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Abstract: Progression of disease within 24 months of initial immunochemotherapy (POD24) is a negative prognostic factor for patients with follicular lymphoma (FL). There is no standard treatment after POD24. Assembling an academic-based cohort from the Lymphoma Epidemiology of Outcomes Consortium for Real World Evidence, we evaluated patterns of care and outcomes for 220 patients with FL with POD24 and retained FL histology. Therapy after POD24 was heterogeneous, with no treatment category accounting for >25% of the total. Among patients initially treated with bendamustine-rituximab, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) was the predominant second-line choice (48%). Among patients initially treated with R-CHOP, aggressive salvage therapy was the predominant second-line choice (38%). Overall response rate to therapy after POD24 was 64% (95% confidence interval [CI], 56-70); complete response rate was 39% (95% CI, 32-46). The median event-free survival for therapy after POD24 was 9.8 months (95% CI, 7.3-12.1); 5-year overall survival (OS) was 71% (95% CI, 65-78). OS was inferior for patients aged >70 years (hazard ratio [HR], 2.31; 95% CI, 1.27-4.20) and those with high-risk FL International Prognostic Index scores at diagnosis (HR, 2.10; 95% CI, 1.23-3.60). No treatment category stood out with more favorable results. Cause of death was predominantly lymphoma related. Patients with follicular histology at their POD24 event had a low cumulative incidence of transformation (1.1% at 5 years). Our study is among the largest cohorts describing contemporary patterns of care for patients with POD24, providing a focused data set useful for interpreting and designing prospective clinical trials in this population., (© 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: We report patient-reported outcomes (PROs) measuring health-related quality of life (HRQoL) from the ROSEWOOD trial (NCT03332017), which demonstrated superior efficacy and a manageable safety profile with zanubrutinib plus obinutuzumab (ZO) versus obinutuzumab (O) in patients with heavily pretreated relapsed/refractory follicular lymphoma (R/R FL)., Methods: PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) and EQ-5D-5L questionnaires at baseline and subsequently every 12 weeks. All QLQ-C30 domains and EQ-5D-5L visual analog scale (VAS) scores were analyzed descriptively. At the key clinical timepoints (weeks 12 and 24), a mixed model for repeated measures (MMRM) analysis was used to evaluate the key PRO endpoints, including global health status, physical and role functioning, and symptoms of fatigue, pain, diarrhea, and nausea/vomiting. Clinically meaningful change was defined as a  ≥ 5-point mean difference from baseline and between the ZO and O arms., Results: Patients were randomized to ZO ( n  = 145) or O ( n  = 72). By week 48, descriptive analysis results indicated that patients in the ZO arm demonstrated improved outcomes in role functioning and fatigue and nausea/vomiting symptoms, compared with those in the O arm. Both groups experienced improvements in pain symptoms. EQ-5D-5L VAS scores showed no observable differences between treatment arms through week 48. MMRM analysis revealed that the global health status/quality of life of patients treated with ZO improved, as did fatigue, at week 12. At week 24, patients in the ZO arm experienced a clinically meaningful improvement in role functioning, pain, and fatigue., Conclusions: In patients with R/R FL, ZO was associated with improved PROs compared with O. These findings suggest that zanubrutinib contributed clinically meaningful benefits to patient HRQoL when added to obinutuzumab., Trial Registration: The ROSEWOOD trial is registered on ClinicalTrials.gov (BGB-3111-212; ClinicalTrials.gov identifier: NCT03332017).

Mosunetuzumab is a novel bispecific antibody targeting epitopes on CD3 on T cells and CD20 on B cells with the goal of inducing T-cell mediated elimination of malignant B cells. A recent pivotal phase I/II clinical trial (GO29781) demonstrated that mosunetuzumab induced an overall response rate (ORR) of 80%, complete response (CR) rate of 60%, and a median progression-free survival (PFS) of 17.9 months in patients with relapsed/refractory (R/R) follicular lymphoma (FL) following at least two prior lines of systemic therapy, including alkylator and anti-CD20 antibody-based therapy. Historical data from cohorts receiving therapy for R/R FL can provide some context for interpretation of single-arm trials. We compared the results from the mosunetuzumab trial to outcomes from a cohort of patients with R/R FL from the LEO Consortium for Real World Evidence (LEO CReWE). We applied clinical trial eligibility criteria to the LEO CReWE cohort and utilized matching- adjusted indirect comparison weighting to balance the clinical characteristics of the LEO CReWE cohort with those from the mosunetuzumab trial. ORR (73%, 95% CI: 65-80%) and CR rates (53%, 95% CI: 45-61%) observed in the weighted LEO CReWE cohort were lower than those reported on the mosunetuzumab trial (ORR=80%, 95% CI: 70-88%; CR=60%, 95% CI: 49-70%, respectively). PFS at 12 months was similar in the weighted LEO CReWE (60%, 95% CI: 51-69%) and the mosunetuzumab (58%, 95% CI: 47-68%) trial. Sensitivity analyses examining the impact of matching variables, selection of line of therapy, and application of eligibility criteria provide context for best practices in this setting.

Follicular lymphoma (FL) is the most common type of indolent non-Hodgkin lymphoma. Despite treatment advances that have improved outcomes for patients with relapsed or refractory (R/R) FL, many patients still die from progressive disease or treatment-related toxicities. In the phase Ib/II GO29365 study (clinicaltrials.gov 02257567), the safety and efficacy of polatuzumab vedotin plus bendamustine and rituximab (Pola-BR) versus bendamustine and rituximab (BR) alone, and polatuzumab vedotin plus bendamustine and obinutuzumab (Pola-BG) as a single-arm cohort were evaluated in patients with R/R FL. Following the phase Ib safety run-in, patients were randomized 1:1 to receive Pola-BR or BR alone in the phase II stage; a separate non-randomized Pola-BG cohort was examined in the phase Ib/II expansion stage. Primary endpoints included safety and tolerability (phase Ib) and positron emission tomography complete response (PET-CR) rate by independent review committee (phase II). Overall, 112 patients were enrolled (phase Ib safety run-in: Pola-BR, N=6; phase II randomized cohort: Pola-BR, N=39; BR, N=41; phase Ib/II expansion cohort: Pola-BG, N=26). PET-CR rates were 66.7% (phase Ib safety run-in, Pola-BR); 69.2% (phase II randomized, Pola-BR); 63.4% (phase II randomized, BR); and 65.4% (phase Ib/II expansion Pola-BG). There was a higher occurrence of cytopenias with Pola-BR and Pola-BG than with BR; serious adverse events were more frequent with Pola-BR (61.4%) and Pola-BG (46.2%) than with BR (29.3%). Overall, this analysis does not demonstrate a benefit of adding Pola to BR or BG regimens for patients with R/R FL.

