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Background Because follicular lymphoma (FL) patients have heterogeneous outcomes, the FL international prognostic index (FLIPI) was developed to risk-stratify patients and to predict survival. However, limited data exist regarding the role of FLIPI in the era of routine first-line rituximab (R) and R-chemotherapy regimens and in the setting of community oncology practices. Patients and Methods We evaluated the outcome data from the National LymphoCare Study (NLCS), a prospective, observational cohort study, which collects data on patients with FL in the United States (US) community practices. Results Among 1068 male and 1124 female patients with FLIPI data, most were treated in US community practices (79%); 35% were FLIPI good risk, 30% intermediate risk, and 35% poor risk. FLIPI risk groups were significant predictors of overall survival (OS) and progression-free survival (PFS) for patients who undergo watchful waiting (WW), and those who receive non-R-containing regimens, R-alone, and R-chemotherapy combinations. Conclusions In the setting of contemporary practice with routine R use, stratifying patients into good, intermediate, and poor FLIPI risk groups predicts distinct outcomes in terms of OS and PFS. FLIPI remains an important prognostic index in the R era and should be used in clinical practices to support discussions about prognosis. [ABSTRACT FROM PUBLISHER]

We assessed the incidence, prognostic features, and outcomes associated with transformation of follicular lymphoma (FL) among 2652 evaluable patients prospectively enrolled in the National LymphoCare Study. At a median follow-up of 6.8 years, 379/2652 (14.3%) patients transformed following the initial FL diagnosis, including 147 pathologically confirmed and 232 clinically suspected cases. Eastern Cancer Oncology Group performance status >1, extranodal sites >1, elevated lactate dehydrogenase, and B symptoms at diagnosis were associated with transformation risk. Relative to observation, patients initiating treatment at diagnosis had a reduced risk of transformation (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.46-0.75). The risk of transformation was similar in patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone compared with rituximab, cyclophosphamide, vincristine, and prednisone (adjusted HR, 0.94; 95% CI, 0.62-1.42). Maintenance rituximab was associated with reduced transformation risk (HR, 0.67; 95% CI, 0.46-0.97). Five-year survival from diagnosis was significantly worse for patients with vs without transformation (75%, 95% CI, 70-79 vs 85%, 95% CI, 83-86). The median overall survival post-transformation was 5 years. Forty-seven patients with evidence of transformation at the time of diagnosis shared similar prognostic factors and survival rates to those without transformation. Improved outcomes for transformation in the modern era are suggested by this observational study. This trial is registered at www.clinicaltrials.gov as #NCT00097565., (© 2015 by The American Society of Hematology.)

Purpose: Twenty percent of patients with follicular lymphoma (FL) experience progression of disease (POD) within 2 years of initial chemoimmunotherapy. We analyzed data from the National LymphoCare Study to identify whether prognostic FL factors are associated with early POD and whether patients with early POD are at high risk for death., Patients and Methods: In total, 588 patients with stage 2 to 4 FL received first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Two groups were defined: patients with early POD 2 years or less after diagnosis and those without POD within 2 years, the reference group. An independent validation set, 147 patients with FL who received first-line R-CHOP, was analyzed for reproducibility., Results: Of 588 patients, 19% (n = 110) had early POD, 71% (n = 420) were in the reference group, 8% (n = 46) were lost to follow-up, and 2% (n = 12) died without POD less than 2 years after diagnosis. Five-year overall survival was lower in the early-POD group than in the reference group (50% v 90%). This trend was maintained after we adjusted for FL International Prognostic Index (hazard ratio, 6.44; 95% CI, 4.33 to 9.58). Results were similar for the validation set (FL International Prognostic Index-adjusted hazard ratio, 19.8)., Conclusion: In patients with FL who received first-line R-CHOP, POD within 2 years after diagnosis was associated with poor outcomes and should be further validated as a standard end point of chemoimmunotherapy trials of untreated FL. This high-risk FL population warrants further study in directed prospective clinical trials., Competing Interests: Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2015 by American Society of Clinical Oncology.)

