Habermann, Thomas M.

Abstract The peripheral blood absolute lymphocyte/monocyte ratio at diagnosis (ALC/AMC-DX) predicts survival in diffuse large B-cell lymphoma (DLBCL). However, a limitation of the ALC/AMC-DX is its inability to sequentially assess the host/tumor interaction during treatment. Therefore, we studied the ALC/AMC ratio, as a surrogate marker of host immunity (i.e., ALC) and tumor microenvironment (i.e., AMC), at each RCHOP treatment cycle as a predictor for clinical outcomes. From 2002 until 20011, 107 DLBCL patients originally diagnosed, treated with six cycles of RCHOP, and followed at Mayo Clinic qualified for the study. Using the receiver operating characteristic and internally validated using the k-fold cross validation; an ALC/AMC ratio ≥ 1.1 was identified as the cut-off value at each RCHOP treatment cycle to discriminate for the binary clinical outcome of death/survival. Univariate analysis revealed the ALC/AMC ratio ≥ 1.1 at each RCHOP treatment cycle was a predictor for overall survival (OS) and progression-free survival (PFS). To explore whether the patterns of ALC/AMC ratio recovery during the RCHOP treatment cycles had a prognostic value, we performed an unsupervised hierarchical clustering on the studied ALC/AMC ratio and identified four patient clusters, A-D. Eighty percent of patients in cluster C had an ALC/AMC ratio ≥ 1.1 during all the cycles, the other 20% had an ALC/AMC ratio ≥1.1 in one cycle; in cluster D patients, the ALC/AMC ratio was ≥ 1.1 between cycles 2 and 5 and none had an ALC/AMC ratio < 1.1; in cluster A patients, 73% of patients only had an ALC/AMC ratio ≥ 1.1 in one cycle and 27% in two cycles; and cluster B patients had 85% of patients with an ALC/AMC ratio < 1.1 during all the cycles. Inferior OS and PFS were progressively observed in clusters of patients with fewer cycles achieving an ALC/AMC ratio ≥ 1.1. Patients in clusters C had superior outcomes compared with patients in clusters B. Thus, we dichotomized patients into patients with an ALC/AMC ratio ≥ 1.1 during any cycle versus patients with an ALC/AMC ratio < 1.1 during all cycles. By multivariate analysis, the stratification of patients into ALC/AMC ≥ 1.1 during any cycle versus ALC/AMC < 1.1 during all cycles was an independent predictor for OS [Hazard ratio (HR) = 0.02, 95% CI (0.006-0.08), p< 0.0001], and PFS [HR = 0.06, 95% CI (0.02-0.15, p< 0.0001] when compared with the International Prognostic index The median OS for patients with an ALC/AMC ratio ≥ 1.1 during any cycle versus patients with an ALC/ACM ratio < 1.1 during all cycles was not reached versus 1.7 years with 5 years OS rates of 97% (95% CI, 90%-99%) versus 0%, p< 0.0001, respectively. The median PFS for patients with an ALC/AMC ratio ≥ 1.1 during any cycle versus patients with an ALC/AMC ratio < 1.1during all cycles was not reached versus 0.9 years with 5 years PFS rates of 83% (95% CI, 72%-90%) versus 0%, p< 0.0001, respectively. The ALC/AMC ratio during RCHOP treatment cycles is a predictor for survival and provides a platform to develop therapeutic modalities to manipulate the ALC/AMC ratio during chemotherapy to improve clinical outcomes in DLBCL. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction Approximately 2-8% chronic lymphocytic leukemia (CLL) patients develop diffuse large B-cell lymphoma (DLBCL, so-called Richter syndrome [RS]) over long-term follow-up. The outcomes of patients with RS are variable and poorly understood. Methods CLL patients seen at Mayo Clinic from January 1995 to April 2013 who developed biopsy-proven DLBCL during follow-up were included in this analysis. Clinical characteristics, therapy and overall survival (OS) of all patients with RS were analyzed. Results One hundred and twenty patients with biopsy-proven RS were identified in the Mayo Clinic database. The median age at diagnosis of RS was 67 years (range, 29-88 years), 87 (73%) were male, and 83 (69%) had received prior CLL therapy. The median duration between diagnosis of CLL and development of RS was 3.8 years (range, 0-34.5 years). Stereotyped B-cell receptors were found in 9/30 (30%) RS patients compared to 219/1294 (17%) non-RS patients (OR=2.1, p=0.07). IGHV4-39 gene usage was present in 2/26 (8%) RS patients compared to 57/1354 (4%) non-RS patients (p=0.3). Of the 30 RS biopsy samples in which Epstein Barr virus (EBV) in-situ hybridization studies were performed, EBV was detected in 7 (23%) patients. After a median follow-up of 5.2 years, 86 (72%) patients have died. Causes of death were as follows: progressive DLBCL (n=46, 53%), progressive CLL (n=2, 2%), infection (n=8, 9%), unknown (n=20, 23%) and other (n=10, 12%). The median OS of the entire cohort was 0.9 years (95% CI, 0.5-1.3 years). Tsimberidou and colleagues proposed a prognosis score (RS score) based