Background: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent non-Hodgkin lymphomas (iNHL). Median survival for iNHL is approximately 20 years. Because standard treatments are not curative, patients often receive multiple lines of therapy with associated toxicity-rationally designed, combination therapies with curative potential are needed. The immunomodulatory drug lenalidomide was evaluated in combination with rituximab for the frontline treatment of FL in the phase 3 RELEVANCE study. Ibrutinib, an oral Bruton tyrosine kinase inhibitor, is active in NHL and was evaluated in combination with lenalidomide, rituximab, and ibrutinib (IRR) in a phase 1 study., Methods: The authors conducted an open-label, phase 2 clinical trial of IRR for previously untreated FL and MZL. The primary end point was progression-free survival (PFS) at 24 months., Results: This study included 48 participants with previously untreated FL grade 1-3a (N = 38), or MZL (N = 10). Participants received 12, 28-day cycles of lenalidomide (15 mg, days 1-21 cycle 1; 20 mg, cycles 2-12), rituximab (375 mg/m 2 weekly in cycle 1; day 1 cycles 2-12), and ibrutinib 560 mg daily. With a median follow-up of 65.3 months, the estimated PFS at 24 months was 78.8% (95% confidence interval [CI], 68.0%-91.4%) and 60-month PFS was 59.7% (95% CI, 46.6%-76.4%). One death occurred unrelated to disease progression. Grade 3-4 adverse events were observed in 64.6%, including 50% with grade 3-4 rash., Conclusions: IRR is highly active as frontline therapy for FL and MZL. Compared to historical results with lenalidomide and rituximab, PFS is similar with higher grade 3-4 toxicity, particularly rash. The study was registered with ClinicalTrials.gov (NCT02532257)., (© 2023 American Cancer Society.)

Purpose: The combination of zanubrutinib plus obinutuzumab (ZO) was found to be well tolerated with an early signal of efficacy in a phase Ib study. ROSEWOOD is a phase II, randomized study that assessed the efficacy and safety of ZO versus obinutuzumab in patients with relapsed/refractory (R/R) follicular lymphoma (FL)., Methods: Patients with R/R FL who had received ≥2 lines of therapy, including an anti-CD20 antibody and an alkylating agent, were randomly assigned 2:1 to receive ZO or obinutuzumab (O). The primary end point was overall response rate (ORR) by independent central review (ICR). Secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival, and safety., Results: A total of 217 patients were randomized (ZO, 145; O, 72). Median study follow-up was 20.2 months. The study met its primary end point: ORR by ICR was 69% (ZO) versus 46% (O; P = .001). Complete response rate was 39% (ZO) versus 19% (O); 18-month DOR rate was 69% (ZO) versus 42% (O). Median PFS was 28.0 months (ZO) versus 10.4 months (O; hazard ratio, 0.50 [95% CI, 0.33 to 0.75]; P < .001). The most common adverse events with ZO were thrombocytopenia, neutropenia, diarrhea, and fatigue; incidences of atrial fibrillation and major hemorrhage were 3% and 1%, respectively., Conclusion: The combination of ZO met its primary end point of a superior ORR versus O, and demonstrated meaningful activity and a manageable safety profile in patients with R/R FL. ZO had a favorable benefit-risk profile compared with O, and represents a potential combination therapy for patients with R/R FL.

Introduction/background: Leveraging the Follicular Lymphoma Analysis of Surrogacy Hypothesis database of individual patient data from first-line clinical trials, we studied the clinical course of follicular lymphoma (FL) and investigated clinical factors associated with FL outcomes., Patients and Methods: We examined 2428 patients from 8 randomized trials using multistate survival models with 4 states: induction treatment, progression, death from FL, and death from other causes. We utilized Aalen-Johansen estimator and Cox models to assess the likelihood of FL outcomes and quantify predictors' effects., Results: Two-year progression, FL-related death, and death from other causes estimates were 26.5%, 3.4% and 1.4%, respectively. FL-associated deaths were the primary cause of mortality within 10 years of follow-up. Male sex (hazard ratio: 1.25; 95% confidence interval: 1.05-1.47), > 4 involved nodal areas (1.51; 1.23-1.86), elevated LDH (1.20; 1.01-1.43), low hemoglobin (1.44; 1.15-1.81), and elevated β-2 levels (1.23; 1.02-1.47) increased risk of progression. CD20-targeting agents reduced risks for progression (0.29; 0.22-0.39), death from FL (0.05; 0.01-0.20), and death from other causes without progression (0.13; 0.05-0.33) and following progression (0.52; 0.30-0.92). Estimated 2-year progression rates were 22.3% and 43.5% with or without CD20-targeting agents, respectively. Two-year FL-associated mortality rate was 8.3% among patients without CD20-targeting agents, 5.4% with B-symptoms, 4.9% with elevated LDH, and 9.1% with low hemoglobin., Conclusion: This study identified independent contributions of baseline clinical factors to distinct outcomes for patients with FL following first-line therapy on a clinical trial. Similar analytical approaches are needed to increase understanding of factors that influence FL outcomes in other settings., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: One key clinical challenge remains in how to sequence treatments in follicular lymphoma (FL). The chemoimmunotherapy rituximab cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone (R-CHOP) has been a standard treatment option for two decades. However, there are limited data to suggest in which line R-CHOP should be used for older patients., Patients and Methods: We leveraged population-based surveillance, epidemiology, and end results-medicare data and identified 675 patients aged ≥65 years newly diagnosed with FL from 2000 to 2009 who received R-CHOP in either the first or second line. We estimated restricted mean survival time using Kaplan-Meier curves, propensity scores (PS), and regression models comparing patients who received R-CHOP as a first versus second line., Results: We found that patients who received R-CHOP as first line had significantly longer 9-year RMST than those who received R-CHOP in the second line using Kaplan-Meier curves (P = .01), PS stratification (P = .002), PS matching (P = .005), and the inverse of PS as the treatment weight (P < .0001). The subgroup analyses using linear regression models showed that the 9-year restricted mean survival time of patients who received R-CHOP as the first line was longer in patients aged ≥80 years (P = .002) and with histological grade 1 or 2 (P = .02), compared to those who received R-CHOP as second line., Conclusion: R-CHOP given in the first line was associated with longer overall survival compared to R-CHOP given as second line for older patients with FL., (Copyright © 2022. Published by Elsevier Inc.)

