Habermann, Thomas M.

Abstract Abstract 1525 Background: Nodular lymphocyte predominant Hodgkin Lymphoma (NLPHL) is a more indolent form of Hodgkin Lymphoma that is usually associated with favorable outcomes. However, a number of reports have shown a tendency of transformation to more aggressive types of lymphoma, typically diffuse large B-cell lymphoma (DLBCL). Long-term data on the incidence and outcomes of transformed NLPHL is lacking in the literature. The aim of this study was to evaluate incidence, risk factors and outcomes of DLBCL transformation in NLPHL in a cohort of patients followed at a single institution. Methods: The actively maintained Mayo Clinic Lymphoma Database includes all consenting consecutive patients with lymphoma seen at Mayo Clinic Rochester. This was used to retrospectively identify patients with NLPHL. The study was approved by the Institutional Review Board. Pathology was reviewed by a hematopathologist and all transformations were histologically confirmed by WHO criteria. The clinical characteristics, therapy and outcomes of patients with NLPHL and DLBCL transformation were analyzed. The chi-square test was used to compare variables. Risk of progression was calculated using a person-year approach. Survival and freedom from transformation were estimated and compared using the Kaplan Meier method and log rank tests, respectively. Results: Between 1970 and 2010, 222 consecutive adult patients with NLPHL were identified. The median follow-up was 20 years. Of these, 17 (7.7%) developed a transformation to DLBCL during the course of the disease (Figure 1). The median time to transformation was 35 (6–248) months. Of these 17 patients, 13 (76.5%) were male, 11 (64.7%) had stage I/II and 6 (35.3%) had stage III/IV NLPHL. Transformation was the first relapse in most patients (12 patients, 70.6%) while five patients (29.4%) developed one or more relapses of NLPHL before transformation. Prior therapies for NLPHL were as follows: radiation therapy in 5 (29.4%), chemotherapy in 5 (29.4%) and combined chemotherapy and radiation in 6 (35.3%) patients. The median age at transformation was 45 years (30–87). Most patients (10 patients, 58.8%) presented with signs (palpable lymph nodes) or “B” symptoms. Eight patients (47.1%) had stage III/IV disease at the time of transformation. The most commonly used regimens for treatment of DLBCL were R-CHOP or CHOP (9 patients, 52.9%). Platinum based therapy was administered in 4 (23.5%) patients. Five patients (29.4%) required more than one line of therapy, and autologous stem cell transplant was utilized in two (11.7%) patients. Based on the observed 17 transformations during 2304 patient-years of follow-up, the rate of transformation was 0.74 per 100 patient-years. The five-year overall survival (OS) of patients with transformed disease (calculated from time of transformation) was 76.4%. The most common cause of death was lymphoma (75%). Following treatment for transformation, 5 patients (29.4%) relapsed. The OS in transformed patients was independent of prior therapies, and transformation did not adversely affect overall survival in our cohort (median survival of in 129 months in transformed versus 120 in non-transformed patients, P=0.33). In a univariate analysis of prior therapies, use of radiation therapy was associated with a significant delay in time to transformation (P= 0.0035) (Table 1, figure 2). Conclusions: The risk of transformation in NLPHL is 0.74% per year in this large single institution case series of NLPHL, and appears to be lower than that observed in follicular and other types of low grade lymphoma. The outcomes of patients with transformation were significantly better than reported in other types of transformed lymphoma and did not adversely affect OS. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1563 Intro: Optimal treatment for non-follicular low grade B-cell lymphoma (NFLGL) is not well defined. Clinical trial design for these subtypes would be enhanced by further understanding of early presentation and management. A large prospective observational study was used to identify presenting clinical features, describe patterns of care and compare the prognostic utility of International Prognostic Index (IPI) and the Follicular Lymphoma International Prognostic Index (FLIPI). Methods: The University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) is a prospective, longitudinal observational study designed to collect information on patterns of care and outcomes for patients with newly diagnosed lymphoma. Patients seen at the Mayo Clinic, Rochester MN and the University of Iowa within 9 months of their initial diagnosis of lymphoma are offered enrollment. Baseline patient reported data, clinical data and initial management are collected using a standard protocol and a central pathology review is performed. After enrollment, patients are actively followed for events (disease progression, retreatment, and death) and disease related comorbidities. This analysis includes 198 patients diagnosed with extranodal marginal zone (EMZL), 22 with nodal marginal zone (NMZL), 47 with splenic marginal zone (SMZL), 48 with lymphoplasmacytic lymphoma (LPL), as well as 67 patients with unclassifiable low-grade B-cell lymphoma (B-NOS). Results: 382 newly diagnosed NFLGBL patients were enrolled in the MER from 2002–2009. The median age at enrollment was 63 years (range 22–95). 