Citations

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.

Abstract Abstract 92 BACKGROUND: All somatic cell types, including all B lineage cells, constitutively express a number of DNA repair proteins to maintain genomic stability and thwart tumorigenesis in the face of ongoing constitutive levels of DNA damage. Compromises in expression of these essential DNA repair factors have been shown to readily induce the development of various cancers including B cell lymphomas, suggesting expression levels are tightly regulated and limited in quantity. In germinal center (GC) B cells, however, additional DNA repair capacity is likely required to counterbalance the heightened level of mutagenic activity owing to the induced expression of activation-induced cytidine deaminase (AID) during somatic hypermutation (SHM). AID is a DNA editing enzyme which introduces somatic mutations into immunoglobulin (Ig) V regions at an estimated rate which is almost a million-fold higher than the spontaneous rate in somatic cells. HYPOTHESIS: We hypothesize that to maintain the genomic wellness of GC B cells which are undergoing SHM, there is a need for induction of an accompanying robust DNA repair system. We further hypothesize that inefficient induction of these repair genes may predispose to malignant transformation. METHODS: Using tonsillar tissue sections and purified tonsillar B cell subpopulations, we compared expression levels of various DNA repair genes and related these levels to AID expression across the subsets using immunohistochemistry, real-time RT-PCR, and Western blot analysis. To characterize the nature of signals capable of inducing expression levels of AID and/or DNA repair proteins, peripheral blood B cells were activated in vitro using a panel of stimuli, including coculture with activated CD4 T cells. As a surrogate measure of mismatch repair (MMR) activity in the relative absence of T cell help, we quantitated the number of somatic hypermutations at A/T sites in the Ig heavy chain variable (IGHV) region genes in a collection of IGHV sequences obtained from normal B cells and HIV-related lymphoma cells. RESULTS: Using immunohistochemistry, we observed that, similar to the expression of AID, DNA MMR genes are significantly induced in tonsillar GC B cells. These results were further validated using a more sensitive real-time RT-PCR assay and analysis by Western blotting. By expanding our DNA repair gene panel, we observed that proteins of homologous recombination, base excision repair and DNA single strand break signalling pathway are also similarly induced in GC B cells at RNA, protein, and functional levels compared to their expression in naïve and memory B cells. By contrast, expression of non-homologous end joining and DNA double strand break signalling molecules are unchanged. We have termed this selective induction of repair mechanisms in GC B cells as somatic hyperrepair (SHR). To identify pathways that lead to the activation of AID and SHR, we used an in vitro system and a variety of stimuli and we discovered that multiple B cell stimuli including CpG, CD40L, and anti-BCR could each independently induce the expression of AID while SHR induction strictly required the engagement of CD4+ T cells. This provocative observation suggests a novel role for CD4+ T cells in mitigating tumorigenesis of post-GC B cells through their ability to induce the SHR pathway in cells that have been induced to undergo SHM. To demonstrate the possible role of SHR in lymphomagenesis, we analysed the mutation pattern of IGHV genes from a panel of B cell lymphomas obtained from HIV infected (CD4+ T cell suppressed) patients. We found that HIV-related lymphoma cells displayed a significantly lower frequency of SHM at A/T positions relative to normal memory B cells, indicative of compromised MMR of their precursor cells during GC transit. Our findings resolve the lingering paradox that B cell malignancies are overwhelmingly prevalent under T cell suppression conditions such as HIV infection, post-organ transplant, and aging. Finally, our results also suggest for the first time that mounting efficient tumor suppression for some cells may depend on signals transmitted by neighboring cells and the specific microenvironment. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 684 Background. Obesity has been associated with an increased risk of developing of lymphoma, particularly DLBCL. Genetic variation in several energy balance genes, including leptin (LEP), its receptor LEPR, ghrelin (GHRL) and neuropeptide Y (NPY) have been shown to modulate risk of lymphoma, although their impact on survival is not known. In contrast, recent studies suggest that patients either overweight (Body Mass Index (BMI), 25 to<30 kg/m2) or obese (≥30 kg/m2) may have a superior prognosis in DLBCL, although its impact in FL and in the current treatment era is not known. We evaluated the association of BMI at the time of diagnosis, 2 years prior to diagnosis and at ages 18, 35 and 50 years, along with germline genetic variation in selected energy balance genes with event-free (EFS) and overall (OS) survival in DLBCL and FL. Methods. We evaluated these associations in a prospective cohort of newly diagnosed DLBCL (N=764) and FL (N=649) patients enrolled at the Mayo Clinic and University of Iowa from 2002–2009 as part of the Molecular Epidemiology Resource. Peripheral blood DNA, clinical data and self-reported historical weights were collected at enrollment. Patients received standard disease treatment strategies, and were systematically followed for disease progression, re-treatment, and death. Single nucleotide polymorphisms (SNPs) were genotyped as part of a custom Illumina iSelect panel. The most prevalent homozygous genotype was used as the reference group, and each SNP was modeled as having a log-additive effect in the regression model. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the association of the obesity measures and SNPs with outcome, adjusted for treatment class and subtype specific prognostic factors (IPI, FLIPI). Results. For DLBCL patients (median age 63 years, range 18–92) the median follow-up was 47 months (range 0–101); 58% had an IPI 0–1 risk disease; and 87% received immunochemotherapy. For FL patients (median age 60 years, range 25–94), the median follow-up was 60 months (range 11–110); 24% had FLIPI score 3–5; and main initial treatments were observation (32%), rituximab (R)-monotherapy (12%), CVP +/−R (19%), and anthracycline +/−R (22%). The main results for BMI and prognosis are reported in the Table. For DLBCL, obese patients at diagnosis had better EFS and OS; this association was weaker for BMI at age 50 and 35 years. In contrast, for FL, overweight and obese patients at diagnosis had a poorer EFS and OS, and this was also observed for BMIs two years before diagnosis and at ages 50 and 35 years. In FL, the LEP SNP rs2167270 was associated with inferior EFS (HR=1.25; 95%CI 1.05–1.49) and OS (HR=1.28; 95%CI 0.90–1.83). The NPYSNP rs16147 was associated with inferior FL OS (HR=1.50; 95%CI 1.03–2.17) but was not associated with EFS. None of the energy balance and metabolism SNPs were associated with DLBCL EFS or OS. Conclusions. Higher BMI prior to and at diagnosis, as well as SNPs in LEP and NPY,were significantly associated with FL prognosis, with inferior outcomes in overweight and obese patients. These novel findings in the modern treatment era suggest an important role of obesity pathways in FL prognosis. In DLBCL, we confirm the recent findings of improved survival in DLBCL in obese patients, and extend this to the modern treatment era and BMI earlier in life. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1669 Poster Board I-695 Background The addition of rituximab to chemotherapy significantly improved the results of therapy in aggressive non-Hodgkin's B cell lymphoma (NHL). However, significant number of the patients relapse following initial therapy. Lenalidomide was shown to have significant single agent activity in relapsed aggressive B cell lymphoma (J Clin Oncol 26:4952-7, 2008) however the safety in combination with standard first line immunochemotherapy is unknown. We initiated a phase I/II trial of R2-CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone rituximab and lenalidomide) to establish the safety and efficacy of this therapy in the treatment of patients with newly diagnosed aggressive B cell NHL. Herein, we report the results of phase I portion of this study. Methods A phase I study was designed to define the maximum tolerated dose (MTD) of lenalidomide administered on days 1-10 with R-CHOP chemotherapy (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50mg/m2, vincristine 1.4 mg/m2, all on day 1, prednisone 100 mg/m2 days 1-5 of 21 day