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Background Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400mg/day (n=400) could be optimized by doubling the dose (n=420), adding IFN (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). Methods From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. The impact of patients' and disease factors on survival was prospectively analyzed. At the time of evaluation, at least 62% of patients still received imatinib, 26.2% were switched to 2nd generation tyrosine kinase inhibitors. Results After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival 80% and 10-year relative survival 92%. In spite of a faster response with IM800mg, the survival difference between IM400mg and IM800mg was only 3% at 5 years. In a multivariate analysis, the influence on survival of risk-group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs. other) was significant in contrast to any form of initial treatment optimization. Patients that reached the response milestones 3, 6 and 12 months, had a significant survival advantage of about 6% after 10 years regardless of therapy. The progression probability to blast crisis was 5.8%. Blast crisis was proceeded by high-risk additional chromosomal aberrations. Conclusions For responders, monotherapy with IM400mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease and blast crisis, more life-time can currently be gained by carefully addressing non-CML determinants of survival. Disclosures Hehlmann: Novartis: Research Funding; BMS: Consultancy. Saussele: Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Pfirrmann: BMS: Honoraria; Novartis: Honoraria. Krause: Novartis: Honoraria. Baerlocher: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Bruemmendorf: Novartis: Research Funding. Müller: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Jeromin: MLL Munich Leukemia Laboratory: Employment. Hänel: Roche: Honoraria; Novartis: Honoraria. Burchert: BMS: Honoraria. Waller: Mylan: Consultancy, Honoraria. Mayer: Eisai: Research Funding; Novartis: Research Funding. Link: Novartis: Honoraria. Scheid: Novartis: Honoraria. Schafhausen: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Hochhaus: Incyte: Research Funding; MSD: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; ARIAD: Research Funding.

Background Chronic myeloid leukemia (CML) stem cells are inherently insensitive to tyrosine-kinase inhibitors (TKI). However, an important minority of CML patients was shown to discontinue TKI without experiencing molecular relapse. Underlying mechanisms are currently unknown. Plasmacytoid dendritic cells (pDCs) are critical regulators of immune responses. Following activation, pDC upregulate MHC-class II and other DC activation markers such as CD86 (also known as B7.2). CD86 is a co-stimulatory molecule during T-cell activation, but also ligand of the inhibitory immune checkpoint receptor CTLA-4, which counteracts T-cell activation. The origin and function of pDC in CML biology is unknown. Within a sub-study of the EUROSKI TKI discontinuation trial we prospectively tested the hypothesis that pDC counts and CD86 expression status govern relapse risk following TKI discontinuation. Methods: Using flow cytometry, cell sorting and fluorescence in situ hybridization (FISH), CD86 expression and BCR-ABL status were analyzed in PDCA-2+/CD123+ peripheral blood (pB) pDC of untreated CML patients (CML pDC), normal donors and 123 patients, who had stopped TKI therapy in deep molecular remission within the international EUROSKI study (EUDRACT 2011-000440-22). All 123 EUROSKI patients had given written informed consent to participate in the immunological sub-study of the EUROSKI trial. Fresh samples from 19 EUROSKI centers in Germany were centrally analyzed prior, as well as 1, 2, 3 and 6 months after TKI discontinuation. PB CD86+ pDC counts were calculated per 105 cells in the lymphocyte gate. Decision trees and 10-fold cross validation were employed to establish relapse prediction accuracy for this value. Results CML pDC were BCR-ABL-FISH positive (median: 81%; range, 57 to 100%). In contrast, the proportion of CD86+ CML pDC varied substantially (median: 25.9%, range 3.2% to 82.4%), suggesting that CD86 expression on CML pDC was not a direct consequence of oncogenic BCR-ABL signaling. This was confirmed experimentally in a murine CML model. In contrast to CML pDC, remission pDC were always BCR-ABL FISH negative (n=10), but still displayed a comparable high proportion of CD86 positive pDC (median: 21%; range, 2.2% to 62%). In contrast, normal donor pDC were rarely CD86 positive (median: 6.8%; range, 4.2% to 17%), reinforcing the aberrant, and