Cancer clinical trial eligibility criteria may create patient populations studied in trials that do not reflect the patient populations treated in the real-world setting. Follicular lymphoma (FL) is an indolent lymphoma with heterogeneous presentations across a broad range of individuals, resulting in many acceptable management strategies. We evaluated how first-line clinical trial eligibility criteria impacted the demographic makeup and outcomes of patients with FL for whom systemic therapy might be considered. We compared the characteristics of 196 patients with FL from a single institution to eligibility criteria from 10 first-line FL trials on clinicaltrials.gov. Next, we tabulated eligibility criteria from 24 first-line FL protocols and evaluated their impact on 1198 patients with FL with stages II to IV disease from the prospective Molecular Epidemiology Resource (MER) and Lymphoma Epidemiology of Outcomes (LEO) cohort studies. We found that 39.8% and 52.7% of patients with FL might be excluded from clinical trials based on eligibility criteria derived from clinicaltrials.gov and protocol documents, respectively. Patients excluded because of renal function, prior malignancy, and self-reported serious health conditions tended to be older. Expanding stage requirement from III-IV to II-IV, and platelet requirement from ≥150 000 to ≥75 000 increased population size by 21% and 8%, respectively, in MER and by 16% and 13%, respectively, in LEO, without impacting patient demographics or outcomes. These data suggest that management of older individuals with FL may not be fully informed by recent clinical trials. Moreover, liberalizing stage and platelet criteria might expand the eligible population and allow for quicker trial accrual without impacting outcomes., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Limited data exist regarding the outcome of patients with follicular lymphoma (FL) who relapse or progress after frontline lenalidomide and rituximab (R2). Moreover, mechanisms of resistance to R2 in FL remain unclear, with increased protumoral macrophages suspected as a major contributory culprit to this phenomenon. This retrospective study analyzed the outcome of patients with advanced-stage FL grade 1 to 3A who relapsed or progressed after frontline R2. A multiplex immunofluorescence macrophage panel, including CD47, CD14, CD68, CD115 (also known as colony-stimulating factor 1 receptor [CSF1R]), CD163, CD172a (also known as signal regulatory protein α [SIRPα]), and CD274 (also known as programmed cell death-ligand 1 [PDL1]), was used to stain tissue biopsy specimens collected before initiation of R2 and at the time of progression. Among 156 patients with advanced-stage FL treated with frontline R2, 33 (21%) relapsed or progressed and required second-line therapy, after a median of 33 months (range, 1-122 months). Second-line therapy was chemoimmunotherapy in 16 (48%) patients and other therapy in 17 (52%). The overall response rate was 78%, and complete response rate was 72%. Median progression-free survival was significantly longer in patients who received chemoimmunotherapy compared with other therapy (99 vs 25 months; P = .004). Three macrophage populations were significantly increased in tissue samples collected at progression compared with before frontline treatment: CD68+CD115+ (P = .02), CD68+CD115+CD172a+ (P = .02), and CD68+CD163+CD172a+ (P = .01). Chemoimmunotherapy is an effective treatment strategy for patients with FL who relapse after frontline R2. Therapies targeting specific macrophage populations may yield novel approaches for improving outcomes with frontline R2., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: A previous International Lymphoma Epidemiology (InterLymph) Consortium evaluation of joint associations between five immune gene variants and autoimmune conditions reported interactions between B-cell response-mediated autoimmune conditions and the rs1800629 genotype on risk of B-cell non-Hodgkin lymphoma (NHL) subtypes. Here, we extend that evaluation using NHL subtype-specific polygenic risk scores (PRS) constructed from loci identified in genome-wide association studies of three common B-cell NHL subtypes., Methods: In a pooled analysis of NHL cases and controls of Caucasian descent from 14 participating InterLymph studies, we evaluated joint associations between B-cell-mediated autoimmune conditions and tertile (T) of PRS for risk of diffuse large B-cell lymphoma (DLBCL; n = 1,914), follicular lymphoma (n = 1,733), and marginal zone lymphoma (MZL; n = 407), using unconditional logistic regression., Results: We demonstrated a positive association of DLBCL PRS with DLBCL risk [T2 vs. T1: OR = 1.24; 95% confidence interval (CI), 1.08-1.43; T3 vs. T1: OR = 1.81; 95% CI, 1.59-2.07; P-trend (Ptrend) < 0.0001]. DLBCL risk also increased with increasing PRS tertile among those with an autoimmune condition, being highest for those with a B-cell-mediated autoimmune condition and a T3 PRS [OR = 6.46 vs. no autoimmune condition and a T1 PRS, Ptrend < 0.0001, P-interaction (Pinteraction) = 0.49]. Follicular lymphoma and MZL risk demonstrated no evidence of joint associations or significant Pinteraction., Conclusions: Our results suggest that PRS constructed from currently known subtype-specific loci may not necessarily capture biological pathways shared with autoimmune conditions., Impact: Targeted genetic (PRS) screening among population subsets with autoimmune conditions may offer opportunities for identifying those at highest risk for (and early detection from) DLBCL., (©2022 The Authors; Published by the American Association for Cancer Research.)

Intratumoral injection of G100, a toll-like receptor 4 (TLR4) agonist, was shown pre-clinically to stimulate anti-tumor immune responses and tumor regression. This open-label, multicenter, phase 1/2 trial evaluated the safety, tolerability, and preliminary efficacy of intratumoral G100 injections following localized low-dose radiation in patients with follicular lymphoma (ClinicalTrials.gov #NCT02501473). The study was comprised of a G100 dose escalation (5 or 10 µg/dose, or 20 µg/dose for large tumors); a randomized component comparing G100 to G100 plus pembrolizumab; and G100 20 µg/dose expansion. Adverse events grade ≥3 were uncommon in patients treated with G100, and no unexpected toxicities were observed when combined with pembrolizumab. G100 20 µg ( n  = 18) resulted in an overall response rate of 33.3% and abscopal tumor regression in 72.2% of patients. This early-phase study provides a foundation for combining an intratumoral TLR4 agonist with agents to produce immune-mediated responses in follicular lymphoma with limited added toxicity.