Data from the National LymphoCare Study (a prospective, multicentre registry that enrolled follicular lymphoma (FL) patients from 2004 to 2007) were used to determine disease characteristics, treatment patterns, outcomes and prognosis for elderly FL (eFL) patients. Of 2650 FL patients, 209 (8%) were aged >80 years; these eFL patients more commonly had grade 3 disease, less frequently received chemoimmunotherapy and anthracyclines, and had lower response rates when compared to younger patients. With a median follow-up of 6.9 years, 5-year overall survival (OS) for eFL patients was 59%; 38% of deaths were lymphoma-related. No treatment produced superior OS among eFL patients. In multivariate Cox models, anaemia, B-symptoms and male sex predicted worse OS (P < 0.01); a prognostic index of these factors (0, 1 or ≥ 2 present) predicted OS [hazard ratio (95% CI): ≥ 2 vs. 0, 4.72 (2.38-9.33); 1 vs. 0, 2.63 (1.39-4.98)], with a higher concordance index (0.63) versus the Follicular Lymphoma International Prognostic Index (0.55). The index was validated in an independent cohort. In the largest prospective US-based eFL cohort, no optimal therapy was identified and nearly 40% of deaths were lymphoma-related, representing baseline outcomes in the modern era., Competing Interests: Conflict-of-interest disclosures: C.N discloses consulting/advisory board roles for Genentech, Janssen, Celgene, Astellas, and Gilead. M.B discloses employment and stock options with Genentech. J.R.C discloses consulting/advisory roles with Genentech. K.D discloses employment and stock options with Genentech. C.R.F discloses consulting/advisory roles with Algeta, OptumRx, Biogen Idec, Genentech BioOncology, Roche, Celgene and research funding from Abbott, Celgene, Millennium/Takeda, Spectrum, Gilead, and Janssen/Pharmacyclics. J.W.F has no relevant conflict of interests to disclose. B.K.L discloses honoraria from Genentech, consulting and advisory roles with Genentech, AbbVie, Gilead, and research funding from Genentech, Millennium, Pharmacyclics, and Janssen. M.J.M has no relevant conflict of interests to disclose. A.R has no relevant conflict of interests to disclose. A.D.Z discloses consulting /advisory roles with Genentech, Celegene, Gilead, Amgen, Hospira, Reddy Laboratories and research funding from Genentech/Roche, Gilead, and BMS. X.Z is employed by RTI-HS, which has a research contract with Genentech., (© 2015 John Wiley & Sons Ltd.)

To compare the effectiveness of frontline rituximab-chemotherapy regimens in clinical practice, we examined outcomes for patients with low-grade, stage III/IV follicular lymphoma receiving rituximab (R) with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), R with cyclophosphamide, vincristine and prednisone (R-CVP) or R with a fludarabine-based regimen (R-Flu) as frontline therapy. In total, 611 patients meeting these criteria were identified in the National LymphoCare Study: 47% receiving R-CHOP (n = 287), 31% receiving R-CVP (n = 187) and 22% receiving R-Flu (n = 137). Overall response rates were high (R-CVP 87%, R-CHOP 93%, R-Flu 94%; p = 0.017). Median follow-up was 7.4 years. R-CVP was associated with lower 5-year overall survival (R-CVP 76%, R-CHOP 86%, R-Flu 86%; p = 0.021) and progression-free survival (R-CVP 49%, R-CHOP 58%, R-Flu 64%; p = 0.029). There were no significant differences in survival in Cox models adjusted for baseline clinical factors, practice region/setting and post-treatment R maintenance/observation.

Background: The authors examined the "real-world" effectiveness of rituximab (R) maintenance therapy (R-maintenance) compared with observation after R-based induction therapy in patients with previously untreated follicular lymphoma (FL) in the United States., Methods: The National LymphoCare Study is a prospective, multicenter, observational study that enrolled > 2700 untreated patients with FL diagnosed from 2004 to 2007 at 265 sites in the United States. Among these, patients who achieved at least stable disease after R-based induction therapy were eligible for the current analysis. Patients who initiated R-maintenance within 215 days of completing induction therapy were categorized as the R-maintenance group, and those who did not initiate therapy during this period were categorized as the observation group. The objective of the current study was to determine the effect of R-maintenance on progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS)., Results: A total of 1439 patients completed R-based induction therapy, 1186 of whom met all inclusion criteria (541 patients received R-maintenance and 645 patients were observed). Characteristics that were found to be predictive of receiving R-maintenance were histology grade (1/2), Ann Arbor stage of disease (III/IV), geographic region (region other than the West), and practice setting (community practice). With a median follow-up of 5.7 years, R-maintenance was associated with superior PFS (hazards ratio [HR], 0.68; 95% confidence interval [95% CI], 0.56-0.84 [P = .0003]) and TTNT (HR, 0.66; 95% CI, 0.52-0.84 [P = .0007]). No significant difference in OS was observed (HR, 0.81; 95% CI, 0.58-1.14 [P = .23])., Conclusions: R-maintenance in patients with FL and at least stable disease after R-based induction therapy provided significantly longer PFS and TTNT in comparison with observation, but no significant difference in OS was observed with 5-years of follow-up. This comparative effectiveness study aligns with the results of randomized trials suggesting that similar outcomes occur with R-maintenance in FL with the treatment variations observed in clinical practice., (© 2014 The Authors.Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Background: Drug choice and delivered dose of treatment potentially influence outcome in patients treated for follicular lymphoma (FL). Historically, observational studies have evaluated drug choice. The National LymphoCare Study (NLCS) is a prospective, observational study of patients with FL who were enrolled at academic and community practice sites in the United States between 2004 and 2007. In the current study, the authors report on measures of delivered dose and its impact on outcomes for the most common first-line regimens., Methods: All evaluable patients with FL who were treated with initial rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP); or rituximab plus a fludarabine-containing regimen (R-Flu) were included. Associations between baseline factors, choice of treatment, number of cycles received, completion of therapy, and patient outcomes were assessed., Results: A total of 646 patients received R-CHOP, 297 received R-CVP, and 222 received R-Flu. Characteristics were similar between the 3 groups with the following exceptions. Patients receiving R-CHOP were more often found to have grade 3 FL and patients receiving R-CVP were older and had higher Follicular Lymphoma International Prognostic Index scores. The majority of patients (80%) received ≥ 5 cycles of treatment. Toxicity, but not disease progression, was commonly cited as the reason for the early discontinuation of treatment (51% vs 6%). Time to retreatment was shorter for patients receiving ≤ 4 cycles, regardless of the treatment regimen used. The number of cycles was associated with overall survival, progression-free survival, and lymphoma-related mortality for patients receiving R-CVP., Conclusions: The majority of patients with FL receiving chemoimmunotherapy in the NLCS completed ≥ 5 cycles of treatment. Strategies to improve dose delivery appear unlikely to impact outcomes, except possibly in patients receiving R-CVP. Although early treatment discontinuation appears to be associated with survival, this analysis does not implicate causality., (© 2013 American Cancer Society.)

