Jacobus, Laura

8061 Background: RCHOP is the standard first line therapy for DLBCL but elderly patients often receive suboptimal doses. Relative dose intensity (RDI) less than 70-90% has previously been associated with inferior survival in CHOP treated patients. We now investigate the clinical determinants of immunochemotherapy dose delivery and comparative effectiveness of dose intensity on lymphoma-specific outcomes in persons over the age of 60. Methods: SPORE MER (Molecular Epidemiology Resource) is a prospectively accrued observational study in which University of Iowa and Mayo Clinic patients with a diagnosis of Non Hodgkins lymphoma have been enrolled since 2003. We reviewed data from the Iowa patients along with medical records from DLBCL patients over the age of 60 treated with anthracycline based chemo immunotherapy consecutively enrolled up through to December 2009. Statistical tests of associations between RDI and clinicopathologic factors, as well as survival outcomes, were performed. Results: We identified 92 patients over the age of 60. The median age was 70. 47 subjects experienced at least 1 dose reduction, 26 subjects had dose delays, and 20 subjects were unable to complete therapy. RDI ranged from 0.30-1.70 (median 0.92) for doxorubicin and from 0.29-1.70 (median 0.97) for cyclophosphamide. 24 and 19% of subjects received < 80% of RDI for dox and cy respectively. Age (p< 0.001 for both dox and cy) and performance status (p=0.04 for dox) but not number of medications, ACE27 co-morbidity score, body surface area, nor need for acute care visits were associated with decreased RDI. Adjusted for IPI, RDI did NOT have a significant effect on event-free or lymphoma-specific survival. Conclusions: Among clinical variables, age is the dominant variable associated with delivery dose intensity for chemotherapy in elderly patients treated for DLBCL; and among elderly patients receiving chemo immunotherapy, we did not find an association between dose intensity and lymphoma-specific outcomes. [Table: see text]

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 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.