Background: Novel therapies for relapsed or refractory follicular lymphoma are commonly evaluated in single-arm studies without formal comparison with other treatments or historical controls. Consequently, rigorously defined treatment outcomes informing expectations for novel therapeutic strategies in this population are sparse. To inform outcome expectations, we aimed to describe treatment patterns, survival outcomes, and duration of response in patients with relapsed or refractory follicular lymphoma receiving three or more lines of systemic therapy., Methods: In this multicentre cohort study, we developed a database of patients with relapsed or refractory follicular lymphoma from eight academic centres in the USA using data collected in the LEO Cohort study (NCT02736357) and the LEO Consortium. For this analysis, eligible patients were aged at least 18 years, had non-transformed grade 1-3a follicular lymphoma, and were receiving systemic therapy in the third line or later after previous therapy with an anti-CD20 antibody and an alkylating agent. Clinical data and patient outcomes were abstracted from medical records by use of a standard protocol. The index therapy for the primary analysis was defined as the first line of systemic therapy after the patient had received at least two previous systemic therapies that included an alkylating agent and an anti-CD20 therapy. The main endpoints of interest were overall response rate, progression-free survival, and overall survival. Outcomes were also evaluated in subsets of clinical interest (index therapy characteristics, patient and disease characteristics, treatment history, and best response assessment)., Findings: We screened 933 patients with follicular lymphoma, of whom 441 were included and diagnosed between March 6, 2002, and July 20, 2018. Index therapies included immunochemotherapy (n=133), anti-CD20 antibody monotherapy (n=53), lenalidomide with or without anti-CD20 (n=37), and phosphoinositide 3-kinase inhibitors with or without anti-CD20 (n=25). 57 (13%) of 441 patients received haematopoietic stem-cell transplantation and 98 (23%) of 421 patients with complete data received therapy on clinical trials. After a median follow-up of 71 months (IQR 64-79) from index therapy, 5-year overall survival was 75% (95% CI 70-79), median progression-free survival was 17 months (15-19), and the overall response rate was 70% (65-74; 280 of 400 patients evaluable for response). Patients who were refractory to therapy with an alkylating agent had a lower overall response rate (170 [68%] of 251 patients vs 107 [77%] of 139 patients) and a significantly lower 5-year overall survival (72%, 95% CI 66-78 vs 81%, 73-89; hazard ratio 1·60, 95% CI 1·04-2·46) than patients who were not refractory to therapy with an alkylating agent., Interpretation: Patients with relapsed or refractory follicular lymphoma receive heterogeneous treatments in the third-line setting or later. We observed high response rates to contemporary therapies that were of short duration. These data identify unmet needs among patients with follicular lymphoma, especially those who are refractory to alkylating agents, and might provide evidence by which clinical trials evaluating novel treatments could be assessed., Funding: Genentech and the National Cancer Institute., Competing Interests: Declaration of interests CC reports research funding from Gilead Sciences, Bristol Myers Squibb, Verastem, and GNE. ISL is on advisory boards for Seattle Genetics, Janssen Scientific, and Verastem. YW reports that research funding has been provided to his institution from Incyte, InnoCare, LOXO Oncology, Novartis, and Genentech, and advisory board membership for Lilly Oncology, Incyte/MorphoSys, and TG Therapeutics (but was not personally compensated for his participation). LJN reports honorarium from ADC Therapeutics, Bayer, Bristol Myers Squibb/Celgene, Epizyme, Genentech, Janssen, Gilead Sciences/Kite, Morphosys, Novartis, Pfizer, Takeda, and TG Therapeutics, and research funding from Bristol Myers Squibb/Celgene, Caribou Biosciences, Epizyme, Genentech, Janssen, Gilead Sciences/Kite, IGM Biosciences, Novartis, Pfizer, Takeda, and TG Therapeutics. CS reports honorarium from Bristol Myers Squibb. DC reports honorarium from AstraZeneca. PM reports research funding from Karyopharm and consultancy for ADC Therapeutics, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Cellectar, Epizyme, Gilead Sciences, Incyte, Janssen, Karyopharm, Regeneron, Takeda, Teneobio, and Verastem. JBC reports research funding and advisory board membership for Genentech. BSK reports research funding and consultancy for F. Hoffmann-La Roche and Genentech. JLK reports research funding from the American Association for Cancer Research (underwritten by Pharmacyclics, an AbbVie Company, and Janssen Biotech), the Lymphoma Research Foundation (underwritten by Celgene), Oncternal Therapeutics, and Viracta Therapeutics, and advisory board membership for Janssen Biotech. YM, AM, MW, MCW, AS, and JL report employment by Genentech and ownership of shares in F. Hoffmann-La Roche. JC reports research funding from GNE, NanoString, and Celgene/Bristol Myers Squibb, and advisory board membership for Celgene/Bristol Myers Squibb. CRF reports research funding from 4D, AbbVie, Acerta, Adaptimmune, Allogene, Amgen, Bayer, Celgene, Cellectis, EMD, Gilead, Genentech, F. Hoffmann-La Roche, Guardant, Iovance, Janssen Pharmaceutical, Kite, Morphosys, Nektar, Novartis, Pfizer, Pharmacyclics, Sanofi, Takeda, TG Therapeutics, Xencor, Ziopharm, Burroughs Wellcome Fund, the Eastern Cooperative Oncology Group, the National Cancer Institute, the V Foundation, and Cancer Prevention and Research Institute of Texas Scholar in Cancer Research, and consultancy for AbbVie, Bayer, BeiGene, Celgene, Denovo Biopharma, Genentech, F. Hoffmann-La Roche, Genmab, Gilead Sciences, Karyopharm, Pharmacyclics/Janssen, SeaGen, and Spectrum. BKL is a consultant for Genentech. MJM reports research funding from Morphosys, Genentech, Bristol Myers Squibb, and Nanostring, and is an advisory board member for Pfizer, Morphosys, and Kite Pharma. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Observational studies and stand-alone trials indicate that patients with follicular lymphoma (FL) who experience disease progression within 24 months of front-line chemoimmunotherapy (POD24), have poor outcomes. We performed a pooled analysis of 13 randomized clinical trials of patients with FL in the pre- and postrituximab eras to identify clinical factors that predict POD24. Logistic regression models evaluated the association between clinical factors and POD24. Cox regression evaluated the association between POD24 as a time-dependent factor and subsequent overall survival (OS). A landmark analysis evaluated the association of POD24 with OS for the subset of patients who were alive at 24 months after trial registration. Patients without progression at 24 months at baseline had favorable performance status (PS), limited-stage (I/II) disease, low-risk FL International Prognostic Index (FLIPI) score, normal baseline hemoglobin, and normal baseline β2 microglobulin (B2M) level. In a multivariable logistic regression model, male sex (odds ratio [OR], 1.30), PS ≥2 (OR, 1.63), B2M (≥3 mg/L; OR, 1.43), and high-risk FLIPI score (3-5; OR, 3.14) were associated with increased risk of progression before 24 months. In the time-dependent Cox model and the 24-month landmark analysis, POD24 was associated with poor subsequent OS (hazard ratio, 4.85 and 3.06, respectively). This is the largest pooled analysis of clinical trials data validating POD24 as a robust indicator of poor FL survival and identified clinical predictors of early death and progression that can aid in building comprehensive prognostic models incorporating clinical and molecular predictors of POD24., (© 2022 by The American Society of Hematology.)

The impact of body mass index (BMI) on survival in lymphoma remains controversial. We leveraged a prospective cohort of lymphoma patients enrolled to SPORE Molecular Epidemiology Resource between 2002 and 2015 to assess the association of BMI before diagnosis, BMI at diagnosis, and BMI change over time with lymphoma-specific survival (LSS). A total of 4009 lymphoma patients (670 diffuse large B-cell lymphoma (DLBCL), 689 follicular lymphoma (FL), 1018 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and 1632 other subtypes) were included. Significantly shorter LSS after diagnosis was observed for FL patients who were obese before diagnosis (HR: 3.02, 95%CI: 1.43-6.41, p =.004) and for those with a  ≥ 5% increase in BMI from diagnosis to 3-year follow-up (HR: 3.53, 95%CI: 1.22-10.2, p =.020). In contrast, obesity prior to or at the time of diagnosis was not associated with LSS in DLBCL and CLL/SLL. The impact of weight control after diagnosis in FL patient warrants investigation.

Background: Although many patients with follicular lymphoma (FL) undergo routine radiographic surveillance during their first remission, no consensus exists on the modality, duration, frequency, or need for routine imaging studies. The authors retrospectively examined the effect of surveillance imaging on relapse detection and overall survival (OS) in patients with FL., Methods: Patients with newly diagnosed FL who had a response to induction therapy were identified from the Lymphoid Malignancies Enterprise Architecture Database (LEAD) at Emory University and from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic. Patients were evaluated for both relapse and method of relapse detection (ie, clinical concerns vs radiologic detection through surveillance imaging in an asymptomatic patient)., Results: Of 148 patients in the LEAD cohort, 55 (37%) relapsed, and the majority (n = 35; 64%) of relapses were detected clinically. In the MER cohort, 63 of 177 relapses (54%) were detected clinically. There was no significant difference in OS from the date of diagnosis between the 2 methods of relapse detection in the LEAD (hazard ratio [HR], 0.61; 95% CI, 0.13-2.94; P = .54) and MER (HR, 1.02; 95% CI, 0.47-2.21; P = .96) cohorts. Similarly, there was no significant difference in OS from the date of relapse between the 2 methods of relapse detection in the LEAD (HR, 0.47; 95% CI, 0.10-2.27; P = .35) and MER (HR, 1.02; 95% CI, 0.47-2.21; P = .96) cohorts., Conclusions: These findings suggest a limited role for routine surveillance imaging in patients with FL who complete front-line therapy. Future studies should evaluate which patients may benefit from a more aggressive surveillance approach and should explore novel methods of relapse detection., (© 2021 American Cancer Society.)