52% were male. The most common types of initial therapy after diagnosis were observation (41 %), alkylator- based chemotherapy +/− rituximab (R) (17%), radiation therapy alone (15%) and R monotherapy (13%). At median follow-up of 60 months (range 1–121), 51 patients were deceased and 155 had an event. The clinical characteristics that comprise the IPI and FLIPI were similar across the subtypes. Approximately half of the cases presented at low risk (55% IPI; 48% FLIPI). A majority had a normal LDH (81%), limited nodal involvement (91% had ≤ 4 groups), normal hemoglobin (71% ≥12 g/dL), good performance status (95% 0–1), and advanced stage (57% stages III-IV). There were notable differences among the NFLGBL subtypes. Patients with SMZL and LPL presented with high risk FLIPI of 3–5 (49% and 46% respectively) and high to high-intermediate IPI of 3–5 (21% and 13%). Abnormal LDH and anemia (< 12 g/dL) were more frequent in patients with SMZL (40%; 56%) and LPL (25%; 62%). EMZL presented with lower stages (70% stage I-II) and NMZL presented with increased nodal involvement (38% >4 sites). SMZL had the highest rates of surgical resection (21%) and EMZL was more frequently treated with radiation therapy (25%). LPL (30%) and NMZL (32%) more commonly received alkylator based chemotherapy +/− R. While both IPI and FLIPI differentiated outcome in these patients, FLIPI had higher c-statistics than IPI for both EFS (0.583 vs 0.568) and OS (0.685 vs 0.661), respectively. Conclusions: This large prospective collection of data on NFLGBL patients presenting to academic medical centers provides a modern picture of presentation and management patterns useful to investigators designing clinical trials. FLIPI may have more prognostic utility than IPI in this group of patients. Disclosures: Ansell: Seattle Genetics, Inc.: Research Funding.

Abstract Abstract 1573 Background. Treatment of non-Hodgkin lymphoma (NHL) can lead to the development of cardiovascular disease (CVD). In a previous report, we found that the risk of CVD in patients with NHL diagnosed in the recent treatment era (since 2002) was approximately 1% per year after the initial diagnosis of lymphoma. We evaluated the association of 30 candidate single nucleotide polymorphisms (SNPs) in genes associated with anthracycline-induced cardiotoxicity in children (SLC10A2, SLC28A3, ABCC1, ABCB3, CBR3, FMO2, SPG7) and genes associated with venous thromboembolism (VTE) in adults (ABO, F2/CKPA5, F5, F11, KLKB1, SCUBE1, SLC19A, SELP) with the risk of new onset cardiovascular disease in a cohort of NHL patients. Methods. All patients were from the Mayo component of the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE, and were enrolled from 2002–2008. The MER offers enrollment to all consecutive patients with newly diagnosed NHL who are US residents and age >18 years. Clinical data from the time of diagnosis and treatment data are abstracted from medical records using a standard protocol. Patients are prospectively contacted via telephone or in person per protocol every 6 months for the first 3 years from diagnosis and yearly afterwards to assess disease status and development of comorbid conditions. CVD events, including heart failure (HF), myocardial infarction (MI), arrhythmia, pericarditis, and valvular heart disease, occurring after diagnosis were identified during follow-up and validated against medical records. HF was validated with the Cardiovascular Health Study Criteria and/or the Framingham Criteria. MI was validated using case definition standards of coronary heart disease, while arrhythmia, pericarditis, and valvular heart disease were validated using clinical definitions. Genotyping was conducted using a custom Illumina iSelect platform. Cox regression was used to estimate Hazard Ratios (HRs) and 95% confidence intervals (CI) for individual SNPs with time to CVD, with death modeled as a competing risk. Each SNP was modeled with the most prevalent homozygous genotype used as the reference group, and each SNP was modeled as having a log-additive (per minor allele) effect in the regression model. An ordinal test was used to assess the trend, and p<0.05 was considered statistically significant. Results. There were 805 newly diagnosed NHL patients with no history of CVD at time of lymphoma diagnosis and had genotype data available for analysis. The median age at diagnosis was 61 years (range, 21–93) and 