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Abstract Abstract 1648 Introduction Radioimmunotherapy capitalizes on the radiosensitivity of non-Hodgkin lymphoma (NHL) and the targeted nature of monoclonal antibody therapy. In an attempt to reverse bone marrow infiltration with B-cells and, hence, optimize the biodistribution and tumor dosimetry of 90Y-ibritumomab tiuxetan, we conducted a multicenter, dose escalation, open label study to determine maximum tolerated dose (MTD), safety, and efficacy of a single course of 90Y-ibritumomab tiuxetan after four weekly doses of rituximab in relapsed or refractory low-grade or follicular or transformed CD20+ B-cell NHL. Methods A course of therapy included an initial dose of rituximab 250 mg/m2 plus 5 mCi of 111In- ibritumomab tiuxetan followed by three weekly doses of rituximab at 375 mg/m2 followed two weeks later by rituximab 250 mg/m2 plus 5 mCi of 111In-ibritumomab tiuxetan. Gamma camera imaging for dose estimates was conducted on days 1 and 36 following infusion of 111In- ibritumomab tiuxetan. If dose estimates were in the safe defined limits, and bone marrow on day 29 had less than 25% involvement by NHL, patients received on day 43 250 mg/m2 of rituximab plus a dose of 90Y-ibritumomab tiuxetan. Patients were scheduled to receive 90Y- ibritumomab tiuxetan in one of the dose escalation cohorts (0.4, 0.5, 0.6, 0.7 mCi/kg). Eligible patients were required to have histologically confirmed, relapsed or refractory low-grade or follicular or transformed B-cell NHL with demonstrable monoclonal CD20+ B-cell population in the lymph nodes or bone marrow. Patients with impaired bone marrow reserve, as indicated by prior myeloablative therapies with stem cell rescue, hypocellular marrow, history of failed stem cell collection or external beam radiation therapy to >25% of active bone marrow, and marked reduction in bone marrow precursors of one or more cell lines, were excluded. Results Cohort 1 (0.4 mCi/kg) enrolled 5 patients. Dose escalation was held after significant hematologic toxicity was observed in those patients (1 patient developed grade 4 and 3 grade 3 reversible thrombocytopenia, 4 patients developed grade 4 reversible leukopenia and neutropenia, and 1 patient developed grade 4 febrile neutropenia). One patient in this cohort did not receive the study drug due to the toxicity observed in the previous patients. The protocol was amended and 6 patients were enrolled at a lower dose cohort (0.3 mCi/kg); 1 patient experienced grade 4 neutropenia, whereas grade 3 leukopenia, neutropenia, and thrombocytopenia were seen in 2, 3, and 3 patients respectively. As the 0.3 mCi/kg dose was well tolerated, the 0.4 mCi/kg cohort was expanded to enroll 6 additional patients. In the expansion cohort, Grade 4 leukopenia and neutropenia were seen in 1 and 2 patients respectively; also, grade 3 leukopenia, neutropenia, and thrombocytopenia were seen in 3, 4, and 4 patients, respectively. All hematologic toxicities were reversible and no non-hematologic toxicities were seen with the exception of grade 1 fatigue in 2 patients. Among those who developed hematologic toxicities, the median duration of at least grade 3 leukopenia, neutropenia, and thrombocytopenia were 12 (range, 7–37), 10 (7–30), and 12 (3–44) days, respectively. Six patients had bone marrow involvement by NHL at registration ranging from <5% to 20%. Following 4 weekly doses of rituximab, marrow involvement decreased in all patients with complete clearance in 3 of them. In an intention-to-treat analysis, complete remission, partial remission, stable and progressive disease was achieved in 6 (35%), 8 (47%), 2 (12%), and 1(6%) patients, respectively (fig 1). With a median follow up of 31.7 months (range, 4.3 – 92.6 months), the median progression free survival (fig 2) and time to next treatment (fig 3) were 12.3 and 10.9 months, respectively. The median overall survival has not been reached. Conclusion The MTD of 90Y-ibritumomab tiuxetan administered to patients who have NHL marrow infiltration <25% following 4 weekly doses of rituximab was 0.4 mCi/kg. A 4 weekly course of rituximab decreased NHL marrow infiltration in all patients with marrow involvement and led to complete clearance in 50% of them. Although this regimen was associated with a high response rate, the hematologic toxicity was significant. Disclosures: No relevant conflicts of interest to declare.