on the following variables at the time of RS diagnosis: Eastern Co-operative Group performance status of 2-4, lactate dehydrogenase >1.5 x normal, platelets<100 x 109/L, tumour size >5 cm and >1 prior therapy for CLL. Each parameter was assigned one point, and patients were then assigned to one of four risk groups based on their calculated RS score: 0 or 1, low risk; 2, low-intermediate risk; 3, high-intermediate risk; 4 or 5, high risk. The OS according to the RS score for our group of patients is shown in Figure 1. Median survival in the low, intermediate-1, intermediate-2 and high-risk groups were 2.4 years, 0.7 years, 0.3 years and 0.2 years, respectively (p<0.001). Fifteen (12%) patients received cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) as initial therapy for RS, and 68 (57%) received rituximab in addition to CHOP (R-CHOP). There was no difference in survival among patients who received CHOP compared to R-CHOP (median, 1.8 years. vs. 1.2 years, p=0.5). Twenty-four patients (20%) received non-CHOP-based chemotherapy, and treatment was unknown in 4 (3%) patients. Nine patients (7%) died before definitive therapy could be instituted. Thirteen (11%) patients were able to proceed to stem cell transplantation (SCT): 10 (8%) autologous SCT, 2 (2%) allogeneic SCT and 1 (1%) autologous SCT followed by an allogeneic SCT. Although RS patients who underwent SCT were younger compared to those who did not undergo SCT (median, 59 years. vs. 69 years, p=0.001), no differences in prior CLL therapy or receipt of R-CHOP therapy for DLBCL was noted between the two groups. The median survival of patients who proceeded to SCT was superior compared to those who did not (5.2 years vs. 0.7 years; p=0.005). Conclusion Stereotyped B-cell receptors but not VH4-39 had a suggested evidence of an increased risk of RS in our cohort. Although 90% RS patients received intensive chemotherapy, only 11% patients were able to proceed to SCT. Median survival of RS patients remains dismal at 1 year, and newer therapies are needed to improve outcomes. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding.

Abstract The lymphocyte-to-monocyte ratio at diagnosis (LMR-D) has been reported to be a prognostic factor for clinical outcomes in both T-cell and B-cell lymphomas. However, there are no reports testing the prognostic ability of LMR-D in patients diagnosed with de novo double/triple hit diffuse large B cell lymphoma (DLBCL). Thus, we set out to investigate if the LMR-D is a prognostic factor for survival in de novo double/triple hit lymphomas. From 10/5/1998 until 1/16/2015, thirty-four patients with de novo double/triple hit DLBCL were identified for this study. Double and triple hit were defined by interphase FISH evaluating three fusion signals to identify the BCL2 translocation and IGK/MYC D-FISH probe to identify whether the partner is IG or non-IG. Interphase fluorescence in situ hybridization (FISH) was performed on paraffin sections using probes that included 8q24 (5'MYC, 3'MYC); t (2;8), IGK/MYC; t(8,14), MYC/IGH; t(8;22), MYC/IGL; 3q27 (3'BCL6, 5'BCL'6); and 18q21 (3'BCL2, 5'BCL2). The cohort included 14 females and 20 males. The median follow-up for the cohort was 9.0 months (range: 0.4-72.6 months). Using the median for the LMR-D as the cut-off value, patients with a LMR-D ≥ 1.2 experienced superior overall survival (OS) [Hazard ratio (HR) of 0.127, 95% confidence interval (CI) of 0.019-0.530, p < 0.004] and progression-free survival (PFS) [HR of 0.107, 95 CI of 0.024-0.335, p < 0.0001]. The median follow up for OS for patients with a LMR-D ≥ 1.2 was not reached with a 5-year OS rate of 82% (95% CI of 49%-95%) compared with a median follow-up of 10 months for patients with a LMR-D < 1.2 with a 0% 5 year OS rate, p < 0.003 (Figure 1A). The median PFS for patients with a LMR-D ≥ 2 was not reached with a 5 years PFS of 74% (95%CI, of 43%-91%) compared with a median follow-up of 4.7 months for patients with a LMR-D < 1.2 and 0% 5 year PFS rate, p < 0.0001 (Figure 1B). After adjusting for the International Prognostic Index, multivariate analysis showed that the LMR-D remained an independent prognostic factor for OS [HR = 0.180, 95% CI of 0.254-0.784, p < 0.02] and for PFS [HR of 0.127, 95%CI of 0.029-0.409, p < 0.0003]. In spite of the small cohort of de novo double/triple hit DLBCL, the LMR-D was identified as a prognostic factor for clinical outcomes for this specific set of aggressive lymphomas. Further studies are warranted to confirm our findings. Table.LMR-D ≥ 1.2, N = 18Events = 2LMR-D < 1.2, N = 16Events = 8P < 0.003LMR-D ≥ 1.2, N = 18Events = 3LMR-D < 1.2, N = 16Events = 14P < 0.0001Figure 1AB Figure 1. Figure 1. Disclosures Maurer: Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Off Label Use: New agent in a combination regimen..