53% were male. The most common subtypes were follicular lymphoma (33%), diffuse large B-cell lymphoma (29%), and marginal zone lymphoma (14%). Anthracycline-based chemotherapy as initial therapy or at re-treatment was used in 51% of the patients and radiation therapy was used in 18%. Median follow-up of all cases was 59 months (range, 1–105). There were 36 incident CVD events (4.5%) and 139 deaths (17%). The most common CVD events were arrhythmia (N=17) and heart failure (N=14). There was no association with any of the anthracycline-induced cardiotoxicity genes and risk of CVD overall or in the subgroup of patients (N=406) who received an anthracycline. Of the venous thromboembolism (VTE) SNPs, rs4253399 in F11 (coagulation factor 11) with a minor allele frequency of 0.39 was associated with risk of CVD (HR=2.14; 95%CI 1.35–3.40; p=0.001). When restricted to anthracycline-treated patients, the HR for rs4253399 became stronger (HR=2.56; 95%CI 1.39–4.72; p=0.003), and an ABOSNP (rs660340) with a minor allele frequency of 0.43 became significant (HR=2.14; 95%CI 1.13–4.04; p=0.02). Conclusions. This is the first report that genes involved in VTE also predict CVD risk in NHL patients, particularly those treated with anthracycline chemotherapy. However, SNPs from genes previously associated with anthracycline-induced cardiotoxicity were not associated with CVD risk in this cohort, although those SNPs were identified in children and may not apply to adults. Future research will need to validate these findings and identify additional genetic markers that can be incorporated into risk assessment for CVD in this patient population. Disclosures: No relevant conflicts of interest to declare.

Abstract BACKGROUND: Diffuse large B-cell lymphoma, not otherwise specified (DLBCL), though defined as one disease entity, consists of two main cell-of-origin (COO) subtypes, germinal center B-cell like (GCB) and activated B-cell like (ABC), with the latter predicting a significantly worse prognosis using conventional chemotherapy. Up to 40% of all patients diagnosed with DLBCL will experience relapse, and outcomes are generally poor in this setting. In this study, we examine the proportion of GCB vs. non-GCB subtypes at initial diagnosis and at time of relapse, and assess the incidence of reclassification from one subtype to another. 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. All relapse events were validated by review of the medical record. This analysis includes patients diagnosed with DLBCL who underwent initial treatment and subsequently experienced relapse as confirmed by biopsy. Immunohistochemical staining data including CD10, Bcl-6, and Mum-1, were collected from available pathology reports and classified to either GCB or non-GCB subtypes as predicted by the Hans algorithm. We compared subtype classification and individual immunohistochemical data both at the time of diagnosis and relapse. The overall subtype agreement between the two diagnostic time points was assessed. RESULTS: 1023 patients with newly diagnosed DLBCL were enrolled in the MER from 2002 - 2012. Of those, 249 had documented disease relapse. Of those analyzed, a total of 43 patients had COO classification based on the Hans algorithm from tissue biopsy at both diagnosis and relapse. Thirty patients were characterized as GCB DLBCL on initial presentation, and upon relapse 28 were noted to be GCB, while 2 were noted to be the non-GCB subtype. Of the 13 that were characterized as non-GCB on initial presentation, 10 remained non-GCB while 3 were reclassified as GCB. The overall agreement of DLBCL COO phenotypes between initial diagnosis and relapse was 88%. Seven percent of those initially diagnosed as GCB were reclassified as non-GCB subtype; in contrast, 23% of those initially diagnosed as non-GCB had changed to GCB upon relapse. Similar analysis was performed on individual immunohistochemical staining factors including CD10, Bcl-6, and Mum-1, and we observed overall agreement of 88%, 87%, and 91%, respectively. CONCLUSIONS: A majority of patients with relapsed DLBCL exhibit similar COO phenotypes at initial presentation and at relapse, and the incidence of reclassification from one subtype to another is uncommon. This suggests that the initial treatment regimen for DLBCL rarely alters the basic cancer phenotype when immunohistochemistry laboratory technical factors and pathologist interpretive discrepancies are excluded as causes for this change. However, reclassification from GCB to non-GCB subtypes is observed in a minority of cases, which may affect the overall outcome and response to treatment. Further studies are needed using gene expression to categorize COO and to examine the factors surrounding the time of relapse for possible harbingers of relapse as well as the behavior and outcome of reclassified DLBCL. Table Table. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.

