Citations

Abstract Abstract 415 Background: The ability to cure patients (pts) with advanced Hodgkin's Lymphoma (HL) with combination chemotherapy (CC) (MOPP and variants, ABVD and variants) represented a major milestone in oncology research, and CC became a paradigm for other malignancies. Further, the rationale for combined modality therapy (CMT) (radiation (RT) and CC) in HL evolved based on the high frequency of relapse in initially involved sites. As response rates and survival improved, newer treatments such as the combined modality Stanford V regimen were developed to shorten the duration of chemotherapy, add RT to sites of disease and reduce toxicity while maintaining or improving the cure rate. Indeed, the Stanford V regimen was tested and validated in a Phase II co-operative group trial (E1492) (J Clin Oncol 2000; 18:972). In order to investigate this approach against “standard” therapy, we conducted a randomized Phase III Intergroup trial of ABVD vs. the Stanford V regimen for patients with locally extensive or advanced HL. Objectives: The trial was designed to detect a 33% reduction in the failure free survival (FFS) hazard rate with Stanford V compared with ABVD, which corresponds to a difference in five-year FFS of 64% vs. 74%. Method: Patients with locally extensive (defined as clinical Ann Arbor Stage I-IIA/B and bulky mediastinal disease (BMD) (mass > 1/3 maximum intrathoracic diameter on standing postero-anterior chest x-ray or >/−10 cm on computerized tomography) or advanced (Ann Arbor Stage III or IV) HL were randomized to receive either ABVD × 6–8 cycles (C) (51% had 6 C, 35% had 8 C, 14% had <6 C) + 36 Gy (only in pts with BMD) or Stanford V × 12 weeks (95% had 12 weeks) + 36 Gy (for sites >5cm or for macroscopic splenic disease). The log-rank test was used to compare FFS for all eligible patients stratified on extent of disease (locally extensive vs. advanced), and number of International Prognostic Factor Project (IPFP) risk factors (0–2 vs. 3–7). An extended Cox model was also used to address non-proportional hazard between the two arms. Results: 854 pts enrolled from April, 1999 to June, 2006 and 812 were eligible for analysis. 404 pts were randomized to ABVD and 408 to Stanford V. Median age was 33 yrs in both arms (range 16–83). 53% were men and 47% women; 4% had Stage I, 31% had Stage II, 39% had Stage III and 25% had Stage IV disease by Ann Arbor criteria. 35% of pts on ABVD and 35% on Stanford V had BMD. Three % of pts had nodular lymphocyte predominant HL, 77% of pts had nodular sclerosis HL, 14% had mixed cell HL. Age, stage, pathology and risk factors (0–2 vs. 3–7) were similar in both arms. In total, 65% were IPFP score 0–2 and 33% were 3–6. Response rate. There was no difference in response rates (RR) between the two arms (ABVD=72% CR+ CCR, 7.7% PR, 7.9% SD; Stanford V= 69 % CR +CCR, 7% PR and 10 % SD. 8% were not evaluable for response on ABVD and 9% on Stanford V. Toxicity was similar in both groups. The most frequent Grade 3 + 4 toxicity was neutropenia, and was similar between the 2 groups (76% Grade 3 + 4 in ABVD and 70% Grade 3+ 4 in Stanford V). Grade 5 toxicity was <1% in both groups. There was, however, more Grade 3 lymphopenia in Stanford V (78% vs. 42%, p< 0.0001) and more Grade 3 +4 sensory neuropathy in Stanford V (10%) than in ABVD (3%) (p< 0.0001). A total of 26 second primary cancers developed, 12 after ABVD and 14 after Stanford V (p=NS). FFS and OS. For 812 eligible patients, with a median follow up of 5.25 years, 5-year FFS was 73% for ABVD and 71% for Stanford V (p=0.29 by log rank) (Figure left); 5-year OS was 88% for ABVD and 87% for Stanford V (p=0.87 by log-rank, HR=0.97, 95% CI: 0.65 to 1.44) (Figure right) indicating no significant difference in either FFS or OS between the 2 arms. Conclusion: In the largest Phase III intergroup trial of HL in North America, there was no significant difference in RR, FFS, OS, and 5-year toxicity when ABVD (+ RT for BMD) is compared with Stanford V (+RT for nodal sites >5 cm and macroscopic splenic disease). There was more Grade 3 lymphopenia (p< 0.0001) and more Grade 3 + 4 sensory neuropathy (p< 0.0001) on Stanford V. Thus ABVD (plus RT for BMD) remains the standard of care because Stanford V did not meet the objective of 33% improvement in FFS. For some patients, Stanford V, when given as described with RT, remains an acceptable alternative. Disclosures: Friedberg: Genentech: Honoraria. Blum:Seattle Genetics: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Horning:Genentech: Employment.