Abstract Background Rituximab in combination with chemotherapy has been shown to improve overall survival (OS) in pts with FL compared with chemotherapy alone. The effect of MR was evaluated in randomized clinical trials (RCTs) with conflicting results regarding OS. In a previous systematic review and meta-analysis of summary (aggregate) data we demonstrated an OS benefit of MR treatment in pts with relapsed or refractory FL and an improved progression free survival (PFS) in both untreated and relapsed refractory FL. However, pts' disease and treatment characteristics may interact with the effect of MR. To improve identification of sub-groups of pts who may benefit from MR treatment, and to evaluate factors that interact with the effect of MR we conducted an international IPD (raw data) meta-analysis of RCTs of MR for pts with FL. We present the first analysis of this meta-database. Methods In June 2014, we updated an electronic search in Pubmed and the Cochrane Library, conference proceedings and database of clinical trials for randomized trials comparing MR to observation. The investigators of eleven trials that fulfilled inclusion criteria were invited to cooperate. Results of one trial were not reported and this trial could not be included in the meta-analysis. Seven study groups participated in this collaborative project and contributed data on individual pts, including disease characteristics, past treatment, response, survival and adverse events. We examined the effect of pt, disease and treatment characteristics by performing a series of Cox regression analyses stratified by trial. In a sensitivity analysis we combined the assessed log hazard ratios (HR) using a log-rank test for each study and combined the results using a fixed effect meta-analysis. Results We obtained data for 2323 patients randomized in 7 trials of MR compared to observation after induction therapy. The median follow up ranged from 28-114 months. The median age was 57 years (23 - 85 years), and 41% were older than 60 years. 50% of pts were women, 97% had WHO performance status 0-1; 1195 (53%) pts received CHOP/RCHOP, 453 (20%) CVP/R CVP; 1755 (77%) received rituximab containing induction; 33% of pts received 1st induction, 67% ≥2nd. Overall, pts less than 60 years of age (vs. ≥60 years) (p < 0.0001), and women (p = 0.001) had a better prognosis. There was no interaction between sex and the effect of MR (p = 0.65). Pts treated with MR had an improved OS compared to observation (HR 0.76, 95% CI 0.62-0.93, p=0.008, Figure). This was demonstrated also in a sensitivity analysis of 10 studies fulfilling inclusion criteria. There was no statistically significant heterogeneity of treatment effect between trials (p=0.15). In an analysis by treatment line (1st vs. ≥2nd), the estimated effect of MR among patients who received ≥2nd induction was HR of 0.70 (95% CI 0.55 - 0.91), compared to 0.90 (95% CI 0.65 - 1.25) among patients who received 1st induction. However, this difference was not statistically significant (p=0.25). Analysis by the inclusion of rituximab in induction demonstrated among patients who received rituximab in induction a HR of 0.82 (95% CI 0.63 – 1.06), and among those who received induction without rituximab a HR of 0.68 (95% CI 0.49 – 0.93). This difference was not statistically significant (p= 0.35). Analysis by chemotherapy regimen demonstrated an estimated effect for MR among patients who received RCHOP/CHOP of 0.79, 95% CI 0.58 – 1.06, and after RCVP/CVP of 0.65, 95% CI 0.42 – 1.02, with no statistically significant difference between these sub-groups (p = 0.50). Conclusions This is the first report of the collaborative group of maintenance therapy for FL patients. Based on individual patient data, this study demonstrated an improved OS with MR therapy for patients with FL. A sensitivity analysis with all 10 eligible trials supported these results. Results support the effectiveness of MR among patients after their 1st induction as well as after ≥2nd induction, and irrespective of inclusion of rituximab in induction, and the chemotherapy regimen. These results are consistent with those of the summary data meta-analysis that was previously published. The wider CI and lack of statistical significance within sub-groups could be attributed to the sample size. Figure: Pooled HR of death of MR compared to observation in patients with follicular lymphoma. In one study there were no events in one group and it is not represented in the forest plot. Figure:. Pooled HR of death of MR compared to observation in patients with follicular lymphoma. In one study there were no events in one group and it is not represented in the forest plot. Disclosures Vidal: Roche: unrestricted grant Other. Shpilberg:Roche: Consultancy, Research Funding.