This guideline for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) by the American Radium Society was developed by a multidisciplinary expert panel of medical, pediatric, and radiation oncologists convened to formulate guidelines for evaluation and treatment. The guideline development was based on an in-depth literature review and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of the recommendations by the panel. Given the scarcity of compelling data for strong recommendations for a rare lymphoma that has been shown to be more indolent than classical Hodgkin lymphoma, in instances where evidence is not available or equivocal, expert opinion guided the recommendations. Four clinical variants exemplify common scenarios and represent the consensus recommendations for patients with nodular lymphocyte Hodgkin lymphoma. A summary of the available published literature is also presented.

Limited data exist to describe the clinical features and outcomes for elderly patients with follicular lymphoma (FL). The Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) group performed a prospectively planned pooled analysis of individual patient data from first-line randomized controlled trials (RCTs) and examined associations between age (≤70 vs >70 years), clinical characteristics, and FL outcomes. We identified 18 multicenter clinical RCTs in the FLASH database that enrolled elderly patients (>70 years). Primary end points were early disease outcomes, CR24 and CR30, and progression-free survival (PFS) at 24 months (PFS24). Secondary end points were PFS and overall survival (OS). We identified 5922 previously untreated FL patients from 18 RCTs. Patients age >70 years (vs ≤70 years) more commonly had elevated lactate dehydrogenase, hemoglobin <12 g/dL, ECOG PS ≥2, and elevated β2-microglobulin. Median follow-up was 5.6 years. Patients >70 years did not differ from patients ≤70 years in rates of CR24, CR30, or PFS24. With a median OS of 14.6 years for all patients, median OS was 7.4 and 15.7 years for patients >70 and ≤70 years of age, respectively (hazard ratio = 2.35; 95% confidence interval = 2.03-2.73; P < .001). Age >70 years was a significant predictor of OS and PFS due to higher rates of death without progression, but not PFS24, CR24, or CR30. FL patients >70 years treated on trials have similar early disease outcomes to younger patients. There is no disease-specific outcome difference between age groups. Age alone should not disqualify patients from standard treatments or RCTs., (© 2021 by The American Society of Hematology.)

Lenalidomide is an immunomodulatory drug approved in the United States for use with rituximab in patients with relapsed/refractory follicular lymphoma. We reviewed data from trials addressing the safety and efficacy of lenalidomide alone and in combination with rituximab as a first-line therapy and as a treatment of patients with relapsed/refractory follicular lymphoma. Lenalidomide-rituximab has been demonstrated to be an effective chemotherapy-free therapy that improves upon single-agent rituximab and may become an alternative to chemoimmunotherapy., (© 2020 by The American Society of Hematology.)

In 2 randomized phase 3 trials BR resulted in longer progression-free survival (PFS) than frontline R-CHOP in patients with indolent and mantle cell lymphoma. However, in subset analyses of follicular lymphoma (FL), the results were incongruent. We conducted a retrospective matched-pair analysis to compare the outcome of patients with advanced stage FL, receiving frontline BR ( N  = 73) or R-CHOP ( N  = 73), matched by age, gender, stage, and FL International Prognostic Index score. On multivariable analysis, baseline maximum standardized uptake value (SUV max ) >13 was associated with use of R-CHOP ( p  = .001). After a median follow-up of 69 months for the BR arm and 126 months for the R-CHOP arm, 5-year PFS was 80% and 70%, respectively ( p  = .07). After adjusting for SUV max >13, the trend for better PFS in BR was not maintained. Prospective studies are needed to validate the role of pretreatment SUV max as a stratification factor in future randomized therapeutic trials in FL.

Evaluation of tolerability is increasingly relevant for patients with haematological malignancies treated with chronically administered therapies. Adverse events from these agents might affect the ability of patients to tolerate treatment over time. Conventional toxicity tables that include the incidence of high-grade adverse events, defined by the Common Terminology Criteria for Adverse Events, do not provide information on the time profile of these adverse events or reflect the continuous, lower grade symptomatic toxicities that are particularly relevant to treatment tolerability for patients living with indolent disease. Modern approaches to the evaluation and reporting of toxicity that capture the tolerability of treatment to the patient are imperative. In this Viewpoint, we present a focused, pilot, and longitudinal Toxicity over Time analysis of adverse events from lenalidomide and lenalidomide with rituximab in patients with follicular lymphoma treated in the CALGB 50401 (Alliance; NCT00238238) trial to define the trajectory of adverse events and quantify the burden of continuous, low-grade events. Toxicity over Time analyses provided clinically relevant descriptions of neutropenia and fatigue trajectories caused by lenalidomide that were not identified by standard analysis of the maximum grade events defined by the Common Terminology Criteria for Adverse Events. Systematic, rigorous incorporation of patient-reported outcomes in clinical trials will be crucial to our understanding of the tolerability of chronically administered therapies in patients with haematological malignancies., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We examined 83,108 patients with diffuse large B-cell lymphoma (DLBCL) and 43,393 patients with follicular lymphoma (FL) to investigate disparities related to geographic population density, stratified as rural, urban, or metropolitan. We found that urban and rural patients less commonly had private insurance and high socioeconomic status. Urban and rural DLBCL patients were more likely to receive treatment within 14 days of diagnosis (OR 0.93, 95% confidence interval [CI] 0.89-0.98; and OR 0.81, 95% CI 0.72-0.91) while urban FL patients were more likely to have treatment >14 days after diagnosis (OR 1.08, 95% CI 1.01-1.16). Multivariable analyses demonstrated that rural and urban patients had worse overall survival with DLBCL (hazard ratio [HR] 1.09; 95% CI 1-1.19 and HR 1.08; 95% CI 1.04-1.11) and FL (HR 1.11; 95% CI 1.04-1.18 and HR 1.2; 95% CI 1.02-1.41), respectively, suggesting needs for focused study and interventions for these populations.