Abstract Abstract 416 Background: Standard therapy for locally extensive Hodgkin Lymphoma (HL) defined as stage I/II with bulky mediastinal disease [mediastinal mass ratio (MMR) > than 1/3 of the chest diameter on standing postero-anterior chest x-ray or 10 cm on computerized tomography] is combined modality therapy (CMT). E2496 was a North American intergroup, randomized phase III study comparing ABVD versus the Stanford V regimen for patients with locally extensive and advanced stage HL. In this subgroup analysis we compare two CMT approaches, ABVD + radiotherapy (RT) and the Stanford V regimen, in patients with stage I/II bulky mediastinal HL. Methods: Patients with stage I/II HL bulky mediastinal disease were randomized to receive chemotherapy (CT) on either Arm A (ABVD × 6–8 cycles administered q 28 days) or Arm B (12 weeks of Stanford V, administered weekly). Two-3 weeks after completion of chemotherapy, modified involved field RT was delivered at 36 Gy to the mediastinum to patients on ABVD as well as Stanford V. Patients on Stanford V also received involved field RT to any other sites >5 cm at diagnosis. The primary endpoint was failure free survival (FFS) defined as the time to either progression/relapse or death. The log-rank test was used to compare FFS and OS (overall survival) for all eligible patients. Results: Of the 812 eligible patients with advanced HL enrolled on the study 267 had locally advanced bulky mediastinal disease: 136 on ABVD and 131 on Stanford V. Patient characteristics between the two randomized groups were well matched with a median age of 30 years and 86% had stage II disease. On ABVD 61% of patients received 6 cycles, 29% 8 cycles of CT and 77% required some dose modification. In Stanford V 97% completed the assigned 12 weeks of CT and 76% required some dose modification. 82% received RT per protocol in ABVD versus 88% in Stanford V. The overall response (CR+PR) was 82% in ABVD and 86% in Stanford V. At a median follow-up of 5.47 years, there are 19 failures and 6 deaths in the ABVD group and 25 failures with 9 deaths in the Stanford V group. We failed to detect statistically significant differences between ABVD +RT and Stanford V for FFS (5y 85% versus 77% p=0.13, HR=1.56 95% CI (0.87, 2.88) and OS (5y 95% versus 92% p=0.31, HR=1.69 95% CI (0.60, 4.75). No difference in hematologic toxicity was observed between the two arms. Evaluation of pulmonary function and patterns of failure are pending. Conclusions: For stage I/II patients with bulky mediastinal disease, CMT with either ABVD +RT or the Stanford V regimen results in high cure rates and is highly effective. ABVD for 6–8 cycles plus 36 Gy RT remains the US standard of care. Longer follow up is required to assess RT related late effects. Future research efforts should focus on risk stratification to identify; a) the 15–20% of patients destined to relapse after standard therapy and evaluate treatment intensification strategies and b) the 80–85% of patients who are cured with standard therapy and determine whether a subset can achieve the same excellent outcomes with a reduction or elimination of radiation. Planned US cooperative group trials will address these questions, using ABVD as the chemotherapy backbone in conjunction with interim PET imaging for risk stratification. Disclosures: Blum: Seattle Genetics: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Horning:Genentech: Employment.

Abstract Abstract 4610 Introduction: Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). Up to 50% of patients with CLL will develop infectious complications during the course of their disease, and 30–50% of all deaths from CLL are attributed to infections and infectious complications. The risk of infection in CLL is related to immune deficiencies associated with the primary disease process, as well as immunosuppression secondary to treatment. Available research on infectious complications of CLL has focused on patients in clinical trials receiving chemotherapy. Little is known about the natural history of infection in community dwelling patients with newly diagnosed CLL. Method: To explore the natural history of infection in a local, community dwelling cohort of patients diagnosed with CLL, we used the Mayo Clinic CLL database to identify all patients with newly diagnosed CLL seen in the Mayo Clinic Division of Hematology after January 1, 1999 and who resided within 50 mi of Mayo Clinic (Rochester, MN). All patient hospitalizations were reviewed to document infection including cross-referencing with the electronic Mayo Clinic infection database which includes all culture and serology results obtained from hospitalized Mayo Clinic patients. Patients who had positive blood, sputum, cerebrospinal fluid, pleural fluid, or paracentesis fluid culture results were identified. Patients whose cultures were negative were considered to have culture negative infection. Serologies and viral assays (e.g. CMV viral load) were also reviewed to identify infections. Results: In May 2010, there were 2022 patients in the Mayo Clinic CLL Database with the diagnosis of CLL/SLL made between Jan 1999 – Dec 2009. Of these, 336 (17%) patients resided within a 50 mi radius of Mayo Clinic and were considered non-referred, community-based CLL patients. Median age at diagnosis for these 336 patients was 69 yrs (range 27–97) and most had early stage CLL (57% stage 0; 34% stage I-II). With respect to prognostic markers, 206 (70%) patients were CD38 negative, 125 (64%) ZAP-70 negative, 85 (53%) IgVH mutated, and 101 (63%) had either no abnormality or 13q14- as a sole abnormality on FISH analysis. Consistent with being a community dwelling cohort, ~90% (152/165) of patients had co-morbid health problems and ~50% (86/165) had a major comorbidity (e.g. coronary artery disease, cerebral vascular disease, CHF, diabetes, COPD, other malignancy). Although ~17% (43/249) of patients had gamma-globulin levels below the reference range at diagnosis, only 2% (6/249) had an IgG level <500 mg/dL. Median follow-up for all patients was 49 months (range 0–121) and 104 (31%) patients progressed to require treatment for CLL. Although 222 (66%) patients required hospitalization during follow-up, only 38 (11.3%) were hospitalized with infection. Collectively, these 38 patients were hospitalized for infection 139 times (median 2 hospitalizations for infection per patient). Among these 38 patients, 13 had no organism