Abstract Background Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma (NHL) with heterogeneous outcomes and remains largely incurable. Immunochemotherapy (IC) continues to be the standard therapy backbone in the frontline and relapsed settings, though novel agents are increasingly used and investigated. Lenalidomide is an immunomodulatory molecule with known single-agent activity in relapsed lymphoma. It is also active in the frontline setting and has been reported to be effective and tolerated in upfront combination regimens in FL (Fowler et al, Lancet Oncol. 2014, 15(12):1311-8). Here we report our experience with frontline use of R2CHOP (lenalidomide in combination with R-CHOP) in patients with FL. Methods A phase 1/2 study of R2CHOP was conducted in NHL patients with primarily diffuse large B-cell lymphoma (DLBCL). While the phase 2 study was focused on DLBCL patients, treatment-naive patients with stage II-IV, histologically-confirmed FL (grades 1, 2, and 3a) meeting criteria for therapy were eligible for the phase 1 part of the study. Additionally, FL patients were identified in the phase 2 portion of the study after central pathology review. These patients were allowed to complete therapy and were followed accordingly. Treatment consisted of 6 cycles of R2CHOP with lenalidomide given on days 1-10 and R-CHOP given in 21-day cycles. All patients received pegfilgrastim and aspirin (if not on anticoagulation) along with other supportive measures per provider discretion. Primary objectives were safety assessment and efficacy. Results Ten patients with FL (3 had grade 1, 3 had grade 2, and 4 had grade 3a) were enrolled in the R2CHOP phase 1/2 study at Mayo Clinic. One patient was in the phase 1 arm at dose level 2 (lenalidomide 20 mg/d) and 9 patients were in the phase 2 arm (lenalidomide 25 mg/d). The mean age was 60.8 years (range: 41-82). Eight out of ten patients were male; 5/10 had ECOG performance status of 0; 5/10 had an IPI score of intermediate or higher. All patients completed 6 cycles of planned treatment. One patient required lenalidomide dose adjustment due to toxicity. There were no lenalidomide dose interruptions. The overall response rate (ORR) was 100% and the complete response (CR) rate defined by PET imaging was 90%. Eight out of ten remain progression-free and 9/10 are alive at a median follow-up of 4.6 years (range: 2.1-5.3). Estimated progression-free survival (PFS) at 5 years was 79% (95% CI: 56-100%). The main toxicity was reversible myelosuppression with 80% treatment-related hematologic grade 3 or higher adverse events (AEs) (leukopenia 80%, neutropenia 80%, thrombocytopenia 40%, anemia 20%, transaminitis 20%). Rate of nonhematologic grade 3 or higher AEs was 20% (fatigue 10%, pneumonia 10%). Conclusions Frontline therapy with R2CHOP in patients with untreated FL appears to be effective and associated with acceptable toxicity. The observed PET-based CR rate and PFS were promising in this cohort. Whether R2CHOP is superior to lenalidomide/rituximab alone or standard bendamustine/rituximab will require randomized studies. Figure Estimated PFS in FL patients treated with upfront R2CHOP. Figure. Estimated PFS in FL patients treated with upfront R2CHOP. Disclosures Reeder: Celgene: Research Funding; Novartis: Research Funding; BMS: Research Funding; Millennium: Research Funding. Foran:novartis: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; pfizer: Honoraria; karyopharm: Honoraria; medscape: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Nowakowski:Bayer: Consultancy, Research Funding; Morphosys: Research Funding; Celgene: Research Funding.