Abstract Background: The salivary gland is one of the most common sites of involvement by non-gastric extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT). This multicenter, international trial sought to characterize the clinical course, treatment and outcome of patients with salivary gland MALT lymphoma. Methods: Patients were identified from multiple international sites including the Mayo Clinic Lymphoma Database (n=89), three International Extranodal Lymphoma Study Group (IELSG) cohorts (n=138), and the University of Athens (n=21). All patients had biopsy-confirmed MALT lymphoma of the salivary gland by WHO criteria. Clinical characteristics, treatment, and outcomes were obtained from the respective patient databases. Survival probability was estimated using the Kaplan-Meier method and compared between groups with the Wilcoxon or log-rank. The impact of variables on survival was assessed by the Cox proportional hazards model. Results: Patients and clinical features: From 1983 to 2012, 247 patients with MALT lymphoma were included. Clinical characteristics are shown in Table 1. The median age at diagnosis was 59, and the male-to-female ratio was 1:3. The majority of patients (76%) presented with limited stage disease, and the parotid gland was the most common site of involvement (78%). There was a history of antecedent autoimmune disease in 41% of patients, and Sjögren’s disease was the most common (83%). Treatment: Information on initial treatment was available on 242 patients. 137/242 patients (57%) initially received local therapy with either surgery (n=81), radiation (n=26), or both (n=30). Of these, 25 received adjuvant systemic therapy. 90/242 patients (37%) were treated initially with systemic therapy, of whom 54% had localized and 46% had stage IV disease. Rituximab was used alone (n=16) or in combination with chemotherapy (n=26) in 42 of the 90. 15/242 patients (6%) were initially observed. Survival: The median OS for all patients was 18.3 years. PFS following primary therapy was 9.3 years. There was no difference in the outcomes between patients receiving local or systemic therapy in first line for all patients, or for those with stage I or II disease. On univariate analysis age <60, stage, IPI, normal LDH, the presence of Sjögren’s disease, and treatment with rituximab were associated with improved overall survival. Age <60, low to intermediate IPI and normal LDH were associated with improved PFS. On multivariate analysis, age<60, and IPI were associated with improved OS and PFS and Sjögren’s disease was associated with improved OS. Relapse/progression: The site of progression was known in 51 of 76 patients who progressed. 15 (29%) patients progressed in the same salivary gland or regional nodes; in 16 (21%) recurrence involved the contralateral salivary gland; 20 (31%) had distant progression. Relapse histology was identified in 30. The most common pathology at relapse was MALT (n=28), with one patient progressing to diffuse large B-cell lymphoma. A second patient developed a mantle cell lymphoma. Conclusions: Salivary gland MALT lymphoma commonly presents at an early stage, and has a favorable prognosis with a median OS of 18 years. Surgical or radiation therapy does not appear to have benefit over systemic therapy. Patients with Sjögren’s disease appear to have a better survival. The role of rituximab and optimal first-line therapy should be evaluated further in prospective trials. Table 1: Characteristics of 247 patients with salivary MALT Characteristic N (%) Age, median; range 59; 18-93 Sex, Male: Female 62: 185 (25: 75) Primary site of involvement Parotid 193 (78) Submandibular 12 (5) Other/not specified 42 (17) Extent (unilateral: bilateral) 89:21 Missing data 137 Autoimmune disorder* 101(41) Sjögren’s 84 (33) Rheumatoid arthritis 9 (4) Raynaud’s phenomenon 8 (3) Scleroderma 5 (2) Other 19 (8) Stage IE 147 (59) IIE 42 (17) IV 56 (23) Missing data 2 (1) IPI Score Low (0-1) 126 (51) Low-Intermediate (2) 20 (8) High-intermediate (3) 21 (8) High (4-5) 5 (2) Missing data 75 (31) Elevated LDH 17 (7) ECOG PS 0-1 246 2 1 Extranodal sites 1 58 (23) 2 187 (76) Missing data 2 (1) B symptoms 9 (4) * Percents may not equal 100 as some patients had more than one disorder. Figure One: Overall survival of patients with and without Sjögren’s disease Figure One:. Overall survival of patients with and without Sjögren’s disease Disclosures Nowakowski: Celgene, Morphosis: Consultancy. Zucca:Roche, Mundipharma, Novartis, Jannsen, Celgene: Consultancy, Honoraria, Research Funding.