identified on cultures (culture negative infection) while the remaining 25 (66%) had an organism identified during at least hospitalization for infection. Of the 38 patients hospitalized with infection, 18/38 (47%) had a gram positive organism (8 strep pneumonia, 11 staphylococcus Aureus, 2 nocardia), 11/38 (29%) had a gram negative organism (3 E.Coli, 4 Pseudomonas, 4 Hemophilus influenzae), 5/38 (13%) a mycobacterial infection (4 MAC, 1 M. gordonae), 15/38 (40%) a cytomegalovirus infection, 19/38 (50%), cryptococcus and/or cryptosporidium (18 cryptococcus AG, 4 cryptosporidium), and 12/38 (32%) a filamentous fungi infections (12 aspergillous). In aggregate, hospitalization for an opportunistic infection (e.g. cytomegalovirus, cryptococcus, filamentous fungi, myocobacteria, pneumocystis) occurred in 26/336 (8%) CLL patients during follow-up. Being male (OR 2.7; p=0.02), ZAP-70+ (OR 3.9; p=0.004), IGHV unmutated (OR 5.5; p=0.002), and receiving treatment (OR 4.7, p<0.001; Figure) were associated with increased risk of hospitalization for infection. Conclusions: Approximately 8% of newly diagnosed, community dwelling CLL patients will require hospitalization for opportunistic infection at some point during the course of their disease. Gender, disease factors (e.g. ZAP-70, IGHV status), and treatment characteristics are associated with infection risk. Disclosures: Zent: Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; G.S.K.: Research Funding. Shanafelt:Celgene: Research Funding; Hospira: Research Funding; Genentech: Research Funding.

Abstract Abstract 4610 Introduction Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). Up to 50% of CLL patients develop infectious complications, and 30–50% of all deaths in CLL patients are attributed to infections. Despite these data, the available research on infectious complications in CLL is primarily limited to patients participating in clinical trials of chemotherapy, obscuring the distinction between the risk of infection due to the disease’s natural history relative to the risk associated with therapy related immune suppression. METHODS: The Mayo Clinic Rochester (MCR), a tertiary referral center in rural southeastern Minnesota, is also the primary hematology center for southeastern Minnesota, northern Iowa, and western Wisconsin. There are no metropolitan areas or hematology specialty centers within a ∼50 mile radius. To explore the natural history of infection in a community-based cohort of CLL patients, we used the Mayo Clinic CLL database to identify all patients with newly diagnosed CLL who resided within 50 miles of MCR and diagnosed between January, 1999 and December, 2009. The comparison cohort consisted of 689 adult patients who also resided within 50 miles of MCR who were seen for a general medical examination between September, 2002 and December, 2009 and who were enrolled as controls in a case-control study of non-Hodgkin lymphoma. All hospitalizations at MCR among both cohorts were audited to document hospitalization with infection and cross-referenced with the Mayo Clinic infection database, which includes all culture results obtained from hospitalized MCR patients. Serologies and viral assays were also reviewed. Patients whose cultures were negative but who were given a clinical diagnosis of infection (e.g. pneumonia) and who were treated with a full course of antibiotic therapy were considered to have a culture negative infection. RESULTS: In May 2010, there were 2022 CLL patients in the Mayo Clinic CLL Database diagnosed between 1999 and 2009. Of these, 174 (9%) were local CLL patients residing within 50 miles of MCR. Median age at diagnosis for these non-referred CLL patients was 69 years (range 27–97). Most had early stage disease (60% stage 0; 32% stage I-II). On prognostic evaluation, 121 (75%) patients were CD38 negative, 66 (61%) ZAP-70 negative, 47 (50%) IGHV mutated, and 56 (62%) had either no abnormality or 13q14- as a sole abnormality on FISH analysis. 64 (37%) patients progressed to require treatment for CLL during follow-up. After median follow-up of 4.0 years (range 0–11), 32 (18.4%) CLL patients were hospitalized with infection at least once as compared to 20/689 (2.9%) individuals in the control cohort (odds ratio=7.5; p<0.0001) Figure 1A. Even prior to receiving treatment for CLL, the rate of hospitalization for infection remained higher than the control cohort (p=0.002; Figure 1B). The 32 CLL patients hospitalized with infection were admitted with infection a total of 89 times (median 1 hospitalization for infection per patient). A specific infectious organism was identified by cultures or serologies in 60 (63%) of the 89 infections in CLL cases and 10/27 (37%) infections among controls. Hospitalization for an opportunistic infection (e.g. cytomegalovirus, cryptococcus, filamentous fungi, mycobacteria, Pneumocystis) occurred in 5/174 (3%) CLL patients during follow-up compared to 0/689 controls (p<0.001). Finally, we performed a pooled multivariable analysis of all patients (n=863) to identify factors (age, sex, CLL diagnosis, CLL treatment) associated with infection risk. Most factors were independently associated with hospitalization for infection [Age (per year, OR=1.03, p=0.02), sex (male, OR=4.0, p<0.001), diagnosis of CLL (OR=2.1, p=0.09), and treatment for CLL (OR=5.9, p<0.001)]. In univariate analysis of CLL patients [sex (OR=4.2, p=0.01), higher Rai stage (p=0.046), unfavorable (del 17p13; del 11q23) FISH [OR=4.6, p=0.02] and unmutated IGHV [OR=2.8, p=0.07]) were associated with risk of infection. CONCLUSIONS: In this cohort study, patients with newly diagnosed CLL had a 7.5-fold risk of hospitalization for infection relative to the control cohort. After 4 year follow-up, ∼1 in 5 CLL patients required hospitalization for infection. Although CLL treatment was a substantial risk factor for infection, the risk of infection among untreated patients remained higher than controls. Disclosures: Kay: Biothera: Research Funding; Clegene: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Glaxo Smith Kline: Research Funding; Hospira: Research Funding; Novartis: Research Funding; Supergen: Research Funding; Calistoga: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Emergent Biosolutions (Formerly Trubion): Membership on an entity’s Board of Directors or advisory committees. Zent:GlaxoSmithKline: Research Funding; Genentech: Research Funding; Genzyme: Research Funding.

Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin’s lymphoma (NHL) comprising 3 molecular subtypes: germinal center B-cell (GCB), activated B-cell (ABC) and class III. ABC patients (pts) have a poor prognosis. The immunomodulatory drug lenalidomide (Len) produces durable responses in pts with aggressive NHL (Witzig 2011), with preferential activity reported in non-GCB DLBCL (Hernandez-Ilizaliturri 2011). Methods: This randomized, multicenter, open-label, phase 2/3 study was conducted to determine the efficacy and safety of single-agent Len vs single-agent investigator’s choice (IC) in relapsed/refractory DLBCL pts who received ≥2 prior therapies, or were ineligible for stem cell transplantation or further combination chemotherapy. DLBCL subtype (GCB vs non-GCB) was determined by a central pathology lab using immunohistochemistry (IHC) per the Hans method (Hans 2004). Pts were stratified by subtype, then randomized 1:1 to receive Len (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin) until progressive disease (PD), unacceptable toxicity, or voluntary withdrawal. In the event of radiologically confirmed PD, pts in the IC arm were allowed to cross over to Len. The primary endpoint for Stage 1 was overall response rate (ORR), as determined by an Independent Response Assessment Committee. Progression-free survival (PFS), overall survival (OS) and subtype analysis using gene expression profiling (GEP) were exploratory endpoints. Concordance of GEP and IHC was evaluated from 3 separate laboratories. Results: IHC subtyping agreement rate among the 3 laboratories ranged from 87.5%-97.9%, and sensitivity of IHC to detect ABC or GCB subtypes vs GEP ranged from 92.3%-100.0%. By IHC, 102 DLBCL pts (GCB, n=48; non-GCB, n=54) were treated with ≥1 dose of Len or IC (modified intent-to-treat population) in Stage 1. In this heavily pretreated population, >90.0% of pts received ≥2 prior systemic chemotherapies; 25 pts in Len and 32 pts in IC received ≥3 prior systemic chemotherapy regimens. Median age was 65 y in the IC arm vs 69 y in the Len arm. Twenty-nine pts crossed over from IC to Len after confirmed PD. All pts, regardless of subtype or therapy group, experienced ≥1 treatment-emergent adverse event, with neutropenia, anemia, and thrombocytopenia being the most common. Efficacy data are presented in the Table. Pts with GCB or non-GCB DLBCL (per IHC) treated with Len had similar ORR, but the data suggested greater improvements in PFS and OS with Len vs IC in the non-GCB pts. In an exploratory analysis of pts subtyped by GEP, ABC pts treated with Len vs IC-treated showed greater improvements in ORR, PFS, and OS compared with GCB pts. Prespecified criterion to advance to Stage 2 was a 2-sided 15% significance level in ORR in favor of Len based on IHC-defined subtype. The data did not fulfill this requirement, and Stage 2 was not opened. Conclusion: Len monotherapy showed clinical activity in heavily pretreated pts with DLBCL. The data suggest improved ORR, PFS, and OS with Len vs IC in the non-GCB population as defined by IHC, and the difference appears to be more pronounced in the ABC population as defined by GEP. Subtyping by GEP is warranted in further studies of Len in DLBCL. Abstract 628. Table 1.Table. Efficacy DataBy IHCBy GEPOverallGCBNon-GCBGCBABCLen(n=51)IC(n=51)Len(n=23)IC(n=25)Len(n=28)IC(n=26)Len(n=14)IC(n=16)Len(n=11)IC(n=16)ORR, % (95% CI)27.5 (15.9-41.7)11.8 (4.4-23.9) 26.1 (10.2-48.4)12.0 (2.5-31.2)28.6 (13.2-48.7)11.5 (2.4-30.2)21.4 (4.7-50.8)12.5 (1.6-38.3)45.5 (16.7-76.6)18.8 (4.0-45.6)P Value .079 .279 .179 .642 .206PFS, med wk (95% CI)13.6 (8.6-17.7)7.9 (6.3-9.0) 10.1 (8.3-22.3)29.0 (6.3-20.6)15.1 (8.3-24.1)7.1 (5.3-8.4)13.2 (8.3-24.9)7.1 (6.0-20.6)82.0 (7.3-NA)6.2 (4.3-10.1)P Value .041 .550 .021 .506 .105HR (95% CI) 0.64 (0.41-0.99) 0.82 (0.43-1.57) 0.50 (0.27-0.92) 0.77 (0.35-1.68) 0.44 (0.15-1.23)OS, med wk (95% CI)31.0 (16.6-41.3)24.6 (12.7-33.9) 30.0 (14.9-44.4)24.9 (13.7-58.3)32.3 (15.9-48.1)20.4 (10.3-33.9)30.0 (18.0-34.6)20.1 (13.7-36.9)108.4 (9.6-108.4)18.6 (6.6-48.0)P Value .673 .526 .253 .767 .144HR (95% CI) 0.91 (0.59-1.41) 1.23 (0.65-2.34) 0.70 (0.38-1.30) 1.12 (0.52-2.42) 0.47 (0.17-1.33) Abbreviations: CI, confidence interval; HR, hazard ratio; med, median; NA, not applicable/not available. Disclosures Czuczman: Celgene: Consultancy. Off Label