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We aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (⩾VGPR) in 504 newly diagnosed, transplant-eligible multiple myeloma patients. VCD was found to be non-inferior to PAd with respect to ⩾VGPR rates (37.0 versus 34.3%, P=0.001). The rates of progressive disease (PD) were 0.4% (VCD) versus 4.8% (PAd; P=0.003). In the PAd arm, 11 of 12 patients with PD had either renal impairment (creatinine ⩾2 mg/dl) at diagnosis or the cytogenetic abnormality gain 1q21, whereas no PD was observed in these subgroups in the VCD arm. Leukocytopenia/neutropenia (⩾3°) occurred more frequently in the VCD arm (35.2% versus 11.3%, P

Background: Many patients with autoimmune hemolytic anemia (AIHA) do not respond to standard therapy and/or may develop severe complications which can be of fatal outcome. There is some evidence that erythropoiesis-stimulating agents (ESAs) may be helpful in the management of such patients. Methods: We describe the effect of ESAs in 12 new patients with therapy-refractory AIHA (7 of warm type and 5 of cold type) and review 5 previously reported cases. Serological testing was performed using standard methods. Results: All patients responded well to treatment with ESAs. At least 5 of the 17 patients demonstrated complete recovery, and none of the patients developed significant adverse reactions due to treatment with ESAs. Conclusion: The mechanism by which ESAs improves hemolysis in AIHA is not completely clear. In addition to increased production and prolonged RBC survival, it may inhibit eryptosis (programmed cell death). ESAs represent a new option in the treatment of decompensated and/or refractory AIHA of warm and cold type. However, more information is required to assess which patients can be treated with ESAs.

6018 Background: This trial was based on the findings that D in addition to PF in induction treatment and C in addition to PF in RM disease both improved outcome in HNSCC. The question was, whether...

Introduction: Multiple myeloma is a heterogeneous disease with survival ranging from months to more than 10 years. Cytogenetic abnormalities (CA) detected by fluorescence in situ hybridization (FISH) are of major prognostic significance, since e.g. patients with del(17p), t(4;14) or gain 1q21 show dismal outcome. We evaluated CA at primary diagnosis and relapse to investigate clonal evolution in patients treated with upfront autologous stem cell transplantation (ASCT). Methods: We identified 128 patients with paired samples at primary diagnosis before the start of therapy (1st FISH) and at relapse after ASCT (2nd FISH). Forty-four patients were initially treated within the GMMG HD4 trial which compared 3 cycles of conventional induction chemotherapy (Arm A) with a bortezomib-based induction therapy (Arm B) followed by tandem ASCT and thalidomide (Arm A) or bortezomib (Arm B) maintenance. Eighty-four non-study patients (NSP) treated outside clinical trials were included who had received comparable induction therapies (bortezomib: n=45, thalidomide: n=11, other: n=28) before ASCT. FISH was performed on purified plasma cells using probes for 1q21, 5p15, 5q35, 8p21, 9q34, 11q23, 13q14, 15q22, 17p13 and 19q13, immunoglobulin H (IgH) translocations, t(11;14), t(4;14) and t(14;16). McNemar`s test was used to assess differences between FISH assessments. Kaplan-Meier method and Cox regression were used to analyze survival differences between patients without CA or with CA only at 1st, 2nd or both FISH assessments. Last follow-up for the whole cohort was performed in 06/2016. Results: Median time to first progression for the whole cohort was 27.0 months (HD4: 29.8 months; NSP: 25.5 months). There were no significant differences in CA as well as remission after induction therapy or ASCT between the HD4 and NSP cohort. The number of patients with high-risk CA was significantly higher after relapse (odds ratio (OR): 6.33; 95% confidence interval (CI): 1.86, 33.42; p Conclusion: We demonstrate clonal evolution and a higher incidence of high-risk CA at relapse after ASCT in a homogeneously treated group of patients. The most common translocations in myeloma are highly conservative. High-risk CA can emerge on a subclonal level during disease progression or might evolve from initially present subclones which results in similar dismal outcome Disclosures Merz: Celgene: Other: Travel grant; Janssen: Other: Travel grant. Hose:Sanofi: Research Funding; EngMab: Research Funding; Celgene: Other: personal fees outside this work. Bertsch:Janssen: Research Funding; Celgene: Research Funding; Chugai: Research Funding. Schmidt-Wolf:Janssen: Research Funding; Novartis: Research Funding. Scheid:Novartis: Other: funding outside this work; Celgene: Other: funding outside this work; Janssen: Other: funding outside this work. Weisel:Amgen: Consultancy, Honoraria; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Goldschmidt:Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Chugai: Consultancy, Research Funding; Onyx: Consultancy; Millenium: Consultancy; BMS: Other: fees outside this work. Hillengass:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Amgen: Consultancy, Honoraria; BMS: Honoraria; Celgene: Honoraria; Novartis: Research Funding.