BCR-ABL-independent nature of CD86 expression on CML and remission pDC. As a result, healthy donors displayed only between 26 to 84 CD86+ pDC per 105 lymphocytes, whereas EUROSKI remission patients exhibited between 6 to 309 CD86+ pDC per 105 lymphocytes. Based on the important role of CD86 as a high affinity ligand of the inhibitory immune checkpoint receptor CTLA-4, we next asked, whether CD86+ pDC counts are associated with relapse risk after TKI discontinuation. Strikingly, statistical models suggested that a CD86+ pDC count below or above 95 CD86+ pDC/105 lymphocytes optimally separated two relapse categories of EUROSKI patients. Whereas relapse free survival (RFS) (loss of MMR) for patients with more than 95 CD86+ pDC/105 lymphocytes was 30% (n=32), RFS was 69% for patients (n=91) with less than 95 CD86+ pDC/105 lymphocytes (p Conclusion: Our data suggest for the first time a mechanism that governs relapse biology after TKI discontinuation in CML. It is proposed that a chronic engagement of the T-cell inhibitory immune checkpoint receptor CTLA-4 by abundant levels of CD86+ on remission pDC impedes a T-cell-dependent control of CML stem cell survival after stopping TKI. CTLA-4 blocking antibodies such as ipilimumab might therefore prevent molecular relapse and overcome stem cell persistence in CML especially in patients with high CD86+ pDC counts. Figure 1. Relapse free survival after TKI discontinuation according to the number of CD86+ pDC at the time of stopping TKI in the EURO-SKI trial. Figure 1. Relapse free survival after TKI discontinuation according to the number of CD86+ pDC at the time of stopping TKI in the EURO-SKI trial. Disclosures Burchert: Bristol Myers Squibb: Honoraria. Saussele:Novartis Pharma: Honoraria, Other: Travel grant, Research Funding; BMS: Honoraria, Other: Travel grant, Research Funding; Pfizer: Honoraria, Other: Travel grant; ARIAD: Honoraria. Müller:Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Lange:Novartis: Research Funding. Hochhaus:Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mahon:NOVARTIS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria, Speakers Bureau; PFIZER: Consultancy, Honoraria.

Introduction: Treatment of relapsed/refractory (rr) Non-Hodgkinxs lymphoma of B-cell type (B-NHL) is still challenging and new and more effective therapies are urgently warranted. Blinatumomab, a bispecific T-cell engager (BiTE®) antibody construct, engages CD3+ cytotoxic T cells, resulting in T-cell expansion and lysis of CD19+ B cells. In a prior phase I study, blinatumomab treatment resulted in an overall response rate (ORR) of 69% and 55% in diffuse large B-cell lymphoma (DLBCL), respectively for patients treated at 60 μg/m2/d. Based on this study we here present a single-center analysis on long-term outcome of patients with B-NHL after treatment with blinatumomab. We here report first preliminary data on long-term follow-up of patients with rr NHL after blinatumomab treatment. Methods: Patients with rr B-NHL who achieved an objective response (PR or CR) upon blinatumomab treatment were eligible for long-term follow-up analysis. Kaplan-Meier estimates for progression free survival (PFS) probability were calculated from first infusion to relapse or death. Patients without an event were censored at last follow-up. This study was conducted in accordance with the Declaration of Helsinki. Results: Out of 38 treated patients (17 follicular lymphoma (FL), 14 mantle cell lymphoma (MCL), 4 DLBCL, 3 others) 22 received the effective target dose of 60/90 μg/m²/d. 47,4% (CR/PR=28,9%/18,4%, n=38) and 68,2% (CR/PR=40,9%/27,3%, n=22) of the patients experienced response, respectively, whereas only 18,8% of the patients who were not treated with the effective target dose responded to blinatumomab (CR/PR=12,5%/6,3%, n=16). 6 patients are still in ongoing remission. Median overall survival (OS) of all 38 patients was 1560 days, median PFS 204 days and treatment free survival (TFS) 233 days. Median OS in the 22 patients treated with the target dose was 1793 days, median PFS 492 and TFS 752 days, compared to only 412 days median OS, 46 days PFS and 82 days TFS in the patients, who did not receive blinatumomab in an effective dosage. Conclusion: Blinatumomab has the potential to induce durable remissions in patients with rr NHL. Our data suggests that treatment at target dose of 60 μg/m²/d is an important prerequisite to achieve long-term remission. Figure 1. Kaplan Meier analysis shows significantly longer PFS in patients on target dose Figure 1. Kaplan Meier analysis shows significantly longer PFS in patients on target dose Disclosures No relevant conflicts of interest to declare.