Use: This abstract describes a clinical trial of lenalidomide, which is an orally-available immunomodulatory agent under investigation for treating patients with diffuse large B-cell lymphoma.. Davies:GlaxoSmithKlein: Research Funding; Hoffman La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Wagner-Johnston:Celgene: Research Funding. Gascoyne:Celgene: Consultancy, Research Funding. Salles:Pfizer: Honoraria; Gilead: Honoraria; Jansen: Honoraria; Hoffman La Roche: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria. Witzig:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zinzani:Mundipharma: Honoraria; Pfizer: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Millennium Takeda: Honoraria; Celgene: Honoraria; Teva: Membership on an entity's Board of Directors or advisory committees. Wright:Celgene: Research Funding. Staudt:Celgene Corporation: Research Funding. Repici:Celgene: Employment. Song:Celgene: Employment. Manzke:Celgene: Employment.

Abstract Abstract 1638 Introduction: Hodgkin lymphoma (HL) represents the most common subtype of malignant lymphoma in young people in the Western world. Most of the patients can be cured with modern treatment strategies. However, about 20% of patients still die due to relapse or progressive disease. Recently, elevated numbers of tumor-associated macrophages in diagnostic pretreatment and relapse biopsies have been associated with poor long-term outcomes. Furthermore, high expression of CSF1R on the malignant Hodgkin Reed Sternberg cells has been linked to shorter progression-free survival, providing the rationale to test PLX3397, a highly selective inhibitor of CSF1R (also known as Fms) and Kit receptor tyrosine kinases, in HL patients. Patients and Methods: Patients with relapsed or refractory HL were enrolled in this single-agent multicenter trial. All patients had progressed after or were ineligible for autologous stem cell transplantation, had radiographically measurable disease, and had discontinued all previous HL therapy. Patients were treated with oral PLX3397 at a dose of 900 mg/day continuously until occurrence of unacceptable toxicity or disease progression. The primary endpoint was the objective response rate according to the 2007 consensus criteria. Results: A total of 20 patients were enrolled (9 male, 11 female, median age 36 years). Six patients had tumor reduction ranging between 3% and 54% including one partial remission (overall response rate of 5%) (Figure). The median duration of progression-free survival was 56 days. The most common drug-related adverse effects were asthenia, fatigue, hair depigmentation, anemia, leukopenia, and increased LDH, all of which were grade 1 or 2 except for one grade 3 neutropenia. CD14dim/16+ labeled peripheral blood monocytes were markedly reduced in all patients at 4 weeks vs. Baseline (median=83% reduction, range of 44%-96% reduction), confirming inhibition of CSF1R signaling. Increases were observed for adiponectin in 82% of patients (median=2.6-fold, range 1.2 to 12-fold) and for CSF-1 in 94% of patients (median=4.0-fold, range 1.4 to 16.5-fold), also consistent with CSF1R inhibition. Archival formalin-fixed paraffin-embedded lymphoma tissues of sufficient quality were available for 12 patients. Biopsy material was obtained from either initial diagnosis or after relapse. CD68+ and CD163+ macrophages were highly elevated (>25% cellularity) in 42% and 58% of patients, respectively. The number of tumor-associated macrophages was not significantly associated with a reduction in lesion size after PLX3397 treatment in this small study cohort. Discussion: In this phase 2 clinical trial, PLX3397 at a dose of 900 mg/day showed limited activity in this heavily pretreated patient cohort. However, target inhibition of both Fms and Kit was clearly demonstrated. Although the efficacy of single agent PLX3397 in this study population was modest, the manageable safety profile and evidence of target inhibition may warrant further testing in combination therapy trials. Disclosures: Younes: Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Affimed: Research Funding; Gilead: Research Funding; Johnson & Johnson: Research Funding. Gascoyne:Plexxikon Inc.: Consultancy, Research Funding. West:Plexxikon Inc.: Employment. Nolop:Plexxikon Inc.: Employment. Steidl:Plexxikon Inc.: Research Funding.

