ALBERT

Beschreibung: Introduction: As previously reported, the combination of brentuximab vedotin with doxorubicin, vinblastine and dacarbazine (A+AVD) demonstrated a statistically significant improvement in modified progression free survival (modified PFS) compared with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in patients with newly diagnosed Stage III or IV classical HL in the phase 3 ECHELON-1 trial (NCT01712490). The benefit of A+AVD in the ITT population observed in the primary analysis was maintained at 3-years median follow-up [3-year PFS: A+AVD: 83.1% (79.9-85.9), ABVD: 76% (72.4-79.2)] and appears independent of interim PET status, disease stage, and prognostic risk factors. Here we present the efficacy and safety results of longer follow-up at a median 43.3 months. Methods: Newly diagnosed patients with Stage III or IV cHL were randomized 1:1 to receive A+AVD (n=664) or ABVD (n=670) intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. The primary endpoint of the study was modified PFS per independent central review. The present follow-up PFS analysis is exploratory and per investigator assessment, with a cutoff date of June 17th, 2019. Patients with ongoing peripheral neuropathy (PN) at end of treatment were followed for resolution or improvement (defined as improved by ≥1 grade from worst grade as of the latest assessment) during the post-treatment follow-up period. Results: With a median follow-up of 43.3 months, the 42-month PFS per investigator for all patients was 82.4% (95% CI, 79.1-85.2) on the A+AVD arm and 76.2% (95% CI, 72.6-79.4) on the ABVD arm [overall HR 0.697 (95% CI, 0.547-0.890)]. Exploratory subgroup analyses of PET2(+) and PET2(-) patients showed a treatment effect in favor of A+AVD. The 42-month PFS in PET2(-) patients was 85.0% (95% CI, 81.6-87.7) for A+AVD and 79.6% (95% CI, 75.9-82.8) for ABVD [overall HR 0.695 (95% CI, 0.526-0.919)]; in PET2(+) patients 42-month PFS was 68.3% (95% CI, 54.5-78.7) for A+AVD and 51.5% (95% CI, 38.2-63.4) for ABVD [overall HR 0.552 (95% CI, 0.308-0.989)]. Upon continued follow-up, 81% (356/442) of patients with PN in the A+AVD arm had either complete resolution (64%, 283/442) or improvement (17%, 73/442) of their PN events compared with 83% (236/286) with either complete resolution (74%, 212/286) or improvement (8%, 24/286) in the ABVD arm. Among patients with ongoing PN after continued follow-up, the majority were Grade 1/2 events, with 89% (141/159; 59% Grade 1) and 95% (70/74; 65% Grade 1) on the A+AVD and ABVD arms, respectively. Overall survival data are not yet mature; per protocol, the final analysis will be performed after 112 deaths have occurred. Additional follow-up at an estimated median of ~4 years, including data from prespecified subgroups, will be presented. Conclusions: With a median follow-up of 43.3 months, A+AVD continues to provide a robust, durable benefit for patients with previously untreated Stage III or IV cHL compared with ABVD; the benefit is evident regardless of patient status at interim PET [PET2(+) or PET2(-)] and without the need for treatment intensification. PN continued to completely resolve or improve in patients on the A+AVD and ABVD arms. Together, these data further support the clinical advantages of A+AVD versus ABVD as treatment for patients with previously untreated Stage III or IV cHL. Disclosures Bartlett: Affimed Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Dynavax: Research Funding; Forty-Seven: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medimmune: Research Funding; Merck: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria. Dlugosz-Danecka:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Macrogenomics: Research Funding; Roche: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Illes:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Janssen: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Feldman:Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Cell Medica: Research Funding; Amgen: Research Funding; Viracta: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Eisai: Research Funding; Corvus: Research Funding; Roche: Research Funding; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Kyowa Hakko Kirin: Research Funding; Trillium: Research Funding. Smolewski:Roche: Other: Travel Expenses. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding; BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria. Walewski:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Takeda: Honoraria, Research Funding; Incyte: 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; Servier: Honoraria; Gilead: Other: Travel Expenses; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zinzani:Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Hutchings:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Radford:AstraZeneca: Equity Ownership, Research Funding; Novartis: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; GSK: Equity Ownership. Munoz:AstraZeneca: Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Portola: Research Funding; Incyte: Research Funding. Kim:Roche: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J&J: Research Funding; Mundipharma: Research Funding; Celltrion: Research Funding; Donga: Research Funding. Advani:Cell Medica, Ltd: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Kura: Research Funding; Infinity Pharma: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; Stanford University: Employment, Equity Ownership; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Regeneron: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ansell:Mayo Clinic Rochester: Employment; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Trillium: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment. Younes:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding. Gallamini:Takeda: Consultancy; Roche: Consultancy. Miao:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Liu:Takeda: Employment. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Forero-Torres:Seattle Genetics: Employment, Equity Ownership, Honoraria, Research Funding.

