses achieved then decided on discontinuation of IM or dose escalation up to 800 mg/d, and finally, on application of donor lymphocyte infusions. Results Seventy percent of patients achieved a complete molecular response (CMR), defined as nested PCR-negativity for BCR-ABL in three consecutive samples. Interestingly, in four out of 10 patients who discontinued IM, CMR was durable even after cessation of IM with a median follow-up of 494 days. This suggests the possibility of long-term tumor control in a subset of patients. Conclusion The treatment strategy showed that IM treatment was well-tolerated and highly efficacious in MRD after allogeneic SCT. Moreover, this study demonstrated that evaluation of a molecular end point within a multicenter trial can be a safe and effective tool for clinical decision making.

We assessed reference values in a group of apparently healthy blood donors. A total of 1980 blood donors was recruited and tested for the presence of NT-proBNP using a newly developed electrochemiluminescence immunoassay (ECLIA) method. NT-proBNP clustered in all blood donors below the age of 50 years and an upper limit of normal (ULN) was found to be 84 pg/ml for males and 146 pg/ml for females. Mean NT-proBNP values increased with increasing age which was due to an increasing number of individuals exceeding the ULN. Age- and gender-appropriate NT-proBNP levels decreased with increasing hemoglobin levels. Hemoglobin but not creatinine levels influenced the NT-proBNP concentration in this cohort. The upper limit of normal can be used in clinical studies to further assess groups of diseased individuals to define clinical cutoffs.

Auch wenn in den vergangenen Jahren z. T. eine Verbesserung der Prognose von Non-Hodgkin-Lymphomen (NHL) bereits mit veranderten konventionellen und eskalierten Chemotherapieverfahren indolenter und aggressiver Lymphome erreicht werden konnte, verlauft fur einen grosen Teil der Patienten die Tumorerkrankung noch immer fatal. Da eine weitere Optimierung konventioneller Modalitaten schwer moglich erschien, stellte die Etablierung immuntherapeutischer Ansatze eine attraktive Option dar. Die erfolgreiche Einfuhrung monoklonaler Antikorper in die Behandlung maligner Lymphome hat die Immuntherapie fest etabliert. Weiterentwicklungen dieses passiven Immuntherapieansatzes sind auf dem Weg in den klinischen Alltag. Daneben sind unterschiedliche Verfahren aktiver Immunisierung (Vakzinierung) in praklinischen und fruhen klinischen Entwicklungen, deren Etablierung eine weitere Bereicherung des therapeutischen Armentariums darstellen kann. Zuletzt hat — insbesondere fur Hochrisikopatienten — die allogene Stammzelltransplantation in der jungsten Vergangenheit an Attraktivitat gewonnen.

Background Prolonged persistence of donor-derived T cells after organ transplantation has been proposed to improve long-term allograft survival. However, surviving transplant-derived T cells are also able to mediate devastating graft-versus-host disease (GvHD). Currently, GvHD after organ transplantation is usually refractory to conventional therapy and the disease outcome fatal. Methods Graft-reactive host T cells were generated ex vivo from a patient suffering from a severe and refractory liver-transplant-associated GvHD. To control GvHD, activated alloreactive host T cells were repetitively retransferred into the patient (activated host lymphocyte infusion [aHLI]). Results Adoptive transfer of ex vivo activated alloreactive host T cells (aHLI) led to the control and complete resolution of severe GvHD without inducing allograft rejection. Conclusions aHLI opens a novel therapeutic window to control solid-organ transplant-associated GvHD while preserving allograft integrity.

This phase 2 pilot study was conducted to determine the efficacy and safety of imatinib mesylate in patients with c-kit–positive acute myeloid leukemia (AML) refractory to or not eligible for chemotherapy. Twenty-one patients were enrolled and received imatinib 600 mg orally once daily. Five responses were seen primarily in patients, starting with relatively low blast counts in bone marrow (BM) and peripheral blood (PB): 2 patients who were considered refractory on chemotherapy on the basis of persistence of blasts in PB and BM met the criteria for complete hematologic remission, 1 patient had no evidence of leukemia, and 2 patients achieved a minor response. Treatment with imatinib demonstrated a good safety profile and was well tolerated. Western blot analysis and immunohistochemistry demonstrated c-Kit activation in primary AML cells. Further, imatinib treatment of primary AML cells inhibited c-Kit tyrosine-phosphorylation. Genomic DNA-sequencing of c-KIT showed no mutations in exons 2, 8, 10, 11, 12, and 17. Although some of the responses derived from relatively small reductions in leukemic blasts and may be attributable, in part, to prior chemotherapy, these cases suggest that imatinib has interesting clinical activity in a subset of patients with c-kit–positive AML. Further clinical trials are warranted to explore the clinical potential of imatinib in AML and to identify the underlying molecular mechanism.

