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PurposeTo evaluate the impact of the addition of bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on outcomes in previously untreated patients with non–germinal center B-cell–like (non-GCB) diffuse large B-cell lymphoma (DLBCL).Patients and MethodsAfter real-time determination of non-GCB DLBCL using the Hans immunohistochemistry algorithm, 206 patients were randomly assigned (1:1; stratified by International Prognostic Index [IPI] score) to six 21-day cycles of standard R-CHOP alone or R-CHOP plus bortezomib 1.3 mg/m2intravenously on days 1 and 4 (VR-CHOP). The primary end point, progression-free survival (PFS), was evaluated in 183 patients with centrally confirmed non-GCB DLBCL who received one or more doses of study drug (91 R-CHOP, 92 VR-CHOP).ResultsAfter a median follow-up of 34 months, with 25% (R-CHOP) and 18% (VR-CHOP) of patients having had PFS events, the hazard ratio (HR) for PFS was 0.73 (90% CI, 0.43 to 1.24) with VR-CHOP ( P = .611). Two-year PFS rates were 77.6% with R-CHOP and 82.0% with VR-CHOP; they were 65.1% versus 72.4% in patients with high-intermediate/high IPI (HR, 0.67; 90% CI, 0.34 to 1.29), and 90.0% versus 88.9% (HR, 0.85; 90% CI, 0.35 to 2.10) in patients with low/low-intermediate IPI. Overall response rate with R-CHOP and VR-CHOP was 98% and 96%, respectively. The overall survival HR was 0.75 (90% CI, 0.38 to 1.45); 2-year survival rates were 88.4% and 93.0%, respectively. In the safety population (100 R-CHOP and 101 VR-CHOP patients), grade ≥ 3 adverse events included neutropenia (53% v 49%), thrombocytopenia (13% v 29%), anemia (7% v 15%), leukopenia (26% v 25%), and neuropathy (1% v 5%).ConclusionOutcomes for newly diagnosed, prospectively enrolled patients with non-GCB DLBCL were more favorable than expected with R-CHOP and were not significantly improved by adding bortezomib.

Prospective data are needed to ascertain the impact of iron chelation therapy in patients with myelodysplastic syndromes. The present 5-year prospective registry analysis was conducted to compare clinical outcomes between chelated and nonchelated patients with lower-risk myelodysplastic syndromes and transfusional iron overload. In an interim analysis at 24 months, we previously reported that chelation therapy was associated with longer median overall survival and a tendency toward longer leukemia-free survival and fewer cardiac events. In the present report, we detail findings from the final analysis at 5 years. We confirm, at the conclusion of this 5-year, prospective, non-interventional study, that overall survival was significantly longer in patients who received iron chelation therapy vs those who did not. Causes of death in the overall population were predominantly myelodysplastic syndromes/acute myeloid leukemia followed by cardiac disease. Time to progression to acute myeloid leukemia was also significantly longer in patients receiving chelation therapy, and significantly fewer patients progressed to leukemia vs those not receiving chelation therapy. Limitations of the study include a potential for clinical bias, as patients with longer predicted survival may have been chosen for chelation therapy, the differences present in concomitant conditions at baseline, and the possibility that some high-risk patients were not identified due to limited cytogenetic classification.