Beschreibung: Background: A histologic finding of large cell transformation (LCT) in Mycosis fungoides (MF) is often associated with an aggressive clinical course and inferior prognosis (Arulogun et al. Blood 2008). In patients (pts) with advanced MF (stage IIB-IV), LCT has been established as an independent prognostic factor (Scarisbrick et al. JCO 2015). Although CD30 expression is observed more frequently in MF with LCT vs without LCT, a wide range of CD30 expression levels is observed in LCT lesions and the level of expression lacks prognostic value for MF (Vergier et al. Blood. 2000). The ALCANZA study (NCT01578499) demonstrated significantly better rates of objective response lasting ≥4 months (ORR4) (∆43.8%; p

Beschreibung: Abstract 1702 Poster Board I-728 Background ASCT consolidation in the first remission is the treatment of choice in MCL patients. However lack of adequate response to the first line therapy, elderly age and co-existing co-morbidities makes it feasible for less than a third of patients. Methods Retrospective analysis of 279 MCL cases treated at 10 PLRG centers was performed: 52% of them (144 pts) received Rituximab in induction therapy; 35% (97 pts) were subjected to post-induction therapy (ASTC – 16%, radioimmunotherapy consolidation – 13% and Rituximab maintenance – 6%). There were no significant differences in risk factor distribution among analyzed subgroups. Results 1) At 5 years OS was 40% in the whole group: 77% for those subjected to post-induction therapy vs 25% for those who were not; 5 year PFS is 20%, 48% and 5% respectively (p

Beschreibung: Key Points Frontline FCA increases progression-free survival in CLL and, in a post hoc analysis, also survival in younger patients. With the low-dose approach, no increase in treatment related mortality is seen.

Beschreibung: Ofatumumab is a unique monoclonal antibody that targets a distinct small loop epitope on the CD20 molecule. Preclinical data show that ofatumumab is active against B-cell lymphoma/chronic lymphocytic leukemia cells with low CD20-antigen density and high expression of complement inhibitory molecules. In a phase 1/2 trial evaluating safety and efficacy of ofatumumab in relapsed or refractory follicular non-Hodgkin lymphoma (FL) grade 1 or 2, 4 dose groups of 10 patients received 4 weekly infusions of 300, 500, 700, or 1000 mg. Patients had a median of 2 prior FL therapies and 13% had elevated lactate dehydrogenase. No safety concerns or maximum tolerated dose was identified. A total of 274 adverse events were reported; 190 were judged related to ofatumumab, most occurring on the first infusion day with Common Terminology Criteria grade 1 or 2. Eight related events were grade 3. Treatment caused immediate and profound B-cell depletion, and 65% of patients reverted to negative BCL2 status. Clinical response rates ranged from 20% to 63%. Median time to progression for all patients/responders was 8.8/32.6 months, and median duration of response was 29.9 months at a median/maximum follow-up of 9.2/38.6 months. Ofatumumab is currently being evaluated in patients with rituximab-refractory FL. This trial was registered at www.clinicaltrials.gov as #NCT00092274.