GB virus C (GBV-C), which is not known to be pathogenic in humans, replicates in lymphocytes, inhibits the replication of human immunodeficiency virus (HIV) in vitro, and has been associated with a decreased risk of death among HIV-positive persons in some, but not all, studies. Previous studies did not control for differences in the duration of HIV or GBV-C infection.We evaluated 271 men who were participants in the Multicenter Acquired Immunodeficiency Syndrome Cohort Study for GBV-C viremia (by means of a reverse-transcriptase-polymerase-chain-reaction assay) or E2 antibody (by means of an enzyme-linked immunosorbent assay) 12 to 18 months after seroconversion to positivity for HIV (the early visit); a subgroup of 138 patients was also evaluated 5 to 6 years after HIV seroconversion (the late visit).GBV-C infection was detected in 85 percent of men with HIV seroconversion on the basis of the presence of E2 antibody (46 percent) or GBV-C RNA (39 percent). Only one man acquired GBV-C viremia between the early and the late visit, but 9 percent of men had clearance of GBV-C RNA between these visits. GBV-C status 12 to 18 months after HIV seroconversion was not significantly associated with survival; however, men without GBV-C RNA 5 to 6 years after HIV seroconversion were 2.78 times as likely to die as men with persistent GBV-C viremia (95 percent confidence interval, 1.34 to 5.76; P=0.006). The poorest prognosis was associated with the loss of GBV-C RNA (relative hazard for death as compared with men with persistent GBV-C RNA, 5.87; P=0.003).GBV-C viremia was significantly associated with prolonged survival among HIV-positive men 5 to 6 years after HIV seroconversion, but not at 12 to 18 months, and the loss of GBV-C RNA by 5 to 6 years after HIV seroconversion was associated with the poorest prognosis. Understanding the mechanisms of interaction between GBV-C and HIV may provide insight into the progression of HIV disease.

Patients with no prior chemotherapy and with advanced and progressive follicular lymphoma (FCL) or mantle cell lymphoma (MCL) were enrolled into a treatment protocol combining CHOP/rituximab-CHOP therapy with subsequent consolidation high-dose therapy (HDT) to evaluate the safety and feasibility of this treatment. Overall, 15 patients were enrolled and 13 patients completed the entire treatment protocol without major toxicities or increased infectious complications. One patient withdrew consent after achieving complete remission (CR) prior to HDT. One patient was taken off study with signs of disease progression after induction treatment. All patients showed stable engraftment after HDT. Response rates appear to be favorable, indicating an additional effect of rituximab and HDT. Overall, 12 of 13 patients achieved CR/CRu and one patient partial remission. Follow-up of immune reconstitution displayed transient severe combined immunodeficiency with slow normalization of the cellular and humoral compartments without a significant increase of infectious complications. Taken together, high-dose chemotherapy can be safely given following treatment with CHOP+rituximab. Efficacy in this small cohort of patients was encouraging with sustained remissions in both FCL and MCL patients. Upfront HDT should be considered as a therapeutic option especially in young and/or high-risk patients.

Here, we describe a patient diagnosed with chronic myelogenous leukemia who relapsed after matched unrelated donor SCT. The patient was treated with imatinib mesylate and donor lymphocyte infusions, and achieved a complete molecular remission. Additionally, safety and efficacy of imatinib mesylate in a total of 134 patients from 8 centers who underwent allogeneic or syngeneic stem cell transplantation (SCT) and had a relapse of Philadelphia chromosome positive leukemia was reviewed. Data was compiled from abstracts accepted as oral or poster presentations at the ASH (American Society of Hematology) 2001 and EBMT (European Group for Blood and Marrow Transplantation) 2001 & 2002 meetings and additionally literature published on this patient group. Efficacy of imatinib therapy was assessed by morphology, cytogenetic analysis, and determination of donor chimerism. In the evaluable population, hematologic and cytogenetic responses were observed in 66% and 60% of the patients, respectively. Fifty-one of 114 (45%) patients achieved a complete cytogenetic response. No response or progress of disease was noted in 22 out of evaluable 91 patients. The observation period was limited to a maximum of 28 months. A significant improvement in donor chimerism was frequently observed. Only five cases of significant GVHD were reported. Preliminary results show that imatinib mesylate has the potential to positively influence the ratio of donor and recipient cells without inducing a high incidence of severe GVHD. The data suggest that earlier start of imatinib mesylate prior to hematologic relapse in minimum residual disease (MRD) positive patients is a promising treatment concept.

