Martin, Peter

PURPOSE Although most patients with follicular lymphoma (FL) can expect an indolent course, progressive lymphoma remains the primary cause of death during the first decade after diagnosis. Progression of disease within 24 months (POD24) of starting first-line (1L) immunochemotherapy defines a high-risk population with poor survival, but better risk stratification at diagnosis is needed. METHODS The FLIPI24 model was developed and internally validated to predict 24-month event rates using individual data from 4,485 patients treated with 1L immunochemotherapy from 10 observational cohorts of FL. Overall and cause-specific survival was further evaluated in FLIPI24 risk groups. External validation in the 1L immunochemotherapy setting was performed using the prospective observational Lymphoma Epidemiology of Outcomes (LEO) cohort (N = 565) and three randomized phase III trials (N = 3,192); extension to all patients with FL (any 1L therapy) was performed in the LEO cohort (N = 1,445) and its Molecular Epidemiology Resource subcohort (N = 1,074). RESULTS The FLIPI24 model uses age and four blood-based variables (hemoglobin, lactate dehydrogenase, beta-2 microglobulin, and WBC count). FLIPI24 showed consistent performance across validation and extension data sets, which was superior to existing prognostic tools. Across the four external immunochemotherapy validation data sets, patients with high-risk FLIPI24 (23%-32% of patients) had significantly higher 24-month event rates (22%-35%) and inferior 5-year overall survival (77%-83%) compared with patients with low-risk FLIPI24 (29%-31% of patients, 24-month event rates: 10%-12%; 5-year OS: 96%-97%). Results were consistent when evaluating lymphoma-related death and when extended to all patients with FL. CONCLUSION The FLIPI24 model robustly stratifies, at diagnosis, patients with FL at increased risk of lymphoma-related death versus patients with very low lymphoma-related mortality during the first decade after diagnosis. FLIPI24 can be used to enrich future clinical trial designs in newly diagnosed FL.

ABSTRACT Newly diagnosed patients with non‐Hodgkin lymphoma (NHL) often have a history of other diseases, and these comorbidities can impact patient treatment and management options, as well as overall survival (OS). We developed the Lymphoma Epidemiology of Outcomes (LEO) comorbidity index (LCI) as a sum of 10 comorbidities adapted from the Self‐Report‐Generated Charlson Comorbidity Index (SRG‐CCI) for use in the LEO cohort, a national prospective study of newly diagnosed NHL. Of the 5502 participants with self‐reported comorbidity data, 3107 (56.4%) were male and the mean age at diagnosis was 60.9 years (range, 18–99 years). The LCI ranged from 0 to 6, with 48.6% having 0, 30.2% having 1, 21.2% having 2 or more comorbidities. With a median follow‐up of 62.4 months among surviving participants, 2099 patients had an event and 1219 died. Continuous LCI similarly predicted both 1‐year mortality (c‐statistic = 0.654) and OS (c‐statistic = 0.655), while it showed a weaker but still statistically significant predictive ability for lymphoma‐specific (c‐statistics = 0.617) and event‐free (c‐statistic = 0.574) survival. Participants with 1 (HR = 1.21, 95% CI 1.05–1.39) and 2+ (HR = 1.80, 95% CI 1.56–2.08) comorbidities had inferior OS compared to those with no comorbidities after adjustment for age and sex (c‐statistic = 0.654), and performance strengthened after adjustment for the International Prognostic Index (c‐statistic = 0.672). LCI predicted OS most strongly in marginal zone (c‐statistics = 0.748) and weakest in T‐cell (c‐statistic = 0.579) lymphoma. The cumulative incidence of death due to lymphoma, lymphoma treatment, and other causes all increased with increasing comorbidities, with the greatest increase observed for death due to other causes. The LCI performs comparable to other published comorbidity indices, supporting its use in the LEO cohort to better model real‐world outcomes and more generally providing an approach to implementing comorbidity indices in cancer survivorship cohorts.

PURPOSE Bone marrow biopsies (BMB) are performed before/after therapy to confirm complete response (CR) in patients with lymphoma on clinical trials. We sought to establish whether BMB add value in assessing response or predict progression-free survival (PFS) or overall survival (OS) outcomes in follicular lymphoma (FL) subjects in a large, multicenter, multitrial cohort. METHODS Data were pooled from seven trials of 580 subjects with previously untreated FL through Alliance for Clinical Trials in Oncology (Alliance) and SWOG Cancer Research Network (SWOG) completing enrollment from 2008 to 2016. RESULTS Only 5/580 (0.9%) had positive baseline BMB, CR on imaging, and subsequent positive BMB ( P < .0001). Therefore, BMB were irrelevant to response in 99% of subjects. A sensitivity analysis of 385 FL subjects treated on an Eastern Cooperative Oncology Group study was included. In the Eastern Cooperative Oncology Group cohort, 5/385 (1.3%) had BMB that affected response assessment. Since some subjects do not undergo confirmatory BMB, we performed a landmark survival analysis from first radiologic CR with data from 580 subjects from Alliance and SWOG. Of subjects with CR on imaging (n = 187), PFS and OS were not significantly different among those with negative BMB to confirm CR (n = 47) versus those without repeat BMB (n = 140; PFS: adjusted hazard ratio, 1.10, 95% CI, 0.62 to 1.94, log-rank P = .686; OS: hazard ratio, 0.59, 95% CI, 0.23 to 1.53, log-rank P = .276). CONCLUSION We conclude that BMB add little value to response assessment in subjects with FL treated on clinical trials and we recommend eliminating BMB from clinical trial requirements. BMB should also be removed from diagnostic guidelines for FL except in scenarios in which it may change management including confirmation of limited stage and assessment of cytopenias. This would reduce cost, patient discomfort, resource utilization, and potentially remove a barrier to trial enrollment.

SummaryBendamustine (B) with rituximab (R) is a standard frontline treatment for medically fit follicular lymphoma (FL) patients. The safety and efficacy of maintenance rituximab (MR) after BR induction has not been formally compared to observation for FL, resulting in disparate practice patterns. Prospective trials have shown benefit of MR after R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or R‐CVP (rituximab, cyclophosphamide, vincristine, prednisone), yet recent data from the GALLIUM study comparing outcomes of patients treated with chemotherapy with R or obinutuzumab (G) showed higher than anticipated fatal adverse events with BR/BG. In order to assess the efficacy and tolerability of MR after BR, we retrospectively collected data on 640 newly diagnosed patients treated with FL. We found that patients who achieved partial remission (PR) after ≥4 cycles of BR had improved duration of response (DOR) with MR vs. no maintenance, whereas those in complete remission did not. These findings were confirmed in a validation cohort. In the entire study population, the known fatal adverse event rate after BR was 2·5% and did not significantly differ in those receiving MR versus no maintenance. [Correction added on 14 January 2019, after online publication: The preceding sentence has been corrected in this current version.] Within the limitations inherent to retrospective analysis, these data suggest that FL patients with a PR to BR experience prolongation of remission with MR with an acceptable safety profile.