Abstract Abstract 1545 Introduction: The diagnosis of peripheral T-cell lymphoma (PTCL) is difficult and accurate diagnosis and subclassification relies on correlating histologic, immunophenotypic, molecular genetic, and clinical data. Evidence-based guidelines for the appropriate diagnostic work-up of PTCL are lacking. The objective of this study was to evaluate a large series of PTCLs by experienced hematopathologists with a tiered approach to immunohistochemistry (IHC) and molecular genetic characterization to document overall diagnostic accuracy and clinical relevance using this approach. Methods: 7 experienced hematopathologists from 5 institutions reviewed 374 cases of peripheral T and NK cell lymphomas (referred to collectively as PTCL). 6 cases of cutaneous T-cell lymphoma were excluded after final review in addition to 29 non-PTCL cases submitted as control cases to mimic diagnostic practice during the review. Cases received tier 0, 1 and 2 diagnoses by 3 independent pathologists, based on review of hematoxylin and eosin (HE) stain with basic demographic data, panel 1 IHC (CD3, CD5, CD10, CD20, CD21, CD30, CD45, PAX5), and panel 2 IHC (CD2, CD4, CD7, CD8, CD23, PD1, CD56, EBER, ALK, TIA1, TCRg, TCRbF1), respectively. A tier 2b diagnosis was then rendered after gene rearrangement data were available. A final consensus diagnosis was rendered after discussion of each case by the 3 reviewers with all available clinical data. Overall survival (OS) was assessed using Kaplan-Meier (KM) curves and Cox proportional hazards models. Results: 1122 individual diagnoses leading to 339 final consensus PTCL diagnoses were rendered. 341 (91%) cases had complete phenotypic data and 241 had gene rearrangement data. There was no bias of missing data according to final diagnosis subtype. Reviewer diagnoses using specific WHO subclassification were 16.3%, 36.9%, 82.7%, and 85.9% for tier 0, 1, 2, and 2b, demonstrating a significant increase in diagnostic certainty after a complete IHC panel. Gene rearrangement only contributed to a change in diagnosis in 51/650 (8%) individual reviews. Across all 374 cases, a small number of cases (n=28, 7.5%) showed no agreement among the 3 independent reviewers after tier 2b and required debate. These generally represented refinement of the subclassification of a PTCL. The most common disagreements were between PTCL, not otherwise specified (nos) vs. unclassifiable T-cell lymphoma, and PTCL, nos vs. angioimmunoblastic T-cell lymphoma (AITL). Currently, OS data was available in 198 cases and 52% have died (median age follow-up of 15 months for those still alive, range 0–160 mo). Figure 1 shows the KM survival curves for types with more than 10 cases. Of note, unclassifiable PTCL cases had poor OS, comparable to PTCL nos; a trend was seen for CD30+ ALK- ALCL to have a longer OS compared to PTCL nos (HR=0.5, 95% CI: 0.21–1.19, P=.09). EBER positivity in tumor cells was associated with poor OS in the cohort of all PTCL patients (HR=2.32, 95% CI: 1.28–4.23, p=0.006, Figure 2); the association was similar when nasal NK/T-cell lymphoma cases were excluded (HR=2.50, 95% CI: 1.00–6.26, p=0.05). Trends for poor prognosis were also seen for TIA-1 expression in PTCL, nos (HR=1.9, 95% CI 0.91–3.96, P=.09) and PD1 expression in AITL (HR=6.25, 95% CI 0.85–46.09, P=.07). Clinical data collection is still ongoing and will be updated. Conclusions: We demonstrate the diagnostic accuracy among experienced hematopathologists of a defined IHC panel, showing an overall ability to reach consensus diagnosis of 93% in PTCL cases. The resulting consensus diagnostic subtypes showed expected outcomes relative to other large series of PTCLs, and EBER positivity is a poor prognostic marker among T and NK cell lymphomas. A tiered approach to IHC is recommended when a PTCL is under differential diagnostic consideration since the first tier can often resolve the main question of whether a lesion is reactive or lymphoma. This can lead to more efficient use of the expanded tier 2 panel that will enable diagnosis and specific subclassification of PTCL. Gene rearrangement studies are not required in the great majority of cases. This evidence-based approach to the diagnosis of PTCL should inform practicing pathologists, clinical trial design, and policy makers regarding required ancillary studies in this group of diseases. Disclosures: Hsi: Allos: Research Funding. Said:Allos: Research Funding. Macon:Allos: Research Funding. Rodig:Allos: Research Funding. Gascoyne:Seattle Genetics: Research Funding. Ondrejka:Allos: Research Funding. Dorfman:Allos: Research Funding. Maurer:Allos: Research Funding. Dogan:Allos: Research Funding.