Abstract Background: Follicular lymphoma (FL) is an indolent lymphoma generally considered incurable with current standard therapies. Recent advances have resulted in prolongation of overall survival (OS) for patients with FL such that death from competing causes may now limit the mortality impact of FL in some patient groups. Identification of patients for whom FL related mortality is expected to be minimal, or conversely those at high risk of disease related mortality, is highly clinically relevant. We recently reported (Maurer et al, JCO 2014;32:1066-73) that event-free survival (EFS) at 24 months from diagnosis is a robust endpoint for disease related outcome in patients with diffuse large B cell lymphoma (DLBCL). Here we use the same approach to assess if landmark timepoints of EFS can stratify subsequent OS in FL. Methods: All newly diagnosed grade 1-3a FL patients enrolled on the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2011 were eligible. Patients with grade 3b FL, transformation, or presence of DLBCL at diagnosis were excluded. EFS was defined as time from diagnosis to progression, relapse, re-treatment, or death due to any cause. EFS12 was defined based on EFS status 12 months after date of diagnosis; we also assessed EFS at 24 months. OS was defined as time from a specific timepoint (diagnosis, event, or EFS12) until death due to any cause. OS was compared to age and sex matched survival in the general US population using an expected survival approach and standardized mortality ratios (SMR) and 95% confidence intervals (CI). Outcomes were examined in all patients as well as selected subsets defined by initial treatment. Replication was performed using a Lyon, France hospital registry of newly diagnosed grade 1-3a FL patients enrolled from 2002-2010 with survival compared to French population data. Results: 936 patients with grade 1-3a FL were eligible from the MER. The median age at diagnosis was 60 years (range 19-91) and 53% were male. 86% had grade 1-2 disease and 14% grade 3a disease. 23% had high-risk disease (FLIPI score ≥3). 347 (37%) were initially treated with alkylator or anthracyline based immunochemotherapy (IC), 113 (12%) rituximab monotherapy (RM), and 318 (34%) were initially observed; the remaining patients received radiation for limited stage disease (8%), chemotherapy without rituximab (4%), or other therapy (5%). At a median follow-up of 59 months (range 1-131), 403 patients (43%) had an event and 120 patients (13%) had died; 155 patients (17%) failed to achieve EFS12. From diagnosis, patients with FL had inferior OS compared to the general population (SMR=1.24, 95% CI: 1.03-1.48, p=0.018); results were similar for patients with grade 1-2 (SMR=1.23) and grade 3a (SMR=1.29) disease. The survival deficit was eliminated in patients who achieved EFS12 (SMR=0.85, 95% CI: 0.66-1.09, p=0.20, Fig 1a), and so we did not pursue modeling EFS24. In contrast, patients with a non-death event (relapse, retreatment, or progression) within 12 months of diagnosis had inferior subsequent OS (SMR=3.90, 95% CI: 2.89-5.25, p=4.8x10-19, Fig 1b). These results were replicated in 153 FL patients from the Lyon registry: patients who achieved EFS12 had equivalent subsequent OS to the general French population (SMR=0.82, 95% CI: 0.39-1.72, p=0.60, Fig 1c), while patients who failed to achieve EFS12 had poor subsequent OS (SMR=4.16, 95% CI: 1.34-12.91, p=0.013, Fig 1d). In subset analysis of the MER, patients achieving EFS12 initially treated with IC (SMR=0.98, 95% CI: 0.63-1.54, p=0.93), RM (SMR=0.66, 95% CI: 0.31-1.38, p=0.27), or observation (SMR=0.73, 95% CI: 0.47-1.15, p=0.18) had equivalent OS to the population. In contrast, for patients not achieving EFS12, OS after event was inferior for those treated with IC (SMR=15.0, 95% CI: 10.22-22.05, p=2.0x10-43) or RM (SMR=4.96, 95% CI: 1.24-19.84, p=0.023), while trending towards inferior for those initially observed (SMR=1.55, 95% CI: 0.81-2.99, p=0.19). Summary: Events within the first 12 months of diagnosis are associated with poor OS in FL, especially in patients treated with IC, while patients achieving EFS12 have excellent subsequent survival, overall and in the main treatment subsets. Prognosis for FL patients should be recalibrated at 12 months from diagnosis. EFS12 will be useful in counseling and should be considered as an endpoint in studies of newly diagnosed FL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction Non-Hodgkin lymphoma responds to single agents such as cyclophosphamide, combination therapy such as CVP and immunotherapy with monoclonal antibodies such as rituximab. There is no consensus on the optimal treatment for relapsed low grade or mantle cell lymphoma. Based on the success and tolerability of combining alkylating agents with proteasome inhibitors in multiple myeloma, a phase II clinical trial of rituximab, cyclophosphamide, bortezomib, and dexamethasone (R-CyBor-D) was designed to explore the efficacy and safety of this combination in relapsed low grade and mantle cell lymphoma (MCL). Methods This trial enrolled relapsed patients at Mayo Clinic from October 2008 to March 2014. Eligibility required age≥18; biopsy proven follicular grades 1 or 2 lymphoma (FL), MCL, small