Beschreibung: HuMax-CD20 is a fully human monoclonal IgG1 antibody targeting a unique extracellular epitope of the CD20 molecule on B-cells. HuMax-CD20 stops growth of engrafted B-cell tumors in SCID mouse tumor models more efficiently than Rituximab®, and i.v. infusion of HuMax-CD20 in cynomolgus monkeys has led to profound, long lasting, dose-dependent B-cell depletion. A total of 40 patients with CD20+ relapsed or refractory follicular non-Hodgkin’s lymphoma grade I-II will be enrolled in this open-label, dose-escalating, international, multi-center clinical trial. Cohorts of 10 patients will receive i.v. infusions at doses of either 300, 500, 700 or 1000 mg once weekly for 4 weeks. The patients are followed for 12 months. Patients receive oral acetaminophen and i.v. antihistamin before infusion. In case of adverse events of CTC grade 3 or higher, i.v. glucocorticosteroids are given. The endpoints are CT scan verified tumor response according to the Cheson criteria, B-cell depletion in peripheral blood and lymph nodes, time to next anti-lymphoma treatment, duration of response, BCL2 conversion, pharmacokinetics, and adverse events. Tumor and bone marrow biopsies and CT scans are assessed centrally. The first 17 patients treated with HuMax-CD20 are the subject of this report. Mean age is 60 years. In the 300 mg group all 10 patients have received all 4 infusions. Seven patients have been enrolled in the 500 mg group; three of them have received 4 infusions, two have received 3 infusions, and two patients have received 2 infusions. Baseline B-cell count was in the range of 11-382 x 106 cells per L with a median of 114 x 106. One week after the first infusion the median B-cell count available in 16 patients was 8 x 106 cells per L with a range of 0–19 x 106. In six of the 16 patients no B-cells were detected. B-cell counts measured one week after the 4th infusion are available for 10 patients. Eight patients had no detectable B-cells, one patient had 11 x 106 and one had 34 x 106 cells per L. B-cell counts eight weeks after the 4th infusion are available for two patients. No B-cells were detectable in these two patients. No dose limiting toxicity has been reported with administration of 300 or 500 mg. One serious adverse event assessed as not related to HuMax-CD20 has been reported in the 300 mg group. Infusion related adverse events have primarily been seen during the first infusion of HuMax-CD20. The events have, as expected, predominantly been signs and symptoms of cytokine release, e.g. pruritus, dyspnoea, rigors/chills, nausea, hypotension, urticaria, fatigue, fever and rash. In 15 of the 17 patients, 51 adverse events have been reported. Nine adverse events were CTC grade 3, 16 were grade 2, and 26 events were grade 1. In conclusion, this analysis based on preliminary data for the first 17 patients treated with HuMax-CD20 demonstrated significant depletion of peripheral blood B-cells and a favorable safety profile. An updated report of results for all 40 patients including preliminary tumor response data will be presented.

Beschreibung: This prospective study aimed to develop reproducible diagnostic criteria for sporadic Burkitt lymphoma (BL), applicable to routine practice, and to evaluate the efficacy of dose-modified (dm) CODOX-M/IVAC in patients diagnosed using these criteria. The study was open to patients with an aggressive B-cell lymphoma with an MKI67 fraction approaching 100%. Immunophenotype and fluorescent in situ hybridization (FISH) were used to separate BL from other aggressive B-cell lymphomas. BL was characterized by the presence of a cMYC rearrangement as a sole cytogenetic abnormality occurring in patients with a germinal center phenotype with absence of BCL-2 expression and abnormal TP53 expression. A total of 128 patients were eligible for the study, of whom 58 were considered to have BL and 70 to have diffuse large B-cell lymphoma (DLBCL). There were 110 clinically fit patients who received dmCODOX-M (methotrexate, dose 3 g/m2) with or without IVAC according to risk group. The 2-year progression-free survival was 64% (95% confidence interval [CI] 51%-77%) for BL, 55% (95% CI 42%-66%) for DLBCL, 85% (95% CI 73%-97%) for low risk, and 49% (95% CI 38%-60%) for high-risk patients. The observed differences in outcome and other clinical features validate the proposed diagnostic criteria. Compared with the previous trial LY06 with full-dose methotrexate (6.7 g/m2), there was a reduction in toxicity with comparable outcomes. This study was registered at www.clinicaltrials.gov as NCT00040690.