cycle) utilizing 3+3 dose escalation design. Lenalidomide dose escalation levels were 15 mg, 20 mg and 25 mg. All patients received 6 mg pegfilgrastim injection on day 2. Dose limiting toxicity (DLT) was defined as any grade 3 or more non-hematological toxicity or a hematological toxicity requiring a delay of the next cycle of chemotherapy due to cytopenia. The latter criterion was to ensure maintenance of the dose intensity and schedule of RCHOP; a potentially curative therapy in this setting. Eligible patients were adults newly diagnosed with CD20 positive diffuse large cell or follicular grade III B cell lymphoma, ECOG PS 0-2 and good organ function. There was no upper age restriction to participate in this study. Results Twelve patients were enrolled in phase I of this study. The median age was 69 years (range, 49-82) and 58% (7/12) of patients were males. Ten patients (83%) had DLBCL and two (17%) patients had follicular grade 3B lymphoma. International prognostic index was intermediate, high- intermediate and high in 6, 4 and 2 patients respectively. Patients distribution by lenalidomide dose was: 3 patients received 15 mg/day, 3 received 20 mg/day and 6 received 25 mg/day on days 1-10. Non-hematological toxicities included: grade 3 toxicity - neuropathy in one patient (8.3%), grade 2 toxicities were: infection in 17% (2/12) patients (skin in one patient, otitis media, and urinary tract infection in one patient); nausea 8% (1/12), rash 8% (1/12) and alopecia 41% (5/12). The most common toxicity to R2-CHOP was myelosuppresion. Grade 3 and 4 neutropenia occurred in 17% (2/12) and 41% (5/12) of patients, respectively. The neutropenia was of short duration, and no patients developed neutropenic complications. Grade 3 thrombocytopenia was seen in 8% (1/12). Most importantly, there were no delays in chemotherapy due to cytopenias. No DLT was seen. The 25 mg/day days 1-10 dose of lenalidomide was taken forward to an ongoing phase 2 trial. Conclusion Lenalidomide at a dose of 25 mg/day for days 1- 10 combined with R-CHOP chemotherapy is well tolerated. The addition of lenalidomide did not affect hematological recovery and did not result in treatment delays. This dose and schedule is now being evaluated in the phase II part of the trial. Disclosures Zent: Genentech, Bayer, Genzyme, Novartis: Research Funding. Witzig:Novartis: Research Funding.

AbstractBackgroundHuman pegivirus (HPgV) is a single-strand RNA virus belonging to the Flaviviridae. Although no definitive association between HPgV infection and disease has been identified, previous studies have suggested an association of HPgV viremia with risk of lymphomas.MethodsWe conducted a systematic review and meta-analysis, including 1 cohort study and 14 case-control studies, assessing the association of HPgV viremia with adult lymphomas. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model, overall and by geographic region and lymphoma subtype.ResultsThe overall OR for lymphoma was 2.85 (95% CI, 1.98–4.11), with statistically significantly elevated ORs observed in 8 of 15 studies. There was a small amount of heterogeneity among studies (I2 = 28.9%; Q = 18.27, P = .16), and the funnel plot provided no evidence for publication bias. The strongest association with lymphoma risk was observed for studies from Southern Europe (OR, 5.68 [95% CI, 1.98–16.3]), whereas weaker ORs (with 95% CIs) were observed for studies from North America (2.24 [1.76–2.85]), Northern Europe (2.90 [.45–18.7), and the Middle East (2.51 [.87–7.27]), but all of similar magnitude. Participants with HPgV viremia had statistically significantly increased risks (OR [95% CI]) for developing diffuse large B-cell (3.29 [1.63–6.62]), follicular (3.01 [1.95–4.63]), marginal zone (1.90 [1.13–3.18]), and T-cell (2.11 [1.17–3.89]) lymphomas, while the risk for Hodgkin lymphoma (3.53 [.48–25.9]) and chronic lymphocytic leukemia (1.45 [.45–4.66]) were increased but did not achieve statistical significance.ConclusionsThis meta-analysis supports a positive association of HPgV viremia with lymphoma risk, overall and for the major lymphoma subtypes.

Abstract In this month's CME article, an analysis of over 1300 patients with diffuse large B-cell lymphoma (DLBCL), Wang et al demonstrate that the approximately 13% of patients with concurrent indolent lymphoma at diagnosis had the same prognosis as those patients with isolated DLBCL.