Abstract We have recently reported that event-free survival at 24 months from diagnosis (EFS24) is a robust endpoint for assessment of disease related outcome for newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) treated with anthracycline-based immunochemotherapy (IC). Patients who achieve EFS24 following IC have a subsequent overall survival that is equivalent to the age and sex matched general population. The IPI was developed in the pre-rituximab era using OS/EFS endpoints. While the IPI is associated with outcome in the IC era, the original survival estimates for the IPI risk groups are outdated. The IPI is also a discrete risk classifier, with only 6 possible groups. Here we remodel the IPI using EFS24 as the endpoint in a large international cohort of patients treated with IC. This model provides an individual level 0-100% risk of failing to achieve EFS24 for each patient and can be used for patient prognosis, treatment stratification, and risk assessment. Methods Newly diagnosed DLBCL patients treated with immunochemotherapy from the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource, NCCTG N0489 clinical trial, GELA LNH2003B program, and a Lyon, France based hospital registry were included in the original EFS24 study. Patients with a relapse, progression, unplanned re-treatment, or death due to any cause within 730 days of diagnosis were considered a failure for the EFS24 endpoint. Patients alive and progression/relapse free at 730 days from diagnosis with no subsequent treatment following initial IC were considered a success for the EFS24 endpoint. Variables selected for potential model inclusion were the IPI components (age, stage, ECOG PS, number of extranodal sites, and LDH), as well as standard clinical variables typically reported in studies of DLBCL: presence of B-symptoms, bone marrow involvement, bulky disease (>10 cm), and sex. The IPI24, a prognostic model for EFS24, was developed using logistic regression models. Model building began by fitting the classic IPI score (0-5), then allowing individual IPI variables to carry different model weights and number of categories, followed by dropping insignificant variables, finally adding any additional significant variables. Model performance was assessed using bias corrected c-statistics, AIC, and R2 values. Model selection was done using the complete case set with multiple imputation on the full dataset used to refine parameter estimates for the final model. Results 1596 total patients were available for modeling. The median age was 62 (range 18-93) and 53% were male; 33% were IPI 0-1, 25% were IPI 2, 25% were IPI 3, and 17% were IPI of 4-5. The failure rate for achieving EFS24 was 29%. All variables but sex (p=0.33) were univariately associated with EFS24 (p<6.4x10-5). The original IPI had good prognostic ability for EFS24 (c=0.696, p=2.2x10-32). Allowing multiple categories for ECOG PS, stage, and age (continuous) improved model fit and prognostic ability (c=0.727). The number of extranodal sites was not significant when IPI variables were modeled separately and was removed from the model. Sex and bulky disease were additional significant variables when added to the model. Thus, the final IPI24 model contained the following risk predictors: male sex, ECOG PS (0 vs. 1 vs 2 vs 3-4), stage (I vs. II, vs. III vs. IV), LDH (elevated vs. normal range), bulky disease > 10cm, and age (continuous). This model resulted in improved fit and prognostic ability (c=0.749) over the standard IPI (c=0.696, bootstrap p<0.001). Model validation was performed on an additional 158 patients from the SPORE MER and showed good concordance (c=0.697). Additional validation is planned in a larger set of independent patients. Conclusion The IPI24, generated using standard clinical variables, yields an individual risk prediction for failing to achieve EFS24 following IC for treatment of DLBCL. The IPI24 has superior prognostic ability to the standard IPI and can be implemented in the clinic using a nomogram or as a simple electronic application. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1640 Background: The introduction of radioimmunotherapy (RIT) into clinical practice for the treatment of follicular lymphoma (FL) occurred at a time at which many patients did not have prior exposure to rituximab. Clinical trials in the relapsed/refractory setting, as well as consolidation in the upfront setting have included a small number of patients that had been previously treated with rituximab or a rituximab containing treatment regimen. We evaluated the effect of prior rituximab therapy on the efficacy of RIT. METHODS: The prospective lymphoma database was queried for all patients having received a single dose of yttrium-90 ibritumomab tiuxetan for relapsed/refractory FL which had previously been treated with systemic therapy (patients receiving only prior external beam radiation therapy were excluded). The database includes all consecutive adult patients diagnosed with lymphoma seen at Mayo Clinic Rochester. The diagnosis of follicular lymphoma was as by WHO classification and centrally reviewed. Patients with evidence of histologic transformation to diffuse large B cell lymphoma prior to RIT were excluded. Time to treatment failure (TTF) was defined as the time from RIT to next anti-lymphoma therapy. RESULTS: 111 patients were identified. 57 (51%) were male. Median age at time of RIT was 58 (19–88). Median time from diagnosis to RIT was 35 (6–281) months in patients having received prior treatment with rituximab and 47 (12–272) months in those who had not (p=0.19). 63 (57%) of patients received prior treatment with rituximab or rituximab containing chemotherapy. Median number of prior therapies was 2 (1–10), which was not different between the rituximab treated or untreated groups [2(1–6) vs 2(1–10) p=0.12]. Median TTF was 10.0 months in the patients having received prior rituximab and 10.1 months in those that had not (p=0.29). Figure 1. The median overall survival from RIT was not reached, but appeared similar (Kaplan-Meier estimate 125 months without prior rituximab exposure vs 95 months with prior rituximab exposure; p=0.33). CONCLUSIONS: Prior rituximab exposure does not seem to adversely impact the time to treatment failure or overall survival in those patients treated with RIT. While the data leading to the approval of RIT were accrued prior to the routine clinical use of rituximab, our data demonstrate similar clinical benefit of RIT in patients with prior exposure to rituximab or rituximab containing therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1591 Background: The serum free light chain (FLC) assay quantitates free kappa and free lambda immunoglobulin light chains. We previously showed elevated FLC are present in approximately 1 in 3 diffuse large B cell lymphoma (DLBCL) patients from both a phase II cooperative group clinical trial and a large clinic based epidemiology cohort. Approximately 10% of DLBCL patients had elevated FLC that was monoclonal in these series. Patients with monoclonal elevated FLC have very poor outcome with almost 50% of patients progressing in the first 15 months following initial treatment with immunochemotherapy. Unlike patients with polyclonal FLC elevation, where a variety of host effects may cause a rise in both kappa and lambda, it is likely the excess FLC in monoclonal patients is directly related to the tumor. DLBCL are a heterogenous group of tumors that can be classified into germinal center (GCB) or activated B cell (ABC) groupings using immunohistochemistry (IHC) staining algorithms. Here we examine the association of monoclonal free light chains with ABC vs. GCB DLBCL tumors. Methods: Newly diagnosed DLBCL patients were prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) or NCCTG clinical trial N0489. Serum FLC was quantitated from enrollment research serum draws using the Freelite FLC assay (The Binding Site, Ltd., Birmingham, UK). Monoclonal elevated FLC was defined as an elevated kappa or lambda with a corresponding abnormal FLC ratio. Immunohistochemistry (IHC) staining was performed on paraffin tissue from research tissue microarrays (TMAs). Results: IHC tissue staining was available from 12 patients with monoclonal elevated FLC unrelated to renal failure. Germinal center markers were predominantly negative: 2 of 11 were LMO2 positive (18%), 1 of 12 was CD10 positive (8%), and zero cases out of 11 were GCET1 positive. FoxP1 was positive in 5 of 9 cases (56%) and MUM1 was positive in 4 of 12 cases (33%). By the Tally algorithm, 10 of 11 cases (91%) were ABC type DLBCL The percentage of ABC patients by the Tally algorithm in the corresponding DLBCL patients without monoclonal FLC was 45% (N=108, p=0.004). Conclusions: Approximately 10% of DLBCL patients have elevated monoclonal FLC and these patients have poor prognosis. Elevated monoclonal FLC may be a serum marker for ABC-type lymphoma, as the tumors from patients are predominantly negative for germinal center stains and ABC by the Tally algorithm. The secretion of light chains by the tumor suggests an activated B cell clone and the poor prognosis is characteristic of ABC type DLBCL and. Given the likelihood of the excess monoclonal FLC being tumor related, the potential exists for tracking of tumor response and progression via serum FLC in these patients. Replication of these findings in an additional cohort of DLBCL patients is planned. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Primary Mediastinal Large B-cell Lymphoma (PMLBCL) is a biologically and pathologically distinct subset of large B-cell lymphoma of thymic origin. The natural history of PMLBCL is not well defined. While earlier reports suggested that PMLBCL is an aggressive disease with a poorer prognosis when compared to other large cell B cell lymphomas, recent studies report more favorable results. Some of the outcome variability reported in previous studies may be related to the inclusion of other pathological lymphoma subtypes involving mediastinum. Thus, we reviewed the pathology and clinical course of patients with PMLBCL seen at our institution. Methods: We reviewed the biopsies on all patients diagnosed with mediastinal B-cell non-Hodgkin lymphoma (NHL) between 10/1983 and 10/2004. The pathological criteria for diagnosis of PMLBCL was a diffuse infiltrate of neoplastic CD20+ large B-cells within the mediastinum that frequently had "clear" cytoplasm and were often associated with fibrosis. We then reviewed the clinical data for patients with a pathological diagnosis of PMLBCL. Results: 121 patients were diagnosed with mediastinal B cell NHL and had tissue available for review. Of these, 88 fulfilled the pathological diagnostic criteria for PMLBCL. The median age at presentation was 37 years (range 18–83). The male to female ratio was 1.06. Age adjusted IPI was: 0, 1, 2, 3 in 18%, 56%, 18% and 8% of the patients respectively. The most commonly used treatments were: CHOP (70%), R-CHOP (22%) and ProMACE-CYTABOM (6%). 62% of the patients received adjuvant radiotherapy. 24% of the patients received high dose chemotherapy with autologous stem cell transplantation (2 patients in first remission). The median follow up was 66 months. The 2 and 5 year survival was 72% and 68% respectively. On univariate analysis, age >60 (p=0.012) and presence of B symptoms (p=0.0094) were associated with an adverse outcome. On multivariate analysis, only the presence of B symptoms (p=0.039) was an independent predictor of shortened overall survival. The 2 year survival of patients with age adjusted IPI of 0–1 or 2–3 was 86% and 68% respectively (p=0.023). Patients treated with adjuvant radiation therapy had a 5 year survival of 74% versus 53% in patients who did not receive adjuvant radiation (p=0.042). However, there was a higher percentage of Ann Arbor stage 3 and 4 disease patients found in the group who did not receive radiotherapy treatment (66% vs 17% respectively). Conclusions: The overall survival rates seen in patients with a confirmed pathological diagnosis of PMLBCL were superior to that reported in earlier studies and similar to that reported with the use of more intensive chemotherapy regimens. While many authors report a high proportion of female patients with PMLBCL, we did not observe any gender differences. While patients receiving adjuvant radiation therapy had a better outcome than those that did not, the retrospective nature of this study and differences in stage distribution preclude conclusions regarding the role of adjuvant radiation therapy. Randomized studies will be necessary to assess the optimal treatment for PMLBCL.

Abstract Abstract 3652 Purpose: Gene expression profiling has shown biologically distinct cell of origin categories for diffuse large B-cell lymphoma (DLBCL): germinal center B-cell like (GCB), and activated-B-cell like (ABC). GCB, DLBCL patients experienced better clinical outcomes compared with ABC, DLBCL patients. However, gene microarray technology is not broadly available in a non-research setting. Absolute lymphocyte count (ALC) at diagnosis is a prognostic factor for survival in DLBCL. Recently, gene-expression profiling and immunohistochemistry-based studies in non-Hosgkin's lymphoma demonstrate the important role of monocytes and their progeny, particularly lymphoma-associated macrophages, in promoting lymphomagenesis. thus, we studied if the peripheral blood absolute lymphocyte count/absolute monocyte count at diagnosis (ALC/AMC-DX), as a surrogate biomarker of the host response against the cell of origin in DLBCL, affects survival in DLBCL. Patients and Methods: We perfromed a retrospective analysis of the association between ALC/AMC-DX and survival in 131 consecutive DLBCL patients that were followed at Mayo Clinic from 2004 to 2010, with available tissue immunostaining