Nowakowski, Grzegorz S.

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.