lymphocytic lymphoma/chronic lymphocytic leukemia, marginal zone B-cell lymphoma, or Waldenström’s macroglobulinemia (WM); life expectancy >3 months; ECOG PS 0, 1 or 2; measurable disease; Hb ≥8g/dl, ANC ≥1200/uL, platelet ≥75,000/uL, creatinine ≤1.5xULN, total bilirubin ≤1.5xULN, alkaline phosphatase ≤3xULN, AST ≤3xULN; and willingness to sign informed consent. Women of child bearing potential had pregnancy testing and all patients followed recommendations for contraception. Treatment included rituximab 375 mg/m2 IV on day 1 and oral cyclophosphamide 300 mg/m2, IV bortezomib 1.3 mg/m2, and oral dexamethasone 40 mg on days 1, 8, 15, and 22 in a 28-day cycle. Treatment was continued two cycles beyond best response or a maximum of 12 cycles. Allopurinol 300 mg on days 0-14 for the first cycle was strongly recommended. Results 21 patients were enrolled prior to study closure due to slow accrual. Bortezomib was initially given on days 1, 4, 8, and 11 in the first 16 patients, but was subsequently modified to days 1, 8, 15, and 22 due to significant peripheral neuropathy (PN). Median age was 69 years (range 51-80) and 13 (62%) were male. 62% had stage IV disease and 17 (81%) had 2 or more prior treatments with 3 (14%) having prior autologous stem cell transplantation. Histologies included FL-I (n=6), FL-II (n=2), MCL (n=8), and WM (n=5). Patients completed a median of 4 cycles of treatment (range 1-12), discontinuing due to 9 (43%) completion per protocol, 4 (19%) progression, 5 (24%) adverse events, 1 (5%) patient refusal, and 2 (10%) other reasons. Median follow-up is 32.8 months (0.9-54.8). CR or PR as best response was observed in 13 (62%, 95% CI 38-82%; 4 CR [19%], 9 PR [43%]) patients. By histology, CR or PR was observed in 7 (88%) FL patients (4 CR, 3 PR); 2 (25%) MCL patients (both PR), and 4 (80%) WM patients (all PR). CR or PR was observed in 10/16 (62%; 4 CR, 6 PR) before and 3/5 (60%; all PR) after the change in bortezomib schedule. Among 13 patients with CR or PR, median duration of response was 25.9 months (95% CI 8.0-not reached). Median PFS and OS were 11.6 months (95% CI 3.8-not reached) and 54.8 months (95% CI 24.6-54.8), respectively. At least one Gr≥3 adverse event at least possible related was observed in 14 (67%) patients, the most common being leucopenia (7, 33%), neutropenia (7, 33%), thrombocytopenia (6, 29%), anemia (5, 24%), PN (5, 24%), and fatigue (3, 14%). Peripheral sensory neuropathy at least possibly related was Gr1, Gr2, and Gr3 in 5 (24%) patients each, with a lower rate observed for patients after the change in bortezomib schedule (before 13/16 [81%] Gr≥1, after 2/5 [40%] Gr≥1). Among 14 patients who completed a baseline and at least one post-baseline FACT/GOG-NTX additional concerns questionnaire, 10 (71%) reported clinically meaningful (≥3-point) worsening in patient-reported neurotoxicity (8/11 [73%] before and 2/3 [67%] after the change in bortezomib schedule). Conclusions Our results suggest R-CyBor-D is a safe and effective combination in patients with relapsed low grade and mantle cell lymphomas. High response rates were seen in FL and WM. The majority of significant AE’s were hematologic. However, sensory neuropathy was common with twice weekly dosing of bortezomib and lessened with weekly dosing. Determination of optimal treatment regimens in this population remains an unmet need. Additional clinical trials including larger patient numbers are necessary to confirm these observations. This trial was sponsored by Millennium Disclosures Off Label Use: bortezomib was used in combination therapy to treat relapsed low grade lymphomas and Waldenstrom's macroglobulinemia. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Tiedemann:Janssen: Honoraria. Reeder:Millennium, Celgene, Novartis: Research Funding.

Abstract Purpose: The purpose of this study was to examine whether quality of life (QOL) scores at diagnosis predict survival among patients with aggressive lymphoma, controlling for clinical variables and histological subtype. Patients and Methods: Newly diagnosed lymphoma patients were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource. Eligibility criteria included age ≥18 years; exclusion criteria included HIV-positive, non-US residency, and inability to participate in an interview conducted in the English language. All pathology was reviewed by a lymphoma hematopathologist. For purposes of this analysis, we considered “aggressive lymphoma” to include the histological subtypes diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) grade III, mantle cell lymphoma, T-cell lymphoma excluding mycosis fungoides and cutaneous types, and other (Burkitt lymphoma, high grade B-cell lymphoma NOS, grey zone, etc). Baseline QOL was measured at time of registry enrollment with the Functional Assessment of Cancer Treatment-General scale (FACT-G), which measures 4 QOL domains: physical, social/family, emotional, and functional well-being (WB); a single item Linear Analogue Self Assessment (LASA) for measuring overall QOL; and a LASA measuring spiritual WB. Patients who did not complete ≥80% of FACT-G QOL questions were excluded. Clinical data were abstracted and patients were systematically followed for event-free and overall