In addition to bacterial virulence factors, host immune response plays a pivotal role in the outcome of chronic Helicobacter pylori infection. The capacity of the host to mount an interleukin-1β (IL-1β)-driven response is influenced by sequence variants in the IL-1/IL-1RN cluster.[1][1] El-Omar

Abstract 2860 Introduction: In the last decade, important progress has been achieved in the treatment of CLL through the use of purine analog-based chemoimmunotherapies. Several conditions remain a challenge, often with a poor outcome. Amongst these therapeutic problems are Richter's transformation (RT), refractoriness to F-based therapies (Fref), and the occurrence of AIC, which are sometimes induced by F. Fref and RT pts have a very poor prognosis with an estimated overall survival (OS) of only 10 and 8 months (mos), respectively. Therefore, therapeutic alternatives are urgently warranted. CHOP-R has improved the outcome of pts with aggressive non-Hodgkin's lymphoma. To test the efficacy and tolerability of the CHOP-R regimen in CLL patients with RT, Fref, or AIC, the GCLLSG initiated a prospective phase II trial. Material and Methods: 62 patients were included in the study. Due to protocol violations, 2 patients were excluded. Within the group of Fref pts, the medical review detected 11 patients who had received pre-treatment with F (Fpret), but were not refractory according to the updated guidelines (Hallek et al., Blood 2008). Thus, 26 pts were classified as Fref/pret, 19 pts as AIC and 15 pts as RT. All patients received CHOP every 3 weeks (cyclophosphamide 750mg/m2, adriamycin 50mg/m2 and vincristine 1, 4mg/m2 d1; prednisone 100mg/m2 d1–5). Rituximab was added starting with the 2nd cycle (375mg/m2 on each d0, and 21 days after the last CHOP-R). RT pts received up to 8, Fref/pret and AIC up to 6 courses of CHOP-R. In case of PD after 3 cycles, pts went off-study. The primary endpoints were remission rate, quality and duration of response. Results: 79%, 73%, and 40% of AIC, Fref/pret, and RT pts were male, respectively. The median age was 65 years (y) for Fref/pret-pts, 66y in the AIC and 69y in the RT group. Binet stages for Fref/pret pts were: A: 8%; B: 27% C: 65 %. All but 3 AIC pts were at Binet stage C. Initial RT stages according to Ann Arbor were: II: 13%, III: 13%, IV 73%. The median number of previous therapies were 3 for Fref/pret, 2 for AIC and 2 for RT. A total of 314 cycles were administered, with a median number of 3 cycles for AIC and Fref pts and a median number of 4 cycles for the RT group. Due to toxicity 73% of cycles in the Fref/pret group, 66% in the AIC and 87% in the RT group were dose-reduced. 69% of Fref/pret-pts and 58% of AIC-pts received full 6 cycles of therapy and only 40% of RT-pts completed 8 cycles of therapy. Treatment was stopped in 6 pts because of PD. Due to treatment related toxicity treatment was stopped in 16 pts (27%). Treatment related mortality was 3% (2 pts). Treatment toxicity was reported according to NCI common toxicity criteria (CTC) version 2.0. Adverse events grade 3 or 4 for anemia, neutropenia and thrombocytopenia were documented in 75%, 55% and 65% of patients, respectively. Infections were the most common non-hematologic toxicity and occurred in 67%; severe infections CTC grade 3 or 4 occurred in 28%. All 26 Fref/pret-pts were available for response evaluation. CHOP-R achieved 54% PR, 35% SD and 12% PD. The median progression-free survival (PFS) and median treatment-free survival (TFS) were 11 and 14 mos. OS was 27 mos with a significant difference concerning F-ref (n=15) and F-pret (n=11) pts (17 vs. 35m; p=0.05). We evaluated the response of all 15 RT-pts with 60% PR, 7% CR, 13% SD and 20% PD. The PFS was 15 mos, TFS was 17 mos and OS 27 mos. 17 AIC pts were available for response evaluation with 82% PR, 6% SD and 12% PD. The PFS and TFS were only 14 and 16 mos. The OS was 50 mos. The population had a high incidence of unfavourable genetic markers: deletion of chromosome 17p [del(17p)] was detected in 24%, del(11q) in 34% and unmutated IGHV in 70%. 85% had high levels of serum thymidine kinase (sTK > 10 U/l), and 49% had high levels of ß2-microglobulin (ß2M > 3.5 mg/l). Patients with del(17p) had an unfavourable response rate and achieved significant less a PR or CR (36% vs. 76%; p=0.03). Multivariate analyses showed that del(17p) and ECOG performance status had a negative prognostic impact on OS (p Conclusion: CHOP-R achieves promising response rates in CLL patients with Fref and RT and very good response rates in patients with AIC. However, the progression-free survival and overall survival remain unsatisfactory. Therefore, CHOP-R might be used as induction therapy prior to allogeneic stem cell transplantation in physically fit patients. Disclosures: Eichhorst: Hoffmann La Roche: Honoraria, Research Funding, Travel Grants; Mundipharma: Research Funding, Travel Grants; Gilead: Consultancy. Dreyling:Roche: Research Funding, Scientific advisory board, Speakers Bureau. Bergmann:Celgene: Honoraria. Stilgenbauer:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Fink:Hoffmann La Roche: travel grants. Fischer:Hoffmann La Roche:. Wendtner:Hofmann-La Roche: Consultancy, Honoraria, Research Funding. Hallek:Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Honoraria.