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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.

This 5-year, prospective registry enrolled 600 lower-risk MDS patients (pts) with transfusional iron overload. Clinical outcomes were compared between chelated and nonchelated pts. At baseline, cardiovascular comorbidities were more common in non-chelated pts, and MDS therapy was more common in chelated pts. At 24 months, chelation was associated with longer median overall survival (52.2 months vs. 104.4 months; p

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.

8559 Background: The role of local pathologists in promoting patient (pt) accrual and evaluating eligibility criteria involving a complicated immunohistochemical (IHC) algorithm has rarely been investigated. The phase II PYRAMID trial (NCT00931918) is assessing R-CHOP ± bortezomib for newly diagnosed pts with non-germinal-center B-cell (non-GCB) subtype DLBCL. In this trial, local pathologists were encouraged to perform DLBCL subtyping at the point of biopsy, identify suitable pts for the trial, and facilitate accrual. Methods: Determination of GCB vs non-GCB subtype is per the Hans method, an algorithm based on IHC for CD10, BCL-6, and IRF4/MUM1. In stage 1, pathologists demonstrated IHC subtyping proficiency by evaluating a tissue microarray (TMA) of 12 DLBCL cases; those with ≥80% of samples in agreement with central lab results were certified for determining trial eligibility. In stage 2, to broaden participation, pathologist certification occurred via teleconference outlining trial eligibility criteria, tissue subtyping requirements, and determining pathologists’ experience with the Hans method. Results: 182 pathologists have been certified for local subtyping, 50 via TMA and 132 by teleconference. 66/88 active study sites have ≥1 certified pathologist. Only 1 of the 10 top enrolling sites lacks a certified pathologist. 52% (84/162) of pts have been enrolled based on local pathologist subtyping prior to central lab confirmation. Discordance with central lab results occurred in 9/84 cases (11%). Enrollment rates pre- and post-local pathologist certification were 0.053 and 0.096 pts/site/month; an improvement of 81%. Trial accrual correlates with the presence of a certified local pathologist (p=0.0026). The rate of ineligible GCB cases sent for central lab testing was lower from sites with a certified pathologist (23% [69/299 cases] vs 38% [40/106 cases] for sites without). Conclusions: Engagement of local pathologists in trials requiring pathology selection can significantly improve accrual. This study demonstrates the effectiveness of various training modalities in improving selection by local pathologists using a complex IHC algorithm. Clinical trial information: NCT00931918.

7096 Background: The objective was to evaluate the types, frequency and adherence of molecular tests utilized in patients (pts) with CML-CP who initiated 1st-line TKI therapy in the community practice (prac) setting. Methods: A retrospective study of newly diagnosed CML-CP pts; initiating 1st-line TKI during 06/2007 and 03/2011, with ≥18-mo follow-up was conducted. Data was collected from iKnowMed, various local & national labs to evaluate whether qRT-PCR test results was reported in International Scale (IS) or not (non-IS). The proportion (prop) of pts tested for molecular response in 3-mo intervals was tallied. Results: The study identified 189 pts (mean age 57 yrs, 53% male), 15% had no cytogenetic (cyto, FISH included) or molecular test (MT) recorded during 1st-line TKI therapy. The median number of MT was 6 (range: 1-28). In 3-mo intervals, the prop of pts tested for cyto responses were: 0-3 mos (24%), 3-6 mos (21%), 6-9 mos (24%), 9-12 mos (22%), 12-15 mos (10%), and 15-18 mos (7%). The prop of pts had MT in the 3-mo intervals were: 34%, 47%, 54%, 47%, 51% , and 55%. Regional patterns show the Northeast (defined by U.S. census regions) had a higher prop of pts for MT at almost all of these intervals. The number of physicians seeing CML pts correlated with the prop of pts monitored at each interval. Of the 1,226 MT ordered, 25% were reported on IS, 9% were unknown and 69% were on non-IS (Data reported: 48% log reduction, 45% BRC-ABL%, 7% other). Labs in the Midwest report on IS most often (61%), followed by the Northeast, Western (29% for both), and the South (13%). As the prac size increased, so did the utilization of IS. Conclusions: A low prop of CML pts were monitored for cyto and molecular responses. Only a quarter of the MT results were reported in IS. These results suggest gaps in CML management that could be closed with effective educational programs stressing the importance of monitoring and using IS reporting labs.