survival (EFS, OS). QOL scores were transformed to a 0-100 scale for modeling. Generalized additive models were used to account for timing of QOL assessment in relation to treatment and diagnosis; residuals from these models were then used to assess association between QOL measures and outcome via univariate and multivariable (adjusted for IPI and subtype) Cox proportional hazards models. Results: From September 2002 to December 2009, 701 patients with aggressive lymphoma who completed baseline QOL questionnaires were enrolled and eligible for this analysis. ; Subtype was 60% DLBCL, 14% mantle cell, 11% FL grade III, 13% T-cell, and 1% other subtypes. The median age was 62 years (range 18-92), and 58% were male. At a median follow-up of 71 months (range 6-128), 316 patients (45%) had an event and 228 patients (33%) died. Patient-reported QOL was prior to therapy in 330 patients (47%) and after initiation of therapy in 371 (53%). The median overall FACT-G total score was 83 (IQR 70-93), and the median scores on the functional WB, physical WB, emotional WB, and social/family WB were 18 (13-23), 22 (17-26), 18 (16-21), and 25 (22-27), respectively. 42 patients (6%) reported a clinically deficient QOL score on the FACT-G (score ≤50 on 0-100 scale). When comparing QOL scores between those who were on active therapy versus those who were not yet treated, physical WB (p<0.0001) functional WB (p=0.00014), and total FACT-G (p=0.0013) were lower in those on active treatment. All QOL measures but emotional WB were significantly associated with OS (all p<0.04), and all but LASA spiritual WB remained significant after adjusting for IPI and NHL subtype. Associations were stronger for OS than EFS. For OS, the strongest associations were with total FACT-G (adjusted HR=0.86, 95% CI: 0.79-0.94, p=0.00062) and functional WB (adjusted HR=0.88, 95% CI: 0.83-0.93, p<0.0001). The one-question QOL LASA was also associated with OS (adjusted HR=0.92, 95% CI: 0.87-0.97, p=0.0041). The strongest association with EFS was with functional WB (adjusted HR=0.92, 95% CI: 0.88-0.97, p=0.0015). Patients with a clinically deficient QOL (baseline overall QOL ≤50) had a median OS of 59 months compared to 121 months for patients with baseline QOL >50, p=0.0002, figure 1. In a sensitivity analysis, raw QOL was modeled for OS and EFS in the subset of patients with QOL assessed prior to treatment; hazard ratios were consistent with the adjusted QOL HR in all patients. Conclusions: In this large sample of patients with aggressive lymphoma, baseline QOL is predictive of OS and EFS, even after adjustment for known factors related to survival (IPI and histological subtype). This provides evidence that patient-reported outcomes are as important as other more objective previously confirmed IPI measures. QOL should be assessed at diagnosis as a prognostic factor in patients with aggressive lymphoma. Figure 1 Association of QOL with overall survival. Figure 1. Association of QOL with overall survival. Disclosures No relevant conflicts of interest to declare.

Abstract To date, whole genome and exome sequencing studies of follicular lymphoma (FL) have primarily focused on identification of small site mutations that are recurrent in FL tumorigenesis or involved in tumor clonal evolution. A comprehensive genomic and transcriptomic survey of various mutation types including large structural variants (SVs) in FL cases with detailed clinical annotations and long-term follow-up has not been accomplished. To gain insight into genetic biomarkers that may predict clinical features, we performed exome and whole genome mate-pair sequencing of fresh frozen tumor and paired peripheral blood DNAs, and transcriptome sequencing of tumor RNAs, from 8 FL patients. The patients we selected were either below the median age of FL onset (n=7, median 54.5 yrs) or had a family history of lymphoma (n=1). These patients were clinically diverse, and included patients who had Grade 1 or 2 disease (n=4), classified as “indolent”; and patients with Grade 3a disease (n=2) or who subsequently had pathologic transformation (n=2), classified as “aggressive”. The coding regions of the genome (exome) were captured using Agilent SureSelect Target Capture Kit V2.0, and sequenced at 100-bp paired-end. The single nucleotide variants (SNVs) and small insertions and deletions (INDELs) were called using The Genome Analysis Toolkit (GATK), and the exon level copy number variants (CNVs) we identified using patternCNV. The whole-genome mate-pair libraries of both normal and tumor DNAs with 3kb insert sizes were sequenced paired end at 50-bp. The large SVs of CNVs, large INDELs, translocations, and inversions were identified using the SnowShoes-SV algorithm. The RNA sequencing libraries of 8 FL tumors were constructed using Illumina TruSeq protocol, and sequenced at 50-bp paired end. The RNA-Seq data were analyzed using TopHat and the fusion transcripts were identified using SnowShoes-FTD. Our analysis of SNVs and INDELs revealed mutations in previously reported genes including MLL2, CREBBP, TNFRSF14, and histone cluster genes (HIST1H2AM, HIST1H2BD). In addition, we identified novel recurrent mutations in cysteine-rich PAK1 inhibitor (CRIPAK) in 25% of the