Background: The well-described prognostic impact of tumor characteristics and biology in multiple myeloma (MM), such as the combination of cytogenetics, the International Staging System (ISS) and lactate dehydrogenase (LDH, Moreau et. al., JCO, 2014) as well as frailty (Palumbo et al., Blood, 2015) significantly influence patient outcomes. However, only limited data on the impact of infections during therapy exist (Rajkumar et al., Lancet Oncology, 2010). Therefore, we hypothesized that severe infections during induction therapy (IT) in transplant-eligible MM influence dosage of therapies, treatment responses after IT and survival. Patients and Methods: From 05/2005 until 05/2008, 399 patients were randomly assigned to receive IT with either three cycles of VAD (vincristine, VIN, i.v. 0.4mg, days 1-4; doxorubicine, DOXO, i.v. 9mg/m2, days 1-4; dexamethasone, DEX, p.o. 40mg, days 1-4, 9-12, 17-20; n=201, arm A) or PAD (bortezomib, BTZ, i.v. 1.3mg/m2, days 1, 4, 8, 11; DOXO i.v. 9mg/m2, days 1-4; DEX p.o. 40mg, days 1-4, 9-12, 17-20; n=194, arm B), followed by high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT) and either thalidomide (arm A) or bortezomib (arm B) maintenance within the German part of the joint GMMG-HD4/HOVON65 trial (Sonneveld et al., JCO, 2012). After exclusion of ineligible patients, 395 patients (99.0%) were evaluable for analyses. Any severe infection (equal or greater grade 3, according to the Common Terminology Criteria for Adverse Events, Version 4.0) during IT (at least once, defined from first until last date of application of IT medication) occurred in 105 patients (VAD n=53/198 and PAD n=52/192, 26.9% of all patients, missing data n=5). Results: Among patients with a severe infection during IT in the VAD and PAD arms, total DEX and DOXO doses (equal dosage in VAD/PAD group) were significantly lower (median DEX dose (mg/m2): 689.0 [77.7, 1014.1] vs. 742.3 [0.0, 1324.1], p Overall survival (OS) was significantly shortened in patients with at least one severe infection during IT (median OS: 81.8 months vs. not reached, p=0.04, Figure 1A). OS plots diverged in the early period of observation (< 3 months), driven by infection-related deaths (n=8). A landmark analysis 3 months after registration demonstrated approximated survival curves without significant differences in OS (median OS: 78.8 months vs. not reached, p=0.30, Figure 1B). Similarly, progression-free survival (PFS) was shortened, though not significantly (median PFS: 30.2 vs. 35.0 months, p=0.08). However, since not just death accounts as PFS event, the impact of infection-related deaths on PFS remains smaller than on OS. Accordingly, landmark analyses after 3 months from registration showed again closer survival curves (median PFS: 28.5 vs. 32.4 months, p=0.36). Conclusions: Severe infections have a critical impact on the applied doses of IT and outcome in the early, vulnerable phases of MM therapy. OS for transplant-eligible MM patients with severe infections during IT was significantly shortened, mainly driven by early infection-related deaths (< 3 months). A reduction of DEX doses during PAD/PAd IT in the subsequent GMMG study generation (GMMG-HD4/HOVON65: 480mg/cycle to GMMG-MM5: 240mg/cycle) and the recommendation of antibiotic/antiviral prophylaxis throughout the whole IT led to a reduced rate of severe infections of 12% (PAd) in the GMMG-MM5 trial. Further analyses are needed to elucidate how severe infections can be avoided, and whether there is an overlap between the subgroup of patients with severe infections during IT and patients with known adverse prognostic factors or reduced fitness/pre-existing conditions. (A) Overall survival and (B) landmark analysis on overall survival 3 months after start of induction therapy of patients with or without at least one severe infection (equal or greater grade 3) during induction therapy. Figure 1. Impact of severe infections on overall survival. Figure 1. Impact of severe infections on overall survival. Disclosures Mai: Janssen-Cilag: Other: Travel Grant; Onyx: Other: Travel Grant; Mundipharma: Other: Travel Grant; Celgene: Other: Travel Grant. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Pfreundschuh:Roche: Honoraria; Amgen, Roche, Spectrum: Research Funding; Boehringer Ingelheim, Celegene, Roche, Spectrum: Other: Advisory board. Duehrsen:Janssen: Honoraria. Hillengass:Janssen-Cilag: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Other: Travel support; Sanofi: Research Funding. Scheid:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Weisel:BMS: Consultancy, Honoraria, Other: Travel Support; Onyx: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Support; Novartis: Other: Travel Support; Noxxon: Consultancy. Blau:MSD: Honoraria; Celgene: Honoraria, Research Funding; AMGEN: Honoraria; JAZZ pharm: Honoraria; BMS: Honoraria; Shire: Honoraria; Baxalta: Honoraria; Janssen: Honoraria, Research Funding. Goldschmidt:Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Research Funding, Speakers Bureau.

During the course of chronic myeloid leukemia (CML) progression to blast crisis (BC) is thought to be caused by genetic instability such as cytogenetic aberrations in addition to the translocation t(9;22)(q34;q11). We have shown previously that major route ACA indicate an unfavorable outcome (Fabarius et al., Blood 2011). We now investigate whether there is a correlation in time between appearance of major route ACA and increase in blast count. Methods: Cytogenetic data and blast count in the peripheral blood were available from 1,290 CML patients recruited to the German CML-studies III (621 patients) and IIIa (669 patients) from January 1995 to January 2004. Treatments were interferon-alpha-based or related allogeneic stem cell transplantation (HSCT). Presence of ACA and major route ACA was considered as a time-dependent covariate. Multivariate proportional hazards models were estimated taking Euro CML score, study III vs. IIIa and stem cell transplantability into account. Cumulative incidences of blast increases were calculated starting at the date of the first ACA or major route ACA, respectively, regarding death as a competing risk. Patients were censored at the date of HSCT with an unrelated donor. Results: 1,287 patients were evaluable with median observation times of 13 and 12 years and a 10-year survival of 48% and 61% in CML studies III and IIIa, respectively. 258 patients progressed to BC with a cumulative 10-year incidence of 20%. 195 patients displayed ACA during the course of disease. 45 patients (15.7%) showed ACA already at diagnosis. 44 patients showed unbalanced minor route, 29 balanced minor route aberrations, 23 -Y. 109 patients showed major route aberrations including 10 with other prior ACA. In a multivariate analysis on 1,257 patients, patients with ACA had a hazard ratio (HR) for a blast increase of between 2.0-2.2 (p 5 years after the diagnosis of any ACA the cumulative incidence for a blast increase was 30% (95%- confidence interval (CI): 23-38%), of a major route ACA 40% (95%- CI: 28-49%). The 6-year probability of death without blast increase was 10%. 14 additional patients received an unrelated transplant of which 6 died. We conclude that ACA, particularly major route ACA, precede an increase of blasts. Major route ACA have to be considered as a prognostic indicator for disease progression at any time. Table 1. Blast increase to HR (univariate): ACA vs. no ACA HR(multivariate)*: ACA vs. no ACA HR (univariate): major route ACA vs. no major route ACA HR (multivariate)*: major route ACA vs. no major route ACA ≥30% 2.409 2.139 2.646 2.203 ≥20% 2.413 2.144 2.656 2.211 ≥15% 2.415 2.161 2.868 2.426 ≥10% 2.416 2.160 2.799 2.357 ≥5% 2.286 2.047 2.719 2.278 ≥1% 2.209 1.999 3.171 2.684 *adjusted to Euro-Score, study (III vs. IIIa) and transplantability Disclosures Saussele: ARIAD: Honoraria; BMS: Honoraria, Other: Travel grant, Research Funding; Pfizer: Honoraria, Other: Travel grant; Novartis Pharma: Honoraria, Other: Travel grant, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Scheid:Janssen-Cilag: 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. Baerlocher:Geron Corporation: Research Funding; Novartis: Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Müller:BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Pfirrmann:BMS: Consultancy, Honoraria; Novartis Pharma: Consultancy, Honoraria. Baccarani:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hehlmann:BMS: Consultancy; Novartis Pharma: Research Funding.