Abstract Background: The combination of MPD and amyloidosis is rare, and this patient population's clinical outcome is not well studied. Methods: Pts with a MPD and amyloidosis were identified via an clinical note search engine that searches through the electronic medical records of patients seen at Mayo Clinic Rochester, Jacksonville, and Scottsdale between 1990 and 2016. Terms used included amyloid or amyloidosis, chronic myelogenous leukemia or CML, essential thrombocytopenia or ET, and polycythemia vera or PV. Demographic and clinical data were abstracted from the medical record. Pts with both disorders were analyzed and their mortality rates along with median time to death were calculated. Prevalences at the Mayo Clinic were calculated for the years 2014 and 2015. Results: Twenty-three pts diagnosed with both a MPD and amyloidosis were identified. Thirteen (56.5%) were male, 10 (43%) were female. Eleven (47.8%) were initially diagnosed at the Mayo Clinic. Types of amyloidosis were as follows: Eleven (47%) had immunoglobulin light-chain (AL), four had localized (17%), two (8.7%) had wild-type transthyretin (ATTR), one (4.3%) had mutant ATTR, and five (21.8%) were unknown. Types of MPD were as follows: Seven (30%) had polycythemia vera (PV), seven (30%) had chronic myelogenous leukemia (CML), five (22%) had myelofibrosis, and four (17%) had essential thrombocytosis (ET). Fifteen (65%) were initially diagnosed with a MPD. Median time to last follow-up from second diagnosis was 1.7 years, and median time to death following second diagnosis was 1.4 years. The mortality rate was 87% in the total population. The median time to death for AL and PV was 2.7 years, AL and CML 1.0 years, and AL and ET 1.17 years. Myelofibrosis did not occur with AL. The most common combination was AL and PV, which accounted for five (22%) of the cases. Treatment regimens for the patients with AL were varied. Multiple drugs were combined with dexamethasone including melphalan, velcade, pomalidomide, lenalidomide, doxorubicin, and revlimid. Cyclophosphamide, bortezomib, and dexamethasone (CyBorD) were used in two cases. The mean time to diagnosis of amyloidosis from symptom onset was 10.3 months. Prevalences of AL and a MPD in 2014 and 2015 at the Mayo Clinic were 2.8% and 1.5%, respectively. Conclusions: The mortality rate for the combined diagnoses is high. The most common combination of diagnoses was that of AL and PV, which was associated with a mean time to death of 2.7 years. Disclosures Al-Kali: Celgene: Research Funding; Onconova Therapeutics, Inc.: Research Funding.

Abstract The anti-CD20 monoclonal antibody rituximab (R) is widely used to treat B-cell malignancies including follicular lymphoma (FL). A better understanding of activity and resistance mechanisms is necessary for improving treatment outcomes. We previously reported that genetic variants in the complement pathway are associated with event-free survival of FL patients following R therapy. This correlation was particularly high for SNP rs3766404, located in intron 6 of Complement Factor H (CFH). Subjects with the minor allele of this SNP experienced inferior event-free survival. Five CFH related proteins (CFHR1-5) share a similar and sometimes overlapping function with CFH, including suppression of complement activation. Genetic variations within the CFH family locus are linked to a variety of complement-mediated disorders such as age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome. Interestingly, AMD patients with the minor allele of rs3766404 frequently have deletion of CFHR3 and CFHR1, suggesting that loss of these proteins functionally impacts complement regulation. The current studies were designed to better understand the relationship between R therapy of FL and CFH family proteins. CFH and CFHR1 protein levels were quantified in serum samples from both normal subjects (n=59) and FL (n=108) subjects from the Iowa/Mayo Lymphoma SPORE Molecular Epidemiology Resource. No correlation was observed between the quantity of CFH in serum and SNP genotype in either cohort. However, in both cohorts, individuals homozygous for the minor allele in SNP rs3766404 lacked detectable expression of CFHR1. Homozygotes for the major allele expressed the highest levels of CFHR1, and heterozygotes expressed intermediate levels. Among FL subjects treated with R as a component of initial therapy, increased levels of CFHR1 were associated with improved event-free survival (hazard ratio 0.48, 95% confidence interval 0.28-0.82, p=0.0051). In contrast, CFHR1 levels had no impact on outcome among the FL subjects who did not receive R as a component of initial therapy. This subset of FL subjects included those observed off therapy. The effect of CFHR1 levels on outcome for those subjects treated with R versus those not treated with R was statistically different (p=0.0023 based on a Cox proportional hazard model). There was no correlation between CFH levels and outcome in any population. CFHR1 binds the complement component C3b, inhibiting downstream complement activation. We previously demonstrated that complement can inhibit R activity in vitro. Specifically, C3b deposition can have a negative impact on antibody–mediated tumor cell killing by interfering with R-induced NK cell activation and antibody dependent cellular cytotoxicity. Our current finding that higher CFHR1 correlates with improved outcome following R therapy provides further evidence that the effect of complement on therapeutic monoclonal antibodies is complex. These findings may have implications for predicting response to, and optimization of, anti-CD20 and other antibody therapies. Ongoing studies are exploring this possibility in additional patient cohorts, the potential role of other CFH family members, and the underlying biology associated with these observations. Disclosures: Link: Genentech: Consultancy; Millenium: Consultancy; Pharmacyclics: Consultancy; Spectrum: Consultancy; Genentech: Research Funding; Millenium: Research Funding; Pharacyclics: Research Funding.