Abstract Background The international prognostic score (IPS) (Hasenclever et al., NEJM 1988) uses 7 factors (age> 45, male sex, hemoglobin<10.5, stage IV, leukocytosis > 15,000, and lymphopenia< 600) to predict a 5 year freedom from progression (FFP) of 42%-84% and overall survival (OS) of 56%-89% for patients with advanced HL. Constructed from a retrospective analysis of patients treated before 1992, the IPS continues to be the most commonly used risk stratification index for advanced HL. Recent studies suggest that the predictive range of the IPS has narrowed due to improved outcomes of patients treated with current therapy (Moccia et al. JCO 2012). In this report we prospectively evaluated the ability of the individual components of the IPS to predict outcome in patients enrolled on the US Intergroup trial E2496. Methods All seven IPS (IPS-7) variables were recorded for all patients at study entry. FFP was defined as the time from study entry to disease progression or relapse; deaths that occurred during remission that were not preceded by disease progression/relapse were censored. OS was defined as the time from study entry to death from any cause. Kaplan-Meier methodology was used to construct survival curves. Univariate and multivariate analysis (MVA) was performed using Cox proportional-hazards models. We subsequently constructed an alternative prognostic score utilizing the factors which were significant on MVA (PS-3). Results From 1996-2006, 854 patients with advanced HL, were randomized to treatment with either ABVD or Stanford V, with no significant differences in outcome (Gordon et al, JCO 2013). While the IPS-7 remained prognostic it did not stratify the lowest risk patients (0-1 risk factor) or patients with 3-5 risk factors, as its predictive range was narrowed due to improved clinical outcomes (Fig 1a and 2a). Table 1 shows the univariate and multivariate analysis for IPS-7 and outcomes. In contrast to the original IPS-7, on MVA, only two factors, hemoglobin and stage were significant for FFP, and three factors for OS: hemoglobin, stage, and age. We then evaluated a new 3 factor score (PS-3) utilizing variables significant on the MVA. The PS-3 was significant for both FFP (p=0.0001) and OS (p<.0001) and clearly separated patients into 4 distinct risk groups with either: 0, 1, 2 or 3 risk factors. The five year FFP was 83%, 74%, 68%, and 63% and OS was 95%, 85%, 75%, and 52% for patients with 0, 1, 2, and 3 risk factors, respectively (Table 2, Fig 1b and 2b). Conclusion In E2496, for patients with advanced HL, the PS-3 may stratify patients more clearly compared to IPS-7 and provide a simpler model to assess risk. Studies comparing PS-3 with IPS-7, and are ongoing. The incorporation of novel biomarkers and biologic factors into PS-3, as well as validation with other data sets is warranted. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Follicular lymphoma (FL) is the second most common nodal lymphoma worldwide and remains incurable for most patients (pts). FL is recognized to be a highly heterogeneous disease and a subset of pts experience remarkable poor outcome. In a recent study, 19-26% of pts receiving first-line R-CHOP experienced progression of disease (POD) within 24 months after diagnosis and had a 5-year (yr) overall survival (OS) of only 34-50%, as compared to a 5-yr OS of 90-94% for pts without POD within 24 months (Casulo et al., J Clin Oncol 2015). Consequently, event-free survival at 12 (EFS12) and 24 months (EFS24) have been suggested as novel surrogate endpoints for poor overall survival in clinical trials and useful for patient counseling (Maurer et al., ASH 2014). We have previously shown that a clinicogenetic risk model (m7-FLIPI) that includes the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the FL International Prognostic Index (FLIPI), and the Eastern Cooperative Oncology Group (ECOG) performance status, improves risk stratification for failure-free survival (FFS) and OS in pts with FL receiving first-line immunochemotherapy (Pastore et al., Lancet Oncology 2015). An online tool is available at: http://www.glsg.de/m7-flipi. It would be advantageous to determine prognosis prior to front-line therapy rather than after POD. Thus, we aimed to investigate the predictive utility of the m7-FLIPI for early POD. Patients and Methods: Clinical and mutation data were available from two independent cohorts: 151 pts who received R-CHOP and IFN maintenance as part of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG), and 107 pts from a population-based registry of the British Columbia Cancer Agency (BCCA) who received R-CVP. Among the latter, 93 (87%) received R-maintenance by intention to treat. All pts had symptomatic, advanced stage or bulky disease considered ineligible for curative radiotherapy, and a biopsy specimen obtained </=12 months prior to the initiation of first-line therapy. POD was defined as progression, relapse, or death due to any cause. POD12 and POD24 were defined based on POD status at 12 and 24 months after therapy initiation, respectively. Logistic regression analysis was performed to assess if m7-FLIPI was predictive of early POD using the statistical software R (version 3.1.2). Results: In the GLSG cohort, median age was 57 yrs (range 27-77), 51% had high-risk FLIPI, and 5-yr failure-free survival (FFS) and OS rates were 66% and 83%, respectively (median follow-up for OS 7.7 yrs). In the BCCA cohort, median age