for CD10, BCL6, MUM 1, and BCL 2 (Hans' algorithm) to identified GCB and ABC DLBCL patients. Receiver operating characteristic (ROC) and area under the curve (AUC) analyses were used for ALC/AMC-DX cut-off value determientaion and proportional-hazards models wee used to compare survival based on the ALC/AMC-DX. Results: The cohort included 91 (70%) GCb DLBCL patients and 40 (30%) ABC, DLBCL patients. All patients were treated with rituximab, cyclosphosphamide, adriamycin, vincristine, and prednisone (R-CHOP-21). The median follow-up period was 2.1 years (range 0.1–6.9 years). An ALC/AMC-DX >= 1.5 was the best cut-off value for survival with an empircal AUC of 0.83 (95% CI, 0.77 to 0.89), a sensitivity of 83% (95% CL, 72% to 92%) and specificity of 79% (95%CI, 72% to 85%). The cut-off value for ALC/AMC-DX >= 1.5 was validated by the k-fold cross validation method, showing a cross validation ROC with an AUC of 0.89 (95%CI, 0.80 to 0.95) for an ALC/AMC-DX >=1.5. Using Kaplan-Meier analysis, the overall survival (OS), defined as the time from diagnosis to last follow-up or death due to any cause; and progression-free survival (PFS), defined as the time from diagnosis to death of any cause, relapse, progression, or last follow-up, based on ALC/AMC-DX >= 1.5 were evaluated. patients with an ALC/AMC-DX >=1.5 experienced a superior OS and PFS compared with patients with an ALC/AMC-DX < 1.5: [OS: median was not reached vs 20.8 months, 5-years OS rates of 83% (95%CI, 70% to 95%) vs 36% (95%CI, 20% to 55%), p < 0.0001, respectively; and PFS: median was not reached vs 10.8 months, 5-years PFS rates of 70% (95%CI, 58% to 88%) vs 28% (95% CI, 17% to 46%), p < 0.0001, respectively]. Multivariate Cox stepwise regression analysis identified cell of origin, International Prognostic Index (IPI) and ALC/AMC-DX as the strongest predictors for OS and PFS, with ALC/AMC-DX out-performing cell of origin and IPI: OS [HR = 0.17, 95%CI, 0.07 to 0.36, p < 0.0001] and PFS [HR=0.21, 955CI, 0.11 to 0.39, p < 0.001]. conclusion: ALC/AMC-DX is independent of the cell of origin to predict survival and provides a single biomarker to predict clinical outcomes in DLBCL. Confirmatory studies are required. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: The PI3K/mTORC pathway is upregulated in DLBCL and can be targeted with mTORC1 inhibitors such as everolimus. Everolimus has demonstrated single agent activity in relapsed DLBCL (Leukemia. 2011; 25(2):341-7). These data provide the rationale to combine everolimus with standard RCHOP-21 to improve the effectiveness of upfront therapy for DLBCL. Methods: A phase I study was designed to determine the maximum tolerated dose of everolimus on days 1-10 or 1-14 in combination with RCHOP-21 along with a feasibility cohort to examine response in patients with newly diagnosed CD20+ DLBCL. Response assessment was evaluated using PET/CT and standard criteria. Results: We previously reported (J Clin Oncol 33, 2015 suppl; 8518) that in the phase I portion of trial N1085 that the dose of everolimus recommended for further study was everolimus 10 mg daily days 1-14; RCHOP day 1 and pegfilgrastim 6 mg day two for each of six 21-day cycles. The trial has now completed enrollment with a total of 26 patients. Two phase I patients were replaced during cycle 1 for personal, non-medical issues leaving 24 eligible patients for response assessment. The median age was 59.5 years (23 - 78); 42% were female; 18 (75%) stages III/IV; 12 (50%) had an elevated LDH; 29% had a high IPI score; and 4 (17%) had B-symptoms. Genotype was performed by immunohistochemistry using the Hans algorithm and 54% (13/24) were non-GCB; 13 (5 GCB, 8 non-GCB) had FISH for double hit and all were negative. Twenty-one (88%) patients received everolimus at 10 mg d1-14; the other three patients received 10 mg d1-10. Twenty-two (92%) patients received all 6 cycles. All patients have now completed therapy and the overall response rate was 96% (23/24) with 23 patients attaining functional CR by PET/CT. The remaining patient went off study for refusal in cycle 1, received further RCHOP-21 off study, and attained a CR off study. The median follow-up for the 24 patients is now 16.8 months (7.3 - 35.7) with 20 patients having ≥12 months of follow-up and 8 patients having ≥24 months of follow-up. To date, none of the 24 patients have died and none have experienced relapse with DLBCL. One patient relapsed 16 months from DLBCL diagnosis with a biopsy-proven follicular grade 1 NHL and received off-study Zevalin and achieved a second CR. The most common grade 3/4 toxicity was hematologic with 71% of