tumors. In a secondary analysis performed by Sanger sequencing or re-analysis of publically available RNA sequencing data, we identified CRIPAK mutations in 44% of FL (n=32) and 28% of DLBCL tumors (n=102). Bioinformatics analysis shows that the coding region of CRIPAK is highly enriched with the protein functional domain, post-SET, which is usually found in histone lysine methyltransferases (HMTase) genes including MLL2 and EZH2 that are known to be important in lymphomagenesis. Interestingly, CRIPAK is part of the same regulatory network consisted of previously identified lymphoma genes including MLL2, EZH2, CREBBP, and EP300, according to the shortest path algorithm by MetaCore (Philadelphia, Pennsylvania). Recurrent SVs identified in the FL tumors included the well-known IGH-BCL2 translocation, or t(14;18), in 6 out of 8 cases (75%) and the chr1q amplifications in 4 out of 8 (50%) tumors. Other non-recurrent large CNVs involving entire chromosomes or chromosome arms, as well as other inter- and intra-chromosomal structural variants were detected in individual tumors. In addition, we identified and validated 6 fusion transcripts from the transcriptome sequencing data in 3 out of 8 cases (38%). While our sample size is small, we found that SNVs and INDELs in MLL2, CREBBP, TNFRSF14, CRIPAK, and histone cluster genes, as well as t(14;18), did not distinguish indolent or aggressive tumors. However, all aggressive (4/4, 100%) and none of the indolent tumors had gains in chr1q; and the presence of RNA fusion transcripts were observed in aggressive tumors only (3/4, 75%). Additionally, we found that aggressive tumors had higher numbers of genes with point mutations (SNVs and short INDELs) (40 ± 7.6 vs. 26 ± 2.6; aggressive vs. indolent), higher numbers of genes impacted by copy number aberrations (1060 ± 263.7 vs. 233 ± 133.9), and higher numbers of large SVs (24 ± 10 vs. 6 ± 1.6). Taken together, our comprehensive analysis of 8 FL tumors reveals genetic diversity among newly diagnosed FL patients, identifies novel and recurrent mutations in CRIPAK, and finds that high tumor complexity and DNA instability may be indicators of aggressive disease. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 689 Background: Lenalidomide was demonstrated to have significant single agent activity in relapsed aggressive B cell lymphoma (J Clin Oncol. 2008;26:4952–7, Ann Oncol. 2011;22:1622–7). In a phase I study, we previously demonstrated that Lenalidomide 25 mg day 1–10 of the cycle can be combined with RCHOP21 and this combination does not result in dose delays or increased toxicity (Leukemia 2011;12:1877–81). We now present phase 2 results of R2CHOP in treatment of patients with aggressive B-cell lymphoma. Methods: Eligible patients were adults with newly diagnosed CD20 positive diffuse large B cell (DLBCL) or grade 3 follicular lymphoma (FL). The response was evaluated using PET/CT by standard criteria (J Clin Oncol. 2007;25:579–586). The progression free survival (PFS) was defined as time from diagnosis to disease progression or death. Results: 51 patients - 6 enrolled at the MTD in phase 1 portion of the study and 45 in phase 2 portion were included in the analysis. The median age was 65 years (range, 19–87). 35% of patients were 70 and older. 63% (32/51) were males. 47 patients (92%) had DLBCL and 4 (8%) patients had FL grade 3. The international prognostic index (IPI) was low, low-intermediate, high-intermediate and high in 8 (15%), 18 (35%), 18 (35%) and 7 (14%) patients respectively. 31 patients (60%) had stage 4 disease. Hematological toxicities were: grade 3 and 4 thrombocytopenia (20% and 20% of patients respectively); grade 3 and 4 neutropenia (18% and 71% of patients respectively). Overall 27% of patients experienced a grade 3 or higher non-hematological toxicity at least possibly related to treatment. The most frequent were febrile neutropenia (10%), nausea (4%), urinary tract infection (4%), vascular access complication (4%), and dehydration (4%). 1 patient (2%) developed thrombosis. There was one death (2%) secondary to bowel perforation/sepsis. For 47 patients evaluable for response, the overall response (ORR) and complete response (CR) rates were 98% and 83% respectively. The PFS was 73% at 12 months (Figure). Since the enrolled patients represented a relatively high-risk group (49% intermediate high or high IPI, significant proportion of elderly male patients), the PFS in R2CHOP was compared to PFS in a contemporary cohort of 87 consecutive patients with DLBCL participating in Mayo Clinic Lymphoma Database and treated with standard RCHOP alone. The PFS was 62% at 12 months in this cohort and was inferior to R2CHOP (Figure). Conclusion: Lenalidomide combined with standard R-CHOP21 chemotherapy (R2CHOP) demonstrates predictable safety profile. The ORR and CR rates and PFS are encouraging in elderly high IPI patients, and compared favorably to the R-CHOP treated historical cohort with similar clinical characteristics. A randomized trial will be needed to confirm the benefits of this novel combination. Disclosures: Off Label Use: lenalidomide in treatment of NHL. Reeder:Celgene: Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding; Celgene Corporation: Consultancy.