Abstract Background. Diffuse large B-cell lymphoma (DLBCL) is curable for the majority of patients treated with anthracycline based immunochemotherapy (IC). While most patients achieve response to initial therapy, a subset of patients are refractory to initial IC or become refractory to subsequent salvage therapies. Prognosis in this setting is very poor. Here we determine the incidence of refractory disease from a large cohort of DLBCL prospectively followed from diagnosis in the IC era and assess outcomes in these patients. Methods. Patients were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) within 9 months of diagnosis. Patients were followed for relapse, retreatment, and death; all events were validated by medical record. This analysis includes patients with DLBCL or primary mediastinal B-cell lymphoma (PMBCL) who received initial treatment of anthracycline based immunochemotherapy; patients with primary CNS lymphoma or post-transplant lymphoproliferative disorders were excluded. Response to therapy was retrospectively classified per 2007 Revised Response Criteria for Malignant Lymphoma from available clinical and radiology records. Refractory disease was defined as having a best response to any systemic therapy of stable disease (SD), progressive disease (PD), or relapse within 12 months of autologous stem cell transplantation (SCT). We also examined patients with transient response to IC as defined by achieving an interim response (CR or PR) but having progressive disease at or prior to the end of the planned number of cycles of IC. Results. 1039 patients with DLBCL or PMBCL lymphoma were enrolled in the MER from 2002-2012 and treated with R-CHOP or comparable IC. Median age at diagnosis was 62 years (range 18-91) and 577 (56%) were male. At a median FU of 60 months (range 1-148), 136 patients developed refractory disease. The median age at diagnosis of patients with refractory disease was 62 years (range 19-87). The cumulative incidence of refractory DLBCL was 11.3% at 2 years (95%: CI: 9.5-13.4) and 13.1% at 5 years (95% CI: 11.2-15.4). The median overall survival after becoming refractory was 4.7 months (95% CI: 4.1-5.5) with a 1 year survival rate of 21% (95% CI: 15%-30%). The median number of therapies before becoming refractory was 2 with 35 patients becoming refractory following their first therapy (i.e. IC), 83 patients becoming refractory after their 2nd therapy, and 23 patients becoming refractory after their 3rd or later therapy; 27 patients had received stem cell transplant prior to becoming refractory. Outcomes were poor regardless of when patients became refractory (figure). Patients received a median (range) of 2 (0-8) treatments after becoming refractory with 40% (N=54) attempting subsequent platinum based salvage therapy and 14% (N=9) proceeding to ASCT, of which only 6 remain alive in long-term remission. 41 patients (30%) were treated on clinical trials after becoming refractory. Response rate for the first therapy after becoming refractory was 21%, while 29% of patients had a response to any subsequent therapy. Once patients became refractory, there was no difference in survival based on response at end of initial IC (p=0.33), cell of origin at diagnosis (p=0.64), IPI at diagnosis (p=0.33), or age when refractory (p=0.66). Outcomes in patients with transient response to IC (n=58) were poor, with the majority (N=37, 63%) becoming refractory to subsequent therapy. Median OS after first relapse was 6.7 months in patients with transient response to IC, which was equivalent to patients refractory to IC (p=0.99). The majority of patients with transient response to IC (69%) were next treated with platinum based salvage therapy which had a response rate of 40%. Ultimately 15 of the 58 patients (26%) proceeded to transplant, of which only 5 (9%) achieved long-term remission. Conclusions. Approximately 13% of patients with DLBCL become refractory to treatment in their disease course. Outcomes once patients become refractory are extremely poor regardless of when patients become refractory. Standard prognostic factors are no longer predictive of outcome and stem cell transplant had limited benefit in this group of patients. Patients with transient response to initial immunochemotherapy should be included when classifying patients as refractory. New therapy strategies are needed in the refractory setting. Figure 1. Figure 1. Disclosures Maurer: Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding. Farooq:Kite Pharma: Research Funding. Cerhan:Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding.