Background: Racial differences in follicular lymphoma (FL) in the United States have not been investigated., Methods: The National LymphoCare Study is a multicenter, longitudinal, observational cohort study collecting data on treatment patterns and outcomes for patients with newly diagnosed FL in the United States between 2004 and 2007 without any predefined, study-specific intervention. The authors investigated differences between white (W) patients, African American (AA) patients, and Hispanic (H) patients., Results: Among 2744 enrolled patients, there were 95 (3%) AA patients, 125 (5%) H patients, and 2476 (90%) W patients. Compared with W patients, more AA and H patients were diagnosed at age <45 years (P < .0001). H patients more commonly were diagnosed with grade 3 FL compared with AA and W patients (29%, 13%, and 18%, respectively; P = .019) and more commonly received rituximab plus chemotherapy as initial therapy compared with W patients (66% vs 50%; P = .036), while AA patients less commonly received anthracyclines (49% vs 64% in W patients; P = .027). H and AA patients who received rituximab plus chemotherapy were less likely than W patients to receive maintenance rituximab (27% vs 31% vs 40%, respectively; P = .031). At a median follow-up of 52 months, progression-free survival was similar between AA and W patients but was longer in H patients, and there was no difference in overall survival., Conclusions: In the largest prospective cohort to date of AA and H patients with FL in the United States, AA and H patients were younger at presentation. Although racial differences in treatment patterns for FL were noted, additional follow-up is needed to determine the impact of these differences on survival., (Copyright © 2012 American Cancer Society.)

Purpose: The optimal management of stage I follicular lymphoma, according to consensus guidelines, is based on uncontrolled experiences of select institutions. Diverse treatment approaches are used despite guidelines that recommend radiation therapy (XRT)., Patients and Methods: We analyzed outcomes of patients with stage I follicular lymphoma enrolled onto the National LymphoCare database., Results: Of 471 patients with stage I follicular lymphoma, 206 patients underwent rigorous staging as defined by both a bone marrow aspirate and biopsy and an imaging study (a computed tomography [CT] scan of the whole body, a positron emission tomography [PET]/CT scan, or both). Rigorously staged patients had superior progression-free survival (PFS) compared with nonrigorously staged patients (hazard ratio [HR], 0.63). Treatments given to rigorously staged patients were rituximab/chemotherapy (R-chemo; 28%), XRT (27%), observation (17%), systemic therapy + XRT (13%), rituximab monotherapy (12%), and other (3%). With a median follow-up of 57 months for PFS, there were 44 progression events (in 21% of patients) for rigorously staged patients. For these patients, PFS was significantly improved with either R-chemo or systemic therapy + XRT compared with patients receiving XRT alone after adjustment for histology, LDH, and the presence of B symptoms. There were no differences in overall survival., Conclusion: In this largest, prospectively enrolled group of patients with stage I follicular lymphoma, variable treatment approaches resulted in similar excellent outcomes, which challenges the paradigm that XRT should be standard for this presentation.