We examined safety and efficacy of STI-571 in 24 bcr/abl-positive patients with CML post PBSCT. At start of STI-571 therapy, nine patients presented in blast crisis (BC) or in accelerated phase (AP), and 15 in chronic phase (CP). Patients were evaluated for hematologic, cytogenetic and molecular response, survival and toxicity. In general, STI-571 was well tolerated in this heavily pretreated group of patients with a non-hematologic and hematologic toxicity profile similar to that observed in a previous phase I trial at comparable doses. Five of nine patients with CML in transformation (AP, BC) were evaluable for hematologic response. Two of five patients had transient reductions in WBC and blasts, and three patients achieved a sustained hematologic response (>4 weeks). Cytogenetic analysis in these patients revealed numerical and/or structural responses. In CML chronic phase, STI-571 induced complete hematologic responses in all patients and major cytogenetic responses in 61% of patients with a complete cytogenetic response rate of 46%. This report indicates that STI-571 is a safe and effective drug in heavily pretreated patients. No apparent additional side-effects were noted in this patient cohort. The high rate of complete hematologic and complete cytogenetic responses in CP patients is remarkable, as intensive treatment approaches plus IFN-alpha failed to be efficient in achieving long-term stabilization of CML in this patient cohort.

TPS7575 Background: Approximately 50% of patients (pts) with advanced DLBCL are refractory to or relapse following first line R-CHOP therapy. Pts with R/R DLBCL have limited treatment options and a poor prognosis. This study assesses immunotherapy-based regimens containing avelumab (a fully human IgG1 anti–PD-L1 antibody) in combination with utomilumab (a novel 4-1BB agonist), azacitidine, rituximab, and/or conventional chemotherapy (CT; bendamustine) in pts with R/R DLBCL. Methods: JAVELIN DLBCL (NCT02951156) is a global, multicenter, randomized, open-label, 2-component(phase 1b followed by phase 3) study of avelumab-based combination regimens in R/R DLBCL. In phase 1b, up to 84 pts will be randomized 1:1:1 to receive avelumab/rituximab/utomilumab, or avelumab/azacitidine/utomilumab, or avelumab/rituximab/bendamustine. The primary phase 1b objectives are preliminary assessments of dose-limiting toxicities (n = 6 per arm) and efficacy (objective response [OR]; n = 28 per arm). One regimen from phase 1b will be selected for phase 3 evaluation in 220 additional pts randomized 1:1 to the chosen regimen or investigator’s choice CT (rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin). The primary phase 3 objective is to demonstrate progression-free survival (PFS) superiority of the avelumab-based regimen over CT. Overall survival is a key secondary endpoint. Eligible pts have completed up to 4 lines of prior rituximab/multiagent CT, and/or have failed autologous stem cell transplantation (ASCT), or are not eligible for intensive CT or ASCT. Other eligibility criteria include ECOG PS ≤1 and no prior therapy with a checkpoint inhibitor. Treatment with avelumab, utomilumab, and azacitidine will be continued until the pt no longer receives clinical benefit; rituximab and bendamustine are limited to 8 and 6 cycles, respectively. OR and PFS will be assessed per Lugano disease classification criteria. Other secondary efficacy endpoints include disease control, duration of response, time to response, and minimal residual disease burden. Safety, PK, immunogenicity, pt-reported outcomes, and biomarkers will also be evaluated. Clinical trial information: NCT02951156.

TPS7571 Background: Patients ineligible for stem cell transplantation (SCT) or who relapse after SCT, and those who fail to respond to second-line or salvage chemotherapy, represent an unmet medical need for which new therapeutic strategies are required. MOR208 is a novel Fc-enhanced, humanized, monoclonal antibody directed against CD19. Significant single-agent activity of MOR208 in patients with R-R DLBCL (Jurczak et al., J Clin Oncol 34, 2016 [suppl; abstr 7545]) and enhancement of MOR208-mediated cytotoxicity by BEN in preclinical studies, provide a strong rationale to study MOR208 + BEN in patients with R-R DLBCL. Methods: B-MIND is a randomized (1:1), two-arm, multicenter, open-label, adaptive design, phase II/III study of MOR208 + BEN vs RTX + BEN in adult patients with histologically confirmed DLBCL who have relapsed after or are refractory to 1 to 3 prior lines of therapy and who are not candidates for high-dose chemotherapy and autologous SCT. At least 1 prior therapy line must have included a CD20-targeted therapy. Other key inclusion criteria: age ≥18 years; measurable disease; availability of tumor tissue for central pathology review; ECOG 0–2, and adequate major organ systems function. Key exclusion criteria: primary refractory DLBCL; central nervous system involvement, and known double/triple hit DLBCL genetics. The safety of the combination will be assessed in an initial phase II evaluation. Treatment will comprise 6 cycles of MOR208 (12 mg/kg IV) + BEN (90 mg/m2 IV) or RTX 375 mg/m2 IV + BEN. Patients achieving a response after cycle 6 will continue to receive antibody treatment for up to 18 additional cycles. Primary endpoint: progression-free survival (PFS); secondary endpoints include: best overall response, overall survival, safety, quality of life, immunogenicity and pharmacokinetics. Enrollment of 330 patients is anticipated in Europe, US and Asia-Pacific countries. Fourteen patients have been randomized to date. Clinical trial information: NCT02763319.