Background: Peripheral neuropathy (PN) is an important, dose-limiting toxicity of bortezomib (BTZ). Subanalysis of the phase 3 VISTA trial of intravenous (IV) BTZ in newly diagnosed MM patients identified baseline neuropathy as only clinical risk factor for Bortezomib-induced peripheral neuropathy (BiPN). Since subcutaneous (SC) application reduces rates of BiPN, BTZ is mainly applied subcutaneously in current clinical trials and general practice. Data on clinical risk factors for BiPN in the era of SC BTZ are limited. We analyzed risk factors for PN in patients treated with SC or IV BTZ in the prospective randomized MM5 phase III trial of the German Myeloma Multicenter Group (GMMG). Methods: Primary end-points of the MM5 trial were response to VCD (BTZ 1.3 mg/m2, days 1, 4, 8, 11; Cyclophosphamide 900 mg/m2 IV; day 1, Dexamethasone 40 mg/d, orally, days 1-2, 4-5, 8-9, 11-12) compared to PAd (BTZ 1.3 mg/m2, days 1, 4, 8, 11; Doxorubicin 9 mg/m2 IV, days 1-4; Dexamethasone 20 mg/d, orally, days 1-4, 9-12, 17-20) induction therapy with respect to remission and progression-free survival (PFS). Induction therapy was followed by stem cell mobilization and harvest, high-dose therapy and Lenalidomide-based consolidation/maintenance therapy. From 07/2010 until 11/2013, 604 patients were randomly assigned to receive 3 cycles of PAd or VCD. Based on the results by Moreau et al, administration of BTZ was changed from IV to SC in 02/2012 after 314 patients were enrolled. We performed univariate and multivariate testing to analyze the association of different factors with the occurrence of PN ≥ grade 2 according to NCI CTCAE version 4.0 after completion of induction therapy. Factors included: Treatment arm (PAd vs. VCD), route of administration (IV vs. SC), existing baseline PN as well as baseline ISS, creatinine ≥2.0 mg/dl , body mass index (BMI), hemoglobin and calcium levels. Fisher's exact test was used for univariate analyses. A multivariate logistic regression model was adapted to analyze the influence of all factors on the occurrence of PN. In this model the impact of a single factor on PN is measured by an odds ratio (OR) based on a characteristic effect (change of one unit for categorical factors and change of interquartile range for continuous factors). Results: Of the analyzed patients, who received at least one dose of trial medication (PAd: n=150 IV/140 SC; VCD: n=154 IV/140 SC), 61 patients (10.2%) developed PN ≥ grade 2. Rates of PN were higher in patients treated with PAd (n=40; 13.5%) compared to VCD (n=21; 7.0%). Neither the presence of higher ISS stage at baseline, nor the route of administration had an impact on development of PN after 3 cycles of induction therapy in univariate analyses. However, PN was more frequent in IV-treated patients during the third cycle of induction therapy (IV: 7.6%; SC: 1.8%, p = 0.001). Median baseline BMI was significantly higher in patients who developed PN (26.9 kg/m2; 19.5-43.7 kg/m2) compared to patients without PN (25.7 kg/m2; 16.7-44-6 kg/m2, p=0.04). Also baseline hemoglobin levels were higher in patients with PN (12.0 g/dl; 6.8-15.9 g/dl) compared to patients without PN (10.8 g/dl; 5.8-16.3 g/dl, p=0.004). While baseline calcium levels were significantly lower in patients with PN (2.3 mmol/l; 1.6-3.5 mmol/l) compared to patients without PN (2.4 mmol/l; 1.6-5.4 mmol/l, p=0.04), baseline creatinine were not different in both groups. Multivariate logistic regression adjusting for the above mentioned factors confirmed the effect of VCD treatment compared to PAd on the development of PN (OR 0.49, 95% confidence interval (CI) [0.28, 0.89], p=0.02) and the importance of pre-existing PN (OR 3.12, 95% CI [1.26, 7.76], p=0.01). Also baseline calcium (OR 0.71, 95% CI [0.51, 0.99], p=0.04) and hemoglobin levels (OR 1.53, 95% CI [1.01, 2.33], p=0.05) proved to have an impact on the development of PN in the multivariate model. Conclusion: We confirm the importance of pre-existing neuropathic symptoms and the combination partners for BTZ on the development of PN in patients with newly diagnosed MM. We provide first evidence that clinical baseline characteristics, like calcium and hemoglobin levels, might predict the development of PN. This is in line with preclinical studies showing that dysregulation of calcium homeostasis and oxidative stress in the dorsal root ganglion plays a role in the pathogenesis of BiPN. Disclosures Merz: Janssen: Other: Travel grants; Celgene: Other: Travel grants. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Blau:Janssen: Honoraria, Research Funding; MSD: Honoraria; Celgene: Honoraria, Research Funding; AMGEN: Honoraria; JAZZ pharm: Honoraria; BMS: Honoraria; Shire: Honoraria; Baxalta: Honoraria. Scheid:Janssen: Honoraria; Celgene: Honoraria. Mai:Mundipharma: Other: Travel Grant; Celgene: Other: Travel Grant; Janssen-Cilag: Other: Travel Grant; Onyx: Other: Travel Grant. Hose:Takeda: Other: Travel grant; EngMab AG: Research Funding. Weisel:Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Other: Travel Support; Noxxon: Consultancy; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support. Duerig:Janssen: Consultancy, Honoraria; Celgene: Honoraria. Goldschmidt:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background: We reported better PFS and OS in transplant eligible patients with newly diagnosed Multiple Myeloma (MM) who were treated with bortezomib during induction and maintenance, when compared with standard treatment in the HOVON-65/GMMG-HD4 trial. (P. Sonneveld et al., J Clin Oncol 30:2946-2955, 2012). Here the long-term follow up data are presented. Methods: 827 eligible patients were randomized to induction therapy with VAD (vincristine, doxorubicin, dexamethasone) or PAD (bortezomib, doxorubicin, dexamethasone) followed by high-dose melphalan (once or twice) and autologous stem cell transplant. Maintenance consisted of daily thalidomide (T) 50 mg (VAD arm) or 2-weekly bortezomib (B) 1.3 mg/m2 (PAD arm) for 2 years. The primary endpoint was progression-free survival (PFS) adjusted for ISS stage. Results: After a median follow up of 91.4 months (maximum 119) 410 patients are alive. Response rates were VAD/HDM/T: CR 25%, ≥VGPR 56%, ≥PR 83%; PAD/HDM/B: CR 37%, ≥VGPR 76%%, ≥PR 91%, The median duration of maintenance therapy was 14 months (thalidomide) and 23 months (bortezomib), respectively. Main reasons for discontinuation were toxicity (T: 31%; B: 11%), disease progression (T: 33%; B: 36%) or normal completion (T: 28%; B: 48%). Of 827 patients in the analysis, 206 are alive without progression/relapse. PFS was significantly better in the bortezomib arm, i.e. median 34 versus 28 months (HR=0.77, 95% CI=0.65-0.90, p=0.001). Median overall survival (OS) was 90 months in the bortezomib arm vs 83 months in the control arm, but 42% at 9 years in both arms. We used the restricted mean survival time (RMST) method to compare OS between the two treatment arms In univariate analysis. The difference in RMST8y was 4.8 months (95% CI 0.2-9.5, p=0.04) in favor of the bortezomib arm. A landmark analysis in patients who had received HDM starting at 12 months showed a significant PFS advantage of bortezomib in all patients (p=0.02), in patients in VGPR/PR (p=0.02) but not in CR (p=0.19). For OS there was no advantage for bortezomib in either group. PFS at 60 months in bortezomib treated patients was not different when single vs double HDM/ASCT was administered, i.e. 28% vs 27%. However, OS at 60 months was 71% vs 60% in favor of double HDM/ASCT (p=0.04). Subgroup analysis was performed based on presence/absence of adverse FISH (CA) in 395 patients treated with double HDM/ASCT. PFS at 60 months for each abnormality (CA or no CA) in bortezomib vs standard arm is given in Table 1 Table 1.PFS at 60 months, %OS at 60 months, %FISHnBortezomib armpStandard armBortezomib armpStandard Armt(4;14) yes/no50/29516% vs 27%0.048% vs 24%52% vs 75%0.0133% vs 64%add(1q) yes/no113/23116% vs 32%0.00510% vs 28%57% vs 79%0.00143% vs 70%del(17p) yes/no39/31222% vs 27%0.475% vs 24%65% vs 72%0.4818% vs 66% These data show that bortezomib treatment combined with double HDM/ASCT significantly improves PFS and OS in patients with del(17p) and almost abrogates the negative impact of this CA. In t(4;14) and add(1q) some improvement is observed, however the negative impact remains significant. In high-risk patients presenting with elevated creatinine >2 mg/dL bortezomib significantly improved PFS at 60 months (32% vs 5%) (p=0.001) and OS at 60 months (66% vs 21% months (p Conclusions: We conclude that bortezomib leads to a significant and lasting improvement of PFS and OS. Bortezomib significantly reduces the high-risk impact of del(17p) and renal impairment on survival. This trial was registered as NTR213; EudraCT no. 2004-000944-26.and supported by the Dutch Cancer Foundation, the German Federal Ministry of Education and Research and an unrestricted grant from Janssen. The GMMG group received grants for this trial by Novartis, AMGEN, Chugai and Roche. Disclosures Sonneveld: SkylineDx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Blau:MSD: Honoraria; Celgene: Honoraria, Research Funding; AMGEN: Honoraria; JAZZ pharm: Honoraria; BMS: Honoraria; Shire: Honoraria; Baxalta: Honoraria; Janssen: Honoraria, Research Funding. Zweegman:celgene: Honoraria, Research Funding; takeda millennium: Honoraria, Research Funding; onyx: Honoraria. Weisel:Noxxon: Consultancy; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Other: Travel Support; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel Support; BMS: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding. Broijl:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Scheid:Janssen: Honoraria; Celgene: Honoraria. Potamianou:Janssen: Employment. Hose:Takeda: Other: Travel grant; EngMab AG: Research Funding. Kersten:takeda millennium: Research Funding; janssen: Honoraria, Research Funding; roche: Honoraria, Research Funding. Duehrsen:Alexion: Honoraria; janssen: Honoraria. Lokhorst:Janssen: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Amgen: Honoraria. Goldschmidt:celgene: Honoraria, Research Funding; janssen: Honoraria, Research Funding; novartis: Honoraria, Research Funding; chugai: Honoraria, Research Funding; onyx: Honoraria, Research Funding; millennium: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