patients having grade 4. Five (21%) patients had febrile neutropenia. Only 1 patient had grade 3 hyperglycemia and 3 patients had grade 3 hypertriglyceridemia. Reversible rash and pneumonitis were observed in 1 case each. Conclusions: The mTORC1 inhibitoreverolimus at 10 mg daily d1-14 of a standard RCHOP-21 cycle is tolerable with a 96% CR rate in both GCB and non-GCB DLBCL. With a median follow-up of 16.8 months and 8 patients out ≥24 months, the lack of DLBCL relapse is encouraging. Longer follow-up and a larger trial will be necessary to confirm the benefits of this novel combination. Clinical trial information: NCT01334502 Disclosures Off Label Use: Everolimus is an mTOR inhibitor which has activity in B cell lymphomas. It is being investigated in combination with SOC therapy for newly diagnosed DLBCL to examine potential toxicity as well as potential for enhanced disease response.. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

Abstract Abstract 2687 Background: Patients with early stage (Stages I, II) diffuse large B cell (DLBCL) have been traditionally treated with either CHOP x6 alone or with CHOP followed by involved field external beam radiotherapy (IFRT). With the demonstration of the superiority of rituximab CHOP (RCHOP) in advanced stage DLBCL, RCHOP has been adopted as the chemoimmunotherapy standard of care in early stage disease with or without IFRT. Radioimmunotherapy (RIT) has the advantage of delivering high-energy, short path length radiation in a targeted approach using an anti-CD20 antibody as the carrier. Thus, radiation is potentially targeted to microscopic sites outside of known disease. Goals: To evaluate the complete response (CR) rate and functional CR rate (CR or CRu/PR and PET negative) to a treatment regimen of RCHOP followed by 90Y-ibritumomab tiuxetan (Zevalin, Spectrum Pharmaceuticals) radioimmunotherapy (RIT); only patients not achieving PET negative status after RIT were to be given IFRT. The study goal was to achieve a functional CR rate of ≥75%. Patients and Methods: Eligible patients were those with new, untreated Stages I or II DLBCL as determined by standard CT scanning, adequate blood counts, creatinine and bilirubin <2.0 mg/dl, cardiac ejection fraction >45%, and a performance status 0–2. Stage I patients were required to have ≥1 adverse risk factor (≥60 years, bulky disease, elevated LDH or PS2). Patients received standard RCHOP21 × 2 cycles and then were restaged. Patients in CR received 2 additional cycles; those in PR or CRu received 4 additional cycles. At end of RCHOP a PET scan was repeated and centrally reviewed; those with a PR or functional CR proceeded to Zevalin RIT 0.4 mCi/kg (maximum 32 mCi) within 12 weeks of the last RCHOP. Patients were restaged 12 weeks post-RIT; PET negative patients were observed without maintenance; PET positive patients received 30Gy involved field radiation and then were restaged. Descriptive statistics were used to summarize the patient characteristics, treatment and response. The Kaplan-Meier method was used to estimate failure rates. Results: Between Dec 2004 and Nov 2008, 62 patients were enrolled; after pathology review 53 were considered eligible. 42% (22/53) patients were stage I/IE; 58% (31/53) were stage II/IIE. 57% (30/53) received 6 cycles of RCHOP; 40% (21/53) received 4 cycles; and 2 patients received 1 and 2 cycles, respectively. After immunochemotherapy, 79% (42/53) were in functional CR and 19% (10/53) PR; 1 was unevaluable. Of the 53 eligible patients who completed RCHOP therapy 91% (48/53) proceeded to RIT. After RIT, 87% (46/53; 95% CI: 75–95) were in CR/CRu and 89% (47/53; 95% CI:77–96%) were in functional CR. One patient proceeded to IFRT. The median follow-up is now 4.3 years. Seven (13%) of patients have had tumor progression but only 2 have died (1 of disease). At 4 years, 88% of patients remain progression free and 98% remain alive (Fig 1,2). The median has not been reached for either PFS or OS. There has been one case of myelodysplastic syndrome. Conclusions: Combination immunochemotherapy and RIT is an active regimen for patients with early stage DLBCL. Nearly all patients will achieve functional CR without the requirement of IFRT. The regimen of RCHOP and RIT for early stage DLBCL is worthy of further study. Disclosures: Witzig: Spectrum: Membership on an entity's Board of Directors or advisory committees, Research Funding, uncompensated Other. Off Label Use: Use of Zevalin in treating patients with Stage I-II DLBCL. Kahl:Roche: Consultancy; Genentech: Consultancy, Research Funding. Horning:Genentech: Employment; Roche: Equity Ownership.