Beschreibung: Introduction: Patients (pts) with relapsed/refractory PMBCL (rrPMBCL) are typically treated like those with diffuse large B cell lymphoma (DLBCL), often with limited effective treatment options and poor outcomes. Unlike DLBCL and similar to classical Hodgkin lymphoma, PMBCL has frequent genetic abnormalities leading to over-expression of the programmed death (PD)-1 ligands, PD-L1 and PD-L2. This suggests that rrPMBCL should be sensitive to PD-1 blockade. In the phase 1b KEYNOTE (KN)-013 study (NCT01953692), pembrolizumab was associated with frequent and durable responses (Zinzani, Blood 2017) in pts with rrPMBCL. The international phase 2 KN170 (NCT02576990) study was conducted to extend these findings and evaluate correlative biomarkers of response. Here, we present updated results of all pts in KN013 (n=21) and the first full analysis of pts in KN170 (n=53). Methods: KN013 enrolled pts with rrPMBCL who had failed, were ineligible for, or refused autologous stem cell transplant (ASCT). KN170 enrolled pts with rrPMBCL who had relapsed after or were ineligible for ASCT with ≥2 lines of prior therapy. In KN013, the initial 10 pts received pembrolizumab 10 mg/kg Q2W; the remaining 11 patients and all patients on KN170 received pembrolizumab 200 mg Q3W for up to 2 years. Archival or fresh tumor tissue obtained before pembrolizumab initiation was used for correlative studies. Tumor response was assessed with PET/CT scans by IWG 2007 criteria. The primary endpoint of KN170 was objective response rate (ORR) by blinded independent central review (BICR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety/tolerability. Exploratory endpoints included response by Lugano 2014 criteria and biomarker analyses. Data cutoff dates for this analysis were Apr 4, 2018 for KN013 and April 13, 2018 for KN170. Results: KN013 enrolled 21 pts with a median of 3 prior lines of therapy, of whom 13 (62%) were ASCT-ineligible. KN170 enrolled 53 pts also with a median of 3 prior lines, of whom 39 (74%) were ASCT-ineligible due to chemorefractoriness. In KN013, ORR was 48% (10/21; 95% CI, 26-70), with a CR rate of 33% (7/21). In KN170, ORR was 45% (24/53; 95%CI, 32-60), with a CR rate of 13% (7/53; 11/53 [21% by Lugano criteria]). In KN013, after a median follow-up duration of 29.1 mo (range, 0.6-49.6), median DOR was not reached (range, 1.9+ to 39.8+ mo) (Panel A). 2 patients in KN013 in CR at 2 years remained in CR after a further 12 and 18 mo of follow-up off therapy. After a median follow-up of 12.5 mo for KN170 (range, 0.1-25.6), median DOR was not reached (range, 1.1+ to 22.0+ mo) (Panel A). At data cutoff, no patient who achieved a CR on KN170 had relapsed. In KN013, median PFS was 10.4 mo (95%CI, 3.4 to not reached) with 12-mo PFS rate of 47%; median OS was 31.4 mo with 12-mo OS rate of 65% (Panel B). In KN170, median PFS was 5.5 mo (95%CI, 2.8-12.1) with 12-mo PFS rate of 38%; median OS was not reached (95% CI, 7.3 to not reached) with 12-mo OS rate of 58% (Panel B). In KN013, no new safety signals were observed compared with prior analyses. In KN170, 30 (57%) pts had a treatment-related AE (TRAE). Common (≥5%) TRAEs included neutropenia (19%), hypothyroidism and asthenia (8% each), and pyrexia (6%). 12 (23%) pts had a grade 3-4 TRAE, including 5 (9%) with grade 3 and 2 (4%) with grade 4 neutropenia. Six (11%) pts had an immune-mediated AE including 1 (2%) with grade 4 pneumonitis. There were no treatment-related deaths. Conclusion: Together with the longer follow-up results of KN013, KN170, the largest prospective clinical trial in rrPMBCL, establishes the robust antitumor activity of pembrolizumab in this disease, with exceptionally durable responses and survival in responding patients. These results provided the basis for the FDA accelerated approval of pembrolizumab in patients with rrPMBCL. Disclosures Armand: Otsuka: Research Funding; Adaptive: Research Funding; Merck: Consultancy, Research Funding; Affimed: Consultancy, Research Funding; Pfizer: Consultancy; Infinity: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Rodig:Merck & Co., Inc.: Research Funding; Affimed Inc.: Research Funding; KITE Pharma: Research Funding; Bristol-Meyers-Squibb: Research Funding. Özcan:Jazz: Other: Travel support; Bayer: Research Funding; BMS: Honoraria; MSD: Other: travel support, Research Funding; Janssen: Other: Travel Support, Research Funding; Jazz: Other; Celgene: Other: Travel support, Research Funding; Roche: Honoraria, Research