Purpose To compare progression-free survival between single and tandem high-dose chemotherapy (HDT) followed by autologous stem-cell transplantation in chemotherapy-sensitive metastatic breast cancer patients. Patients and Methods Between February 1997 and June 2001, 187 patients with complete and partial remission were randomly assigned to receive either one or two cycles of HDT, consisting of thiotepa (125 mg/m2/d for 4 days), cyclophosphamide (1,500 mg/m2/d for 4 days), and carboplatin (200 mg/m2/d for 4 days), followed by autologous stem-cell transplantation. Results One hundred seventy one of 187 randomly assigned patients completed first HDT, but only 52 of 85 completed the second HDT cycle in the tandem HDT arm. The rate of complete remission on an intent-to-treat-basis was 33% in the single-dose HDT arm and 37% in the tandem HDT arm (P = .48). The median progression-free survival times in single and tandem HDT arms were 9.4 and 11.2 months, respectively (one-sided P = .06; two one-sided P = .12), whereas median overall survival time tended to be greater after single versus tandem HDT (29 v 23.5 months, respectively; P = .4). In a multivariate analysis for progression-free survival, tandem HDT (hazard ratio [HR] = 0.71; 95% CI, 0.52 to 0.98; P = .03) and achievement of complete remission after induction chemotherapy (HR = 0.59; 95% CI, 0.37 to 0.96; P = .03) were factors for a better progression-free survival, whereas the factor of three or more sites of metastases (HR = 1.66; 95% CI, 1.12 to 2.47; P = .01) was associated with a worse progression-free survival. Conclusion Despite a trend of improved progression-free survival, tandem HDT cannot be recommended for patients with chemotherapy-sensitive metastatic breast cancer because of a trend for shorter overall survival and higher toxicity compared with single HDT.

Background: In patients with relapsed multiple myeloma (MM), Moreau and colleagues (Lancet Oncol, 2011) demonstrated that subcutaneous (SC) administration of bortezomib (BTZ) significantly reduced rates of adverse events (AE) compared to the intravenous (IV) formulation without loss of efficacy. Prospective data on SC BTZ in newly diagnosed MM are limited. We investigated the impact of SC versus IV BTZ in two different induction therapies for patients with newly diagnosed MM treated within the multicenter, prospective randomized MM5 trial of the German Myeloma Multicenter Group (GMMG). Methods: From 06/2010 until 11/2013, 604 patients were randomly assigned to receive 3 cycles of PAd (BTZ 1.3 mg/m2, days 1, 4, 8 and 11; Doxorubicin 9 mg/m2 IV, days 1-4; Dexamethasone 20 mg/d, orally, days 1-4, 9-12 and 17-20) or 3 cycles VCD (BTZ 1.3 mg/m2, days 1, 4, 8 and 11; Cyclophosphamide 900 mg/m2IV; day 1, Dexamethasone 40 mg/d, orally, days 1-2, 4-5, 8-9 and 11-12) for induction therapy. In the MM5 trial, induction therapy is followed by stem cell mobilization and harvest, high-dose therapy and Lenalidomide-based consolidation/maintenance therapy. Primary end points of the ongoing study are response to treatment after induction therapy and progression-free survival. Due to improved AE profile of SC compared to IV BTZ reported by Moreau, the administration of BTZ was changed from IV to SC in 02/2012. Therefore, we were able to perform an explorative analysis of 598 patients who received at least one dose of trial medication (PAd: n=150 IV / 140 SC; VCD: n=154 IV / 140 SC). 14 patients were excluded from the analysis because administration of BTZ was changed after start of induction therapy. We analyzed whether the route of administration influenced the applied cumulative BTZ dose, toxicity and efficacy of PAd and VCD. Results: The cumulative applied BTZ dose was significantly higher in patients treated with SC BTZ (PAd: 28.9 mg; VCD: 28.8 mg) compared to IV-treated patients (PAd: 27.6 mg; VCD: 27.9 mg; p = 0.007). Analysis of reported AEs associated to induction therapy revealed a significantly higher rate in patients treated with IV BTZ (65.1%) compared to SC-treated patients (55.7%, p = 0.02). AE > °II were reported more frequently in the IV group (IV: 52.0%; SC: 43.9%, p = 0.004). In detail, abnormal laboratory findings including leucopenia and thrombocytopenia (IV: 23.0%; SC: 16.4%, p = 0.05), metabolism and nutrition disorders (IV: 12.5%; SC: 5.4%, p = 0.004) and gastrointestinal disorders (IV: 9.9%; SC: 3.9%, p = 0.006) occurred more often in IV-treated patients. Analysis of peripheral neuropathy (PN) ≥ °II revealed no significant differences between IV and SC BTZ during the first two cycles of induction therapy (cycle 1: IV: 1.6%; SC: 2.5%; cycle 2: IV: 2.3%; SC: 3.6%) but PN occurred more often in IV-treated patients during the third cycle of induction therapy compared to the SC group (IV: 7.6%; SC: 1.8%, p = 0.001). Overall response rates (partial response or better) were not influenced by the route of administration in patients treated with PAd (IV: 72.7%; SC: 70.7%; p = 0.79) or VCD (IV: 77.9%; SC: 82.1%; p = 0.39). Analysis of the VCD arm showed that rates of VGPR or better were significantly higher in patients treated with IV BTZ compared to SC-treated patients (IV: 41.6%; SC: 28.6%, p = 0.02). Rates of VGPR or better were also higher for IV-treated patients in the PAd arm but did not reach statistical significance (IV: 36.7%; SC: 31.4%, p=0.39). Patient characteristics including baseline creatinine levels > 2 mg/dl, obesity or age at inclusion > 65 years did not influence efficacy of IV or SC BTZ in both arms. Conclusion: Last year we reported on the favorable toxicity profile and equal efficacy of VCD compared to PAd. With the current analysis we demonstrate that toxicity is further reduced with SC BTZ compared to IV. We therefore recommend VCD as induction therapy. However, we show for the first time a possible loss of efficacy in SC-treated patients. Therefore it remains unclear whether the reduced toxicity justifies the general application of SC BTZ in newly diagnosed, transplant-eligible patients or whether a prolonged treatment (4 x VCD SC) may reduce toxicity while achieving similar efficacy. Further studies are warranted since our results are partially in contrast with the previously presented data in relapsed MM and the ongoing MM5 trial was initially not designed to prospectively investigate the effect of SC or IV BTZ. Disclosures Salwender: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Binding site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Scheid:Celgene: Honoraria; Janssen: Honoraria. Mai:Janssen: Travel support Other. Hose:Novartis: Research Funding. Schmidt-Wolf:Janssen: Consultancy, Honoraria. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; BMS: Consultancy; Noxxon: Consultancy. Duerig:Janssen: Consultancy, Honoraria; Celgene: Honoraria. Goldschmidt:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Polyphor: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Onyx: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau.

