Pitcher, Brandelyn N.

Follicular lymphoma (FL) is an indolent B-cell neoplasm of germinal center origin. Standard treatment regimens consist of anti-CD20 therapy with or without chemotherapy. While high response rates to initial therapy are common, patients ultimately relapse or have progressive disease. Clinical risk factors such as the Follicular Lymphoma International Prognostic Index (FLIPI) have been identified, but there is a need for prognostic and predictive biomarkers. We studied markers of lymphoma cells and tumor microenvironment by immunohistochemistry in tissue samples from patients enrolled in 1 of 4 phase 2 trials of anti–CD20-based biological therapy for previously untreated grades 1 to 2 or 3A FL. Results were correlated with progression-free survival (PFS) and PFS status at 24 months. The 4 trials included 238 patients (51.1% male, median age: 55 y) with stage III, IV, or bulky stage II disease. By FLIPI, 24.6% had low-risk, 56.8% had intermediate-risk, and 18.6% had high-risk disease. The outcome differed significantly for patients treated with lenalidomide and rituximab (CALGB 50803) compared with the other 3 trials (median: PFS not reached vs. 3.0 y, hazard ratio=3.47, 95% confidence interval: 2.11-5.72); therefore, data were stratified by clinical trial (CALGB 50803 vs. all others) and adjusted for FLIPI risk group. Among 154 patients with available tissue, interfollicular BCL6 positivity, interfollicular CD10 positivity, and elevated Ki67 proliferation index ≥30% within neoplastic follicles were each associated with inferior PFS and a high risk of the early event by PFS status at 24 months. We identify promising biomarkers for FL risk stratification that warrant further validation in phase 3 trials.

PURPOSE Alliance/CALGB 50303 (NCT00118209), an intergroup, phase III study, compared dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as frontline therapy for diffuse large B-cell lymphoma. PATIENTS AND METHODS Patients received six cycles of DA-EPOCH-R or R-CHOP. The primary objective was progression-free survival (PFS); secondary clinical objectives included response rate, overall survival (OS), and safety. RESULTS Between 2005 and 2013, 524 patients were registered; 491 eligible patients were included in the final analysis. Most patients (74%) had stage III or IV disease; International Prognostic Index (IPI) risk groups included 26% IPI 0 to 1, 37% IPI 2, 25% IPI 3, and 12% IPI 4 to 5. At a median follow-up of 5 years, PFS was not statistically different between the arms (hazard ratio, 0.93; 95% CI, 0.68 to 1.27; P = .65), with a 2-year PFS rate of 78.9% (95% CI, 73.8% to 84.2%) for DA-EPOCH-R and 75.5% (95% CI, 70.2% to 81.1%) for R-CHOP. OS was not different (hazard ratio, 1.09; 95% CI, 0.75 to 1.59; P = .64), with a 2-year OS rate of 86.5% (95% CI, 82.3% to 91%) for DA-EPOCH-R and 85.7% (95% CI, 81.4% to 90.2%) for R-CHOP. Grade 3 and 4 adverse events were more common ( P < .001) in the DA-EPOCH-R arm than the R-CHOP arm, including infection (16.9% v 10.7%, respectively), febrile neutropenia (35.0% v 17.7%, respectively), mucositis (8.4% v 2.1%, respectively), and neuropathy (18.6% v 3.3%, respectively). Five treatment-related deaths (2.1%) occurred in each arm. CONCLUSION In the 50303 study population, the more intensive, infusional DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. The more favorable results with R-CHOP compared with historical controls suggest a potential patient selection bias and may preclude generalizability of results to specific risk subgroups.

Abstract Background: Older adults represent 50% or more of all newly diagnosed cancer patients annually; these patients have multiple morbidities, complicating treatment decision-making.. Discussions about the risks and benefits of cancer treatments might be improved by having data on estimated all-cause survival. ePrognosis (http://eprognosis.ucsf.edu/carey2.php) is an online tool validated in older adults without cancer. We compared survival estimates using ePrognosis to observed survival in a population of women with early stage breast cancer who volunteered for cooperative group studies. Methods: Participants in CALGB 49907 (n=194) and 369901 (n=809) who were age 70+ were included (total n=1003). Both studies had comparable eligibility: primary, newly diagnosed, invasive, non-metastatic breast cancer. In 49907, eligibly also included PS 0-2; in 369901 there were no PS restrictions, but women who failed a screening cognitive exam were excluded. The Carey 2-year Index from ePrognosis was used to estimate all-cause 2-year survival, based on age, sex, and daily function. Function (needing help from another person to bath and shop for groceries, difficulty walking several blocks and pushing or pulling a heavy object) was derived from the EORTC QLC-30. The Carey index from ePrognosis generates scores from 1-10, with higher scores indicating higher probability of death. Kaplan-Meier methods were used to obtain point estimates and confidence intervals for the observed 2-yr survival. A two sided z-test was used to test the hypothesis that the observed survival rate is equivalent to the predicted survival rate. Results: At two years from study entry, 921 women were alive; 56 had died, and 26 were lost to follow-up/withdrawn. The population was, on average, 76 years old (SD 4.8), primarily white (89.3%), and the majority had hormone receptor positive tumors (79.4%). In our population, the Carey 2-years index predicated survival was not significantly different than observed rates in the 0-2 points and underestimated the survival rates for patients who had 3-6 points and 7-10 points. ePrognosis Prediction49907 & 369901 PatientsPointsPredicted Probability of SurvivalNNumber of DeathsObserved Probability of Overall Survival at 2 years (%, 95% CI)p-value0-295%5332595% (93-97%)0.7433-688%4272394% (92-96%)&lt;0.0017-1064%43881% (65-90%)0.017 Conclusions: In this population of older women with breast cancer, using a few readily available data items, ePrognosis provided accurate survival estimates for women with a low probability of death (0-2 points) and underestimated all-cause survival in women with an increased probability of death (3-10 points). Further studies are needed to assess the validity of this tool in samples of cancer patients with higher risks of 2-year mortality. Extended follow-up to validate the tools in predicting 5- and 10-year all-cause and non-cancer mortality risk will further contribute to decision making in older patients. Citation Format: Kimmick G, Pitcher B, Mandelblatt J, Clapp J, Ballman K, Barginear M, Freedman R, Artz A, Klepin H, Lafky J, Hopkins J, Winer E, Hudis C, Muss H, Cohen H, Jatoi A, Hurria A. All-cause survival estimates compared to observed survival in older women with breast cancer in CALGB 49907 and 369901 (Alliance A151503). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-09-10.

Comorbidity was associated with shorter overall survival but not toxicity or relapse among older women with breast cancer with good functional status.