Abstract Background: High risk CLL patients treated with novel targeted therapies continue to experience disease progression (PD), and more than 50% of these PD patients evolve into Richter's syndrome (RS), (Maddocks, Jama Oncol 2015). Standard chemotherapy for large cell lymphoma has limited efficacy (median overall survival <12 months) in RS. Novel immunotherapy using a PD-1 antibody to block immune checkpoint signals to activate the cytotoxic T -cell has significant efficacy in relapsed Hodgkin lymphoma (Ansell, NEJM 2015). We conducted a phase 2 trial to test the safety and clinical efficacy of the anti-PD-1 antibody pembrolizumab in patients with relapsed/refractory CLL and relapsed low grade B non-Hodgkin lymphoma (B-NHL) (MC1485 trial). Methods: MC1485includes two arms: patients with relapsed/refractory CLL (including RS) and patients with relapsed B-NHL. The main end points of this study are safety and overall response rate. The first 6 patients enrolled in either arm were included in a designed safety interim analysis. Here we report the initial interim analysis from the CLL arm. Relapsed/refractory CLL including RS who had ECOG performance 0-2 and normal organ function were included. Patients with active autoimmune disease or interstitial lung disease were excluded. Pembrolizumab 200 mg was administered intravenously every 3 weeks until progression, excessive toxicity, or completion of 2 years of therapy. Soluble plasma PD-L1 levels were measured in these 6 patients using an established ELISA assay (Frigola, Clin Cancer Res, 2011). CD8+ T cell subsets were assessed for their functional status using an established analysis (Liu, Oncoimmunology. 2013) at baseline and after 2 cycles of therapies. Results: As of July 27th, 2015, 16 relapsed/refractory CLL patients including 5 RS patients were enrolled. The median age was 71 years (58-81). The median number of prior therapies was 3 (1-6). All CLL patients had received chemoimmunotherapy (FCR/PCR). 4 out of 5 RS patients had received anthracycline-containing chemotherapy. 5 out of 8 patients who had received prior ibrutinib therapy progressed on ibrutinib. 8 patients had 17p-/TP53 mutation. Herein, we report preliminary results from the interim analysis of CLL arm including 4 RS and 2 CLL as well as the 5th RS who had response evaluation by PET. The median cycles of therapy administered was 4 (3-7). One patient experienced grade 2 cytokine release syndrome with transient febrile neutropenia, grade 3 headache and skin rashes. These symptoms resolved with steroid therapy. One patient experienced grade 3 myalgia and was also treated with steroids. The other patients in this safety cohort tolerated pembrolizumab well. The most common drug-related adverse events were grade 1 dyspnea (33%, 2/6) and grade 1 anemia (33%, 2/6). Based on investigator assessment using the Cheson 2007 International Working Group Criteria, 4 out of 5 RS patients had responded to therapy. One patient had a complete remission after 2 cycles and remains in remission. One patient had almost complete PET response after two cycles and is classified as PR as her bone marrow have not been re-evaluated yet. Two patients had notable responses with nodal and skin lymphoma improvements before they showed potential evidence of progressive diseases. The remaining 1 RS and 2 CLL had stable disease and continued on therapy at the last follow-up. Soluble PD-L1 levels (sPD-L1, n=6) were measured at baseline and after 2 cycles of therapies. 3 RS patients who had responded to therapy had decreased or stable sPD-L1 levels. The 4th RS and two CLL had increased sPD-L1 levels and had not demonstrated clinical response. CD8 T-cell subset analyses performed blindly (n=4) showed increased CD8 T cell function in one of the 4 patients tested. This patient who demonstrated CD8 T cell functional enhancement is the only patient in the 4 tested patients who had notable response to pembrolizumab. Conclusion: Pembrolizumab is tolerated in relapsed CLL and RS patients. Early efficacy observed in heavily pretreated RS patients including patients progressed on both anthracycline-based treatment and ibrutinib indicate PD-1 inhibition is a promising novel approach in patients with RS. Our CD8 T cell subset analysis may be used as a biomarker assay to predict clinical response in the era of novel immunotherapy. This trial and further correlative analysis is ongoing and will be presented at the ASH meeting. Disclosures Ding: Merek: Research Funding. Shanafelt:Cephalon: Research Funding; Pharmactckucs: Research Funding; Janssen: Research Funding; Hospira: Research Funding; Polyphenon E Int'l: Research Funding; Celgene: Research Funding; Glaxo-Smith_Kline: Research Funding; Genentech: Research Funding. Kay:Tolero Pharma: Research Funding; Hospira: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