Introduction: Treatment of acute myeloid leukemia (AML) in elderly patients remains challenging. Low-dose DNA hypomethylating agents are a therapeutic option in myelodysplastic syndromes and AML. However, the mechanism of action of hypomethylating agents and the role of induction of DNA hypomethylation in the clinical response is still unclear. To unravel the in vivoeffects of sequential cycles of decitabine, we set out to characterize methylomes of leukemic blasts, T cells (presumably not part of the malignant clone) and granulocytes before and during treatment of AML patients enrolled in the randomized phase II DECIDER clinical trial (NCT00867672). We developed a statistical model for longitudinal data analysis to identify the strongest hypomethylation response. Methods: Peripheral blood mononuclear cells (PBMC) from AML patients were collected before and during therapy (i.v. 20 mg/m2 decitabine for 5 days, with or without subsequent oral drug add-on). Leukemic blasts and T-cells were isolated using automatic magnetic sorting of cells (autoMACS) labelled with anti-human CD34, CD117 and CD3 MACS microbeads (Miltenyi Biotec), respectively. Granulocytes were isolated using dextran sedimentation. Cell type specific genome-wide DNA methylation profiles were obtained using Infinium Human Methylation 450 BeadChip arrays. Data were analyzed using R packages RnBeads applying beta mixture quantile dilation for normalization (Teschendorff et al. Bioinformatics, 29:189–196, 2013) and a modified version of NHMMfdr for multiple testing. Results: Peripheral blood blasts (median purity: 92%) were isolated from 20 patients, and T cells (median purity: 94%) from 26 patients before treatment and on days 4 and/or 8 and 15 of treatment cycle 1. From 10 patients, blasts and T cells were also collected during and/or after cycle 2. In total, until now 127 methylomes (46 blasts, 47 T cells, 34 granulocytes) were generated and used for mathematical modelling. Since the trial is still recruiting, genome-wide methylation was interpreted blinded to all clinical data including drug add-on (ATRA, valproic acid). First, the methylation dynamics of each individual CpG site described by a specified summary statistics were identified. Then, inter-probe distance and CpG annotation were incorporated to explain the dependence structure between CpG sites. In order to control the false discovery rate (FDR), we adapted a method proposed for differential DNA methylation (Kuan & Chiang, Biometrics 68: 774–783, 2012). The summary statistics for each CpG site were modelled to follow a non–homogeneous hidden Markov model. Statistical testing was validated by simulations revealing a very high discriminative power for affected CpGs even with very low methylation dynamics. Applying the model to blasts and T cells, extensive differences in the in vivomethylation changes became apparent. In blasts, 13% of CpG (59,920 CpGs of total 460,343 CpGs) showed significant DNA hypomethylation (Δβ>0.1, FDR Conclusions: Our mathematical model revealed significant DNA hypomethylation by day 8, with striking remethylation by day 15 from start of decitabine treatment in AML blasts in vivo. Most of the hypomethylated CpGs resided in non-promoter regions. In contrast, T-cells were much less affected, which might be due to the low cell division rate and the fact that they are non-malignant cells. This model will hopefully allow determination whether the effects of decitabine are targeted or random, by including sequential samples from later treatment cycles. Unblinding of the patients' clinical data will reveal potential biomarkers of response to epigenetic therapy. Disclosures Lübbert: Ratiopharm: received study drug valproic acid, received study drug valproic acid Other; Johnson&Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees, received study drug decitabine Other.

Aim: Analysis of a trial investigating, whether TPFC would be feasible and superior to PFC in patients with RM-HNSCC without limiting comorbidities, based on the findings, that D in addition to PF in induction treatment and C in addition to PF in RM disease both improved outcome in HNSCC. The first analysis was presented at ASCO 2014; here we present the final analysis. Methods: 180 patients were assigned 1:1 to receive either (arm A) P 40 mg/sqm, D 40 mg/sqm, F 2000 mg/sqm days 1 + 8, C 400/250 mg/sqm days 1, 8, 15 q3w or (arm B) standard PFC (P 100 mg/sqm day 1, F 1000 mg/sqm days 1-4, C 400/250 mg/sqm days 1, 8, 15) q3w. Chemotherapy was continued for a maximum of 6 cycles in absence of disease progression or limiting toxicity, followed by C maintenance (500 mg/sqm q2w). Because of excessive toxicity (gastrointestinal and infections) in arm A, P was reduced to 30 and F to 1000 mg/sqm after 20 patients/arm. Results: Median follow-up was 2 years. Toxicity was similar in both arms, with a rate of grade 4 toxicities of 21.3% vs. 30.8% of patients in arms A vs. B. 11.2% vs. 6.6% potentially treatment related deaths were observed in arms A vs. B. Median PFS A vs. B was 5.4 vs. 5.0 mo (HR 0.79, p = 0.375), median OS was 9.8 vs. 9.7 mo (HR 1.39, p = 0.993) and response rates were 38.2% vs. 31.9%, respectively. Conclusions: Despite of the previously described advantage of both components D and C in treatment of HNSCC, the four-drug regimen was not associated with improved median PFS or OS. The efficacy data of the CeFCiD trial are comparable with the results in the EXTREME trial. Disclosure: M. Knoedler: Financial support for conducting this trial by Merck GmbH and Sanofi Aventis for conducting this trial; T. Gauler, A. Dietz, V. Grunwald, J. Stoehlmacher-Williams, O. Guntinas-Lichius and G. Maschmeyer: Merck Serono; U. Keilholz: Merck Serono and Sanofi Aventis. All other authors have declared no conflicts of interest.