The initial approach to the management of follicular lymphoma (FL) is challenging for patients and physicians. Most FL patients present with minimal symptoms; given the lack of a survival benefit to early treatment in this population, a period of observation without therapy is often appropriate. Once there is disease progression beyond low-tumor-burden criteria or symptoms prompting intervention, patients may be considered for an array of potential treatment options. These range from single-agent rituximab (anti-CD20) to various forms of chemoimmunotherapy, including rituximab or the newer anti-CD20 monoclonal antibody obinutuzumab. Unfortunately, prognostic and other clinical factors are of limited value in guiding optimal selection of therapy. Once patients complete initial treatment and achieve a complete or a partial remission, the next decision relates to the pros and cons of maintenance anti-CD20 therapy. Maintenance antibody administration can improve progression-free, but not overall, survival; hence, patient preferences typically drive this decision. Monitoring after remission is achieved should generally be guided by symptoms, physical examination, and laboratory findings, with routine surveillance imaging discouraged in the absence of new clinical issues. Given the wide range of options available and the importance of optimizing quality of life in this chronic health condition, education and shared decision making are pillars in the upfront management of FL to help patients achieve the best possible outcomes., Competing Interests: Conflict-of-interest disclosure: C.R.F. has received research funding from Abbvie, Acerta, Celgene, Gilead, Genentech/Roche, Janssen Pharmaceutical, Millennium/Takeda, Pharmacyclics, TG Therapeutics, Burroughs Wellcome Fund, Eastern Cooperative Oncology Group, National Cancer Institute, and V Foundation and has acted as a consultant for Abbvie, Bayer, Denovo Biopharma, Gilead, OptumRx, Karyopharm, Pharmacyclics/Janssen, and Spectrum. J.P.L. has acted as a consultant for Celgene, Juno, BMS, Sutro, Gilead, Epizyme, Genentech/Roche, Pfizer, Bayer, Biotest, United Therapeutics, Karyopharm, ADC Therapeutics, MEI Pharma, AstraZeneca, and Novartis. L.J.N. has received honoraria from Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics., (© 2018 by The American Society of Hematology. All rights reserved.)

Follicular lymphoma (FL) remains a lymphoma subtype that is remarkably sensitive to immunotherapy-based treatment strategies. Anti-CD20 antibody therapy administered as a single agent and in combination as a first-line treatment and at relapse continues to be the most broadly used therapy for this disease. Autologous and allogeneic stem cell transplantation provide meaningful durable remissions for patients with FL. However, identifying the most suitable patients and the optimal timing for these approaches has become increasingly challenging with the advent of novel therapies. Lenalidomide and phosphatidylinositol 3-kinase inhibitors are emerging as agents that can be applied in the relapsed setting. Other immunotherapy approaches, including checkpoint inhibitors and chimeric antigen receptor T cells, appear promising but remain experimental. Utilization of all forms of immunotherapy requires careful consideration of the unique toxicities associated with these agents and the means to mitigate them by selection of appropriate patients, optimal timing, and the use of supportive care., Competing Interests: Conflict-of-interest disclosure: C.R.F. has received research funding from AbbVie, Acerta Pharma, Celgene, Gilead, Genentech/Roche, Janssen Pharmaceutical, Millennium/Takeda, Pharmacyclics, TG Therapeutics, the Burroughs Wellcome Fund, Eastern Cooperative Oncology Group, the National Cancer Institute, and the V Foundation and has consulted for AbbVie, Bayer, Denovo Biopharma, Gilead, OptumRx, Karyopharm Therapeutics, Pharmacyclics/Janssen, and Spectrum. J.P.L. has consulted for Celgene, Juno, BMS, Sutro Biopharma, Gilead, Epizyme, Genentech/Roche, Pfizer, Bayer, Biotest, United Therapeutics, Karyopharm Therapeutics, ADC Therapeutics, MEI Pharma, AstraZeneca, and Novartis. L.J.N. has received honoraria from Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics., (© 2018 by The American Society of Hematology. All rights reserved.)

Follicular lymphoma (FL) is an incurable but treatable disease with vast treatment options. Despite the abundance of efficacious treatment modalities, there is no universally agreed upon standard approach to treatment, particularly in the relapsed/refractory setting. There is an increasing need for more robust and clinically available tools to risk-stratify patients and identify those likely to experience early relapse, which is currently recognized as the unmet need in FL. Additionally, the use of gene-expression profiling and next-generation sequencing techniques in recent years has led to a wealth of knowledge regarding the molecular drivers of lymphomagenesis. However, much of this knowledge is not currently available in the clinic to inform treatment decisions. Future studies are needed to generate clinically relevant predictive models adept at incorporating patient-specific and molecular features to inform management strategies along the entire disease continuum as treatment decisions should not be made in a vacuum with a one-size-fits-all approach. Sequencing of therapy in the management of relapsed FL should involve personalized decision-making for care plans that balance patient characteristics, preferences, and comorbidities with treatment-related factors such as efficacy, toxicity profile, and mechanisms of action to achieve a durable, quality remission., Competing Interests: Conflict-of-interest disclosure: C.R.F. has received research funding from Abbvie, Acerta, Celgene, Gilead, Genentech/Roche, Janssen Pharmaceutical, Millennium/Takeda, Pharmacyclics, TG Therapeutics, Burroughs Wellcome Fund, Eastern Cooperative Oncology Group, National Cancer Institute, and the V Foundation, and has consulted for Abbvie, Bayer, Denovo Biopharma, Gilead, OptumRx, Karyopharm, Pharmacyclics/Janssen, and Spectrum. J.P.L has consulted for Celgene, Juno, Bristol-Myers Squibb, Sutro, Gilead, Epizyme, Genentech/Roche, Pfizer, Bayer, Biotest, United Therapeutics, Karyopharm, ADC Therapeutics, MEI Pharma, AstraZeneca, and Novartis. L.J.N. has received honoraria from Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics., (© 2018 by The American Society of Hematology. All rights reserved.)

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma and most common indolent non-Hodgkin lymphoma. Lower socioeconomic status is associated with poor outcomes in FL, suggesting that access to care is an important prognostic factor; however, the association between insurance status and FL survival has not been sufficiently examined. The National Cancer Database, a nationwide cancer registry, was used to evaluate 43 648 patients with FL diagnosed between 2004 and 2014. All analyses were performed on 2 cohorts segmented at age 65 years to account for changes in insurance status with Medicare eligibility. Cox proportional hazard models calculated hazard ratios (HRs) with confidence intervals (CIs) for the association between insurance status and overall survival (OS) controlling for the available sociodemographic and prognostic factors. Kaplan-Meier curves display outcomes by insurance status for patients covered by private insurance, no insurance, Medicaid, or Medicare. When compared with patients younger than age 65 years with private insurance, patients younger than age 65 years with no insurance (HR, 1.96; 95% CI, 1.69-2.28), with Medicaid (HR, 1.82; 95% CI, 1.57-2.12), and with Medicare (HR, 1.96; 95% CI, 1.71-2.24) had significantly worse OS after adjusting for sociodemographic and prognostic factors. Compared with patients age 65 years or older with private insurance, those with Medicare only (HR, 1.28; 95% CI, 1.17-1.4) had significantly worse OS. For adults with FL, expanding access to care through insurance has the potential to improve outcomes., (© 2018 by The American Society of Hematology.)

