Flowers, Christopher R.

Purpose Overall survival (OS) is the definitive and best-established primary efficacy end point to evaluate diffuse large B-cell lymphoma (DLBCL) therapies, but it requires prolonged follow-up. An earlier end point assessed post-treatment would expedite clinical trial conduct and accelerate patient access to effective new therapies. Our objective was to formally evaluate progression-free survival (PFS) and PFS at 24 months (PFS24) as surrogate end points for OS in first-line DLBCL. Patients and Methods Individual patient data were analyzed from 7,507 patients from 13 multicenter randomized controlled trials of active treatment in previously untreated DLBCL, published after 2002, with sufficient PFS data to predict treatment effects on OS. Trial-level surrogacy examining the correlation of treatment effect estimates of PFS/PFS24 and OS was evaluated using both linear regression ( R2WLS) and Copula bivariable ( R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80 and neither < 0.7, with lower-bound 95% CI > 0.60. Results Trial-level surrogacy for PFS was strong ( R2WLS = 0.83; R2Copula = 0.85) and met the predefined criteria for surrogacy. At the patient level, PFS strongly correlated with OS. The surrogate threshold effect had a hazard ratio of 0.89. Surrogacy was consistent across comparisons with or without rituximab and with rituximab maintenance trials. Trial-level surrogacy for PFS24 was relatively strong ( R2WLS = 0.77; R2Copula = 0.78) but did not meet prespecified criteria. At the patient level, PFS24 significantly correlated with OS. The surrogate threshold effect had an odds ratio of 1.51. Conclusion This large pooled analysis of individual patient data supports PFS as a surrogate end point for OS in future randomized controlled trials evaluating chemoimmunotherapy in DLBCL. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before OS results are mature.

95 Background: While PA is known to improve quality of life in lymphoma pts, its impact on OS is not known. We studied the effect of PA on OS in lymphoma pts enrolled at diagnosis in the Iowa/Mayo Molecular Epidemiology Resource. Methods: Godin Leisure Score Index (LSI; Range 0-50) was calculated based on level of PA pre-diagnosis (baseline) and 3 years post diagnosis (FU3), with pts grouped by tertile into high, moderate, or low PA. At FU3, pts also reported perceived change in PA since diagnosis. OS was measured as time from assessment (baseline or FU3) until death from any cause. Associations between LSI tertiles and OS were assessed using Cox models adjusted for lymphoma subtype, age and sex. Results: PA level was available for 3060 pts at baseline and 1371 pts at FU3. 95% had an ECOG performance status < 2, 37% had an aggressive subtype, 29% had BMI ≥ 30, and 54% were age > 60. Indolent lymphoma pts with higher PA at baseline had no difference in OS. Higher PA at FU3 had improved OS (moderate vs low HR 0.63, CI 0.42-0.93; high vs low HR 0.53, CI 0.33-0.86). Pts with BMI < 30 who had higher PA at baseline showed no difference in OS. Higher PA at FU3 had improved OS for pts with BMI < 30 (moderate vs low HR 0.68 CI, 0.48-0.98; high vs low HR = 0.41, CI 0.26-0.64). For pts > 60 years, high vs low baseline PA showed improved OS (HR 0.77, CI 0.63-0.93). Higher PA at FU3 (moderate vs low HR 0.68 CI 0.48-0.96, high vs low HR 0.53 CI 0.34-0.83) was associated with OS. At FU3, compared to no change, perceived reduction of PA was associated with worse OS for indolent lymphoma (HR 2.13, CI 1.56-2.91), BMI < 30 (HR 1.95, CI 1.45-2.62), BMI > 30 (HR 2.00, CI 1.21-3.30), age ≤ 60 (HR 3.06, CI 1.72-5.46), and age > 60 (HR 1.98, CI 1.52-2.58). Perceived increase in PA was not associated with OS. Higher PA in pts with aggressive lymphoma, BMI ≥30, and age < 60 was not significantly associated with OS but trended similarly. All results were similar when analyzing by continuous LSI score. Conclusions: Higher levels of PA, especially at FU3, were associated with superior OS. The effect was more pronounced in pts with indolent lymphoma, BMI < 30, or age > 60. Perceived reduction in PA was associated with worse outcomes. PA should be incorporated into lymphoma survivorship plans.

Abstract A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend &lt; 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

This commentary describes the progress of the SEAL [Surrogate Endpoints for Aggressive Lymphoma] research group and invites collaboration in sharing data to continue building a large database of individual patient data from multiple clinical trials in DLBCL.