Background For curative treatment of younger patients with acute myeloid leukemia (AML) double induction with two cycles of intensive cytarabine/ anthracycline based chemotherapy 21 days apart is the current standard of care. In the prospective randomized AML-CG 2008 trial we asked question whether current results could be improved on by a dose-dense regimen (S-HAM – Sequential High-dose cytArabine and Mitoxantrone) in which the interval between cycles was minimized to 3 days. A prior large one-armed study (AML-CG 2004) had demonstrated a high antileukemic efficacy and shortened neutropenia of the S-HAM regimen as compared to a historical control of standard double induction treatment. The first clinical results of the randomized comparison are presented here. Methods All patients with first diagnosis of a de-novo or secondary AML (excluding APL) that were deemed fit for intensive induction chemotherapy by their treating physician were eligible for this study. Younger patients in the standard arm were treated with one cycle of TAD-9 (standard dose cytarabine and daunorubicine 60mg/m2 for 3 days) and a mandatory second cycle of HAM (high dose cytarabine and mitoxantrone) starting at day 21. Elderly patients were treated with one cycle of HAM followed by a second cycle of HAM only in case of residual leukemia in the day 16 bone marrow aspirate. Patients in the experimental arm all received S-HAM (two sequential cycles of high-dose cytarabine on days 1+2, mitoxantrone days 3+4) with a 3 days interval. Patients in the age cohort 60 – 69 could be allocated to the “younger” or “elderly” cohort according to their biological fitness at the discretion of the treating physician. However high-dose cytarabine dosages were allocated according to chronological age with patients Results 396 patients were randomized into the study with an age range of 18 to 86 years (median 58). The 387 evaluable patients (184 standard, 203 experimental) were well balanced according to their clinical characteristics, cytogenetics, molecular genetics and overall risk profile. For the primary endpoint a higher ORR of 77% for S-HAM could be found as compared to 72% in the standard arm which was however not significant because a 15% difference had been postulated for the study. Non-hematological toxicities did not show any significant differences. However this was in clear contrast to hematological toxicities: Importantly the duration of critical neutropenia was highly significantly reduced by more than 2 weeks from 45 days (standard) to 29 days (S-HAM) counted from day 1 of treatment. Similarly critical thrombocytopenia was reduced by 13 days from 46 days to 33 days. The early death (ED) rate between both arms was identical between both arms. However a subgroup analysis demonstrated a significantly reduced ED rate in patients receiving 1g/m2 S-HAM as compared to all other treatment groups. The respective ED rates for the various time intervals (always counted from day d1 of treatment) for the 1g/m2S-HAM group were as follows: Interval d1-14 1%, d1-30 3%, d1-60 5%, d1-90 10%. Data for overall survival will be available in November 2013. Conclusion The dose-dense induction regimen S-HAM was highly feasible in patients up to the 8th age decade. The antileukemic efficacy was high with an ORR of 77% for the whole group of unselected patients. As compared to standard double induction dose-dense S-HAM reduced critical neutropenia by more than two weeks. Moreover the subgroup of patients receiving the 1g/m2 S-HAM regimen experienced the lowest ED rate ever reported in the AML-CG trials. This underlines that in contrast to our general expectations the concept of dose-density is able to combine high antileukemic efficacy with significantly reduced haematological toxicity in AML, characterising this approach as first candidate for the next standard arm for future trials of the study group. Disclosures: Lengfelder: TEVA/ Cephalon: Research Funding.

Background We investigated if bortezomib during induction and maintenance improves survival in newly diagnosed Multiple Myeloma (MM). Methods 827 eligible patients with newly diagnosed symptomatic MM were randomized to receive induction therapy with VAD (vincristine, doxorubicin, dexamethasone; n=414) or PAD (bortezomib, doxorubicin, dexamethasone; n=413) followed by high-dose melphalan (HDM) and autologous stem cell transplant (ASCT). Maintenance consisted of daily thalidomide 50 mg (VAD) or 2-weekly bortezomib 1.3 mg/m2 i.v. (PAD) for 2 years. The primary analysis was progression-free survival (PFS) adjusted for ISS stage. We here report long-term results of this trial (P. Sonneveld et al., J Clin Oncol 2012;30:2946-2955). Results The number of eligible patients, patient characteristics and disease characteristics are similar to those reported before. The response rates during protocol treatment have improved slightly since all patients have now completed treatment: CR+nCR 49% vs 35%, VGPR 26% vs 21% and ≥PR 91% vs 83% (PAD vs VAD). After a median follow-up of 67 months, 111 of patients treated with VAD and 131 of patients treated with PAD were progression-free and alive. Progression-free survival (PFS) defined as time from randomization until progression, relapse or death (censored at date of alloSCT, if applicable), was superior with PAD when adjusted for ISS, (HR=0.78, 95% CI [0.66-0.91], P=.002) and in multivariate analysis (HR=0.76 (95% CI [0.64-0.90], P=.001). For the secondary endpoint overall survival (OS) the PAD arm was superior when adjusted for ISS (HR=0.80, 95% CI [0.65-1.00], P=.047) as well as in multivariate analysis (HR=0.78, 95% CI [0.63-0.97], P=.027). Landmark analysis from start of maintenance for PFS did not show a significant difference between Thalidomide and Bortezomib maintenance, however, for OS the PAD arm was superior (P=.035) (HR=0.71, 95% CI [0.52-0.98]). Subgroup analysis performed on patients with renal failure at presentation (serum creatinine ≥2 mg/dL; 45 VAD, 36 PAD) showed that the PAD arm was significantly superior for PFS (HR=0.44, 95% CI [0.26-0.75], P=.003) and OS (HR=0.38, 95% CI [0.21-0.69], P Conclusions Bortezomib during induction and maintenance improves CR and achieves superior PFS and OS. Subgroup analysis after long follow-up confirms the favourable outcome in patients with renal failure. Comparison of study subgroup analysis suggests that bortezomib treatment combined with double intensive treatment may be beneficial for PFS/OS. This trial has been registered as NTR213; EudraCT no. 2004-000944-26; ISRCTN: 64455289. This trial was supported by the Dutch Cancer Foundation, the German Federal Ministry of Education and Research and an unrestricted grant from Janssen-Cilag-Ortho Biotech. The GMMG study group received further grants to support this trial by Novartis, AMGEN, Chugai and Roche. Disclosures: Sonneveld: Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding. Salwender:janssen: Honoraria. Weisel:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Schmidt-Wolf:janssen: Research Funding; novartis: Honoraria. van de Velde:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. Goldschmidt:janssen: Honoraria, Research Funding; amgen: Research Funding; novartis: Honoraria, Research Funding; chigai: Honoraria, Research Funding; roche: Honoraria, Research Funding.