Abstract Background: There are a number of ongoing clinical trials assessing next-generation immunochemotherapy (IC) regimens (i.e. RX-CHOP) in DLBCL. In addition to standard clinical trial workup, some trials require central pathology review and/or molecular phenotyping before treatment assignment and/or initiation of therapy. There is concern that these studies may be biasing patient selection due to missing patients with aggressive disease who require immediate therapy and cannot delay their treatment to enroll on a study. Here we examine clinical characteristics and outcome stratified by the time from diagnosis to initiation of therapy from a large observational cohort of patients with DLBCL from the R-CHOP era. Methods: Patients were prospectively enrolled in the University of Iowa / Mayo Clinic SPORE Molecular Epidemiology Resource (MER) within 9 months of diagnosis and followed for relapse, retreatment, and death. Clinical management at diagnosis and subsequent therapies were per treating physician. This analysis includes patients with stage II-IV DLBCL or primary mediastinal B-cell lymphoma (PMBCL) who underwent front-line anthracycline based IC; patients with primary CNS lymphoma, PTLD, or a component of low-grade lymphoma were excluded. Time from diagnosis to treatment was defined as the time from date of first lymphoma-containing biopsy to the initiation of IC therapy; delayed therapy was defined as initiating therapy more than 14 days after diagnosis. Event-free survival was defined as time from diagnosis until progression, retreatment, or death due to any cause. EFS24 was defined as progression free status 24 months from diagnosis. Results: 720 patients with stage II-IV newly diagnosed DLBCL or PMBCL and treated with IC were enrolled in the MER from 2002-2012. Median age at diagnosis was 62 years (range 18-92) and 399 patients (55%) were male. 541 patients (75%) had stage III/IV disease and IPI at diagnosis was 0-1 in 166 patients (23%), 2 in 221 patients (31%), 3 in 222 patients (31%) and 4-5 in 111 patients (15%). 233 of 395 patients (59%) were GCB per Hans. At a median follow-up of 73 months, (range 0-163), 349 (49%) patients had an event and 267 patients died (37%); 37% of patients failed to achieve EFS24. Median time from initial lymphoma diagnosis to initiation of IC was 14 days (range 0-79, IQR=8-23). Patients with delay in therapy (>14 days from diagnosis) were more frequently female (50%, p=0.0051) and older than patients who initiated therapy within 14 days from diagnosis (median age at diagnosis of 63 years vs. 60 years, p=0.0008). Patients with delay in treatment initiation had universally less aggressive disease characteristics, including earlier stage, non-elevated LDH, 0-1 extranodal sites, absence of B-symptoms, lower ECOG PS, and lower IPI (see table). In addition, patients with delayed therapy were enriched for GCB subtype per Hans algorithm (p=0.056). Patients with initiation of therapy within 14 day of diagnosis had significantly worse outcome (EFS24 failure=44%) compared to patients with delayed time to initiation of therapy (EFS24 failure=28%, p<0.0001, figure), which remained significant after adjusting for either IPI or aaIPI (both p<0.005). The association between delayed time to initiation of therapy and EFS24 was observed in both GCB (EFS24 failure = 42% vs. 27%, p=0.019) and non-GCB (EFS24 failure = 46% vs. 27%, p=0.014) subsets by Hans. The lower event rate in delayed therapy patients results in an approximately 10% loss of power if the study was powered based on all patients regardless of timing from diagnosis to therapy. Conclusions: Patients with delayed therapy from diagnosis have less aggressive clinical characteristics compared to patients who initiate treatment within 14 days from diagnosis. Studies with a lengthy trial work-up including central pathology review period may be selecting patients with less aggressive disease based on the patient's ability to delay treatment to complete study enrollment requirements. Furthermore, selection of patients with less aggressive disease may result in underpowered studies due to a lower event rate (fewer events) than expected. This retrospective analysis would suggest that trials in DLBCL should consider streamlined enrollment and therapy initiation to avoid potential selection bias and loss of power. Further assessment of implications on trial design and outcomes by cell of origin in this setting is ongoing. Table Table. Figure Figure. Disclosures Maurer: Kite Pharma: Research Funding; Celgene: Research Funding. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Nowakowski:Morphosys: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Research Funding.