3516 Background: The purpose of this study was to quantify different molecules of TIME including T cells, macrophages, and immune checkpoint proteins (ICPs), and determine their association with clinical outcomes and treatment benefit in pts enrolled in C-08, which tested the efficacy of adding bev to 5-fluoruracil+leucovorin+oxaliplatin. Our pre-specified, NCTN-CCSC approved primary objective hypothesized that pts with more CD8 cells would have a better prognosis and receive benefit from bev. Methods: Tissue microarrays were used to assess TIME of 1,509 C-08 pts using m-IF and the Vectra Pathology System. Three m-IF panels were used to quantitatively assess T cells (CD3, CD8, CD45RO, FOXP3), macrophages (CD68, CD163), and ICPs (PD-1, PD-L1, CTLA4, TIM3, LAG3, OX40) in stromal and tumor (panCK) regions. The primary objective was to determine the association between overall survival (OS) and high (top 3rd) v low CD8 expression in both stromal and tumor regions. All markers were tested for associations with OS and recurrence-free interval (RFI) and with bev prediction using Cox models and median cut points. Results: Based on our pre-specified analysis, pts with high CD8 cells had better OS, HR=0.66 (95%CI: 0.49-0.88), p=0.005 but pts with high CD8 cells did not receive bev benefit. All T cells and double stained CD8/PD-1 were associated with better RFI. CD3, CD8, CD68, PD-1, PD-L1, and LAG3 cells were associated with better OS. PD-1 and CD8/PD-1 were associated with RFI in pts with deficient mismatch repair (dMMR) and proficient (p)MMR but TIM3, CD3/CD45RO and CD163 were only associated with RFI in dMMR. Association of CD8 cells with bev benefit (RFI) was seen in dMMR pts, HR 0.27 (95% CI: 0.1-0.73), p=.01 and OS, HR=0.27, (95% CI: 0.12-0.64), p=0.0028 but there was no significant interaction. Single staining CD8, PD-1, and double staining CD8/PD-1 cells were associated with bev benefit in dMMR pts but with bev harm in pMMR pts. However, pts with tumors having >1% of PD-1 and PD-L1 cells (n=197 including 76 dMMR, 100 pMMR, and 21 unknown), received significant bev benefit (int p=.0056). Conclusions: CD8 cells were associated with better OS but were not associated with bev benefit. All T cells and PD-1, PD-L1, and LAG3 cells, were associated with better prognosis in the entire cohort but when pts were stratified for MMR status differences in their association with prognosis and bev benefit emerged. PD-1, CD8, and CD8/PD-1 cells were associated with bev harm in pMMR but bev benefit in dMMR. A significant interaction for the association of high % PD-1 and PD-L1 with bev benefit regardless of MMR status may be a chance finding. However, VEGF has immunosuppressive effects and bev may block these effects in tumors with high PD-L1 and PD-1, regardless of MMR status. NCT: 00096278 PA DOH, U10CA-180868, -180822, -196067, Genentech, Sanofi; NSABP. Clinical trial information: 00096278.

7523 Background: Bendamustine (B) + rituximab (R; BR) is a commonly used 1L treatment for CLL. The CLL10 study reported an ORR of 96% and CR of 31% with BR. Obinutuzumab (GA101; G) is a glycoengineered, type II anti-CD20 monoclonal antibody. A randomized Phase III trial in 1L CLL pts showed that G significantly improved PFS and CR rate compared with R, when used in combination with chlorambucil (Goede 2014). B + G (BG) was evaluated in a subgroup of CLL pts in the GREEN study (Stilgenbauer 2015). We present results of a Phase II study (NCT02320487) evaluating the efficacy and safety of BG as 1L treatment for CLL pts. Methods: 102 pts with previously untreated CLL received BG, consisting of 6 cycles of G (cycle [C] 1: 100mg day (D) 1, 900mg D2, 1000mg D8 and D15; C2–6: 1000mg D1) and B (90mg/m2: C1, D2 and D3; C2–6, D1 and D2). Each cycle was 28 days. Primary endpoint was CR assessed using iwCLL criteria. Secondary endpoints included ORR, PFS, OS, and MRD. Median follow-up at the time of analysis was 11.0 months. Results: Median pt age was 61 yrs (range 35–90); 68.6% were male; 44.1% had Rai stage 3–4. For evaluated pts, IgVH status was 32.9% mutated and 67.1% unmutated. The incidences of trisomy 12, normal cytogenetics, and deletions of 13q, 11q, and 17p were 23.4%, 37.5%, 17.2%, 15.6%, and 6.3%, respectively. Investigator-assessed CR rate was 49.0% (95% CI 39.0–59.1) and ORR was 89.2% (95% CI 81.5–94.5) after 6 cycles. MRD negativity (MRD-) in blood, as measured by 4-color flow cytometry, was achieved in 42.7% of pts at the end of induction response assessment and in 75.5% of pts at any time following treatment. MRD- in bone marrow (BM) was 60.8% in pts with BM samples. The most common AEs (all grades [Gr]) were infusion reactions (72.5%), nausea (52.0%), pyrexia (36.3%), neutropenia (34.3%), fatigue (34.3%), constipation (26.5%), and rash (26.5%). The most common Gr 3–4 AE was neutropenia (26.5%). Incidence of Gr 3–4 infections was 11.8%. Incidence of TLS was 4.9% (all Gr 3). Three pts died; none were deemed related to study treatment or CLL by investigators. Conclusions: BG is an effective regimen for 1L treatment of CLL pts, inducing a high CR rate after 6 cycles of therapy. No unexpected safety signals were observed. Clinical trial information: NCT02320487.