Introduction Epigenetic therapies with azanucleoside DNA hypomethylating agents, alone or in combination with histone deacetylase inhibitors (HDACi), show clinical activity in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), particularly when given at non-cytotoxic doses. They are able to reactivate epigenetically silenced genes including, among others, a number of highly immunogenic proteins dubbed Cancer/testis antigens (CTAs), predominantly the CTAs located on the X chromosome. We have previously shown that decitabine can induce expression of several CTAs, including MAGEB2 and NY-ESO-1, in myeloid cells in vitro and thereby trigger an immune response (Almstedt et al., Leuk. Res. 2010). Induction of a CTA-specific cytotoxic T cell response in vivo was reported also in AML patients treated with azacitidine and sodium valproate (VPA) and correlated with clinical response (Goodyear et al., Blood 2010). To the best of our knowledge, no data have yet been reported on the effect of combination treatment with decitabine and panobinostat or sodium valproate (VPA) on CTA reactivation in myeloid leukemia. Aim We hypothesized that by combining decitabine with HDACi we could further enhance expression of CTAs in myeloid leukemia cells and thereby boost recognition of the malignant cells by the cytotoxic T lymphocytes. Methods The myeloid cell lines U937 and Kasumi-1 were treated with decitabine alone or in combination with the HDACi VPA or panobinostat applied at non-toxic concentrations (>80% cell viability). Expression of CTAs was analyzed by RT-qPCR and Western blot after 48 hours of HDACi treatment. DNA methylation of NY-ESO-1 and MAGEB2 promoter regions was quantified by pyrosequencing. Bone marrow mononuclear cells from 19 AML patients (treated with or without VPA as add-on to decitabine in the ongoing randomized phase II DECIDER clinical trial, NCT00867672) were collected before and on day 15 of treatment, in some patients also after 2 treatment cycles. CTA mRNA expression and promoter DNA methylation were quantified as described above. Results VPA or panobinostat alone did not induce MAGEB2 or NY-ESO-1 expression in vitro. However the pretreatment of cells with decitabine prior to addition of either HDACi resulted in a synergistic dose-dependent reactivation of MAGEB2 and NY-ESO-1 on the mRNA level (confirmed for the latter on the protein level). Pyrosequencing analysis of the heavily methylated NY-ESO-1 and MAGEB2 promoters revealed, as expected, no methylation changes upon HDACi treatment, but a dose-dependent hypomethylation upon decitabine. In recently initiated in vivo studies (DECIDER trial), until now cells from 19 AML patients receiving epigenetic treatment were sequentially analyzed. Induction of MAGEB2 mRNA was observed in 9 patients (from absent to a median of 0.002 relative to GAPDH, range 0.0004-0.043), with concomitant DNA hypomethylation of the MAGEB2 promoter from median 83% pretreatment methylation (range 63%-90%) to 63% posttreatment (range 44%-74%). In 5 patients modest hypomethylation without changes in MAGEB2 expression was observed (from median pretreatment values of 89% [72%-92%] to 82% [58%-87%] posttreatment). Another 5 patients disclosed neither hypomethylation nor reexpression of MAGEB2 (results as yet blinded to treatment arm and clinical response). Conclusions Combined epigenetic treatment with the hypomethylating agent decitabine and the HDACi VPA or panobinostat synergistically induced a dose-dependent reactivation of the CTAs MAGEB2 and NY-ESO-1 in vitro, accompanied by promoter hypomethylation. First translational results of the DECIDER AML trial also indicate in vivo effects of the epigenetic treatment on CTA induction. The unmasking of CTAs to the immune system by epigenetically active drugs can increase anti-tumor immune responses, and thus has clear implications for future clinical trials combining epigenetic therapy and specific immunotherapy in myeloid neoplasia. Disclosures: No relevant conflicts of interest to declare.

Abstract 1639 Introduction: Maintenance using interferon-α (IFN) had previously been shown to be effective in indolent lymphoma (Solal-Celigny et al., NEJM 1993, Hagenbeek et al., JCO 1998). However, data on the impact of IFN in lymphoplasmacytic lymphoma (LPL) and after immuno-chemotherapy are rare. In two GLSG first-line trials which included LPL patients, IFN-maintenance was intended in all patients responding to induction therapy and not assigned to high-dose therapy. We performed a retrospective analysis to compare the clinical outcome in LPL patients who received IFN-maintenance versus no consolidation or maintenance. We adjusted for potential confounders that might have influenced the decision not to start IFN-maintenance. Methods: In the GLSG first-line trials “CHOP vs. MCP” and “CHOP vs. R-CHOP” patients younger than 60 years had been randomized between consolidating high-dose radio-chemotherapy followed by autologous stem cell transplantation (ASCT) and IFN-maintenance. IFN-maintenance was also intended in all responding patients older than 60 years. Patients with LPL achieving a partial or complete remission after MCP, CHOP, or R-CHOP and who did not start ASCT were included in the current analysis. We compared patients in which IFN-maintenance was not started to patients with IFN-maintenance. We investigated patient and treatment characteristics of these groups in order to detect possible reasons why IFN-maintenance was not started. Outcome parameters were remission duration (RD) and overall survival (OS). RD, calculated from the end of induction to relapse or death, was censored at the latest follow-up date in patients without event, but also when a new antilymphoma therapy was initiated without any sign of progression. No censoring was done for any form of dose reduction or stopping of IFN, which was recommended in the trials if inacceptable side effects were observed. RD and OS were analysed by Kaplan-Meier curves and log rank test and we adjusted for potential confounders in multiple Cox-Regression. In order to assess the impact of IFN-maintenance after R-containing induction, we performed a subgroup analysis of R-CHOP treated patients. Results: IFN-maintenance was started in 56 (75%) of 75 responding LPL patients not treated with high-dose therapy. Patients with IFN-maintenance were younger (60 vs. 69 years, p=0.001), but other baseline characteristics (ECOG performance status, haemoglobin, LDH, platelets, β2-microglobulin, IgM) were comparable, as well as the percentage of patients with R-CHOP induction (64% vs. 63%). More patients treated with IFN had achieved a CR (18% vs. 0%). Patients with IFN-maintenance had significantly longer RD (hazard ratio, HR, 0.27, 95% CI 0.12 to 0.59, p=0.001) and OS (HR 0.19, 95% CI, 0.06 to 0.58, p=0.004) which was similarly seen after adjustment for age (RD: 0.32, 95% CI 0.14 to 0.78, p=0.012, OS: 0.30, 95% CI 0.08 to 1.04, p=0.058), or the achievement of a CR. Of 48 patients responding to R-CHOP, IFN-maintenance was started in 36 (75%). RD after 3 years was 87% vs. 41% (p Conclusions: Although this is a non-randomized comparison based on a relatively small patient number, our results suggest that IFN-maintenance is effective in LPL also in the era of immuno-chemotherapy. It seems relevant to keep in mind that interferon-a may be a therapeutic option when other strategies are not possible. It may also be relevant for future investigations in lymphoma therapy. Disclosures: Hoster: Roche: Honoraria. Off Label Use: Interferon-alpha in lymphoplasmacytic lymphoma. Pfreundschuh:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiddemann:Roche: Research Funding.