Funding; Archigen: Research Funding; Novartis: Research Funding; MSD: Research Funding; Abbvie: Other: Travel payment; Takeda: Honoraria, Other: Travel payment, Research Funding. Fogliatto:Novartis: Consultancy; Roche: Consultancy, Speakers Bureau; Janssen: Honoraria, Research Funding. Walewski:Roche, Celegene, Takeda, Janssen-Cilag, and Servier: Membership on an entity's Board of Directors or advisory committees; Roche, Celgene, Takeda, Janssen-Cilag, and Servier: Honoraria; Roche, GSK/Novartis, Takeda, and Janssen-Cilag: Research Funding. Gulbas:Pfizer: Other: Travel expenses; Roche and Janssen: Honoraria; Gilead: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees. Ribrag:Incyte Corporation: Consultancy; MSD: Honoraria; NanoString Technologies: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel; Gilead: Consultancy, Honoraria; Roche: Honoraria, Other: travel; Infinity: Consultancy, Honoraria; epizyme: Consultancy, Honoraria; Amgen: Research Funding; pharmamar: Other: travel; Servier: Consultancy, Honoraria; argenX: Research Funding. Christian:Immunomedics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Perini:Janssen and Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen and Takeda: Speakers Bureau; Janssen and Takeda: Other: Travel expenses. Salles:Merck: Honoraria; Novartis: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria; Acerta: Honoraria; Takeda: Honoraria; Pfizer: Honoraria; Morphosys: Honoraria; Servier: Honoraria; Amgen: Honoraria; Epizyme: Honoraria; Gilead: Honoraria; Janssen: Honoraria. Svoboda:Pharmacyclics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa: Consultancy; Regeneron: Research Funding; TG Therapeutics: Research Funding; KITE: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding. Chatterjee:Merck & Co., Inc.: Employment. Orlowski:Merck & Co., Inc.: Employment. Balakumaran:Amgen: Equity Ownership; Merck & Co., Inc.: Employment, Equity Ownership. Shipp:Bayer: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Merck: Research Funding. Zinzani:PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Beschreibung: Abstract 857 Background: Follicular lymphoma (FL) is an incurable B-cell non-Hodgkin's lymphoma (NHL) representing ∼20% of all NHL. Rituximab (R) is approved for the treatment of CD20+ relapsed/refractory FL, and single-agent bortezomib (Vc; VELCADE®) has shown activity in heavily pretreated patients. Vc and R show additive activity in preclinical models, and the combination was active and well tolerated in a phase 2 study. This randomized, open-label, multi-center, international, phase 3 clinical trial (LYM3001) compared the efficacy and safety of Vc plus R (Vc-R) vs R alone in patients with relapsed or refractory, R-naive or R-sensitive FL. Methods: Patients with grade 1/2 measurable FL who had relapsed/progressed following prior therapy (time to progression [TTP] ≥6 months if prior R-containing therapy), ECOG performance status ≤2, and no peripheral neuropathy grade ≥2 were randomized (1:1) to receive 5-week cycles of Vc-R (Vc 1.6 mg/m2, d 1, 8, 15, 22, cycles 1–5, plus R 375 mg/m2, d 1, 8, 15, 22 in cycle 1 and d 1 only in cycles 2–5) or R alone (administered according to the same schedule as for the Vc-R arm). In both groups, treatment was administered for five cycles or until progression or unacceptable treatment-related toxicity. Randomization was stratified by FLIPI score (0–1 vs 2 vs ≥3), prior R therapy (yes vs no), time since last dose of anti-FL therapy (≤1 vs 〉1 year), and region (US vs EU vs rest of world). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), complete response (CR) rate, TTP, and safety/tolerability. Response and progression were assessed by independent radiology committee (IRC) using the modified International Workshop Response Criteria. Planned sample size was 670 patients to provide 90% power (α=0.05, 2-sided) to detect a 33% improvement in median PFS with Vc-R vs R (i.e. 13.3 vs 10 months). Results: Between April 2006 and August 2008, 676 patients (intent-to-treat [ITT] population) were enrolled from 164 centers in 29 countries across Europe, the Americas, and Asia. Baseline characteristics were well balanced between the two arms; median age was 57 years (range 21–84), 54% were female, 75% were Caucasian and 21% were Asian. The majority of patients (93%) had an ECOG performance status of 0 or 1, 51% and 48% had grade 1 and 2 FL, respectively, and 41%, 35%, and 23% had high, intermediate, and low FLIPI score, respectively; 83% had Ann Arbor Stage III or IV, and 38% had bone marrow involvement at baseline. 