7122 Background: Many patients (pts) with lower-risk myelodysplastic syndromes (MDS) require chronic red blood cell transfusions for symptomatic anemia, which can result in iron overload. We present a 36-month interim analysis of a 5-year US registry that prospectively collected data on clinical events and survival in chelated vs non-chelated, transfused, lower-risk MDS pts. Methods: This multicenter, non-interventional registry enrolled 600 pts ≥18 yr old with lower-risk MDS (WHO, FAB, and/or IPSS risk stratification criteria) and transfusional iron overload (serum ferritin ≥1,000 ng/mL and/or ≥20 packed red blood cell units and/or ≥6 units every 12 wks). The chelated group included pts who had received any chelation. Results: Median age was 76 yr (range, 21–99), 57.8% were male, and risk status was 38.6% IPSS low risk and 61.4% IPSS INT-1 risk. Baseline demographics and IPSS risk status were similar between groups, although transfusion burden trended higher in chelated pts. As of April 30, 2012, 169 pts continued on the registry, and 431 discontinued (345 died, 57.5%; 61 lost to follow-up, 10.2%; and 25 other, 4.2%). In all, 264 pts (44%) received chelation therapy; 200 had ≥6 mos chelation. Overall survival (OS) and time to acute myeloid leukemia (AML) transformation were significantly longer, and the percentage of deaths was significantly lower, in chelated ≥6 mos vs non-chelated pts (P

International Working Group criteria, overall response rate (ORR) was 58% (15/26pts): 5 pts (19%) achieved complete remission (CR), while 10pts (39%) showed an hematologic improvement (HI). 11/26pts (42%) maintained a stable disease (SD). Generally the drug was very well tolerated. The most commonly reported hematologic toxicities were neutropenia (55%) and thrombocytopenia (20%). 4/30pts (13%) died during treatment. The median duration of response was 5 months (range 1–14 months). Surprisingly, 3/15 patients (2 CR and 1 HI erythroid) showed a long duration of response (11, 13 and 14 months, respectively), still ongoing, after discontinuation of AZA. Preliminary data on the lipid signalling pathways suggested a direct correlation between the demethylating effect on PI-PLC-beta1 and responsiveness to treatment. Conclusion: Our study shows that AZA low-dose schedule may be a feasible and effective treatment for low-risk MDS pts and may induce durable responses. Despite AZA safety, extreme caution is needed in pts with age-related comorbidities and/or with severe neutropenia or thrombocytopenia, especially in low-risk MDS. Furthermore, PIPLC-b1 demethylation and gene expression could represent a new biological marker to predict the clinical response to AZA.

18 patients with metastatic or recurrent bronchogenic carcinoma and one patient with a squamous cell carcinoma of the trachea were treated with a combination of CCNU, hexamethylmelamine and methotrexate. Objective remissions were observed in 3/19 (16%): 1 complete, 1 partial (greater than 50%) and 1 incomplete (less than 50%). However, the patient with the complete response was the only drug death, on day 21. Remission duration in the other two patients was 3 and 9+ months respectively. One patient with oat cell carcinoma experienced no tumor progression for 5 months. This combination resulted in severe gastrointestinal toxicity in 5/19, severe thrombopenia in 12/19 and severe neutropenia in 6/19. We conclude that the combination as used here resulted in no increased clinical effectiveness and proved to be quite toxic.

Two cases of disseminated atypical tuberculosis are presented in which the infection anteceded by over four years the development of acute granulocytic leukemia on one and Hodgkin's Disease in the other patient. The presence of disseminated atypical mycobacteriosis in the absence of a clearcut underlying illness suggests a "preneoplastic state." It should alert the clinician to the possibility of a neoplastic disorder which may not become clinically manifest for several years.

Forty patients with various types of myeloproliferative disorders were evaluated immunologically. Serum immunoglobulin levels were within the normal range in most patients and no monoclonal gammopathies were detected. Serum C'3 levels were decreased in 19 of 40 (48%) patients. The response of peripheral blood lymphocytes to phytohemagglutinin was decreased in 26 of 40 (65%) and to pokeweed mitogen in 18 of 28 (64%) patients studied. Lymphocytes from patients with polycythemia vera were least affected. Unstimulated lymphocytes from some patients demonstrated markedly increased thymidine uptake activity. Despite the diminished mitogenic response, only 2 of 33 patients (6%) were anergic by intradermal skin testing. There was no association between depressed lymphocyte response and recent chemotherapy except in chronic myelogenous leukemia where 6 of 8 patients were receiving cytotoxic therapy when studied. These observations suggest that most of our patients with myeloproliferative disorders have abnormal cellular responses in vitro, but that delayed hypersensitivity and humoral responses are minimally affected.

21 patients with metastatic breast cancer, refractory to conventional agents, were treated with a combination of BCNU, vincristine, mitomycin-C and prednisone given every 4 weeks. Only three of the nineteen (15.8%) evaluable patients were observed to have a partial remission, whereas four experienced stabilization of tumor. The sites which responded included skin lesions in two patients and a pleural effusion in 1 patient. This combination resulted in moderate to severe thrombocytopenia in five patients, but was otherwise well tolerated. This pilot study therefore suggests that these four agents in the schedule and doses given do not appear to be superior to any of these agents used singly for advanced, refractory breast cancer.