Background Addition of bortezomib to R-CHOP (VR-CHOP) may overcome the less favorable prognosis of non-GCB subtype lymphoma (Ruan et al. JCO 2011). We report results of a prospective open-label, randomized, phase 2 study evaluating the efficacy and safety of frontline R-CHOP vs VR-CHOP in pts with non-GCB DLBCL. Methods Adult pts with previously untreated non-GCB DLBCL who had ≥1 site of measurable disease, ECOG performance status 0-2, and adequate hematologic, hepatic, and renal function were eligible. Confirmation of non-GCB subtype using the Hans immunohistochemical (IHC) algorithm was required. Hans IHC non-GCB testing was performed in real time at a central US laboratory (48-72 hr turnaround from arrival of FFPE sample). Several centers demonstrated consistent scoring with the central laboratory and were permitted to enroll pts based on local non-GCB subtyping, with retrospective central laboratory confirmation. All pts received 6 cycles of standard R-CHOP in 21-d cycles (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 [max 2 mg], all IV on d 1, and prednisone 100 mg PO on d 1-5). In the VR-CHOP arm, pts also received bortezomib 1.3 mg/m2 IV on d 1 and 4 of each cycle. Follow-up was every 3 mos for up to 2 yrs after enrollment of the last pt. The primary endpoint was progression-free survival (PFS). Secondary endpoints included: overall survival (OS), overall response rate (ORR) and complete response (CR) rate after cycles 2 and 6, and safety. Response/disease progression were investigator-assessed by CT and FDG-PET scan at the end of cycles 2 and 6, and in follow up per 2007 Revised Response Criteria for Malignant Lymphoma. Adverse events (AEs) were graded by NCI-CTCAE v3.0. Sample size (n=~190) was determined to provide 80% power to detect an improvement in 2-yr PFS from 62% with R-CHOP (Fu et al. JCO 2008) to 77% (1-sided log rank; significance level 0.05). Here we present preliminary findings (data cut-off: Jun 2015). Results 206 pts were randomized at 69 sites; of these, 183 (91 R-CHOP, 92 VR-CHOP) had centrally confirmed non-GCB DLBCL and received ≥1 dose of study drug (modified intent-to-treat population). 86% (R-CHOP) and 85% (VR-CHOP) of pts completed study treatment per protocol. 60% of pts received study drug within 4 wks after tumor sample collection. Baseline characteristics were (R-CHOP vs VR-CHOP): male 58% vs 49%; median age 62 vs 65 yrs (>65 yrs 44% vs 46%); AJCC stage III/IV disease 73% vs 72%; extranodal disease 46% vs 52%; bone marrow involvement 11% vs 14%; IPI low/low-int/high-int/high 24/25/38/12% vs 26/28/33/13%. After a median follow-up of 31.5 mos, 2-yr PFS was 77% vs 82% (HR 0.77; 90% CI: 0.45, 1.30; p=0.70). In pts with high-int/high IPI, 2 yr PFS was 64% vs 72% (HR 0.66; 90% CI: 0.34, 1.28; p=0.294), whereas in pts with low/low-int IPI the HR was 1.13 (90% CI: 0.46, 2.75; p=0.821). At data cut-off, 15% and 11% of pts in the R-CHOP and VR-CHOP arms had died (HR: 0.65; 90% CI: 0.32, 1.29); median OS was not estimable in either arm and 2 yr OS rates were 80% vs 82%. In pts with high-int/high IPI, 2 yr OS rates were 79% (R-CHOP) vs 92% (VR-CHOP); in pts with low/low-int IPI, 2-yr OS rates were 98% in both arms. In 86 R-CHOP and 90 VR-CHOP response-evaluable pts, ORRs were 98% vs 92% (52% vs 54% CR). After 2 yrs, 73% of R-CHOP pts and 76% of VR-CHOP pts had not yet received a subsequent anti-lymphoma therapy. The safety population comprised 100 R-CHOP and 101 VR-CHOP pts. In both arms, pts received a median of 6 cycles of therapy (range 1-6). In the R-CHOP and VR-CHOP arms, 71% and 79% of pts had a G≥3 AE, and 31% and 34% had serious AEs, and 55% and 68% reported drug-related G≥3 AEs, the most common of which were neutropenia (34% vs 28%) and thrombocytopenia (8% vs 20%).G≥3 peripheral neuropathy rates were 1% (R-CHOP) and 5% (VR-CHOP). Conclusions These preliminary data suggest no significant efficacy advantage with the addition of bortezomib to R-CHOP in pts with previously untreated non-GCB DLBCL. This may be due to lack of bortezomib effect, time required for Hans IHC testing, IHC missclassification, or pt selection (R-CHOP alone pts had better outcomes/lower event rate than expected). These results have important implications for upcoming studies of new therapeutic strategies in DLBCL that target pt subsets based on cell