Abstract 173 Imatinib (IM) in combination with either of a variety of chemotherapy regimens has become the mainstay of front-line treatment for younger patients with Ph+ ALL, followed by allogeneic SCT as a curative treatment option. Complete remission (CR) rates generally exceed 90% and overall treatment outcomes have improved as judged on the basis of phase II trials, but there is a paucity of long-term outcome data obtained from a large group of prospectively evaluated patients. Moreover, the impact of different front-line IM schedules on the outcome of patients undergoing allogeneic stem cell transplantation in first CR (CR1) as opposed to non-transplanted patients has not been thoroughly evaluated. We previously reported the results of a GMALL study comparing two alternating and concurrent schedules of IM and chemotherapy in successive patient cohorts (A1 and A2, respectively)(Wassmann et al, Blood 2006;108:1469). In a subsequent cohort (A3), IM was started simultaneously with induction chemotherapy according to the GMALL protocol 07/03, i.e. immediately after confirmation of the presence of a Philadelphia chromosome and/or bcr-abl translocation and completion of prephase therapy. We here report the long-term results of a prospective multicenter study of the GMALL study group including a total of 335 patients with newly diagnosed Ph+ ALL who received IM given at a single daily oral dose of 600 mg within 3 successive treatment cohorts. A1: IM administered between induction (IND) and first consolidation cycles (CONS1) and again after CONS1 (n=51); A2: IM given during the second half of IND and then continued throughout CONS1 until SCT (n=105); A3: IM initiated together with start of induction chemotherapy and continued throughout CONS1 until SCT (n=179). Minimal residual disease (MRD) was serially assessed by quantitative RT-PCR, mutational analyses was performed by D-HPLC and direct sequencing. The median age of all patients was 43 years (17-65 y), 57 (17%) patients were 55 years of age or older, 147 (44%) male and 182 (56%) female. CR rates in cohorts A2 and A3 were 89,4% and 85.7%, induction deaths occurred in 5.8% and 11.3% of patients, treatment failure was observed in 4.8% and 3% of pts., respectively. Initial responses are not reported for cohort A1 as only pts. already in CR or PR were eligible for study entry at this stage of the trial. The molecular response rate based on PCR negativity for bcr-abl transcripts after CONS1 was superior in cohort A3 with 33% (26/79) as compared to 12.5% (5/40) and 4.2% (2/47) in cohorts A2 and A1, respectively (p=0.01). Overall treatment outcome improved with earlier initiation and more prolonged administration of IM in the three successive patient cohorts: Overall survival (OS) at 4 years was 31%, 40% and 50% in cohorts A1, A2 and A3, respectively. There was a trend towards lower rates of pre-transplant relapse or treatment discontinuation of patients in CR in cohort A3 (4% and 1.1%, respectively) compared to cohorts A2 (8.7% and 5.8%) or A1 (11.8% and 5.9%). To date, 219 patients (66.4%) underwent SCT in CR1 (A1: n=39; A2: n=74; A3: n=106), with a median age of 39.5 years. The 3 year probability of DFS of pts. in cohort A3 who received myeloablative conditioning regimens combining TBI with cyclophosphamide or etoposide was 72%. DFS was not significantly different between matched sibling and matched unrelated donor SCT. The incidence of relapse after SCT was substantially lower among patients in cohort A3 (11.3%) than those in A2 (24.3%) or A1 (30.8%). Similarly, there was a trend to lower non-relapse mortality after SCT in A3 (20.8%) compared to A2 (25.7%) or A1 (33.3%). For all pts. transplanted in CR1 irrespective of treatment cohort, median OS was 57% after 3 yrs. and 52% after 7 yrs. Patients who did not undergo SCT in CR1 had a dismal outcome, with a median OS of 9.4 months and 14% alive after 3 years. In conclusion, earlier and more prolonged administration of IM in conjunction with chemotherapy is associated with superior treatment outcomes after SCT in newly diagnosed pts. with Ph+ ALL who are considered eligible for allogeneic SCT. SCT in CR1 remains the treatment of choice even in patients who achieve a good molecular response to initial therapy. Reducing induction as well as post-transplant mortality could have the greatest impact on further improving OS and DFS. Disclosures: Ottmann: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

4014 Background: 5-FU based CRT is regarded standard perioperative treatment in LARC. Here we report safety data of a non-inferiority phase III trial investigating (neo-)adjuvant CRT with Cape in comparison with 5-FU. Methods: Patients (pts) aged ≥18 years with LARC UICC stages II or III were recruited in this two-arm, two-strata randomized phase-III trial (arm A: Cape, arm B: 5-FU; stratum [S] I: adjuvant, S II: neoadjuvant). Regimens: Arm A: CRT: 50.4 Gy + Cape 1,650 mg/m2 days 1–38 plus five cycles of Cape 2,500 mg/m2 d 1–14, rep. d 22 (S I: 2 x Cape, CRT, 3 x Cape; S II: CRT, TME surgery followed by Cape x 5). Arm B: CRT: 50.4 Gy + 5-FU 225 mg/m2 c.i. daily [S I] or 5-FU 1,000 mg/m2 c.i. d 1–5 and 29–33 [S II] plus 4 cycles of bolus 5-FU 500mg/m2 d 1–5, rep. d 29 (S I: 2 x 5-FU, CRT, 2 x 5-FU; S II: CRT, TME surgery followed by 5-FU x 4). Primary endpoint was survival, secondary endpoints comprised safety and disease-free survival. Results: Of 401 randomized pts a total of 392 are evaluable (Arm A n=197, arm B n=195; S I n=231, S II n=161). Both arms were well balanced with respect to age, sex, WHO status, T- and N- stages. Regarding duration of treatment, 78% (Cape) and 80% (5-FU) completed all scheduled treatment cycles in S I, and 46% (Cape) and 40% (5-FU) in neoadjuvant stratum S II. In S II a total of 38% (Cape) and 43% (5-FU) did not continue chemotherapy after tumour resection. Concerning early efficacy endpoints in S II, pts treated with Cape (evaluable thus far n=121) exhibited a higher rate of T-downstaging (defined as ypT0–2; 52 vs 39%; p=0.16) and N0 (71 vs 56%; p=0.09). Regarding overall safety (NCI-CTC), pts receiving Cape experienced significantly less leukopenia (25 vs 35%; p=0.04), but more hand-foot syndrome (31 vs. 2%; p [Table: see text]