Abstract Introduction Outcomes have improved in treating lymphoid malignancies but relapse remains an ongoing issue. The mTOR inhibitor, everolimus (RAD) and lenalidomide (LEN) have both shown clinically significant activity as single agents in patients with relapsed and refractory (R/R) Hodgkin (HL) and non-Hodgkin (NHL) lymphomas. The low toxicity and differing mechanisms of action were explored further by combining these active agents. A phase I/II clinical trial of the mTOR inhibitor everolimus (RAD) and lenalidomide (LEN) was designed to explore the tolerability, toxicity and to determine the MTD of this combination for Phase II study. The phase I data is reported here. Methods This Phase I/II trial for patients with R/R lymphoid malignancy opened at Mayo Clinic between January 2011 and May 2013 and utilized a standard cohort of 3+3 design to determine the MTD of the combination. Eligibility required age≥18, biopsy proven relapsed or refractory NHL or HL, ECOG PS 0, 1 or 2, measurable disease, Hb >9g/dl, ANC ≥1200/uL, platelet ≥ 50,000/uL, creatinine ≤1.5xULN and willingness to sign informed consent. Women of child bearing potential had pregnancy testing and all patients followed recommendations for contraception. Dose limiting toxicity was defined in cycle 1 as Gr 4 neutropenia ≥7days or platelets ≤ 25,000 ≥7days, grade 4 infection or grade ≥3 non-Heme toxicity at least possibly related to treatment per CTCAE v4.0. The starting dose (level 0) was RAD 5mg daily + LEN 10 mg/d X 21d in a 28-day cycle. Results Twenty-five patients were enrolled on the phase I portion and 23 are evaluable for analysis. The median age was 63 years (23-82) and 18 (78%) were male. Sixty-five percent had stage IV disease and 43% had 4 or more prior treatments (1- ≥5) including stem cell transplantation in 39%. Histologies included HL (n=3) and NHL (n=20)(DLBCL = 11, FL-III = 2, LPL = 3, MCL = 1, MF = 1, and other = 2). Two DLTs (rash, Gr4 neutropenia) were reported at the starting dose (level 0) and the protocol was amended for DLT definition change. At dose level -1 (RAD 5mg daily + LEN 5mg/d X 21d) a DLT (Gr4 neutropenia) was seen in only 1 of 6 patients so the study was re-opened to dose level 0 and 3 additional patients were treated without developing a DLT. At dose level +1 (RAD 5 mg daily + LEN 15mg/d X 21d) 1 Gr3 rash occurred and 2 patients experienced Gr4 neutropenia. Therefore the MTD was determined to be RAD 5mgdaily + LEN 10 mg/d X 21d. At least 1 Gr≥3 adverse event was seen in 91% of patients. The most common Gr≥3 toxicities were neutropenia (57%), leucopenia (52%), thrombocytopenia (39%), fatigue (22%), and anemia (13%). Eight of 23 patients (35%) had Gr≥3 infection. Five patients discontinued study due to adverse events. One death on study occurred due to disease progression. Three patients continue on therapy. Responses have been seen in 4 patients and 10 patients have stable disease, encouraging signs in this heavily pretreated population. Conclusions This phase I/II trial of everolimus and lenalidomide in malignant lymphoma shows the combination to be tolerable with neutropenia as the main dose limiting toxicity. The MTD of this combination is RAD 5mg daily and LEN 10 mg/d X 21 d. Encouraging responses were seen. The phase II study has opened with 2 patients accrued to date. Updated results will be presented. This trial is sponsored by Novartis and Celgene Disclosures: Reeder: Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding. Off Label Use: lenalidomide and everolimus are not approved for treatment of lymphoma. Nowakowski:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Witzig:Celgene: 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.