of origin. Disclosures Kolibaba: Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; TG Therapeutics: Research Funding; Cell Therapeutics: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Amgen: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Novartis: Research Funding; GSK: Research Funding; Janssen: Research Funding. Tulpule:Millennium Pharmaceuticals Inc.: Research Funding. Flinn:Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Flowers:Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Janssen: Research Funding; Onyx Pharmaceuticals: Research Funding; Acerta: Research Funding; Millennium/Takeda: Research Funding; Spectrum: Research Funding; Onyx Pharmaceuticals: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics: Research Funding; Gilead Sciences: Research Funding; Acerta: Research Funding; Seattle Genetics: Consultancy; Pharmacyclics: Research Funding; Millennium/Takeda: Research Funding; AbbVie: Research Funding; Infinity Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy; OptumRx: Consultancy; AbbVie: Research Funding; Genentech: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; OptumRx: Consultancy; Genentech: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Spectrum: Research Funding. Papish:Genentech: Speakers Bureau; Pfizer: Speakers Bureau; Genomic Health: Speakers Bureau; Novartis: Speakers Bureau. Venugopal:Genentech: Research Funding; Celgene: Research Funding. Hajdenberg:Gilead: Speakers Bureau; AbbVie: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Mulligan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Neuwirth:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Suryanarayan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Esseltine:Takeda Pharmaceuticals, Inc.: Equity Ownership; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Johnson & Johnson: Equity Ownership.

Introduction: We prospectively collected data from lower-risk patients (pts) with MDS in an ongoing US registry in order to assess the association between chelation and clinical outcomes. In addition, we evaluated the association between chelation and overall survival (OS). Here we report outcomes at 5 years. Methods: The registry enrolled 600 pts from 107 US centers. Pts were ≥18 years old with lower-risk MDS (WHO, FAB, and/or IPSS criteria) and transfusional iron overload (serum ferritin ≥1000 µg/L and/or ≥20 packed red blood cell units and/or ≥6 units every 12 weeks). Pts were analyzed by iron chelation status; ie, had never been chelated or had ever used iron chelation, and a subgroup of the latter group—pts with ≥6 mo of chelation. Pts were evaluated every 6 mo for 5 years or until death with respect to characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy. Results: 600 pts (median age, 76 years [range, 21-99], 346 [57.8%] male, 519 [86.6%] Caucasian) were evaluated. IPSS status was similar across chelation groups. Chelated pts (n=271) had a greater median number of lifetime units transfused at the time of enrollment vs nonchelated pts (n=328): 38.5 vs 20.0. At baseline, cardiac and vascular comorbidities (CVC) were significantly higher in nonchelated vs chelated pts (52.4% vs 34.3% [P OS from diagnosis of MDS and time to acute myeloid leukemia (AML) were significantly greater in the chelated vs nonchelated pts (P Patients with ≥6 mo of chelation had numerically fewer deaths in the registry, numerically greater OS, time to death, and time to AML transformation vs pts who had any chelation (Table). Conclusions: Limitations of these analyses include variation in time from diagnosis, duration of chelation, impact of pt clinical status on decision to chelate, and optional conduct of clinical assessments. Nonetheless, the results after 5 years of follow-up of lower-risk pts with MDS suggest iron chelation therapy is associated with improved OS and longer time to AML transformation. Causation has not been established. Abstract 1350. TABLE. Characteristics of Patients Nonchelated, Chelated, and Chelated ≥6 Months Nonchelated n=328 Chelated n=271 Chelated ≥6 Months n=202 Time to death, median (min/max) mo 47.8 (43.4, 53.1) 88.0 (78.4, 103.0) *P Disclosures Paley: Novartis Pharma: Employment. Esposito:Novartis Pharma: Employment. McNamara:Novartis Pharmaceuticals Corporation: Employment. Garcia-Manero:Novartis Pharma: Research Funding.