33% of patients had received 3 or more prior lines of therapy (range 1–6+); 44% had received prior R therapy. The most common prior regimens were CHOP (38%), CVP (25%), single-agent R (17%), R-CHOP (12%), and R-CVP (11%). At a median follow-up of 33.9 months, a total of 440 PFS events were observed by IRC in the ITT population, 212 in the Vc-R arm and 228 events in the R arm. Median PFS improved from 334 days (95% CI: 278, 365) with R alone to 389 days (95% CI: 351, 456) with Vc-R; the hazard ratio was 0.822 (95% CI: 0.681, 0.991). This improvement is statistically significant with a 2-sided P-value of 0.039. The ORR was 63% with Vc-R vs 49% with R (P6 months) was 50% with Vc-R vs 38% with R (P=0.002). The median time to subsequent antilymphoma treatment was significantly improved in the Vc-R vs R arm (700 vs 537 days, P=0.027). Median OS was not reached in either group. Patients received a median 25 weeks treatment in both the Vc-R and R groups (range 5–40 and 5–35 in the Vc-R and R groups, respectively). Adverse events (AEs) were reported for 95% of Vc-R and 78% of R patients. The most common AEs were diarrhea (52% Vc-R, 8% R), nausea (29% Vc-R, 7% R), and pyrexia (25% Vc-R, 10% R). Most AEs were grade 1 or 2. Grade ≥3 AEs were reported in 46% of Vc-R and 21% of R patients; the most common grade ≥3 AEs were neutropenia (11% vs 4%) and diarrhea (7% vs 0%). Peripheral sensory neuropathy was reported in 17% of patients in the Vc-R arm vs 1% in the R arm; 3% vs 0% grade ≥3. 18% and 11% of Vc-R and R patients, respectively, had serious AEs, only 4% and 1% of patients discontinued due to drug-related AEs, and there were 9 and 4 on-treatment deaths, respectively. Conclusion: The addition of weekly Vc to R therapy in patients with relapsed FL was associated with statistically significant improvements in PFS, response rate, and time to next antilymphoma treatment, with acceptable additional toxicity. Disclosures: Coiffier: Johnson & Johnson: Honoraria. Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Mayer:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rule:Johnson & Johnson: Consultancy, Speakers Bureau; Roche: Consultancy. Walewski:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Investigators fee. Crump:Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy. Shpilberg:Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hermann:Millennium Pharmaceuticals: Research Funding. Parasuraman:Millennium Pharmaceuticals: Employment, Equity Ownership. Zhu:Johnson & Johnson: Employment. Enny:Johnson & Johnson: Employment, Equity Ownership. Theocharous:Johnson & Johnson: Employment. van de Velde:Johnson & Johson: Employment, Equity Ownership. Elsayed:Johnson & Johnson: Employment, Equity Ownership.

Beschreibung: Bcl-2 and Bcl-6 protein expression has been reported to predict progression-free (PFS) and overall (OS) survival of patients with Diffuse Large B-cell Lymphoma (DLBCL) in retrospective and prospective clinical studies. Reports on Bcl-2 expression frequency and predictive value have been conflicting. In the current study, paraffin-embedded tissue specimens from 79 newly diagnosed DLBCL patients subsequently treated with CHOP-like chemotherapy without rituximab were studied retrospectively using immunohistochemistry to evaluate expected influence of Bcl-2 and Bcl-6 on clinical outcome. Bcl-2 and Bcl-6 positivity was defined as staining in any of lymphoma cells and it was demonstrated in 78% of Bcl-2 and 58% of Bcl-6 patients. Frequency of Bcl-2 protein expression in our study was much higher then reported by others. Combinations of possible positive/negative staining results: Bcl2+/Bcl6+, Bcl-2+/Bcl-6-, Bcl-2-/Bcl-6+, Bcl-2-/Bcl-6- were found in 46%, 33%, 13%, and 9% of cases, respectively. Complete remission (CR) after initial chemotherapy was achieved in 54 of 74 evaluable patients (73%) and 6 patients (8%) had progressive disease (PD). CR rate was higher and relapse and death rate was lower in patients with Bcl-6+ tumor irrespective of Bcl-2 status. In patients with Bcl-6 negative lymphoma CR rate was higher when Bcl-2 was positive, but relapse and death rate was not affected by Bcl-2. Median OS and PFS were not reached after 21.3 months of follow-up in this group of patients. In the analysis using multivariate proportional hazards regression model, advanced clinical stage (CS III and IV vs. CS I and II) was the only significant factor predicting OS (p 1 (p