was higher (62 yrs, 37-83), but high-risk FLIPI was similarly frequent (50%); 5-yr FFS and OS rates were 58% and 74%, respectively (median follow-up for OS 6.7 yrs). A total of 43 GLSG (28%) and 24 BCCA pts (22%) were classified as high-risk by m7-FLIPI, with a 5-yr OS of 65% and 42%, respectively. In the GLSG cohort, 8 (5%) and 29 pts (19%) had POD within 12 and 24 months, respectively, 4 and 10 pts were censored before POD12 and POD24 (table). High-risk m7-FLIPI pts were significantly more likely to experience early POD with an Odds Ratio (OR) of 20.80 (95% confidence interval (CI) 3.53-395.96; p=0.0052) for POD12 and 6.33 (95% CI 2.67-15.69; p<0.0001) for POD24. Likewise, in the BCCA cohort, 16 (15%) and 28 pts (26%) experienced POD12 and POD24, respectively (table). The OR for high-risk m7-FLIPI pts was 4.69 (95% CI 1.52-14.65; p=0.0068) for POD12, and 5.36 (95% CI 2.03-14.60; p=0.0008) for POD24. In the GLSG and BCCA cohorts, the m7-FLIPI had a sensitivity of 88% and 50%, a specificity of 75% and 82%, a positive predictive value (PPV) of 16 and 33%, and a negative predictive value (NPV) of 96% and 90% to predict POD12. For POD24, sensitivity was 62% and 46%, specificity 79% and 86%, PPV 42% and 54%, and NPV 82% and 82%, respectively. Conclusion: We conclude that patients classified as high-risk m7-FLIPI are highly enriched among those with early progression of disease. However, approximately one-half of patients with progression by 24 months after therapy initiation are classified as low-risk m7-FLIPI. Thus, further efforts are needed to refine the m7-FLIPI and thereby capture additional cases that may benefit from innovative first-line approaches. Table. Population m7-FLIPI N POD12 POD24 GLSG Total 151 8/147* 29/141* High-risk 43 7 18 Low-risk 108 1 11 BCCA Total 107 16/107 28/107 High-risk 24 8 13 Low-risk 83 8 15 *Pts censored were removed Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

Abstract Abstract 3705 Improved outcomes were reported in USA studies in DLBCL (Habermann et al. J Clin Oncol 2006) in a two-staged randomized study of R-CHOP (rituximab, cyclophosphamide, Adriamycin, vincristine, and prednisone) versus CHOP with a second randomization assignment to maintenance rituximab (MR) or observation (OBS) (E4494) and in follicular lymphoma (FL) in patients in a trial with CVP (cyclophosphamide, vincristine, and prednisone) followed by randomization to MR versus OBS in advanced-stage indolent lymphoma (E1496) (Hochster et al. J Clin Oncol 2009). The details of the treatment regimens have been previously described. The German High Grade Lymphoma Study Group has reported differences between men and women in outcomes in DLBCL with improved outcomes in women treated with rituximab (Müller et al. Blood 2012). Methods: Survival outcomes by sex were analyzed using a stratified weighted cox regression, removing the effect of maintenance rituximab in DLBCL (E4494), and a log-rank test in patients with follicular histology (E1496). A Cox regression model was used to evaluate the differences between males and females together with weight (below or above the median). Wilcoxon test and Fisher's exact test were used to compare medians and proportions, respectively. Results: In DLBCL, there were 273 eligible males and 273 females. The median age was 69 in males and 70 in females. There were no differences in baseline patient characteristics among the male and female populations. 138 males and 129 females were treated with R-CHOP. There was no difference in treatment received, with 83% females and 75.3% males receiving 6 cycles or more of R-CHOP treatment (p=0.14). The complete remission (CR) and partial remission (PR) rates after RCHOP were higher in females (82.6%) versus males (71.5%) (P = 0.04). With a median follow-up of 9.45 years, the failure free survival (FFS) and overall survival (OS) were improved in females (P = 0.02, 0.002; HR=0.63, 0.54) compared with males in the R-CHOP group. The outcomes were not different in the CHOP group for FFS (P = 0.81) or OS (P= 0.57) between males and females. Within the R-CHOP group, the failure free survival (FFS) was significantly different between women and men (P = 0.002) and body weight (P = 0.03), but only female sex (P = 0.001) was significant and not weight (P = 0.26) for OS. Of 282 evaluable patients with advanced-stage follicular lymphoma who received initial treatment with CVP, 115 patients were randomly assigned to MR and 113 to OBS. 120 patients were male, and 108 were female. The median age was 58 years in the MR arm and 54 years in the OBS arm. At a median follow-up of 8.04 years, MR markedly improved the PFS (P=0.003) compared with OBS. There were no differences in PFS (P= 0.17) between males and females treated with MR or OS (P = 0.27). In conclusion, in induction therapy with rituximab in DLBCL there is a sex dependent effect with rituximab with males benefiting less than females. In contrast, in patients with follicular lymphoma treated with chemotherapy followed by maintenance rituximab, there were no differences. The differences in outcomes in patients of different sex with DLBCL treated with immunochemotherapy and FL treated with maintenance rituximab will require further analysis of multiple clinical and biologic variables. Disclosures: Fisher: Roche: Advisory Board Other. Cheson:Genentech: Consultancy. Kahl:Genentech, Roche: Consultancy, Research Funding. Horning:Genetech, Roche: Employment, stock (Roche) Other.