The role of positron emission tomography (PET) in the initial assessment of follicular lymphoma (FL) has been a topic of debate. We examined the patterns of utilization of PET staging in FL and assessed the association of PET with survival. Using the SEER-Medicare database, we identified 5712 patients diagnosed with first primary FL between 2000 and 2009. Older age, African-American race, poor performance status, B-symptoms and history of anemia were negatively associated with PET staging. Receipt of PET staging was positively associated with treatment at institutions affiliated with research networks and with residence in areas with higher concentrations of nuclear medicine specialists. PET was associated with improved lymphoma-related (HR 0.69, 95% CI: 0.58-0.82) and overall (HR 0.75, 95% CI: 0.68-0.83) survival. Our findings substantiate the use of PET as the standard of care for imaging in FL patients. Further investigation is warranted to identify mechanisms underlying the apparent survival advantage associated with PET staging in FL.

Positron emission tomography (PET) after induction therapy in follicular lymphoma (FL) is predictive of survival in clinical trials. We describe use of PET and computed tomography (CT) after rituximab-based induction therapy in FL patients followed by the National LymphoCare Study and explore the association between imaging response assessment and survival. Among 1289 patients, imaging consisted of: PET ± CT (35%), CT alone (42%), other/no imaging (24%). Median follow-up was 7.6 years. In unadjusted analyses, positive PET ± CT and CT were prognostic of inferior OS (HR 1.78; 95% CI: 1.16-2.72 and HR 1.61, 95% CI: 1.13-2.29, respectively) and PFS (HR 1.63, 95% CI: 1.21-2.20 and HR 1.45, 95% CI: 1.12-1.89, respectively). Adjusting for FL International Prognostic Index, PET remained predictive of OS (HR 1.54, 95% CI: 1.01-2.36) and PFS (HR 1.54, 95% CI: 1.14-2.07). Residual disease via PET in FL is prognostic of survival in clinical practice.

Purpose Follicular lymphoma (FL) is an indolent cancer, with effective but rarely curative treatment options. As a standard study end point for first-line FL therapy, progression-free survival (PFS) requires extended follow-up (median PFS, > 7 years). To provide patients with earlier access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to formally assess the complete response rate at 30 months (CR30) after initiation of induction therapy as a potential surrogate end point for PFS in first-line FL therapy. Patients and Methods We analyzed individual patient data from 13 randomized multicenter trials of induction and maintenance regimens in first-line FL therapy published after 1990 and with sufficient data to evaluate whether CR30 could predict treatment effects on PFS. Correlation of the CR30 odds ratio with the PFS hazard ratio was evaluated by both linear regression (R 2 ) and bivariate copula (R WLS ) models. Prespecified criteria for surrogacy required either R 2 or R Copula ≥ 0.80, with a lower-bound 95% CI > 0.60. Results Data from eight induction and five maintenance randomized trials in 3,837 evaluable patients were analyzed. The prespecified surrogacy threshold was met, with an R 2 of 0.88 (95% CI, 0.77 to 0.96) and an R WLS or R 2 Copula ≥ 0.80, with a lower-bound 95% CI > 0.60. Results Data from eight induction and five maintenance randomized trials in 3,837 evaluable patients were analyzed. The prespecified surrogacy threshold was met, with an R 2 WLS of 0.88 (95% CI, 0.77 to 0.96) and an R 2 Copula of 0.86 (95% CI, 0.72 to 1.00). Multiple sensitivity and supplemental analyses supported the robustness of the findings. A minimum 11% absolute improvement in CR30 from a 50% control rate predicted a significant treatment effect on PFS (hazard ratio, 0.69). Conclusion This large, prospective, pooled analysis of randomized chemotherapy, immunotherapy, and chemoimmunotherapy trials demonstrates that CR30 is a surrogate end point for PFS in first-line FL treatment trials. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before PFS results are mature.

We aimed to comprehensively study sex differences in disease and patients' characteristics, treatment and outcomes in patients with follicular lymphoma (FL) in the United States (USA) utilizing the National LymphoCare Study registry (2004-2014). Among evaluable males (n = 1277) and females (n = 1375) with FL, females less commonly received anthracyclines and were more likely to receive rituximab monotherapy. Overall response rates were comparable between sex groups. With a median follow-up of 8.1 years, male sex emerged as an adverse factor for PFS (HR, 0.84, 95% CI, 0.72-0.97). Lymphoma-related mortality (HR, 0.46; 0.23-0.93) and overall survival (HR, 0.63; 0.41-0.97) favored females aged ≤60 years. There are subtle differences in outcomes between male and female FL patients diagnosed and treated in the contemporary era. These data represent the largest prospective analysis of FL patients in the USA based on sex and can aid design of clinical trials for this disease. Am. J. Hematol. 91:770-775, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

To examine the effectiveness of an initial management strategy of watchful waiting for follicular lymphoma (FL) in clinical practice, we compared outcomes for patients diagnosed 2004-2007 in the United States initially managed with watchful waiting with outcomes following initial rituximab monotherapy and chemoimmunotherapy. In total, 1754 stage II-IV patients in the National LymphoCare Study underwent watchful waiting (n = 386), rituximab monotherapy (n = 296) or rituximab plus chemotherapy (n = 1072) as initial management strategy. Female patients and those who received treatment in the Northeast or in an academic setting more commonly underwent watchful waiting versus initial chemoimmunotherapy; whereas patients with grade 3 histology, anaemia, elevated lactate dehydrogenase, extranodal involvement, B symptoms or performance status ≥1 more commonly received chemoimmunotherapy. Although time to new treatment and progression-free survival following first- and second-line therapy were improved with chemoimmunotherapy, and time to chemotherapy was improved with rituximab monotherapy, there were no differences in overall survival between watchful waiting and chemoimmunotherapy or rituximab monotherapy. With 8-year overall survival estimates of 74%, initial management with watchful waiting in the context of sequential therapy remains a viable option for FL patients in the modern era. This trial was registered at www.clinicaltrials.gov (NCT00097565)., (© 2016 John Wiley & Sons Ltd.)

