Purpose To 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 Methods After 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/m2 intravenously 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). Results After 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%). Conclusion Outcomes 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.

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.

8040 Background: Phase III trials have shown that bevacizumab (Avastin, BV), an anti-VEGF monoclonal antibody, prolongs progression-free and overall survival in advanced NSCLC pts. To further define clinical outcomes associated with BV treatment among a broader population of NSCLC pts in a real-world setting, the ARIES OCS was initiated. Pt populations in OCSs are often more reflective of pts encountered in practice, permitting examination of treatment benefit and toxicity in subgroups that might be too small for study in traditional randomized controlled trials (RCTs). The NSCLC cohort in ARIES will assess clinical outcomes in the overall cohort as well as subpopulations such as the elderly, pts with poor PS or pts on concurrent anticoagulants (AC). Methods: Pts with advanced NSCLC whose 1st-line therapy includes BV may enroll. 257 sites are enrolling pts; total accrual of 2000 pts is expected. There are no protocol-specified treatments or assessments. Data is collected at baseline (BL) then quarterly, including targeted adverse events (AEs) and BV-related serious AEs. Clinical outcomes will be descriptively summarized by baseline characteristics. Multivariate analyses will be conducted if cohort size is sufficient. Results: As of 9/15/08, 1518 NSCLC pts have enrolled. Median F/U is 7.5 mos. Key BL characteristics: 20% ≥75 yrs; 67% adenocarcinoma; 10% ECOG ≥2; 8% brain metastasis; 5% therapeutic AC. The most common 1st-line chemotherapy regimen was carboplatin/paclitaxel (64%). Key safety outcomes and cohort size of subpopulations are in the Table . Conclusions: The safety of BV in subpopulations of pts in ARIES (elderly pts, pts with ECOG PS ≥2, with brain mets at BL, or on therapeutic AC) is generally consistent with safety results from RCTs. Updated outcomes analyses will be presented at the meeting for >1600 pts and subpopulations. [Table: see text] [Table: see text]

ITP is an autoimmune disease characterized by low platelet counts due to increased platelet destruction and inadequate platelet production. It is often a chronic disorder that requires long-term treatment. Current common treatment therapies for chronic ITP include corticosteroids, intravenous immunoglobulins (IVIG), rituximab, and anti-D antibody. Splenectomy may be required for those patients who do not respond or relapse after these medical therapies, or require intolerable doses to achieve safe platelet counts. Few studies have reported treatment pattern of current therapies for ITP. We report results of an international multi-center retrospective and prospective observational study of adult patients receiving treatments and/or splenectomy for chronic ITP. Patients with a diagnosis of ITP were enrolled from 100 community and academic centers. Date of 1st ITP diagnosis, treatments received and medical history were obtained retrospectively from patient chart data. ITP treatments, dose, response, and duration of response were collected prospectively for 12 months. Among 326 patients with ITP studied (mean age=54 years, male 40.2%), 24% received a splenectomy during this study. In patients who were not splenectomized (n=248), 77% received ITP medications with corticosteroids being the most frequently prescribed medication among patients who received 1 type of ITP treatment. IVIG was most frequently prescribed in patients who received 2 types of ITP treatments, and patients were most likely to receive a splenectomy after receiving 2 or more types of ITP treatments (table). In splenectomized patients, the average duration from ITP diagnosis to splenectomy was 2.79 years (n=74, SD=4.42, min=0, max=23.38). Prior to surgery, splenectomized patients were most likely to receive corticosteroids in patients receiving 1 type of treatment, and IVIG in patients receiving 2 types of ITP treatments. Following surgery, splenectomized patients were also most likely to receive corticosteroids in patients receiving 1 type of ITP medication, and rituximab in patients with 2 types of ITP medications. Overall, patients with ITP are exposed to numerous ITP treatments, among which, corticosteroids were most frequently used in both splenectomized and non-splenectomized patients. All patients receiving a splenectomy also required 1 or more ITP treatments following surgery. These results demonstrate that current ITP therapies are limited in efficacy and durability and often lead to patients receiving multiple types of ITP treatments. Novel ITP therapies with better efficacy and durable response are needed.

7591 Background: The decision to treat indolent B-cell NHL is often based on progressive disease, worsening symptoms, and increasing hematological derangement. When treatment is indicated, these lymphoproliferative disorders are very sensitive to combination chemotherapies. Combination therapy with these agents, pentostatin (P), a purine analog, cyclophosphamide (C), a DNA alkylator, and rituximab (R), an anti-CD20 monoclonal antibody, represents a promising approach in the treatment of these patients. Most regimens have utilized fludarabine (F) as the purine analog but the myelosuppression and immunosuppression of (F) combinations frequently results in severe infections. Methods: Eligibility criteria allow previously treated and treatment-naïve patients diagnosed with low-grade stage III/IV NHL (REAL classification) to be enrolled. Treatment consisted of intravenous infusions of P (4 mg/m2), C (600 mg/m2), and R (375 mg/m2) on day 1 of a 21-day cycle for a total of 8 cycles. Clinical evaluation was performed after cycles 2, 4, 6 and 8. Patients were stratified by disease and by prior treatment status. Results: The intent-to-treat (ITT) population consisted of 54 NHL patients (median age 65, range 30–86) who received a total of 330 cycles (median 6 per patient). The ECOG status was 0 (31%), 1 (58%) and 2 (12%). The overall objective response rate was 71% (CR 15%, Cru 13%, PR 43%). Eight grade 4 neutropenias were documented along with a single grade 4 leukopenia. There were a total of 3 deaths which occurred within 30 days of the last dose. The first death was due to a second primary, NSCLC, diagnosed after treatment began. The second death occurred in an 81 year-old female, who had achieved PR, and her death was due to CHF. The last death, due to MI/CAD, occurred in an 84 year-old woman with SD. Conclusions: This immunochemotherapeutic regimen is active in indolent Grade III/IV NHL and the incidence of significant toxicities was low. Updated trial results will be presented at the ASCO annual meeting. Future trials evaluating the use of R as maintenance therapy following this PCR regimen may also be warranted with an eye toward increasing the overall survival of patients with NHL. No significant financial relationships to disclose.