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: Phase 3 randomized trials have shown that maintenance rituximab (MR) therapy or radioimmunotherapy (RIT) consolidation following frontline therapy can improve progression-free survival for patients with follicular lymphoma (FL), but the cost-effectiveness of these approaches with respect to observation has not been examined using a common modeling framework., Objectives: To evaluate and compare the economic impact of MR and RIT consolidation versus observation, respectively, following the first-line induction therapy for patients with advanced-stage FL., Methods: We developed Markov models to estimate patients' lifetime costs, quality-adjusted life-years (QALYs), and life-years (LYs) after MR, RIT, and observation following frontline FL treatment from the US payer's perspective. Progression risks, adverse event probabilities, costs, and utilities were estimated from clinical data of Primary RItuximab and MAintenance (PRIMA) trial, Eastern Cooperative Oncology Group (ECOG) trial (for MR), and First-line Indolent Trial (for RIT) and the published literature. We evaluated the incremental cost-effectiveness ratio for direct comparisons between MR/RIT and observation. Model robustness was addressed by one-way and probabilistic sensitivity analyses., Results: Compared with observation, MR provided an additional 1.089 QALYs (1.099 LYs) and 1.399 QALYs (1.391 LYs) on the basis of the PRIMA trial and the ECOG trial, respectively, and RIT provided an additional 1.026 QALYs (1.034 LYs). The incremental cost per QALY gained was $40,335 (PRIMA) or $37,412 (ECOG) for MR and $40,851 for RIT. MR and RIT had comparable incremental QALYs before first progression, whereas RIT had higher incremental costs of adverse events due to higher incidences of cytopenias., Conclusions: MR and RIT following frontline FL therapy demonstrated favorable and similar cost-effectiveness profiles. The model results should be interpreted within the specific clinical settings of each trial. Selection of MR, RIT, or observation should be based on patient characteristics and expected trade-offs for these alternatives., (Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: Follicular lymphoma (FL) has been linked with cigarette smoking and, inconsistently, with other risk factors., Methods: We assessed associations of medical, hormonal, family history, lifestyle, and occupational factors with FL risk in 3530 cases and 22639 controls from 19 case-control studies in the InterLymph consortium. Age-, race/ethnicity-, sex- and study-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression., Results: Most risk factors that were evaluated showed no association, except for a few modest or sex-specific relationships. FL risk was increased in persons: with a first-degree relative with non-Hodgkin lymphoma (OR = 1.99; 95% CI = 1.55 to 2.54); with greater body mass index as a young adult (OR = 1.15; 95% CI = 1.04 to 1.27 per 5 kg/m(2) increase); who worked as spray painters (OR = 2.66; 95% CI = 1.36 to 5.24); and among women with Sjögren syndrome (OR = 3.37; 95% CI = 1.23 to 9.19). Lower FL risks were observed in persons: with asthma, hay fever, and food allergy (ORs = 0.79-0.85); blood transfusions (OR = 0.78; 95% CI = 0.68 to 0.89); high recreational sun exposure (OR = 0.74; 95% CI = 0.65 to 0.86, fourth vs first quartile); who worked as bakers or millers (OR = 0.51; 95% CI = 0.28 to 0.93) or university/higher education teachers (OR = 0.58; 95% CI = 0.41 to 0.83). Elevated risks specific to women included current and longer duration of cigarette use, whereas reduced risks included current alcohol use, hay fever, and food allergies. Other factors, including other autoimmune diseases, eczema, hepatitis C virus seropositivity, hormonal drugs, hair dye use, sun exposure, and farming, were not associated with FL risk., Conclusions: The few relationships observed provide clues suggesting a multifactorial etiology of FL but are limited in the extent to which they explain FL occurrence., (Published by Oxford University Press 2014.)

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: Follicular lymphoma (FL) is characterized by multiple relapses and progressively shorter response durations with subsequent therapies. Despite the development of numerous treatment strategies to reduce the risk of progression, optimal therapeutic strategies for patients with FL remain undefined. Radioimmunotherapy (RIT) with an anti-CD20 antibody linked to iodine-131 or to yttrium-90 has emerged as well-tolerated treatment after induction. We conducted a systematic literature review and meta-analyses to quantify the benefits of consolidative RIT., Methods: We searched the CENTRAL and MEDLINE libraries, and conference abstracts for reports on phase II/III clinical trials that assessed RIT consolidation for patients with untreated FL. Extracted data included pretreatment disease status, patient characteristics, treatment regimen, response rates, progression-free survival (PFS), and overall survival (OS). Pooled estimates of complete response (CR), overall response (OR), 2- and 5-year PFS and OS rates were computed by using random effects models., Results: Eight studies (n = 783) were included in the meta-analyses. CR rates after RIT ranged from 69.0% to 96.5%, 2-year PFS ranged from 64.8% to 86.1%, and 5-year PFS ranged from 47.0% to 67.3%. The pooled estimates of the CR rate and OR rate were 82.7% (95% CI, 67.4%-91.7%) and 96.2% (95% CI, 90.4%-98.6%), respectively. The pooled estimates for 5-year PFS and OS were 57.6% (95% CI, 47.8%-66.9%) and 90.1% (95% CI, 83.9%-94.1%), respectively., Conclusions: We believe that these aggregated data can further the discussion on RIT as a consolidation therapy and inform decisions on future study designs Additional studies are needed to compare the benefits of RIT consolidation to maintenance therapy with rituximab., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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.)

Background: Bortezomib has demonstrated efficacy in patients with relapsed B-cell non-Hodgkin lymphoma (NHL) both alone and in combination with other agents; however, limited data exist regarding its toxicity in combination with common frontline therapies for indolent NHL. A phase 1 study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (R-CHOP) was conducted in patients with untreated follicular lymphoma (FL) and other indolent NHLs., Methods: Nineteen patients, including 10 patients with FL, were enrolled. The median patient age was 59 years (range, 29-71 years). Seven patients had a FL International Prognostic Index score ≥3. R-CHOP with the vincristine dose capped at 1.5 mg was administered on a 21-day cycle for 6 to 8 cycles, and 1 of 3 dose levels of bortezomib (1.0 mg/m(2) [n = 1], 1.3 mg/m(2) [n = 6], or 1.6 mg/m(2) [n = 12]) was administered on days 1 and 8 of each cycle using a Bayesian algorithm for dose escalation., Results: The maximum tolerated dose (MTD) of bortezomib with modified R-CHOP was reached at 1.6 mg/m(2). Dose-limiting toxicity was observed in 5 patients (1 patient at a bortezomib dose of 1.0 mg/m(2), 1 patient at a bortezomib dose of 1.3 mg/m(2), and 3 patients at a bortezomib dose of 1.6 mg/m(2)). Neuropathy occurred in 16 patients (84%), including 2 patients (11%) who experienced grade 3 sensory neuropathy. Grade 4 hematologic toxicity occurred in 4 patients. Of 19 evaluable patients, 100% responded, and the complete response rate was 68%. At a median follow-up of 32 months, the 3-year progression-free survival rate was 89.5%., Conclusions: Bortezomib combined with modified R-CHOP produced high response rates without substantial increases in toxicity. A phase 2 study of R-CHOP and bortezomib given at this established MTD is currently ongoing., (Copyright © 2012 American Cancer Society.)

Purpose: Vaccination with hybridoma-derived autologous tumor immunoglobulin (Ig) idiotype (Id) conjugated to keyhole limpet hemocyanin (KLH) and administered with granulocyte-monocyte colony-stimulating factor (GM-CSF) induces follicular lymphoma (FL) -specific immune responses. To determine the clinical benefit of this vaccine, we conducted a double-blind multicenter controlled phase III trial., Patients and Methods: Treatment-naive patients with advanced stage FL achieving complete response (CR) or CR unconfirmed (CRu) after chemotherapy were randomly assigned two to one to receive either Id vaccine (Id-KLH + GM-CSF) or control (KLH + GM-CSF). Primary efficacy end points were disease-free survival (DFS) for all randomly assigned patients and DFS for randomly assigned patients receiving at least one dose of Id vaccine or control., Results: Of 234 patients enrolled, 177 (81%) achieved CR/CRu after chemotherapy and were randomly assigned. For 177 randomly assigned patients, including 60 patients not vaccinated because of relapse (n = 55) or other reasons (n = 5), median DFS between Id-vaccine and control arms was 23.0 versus 20.6 months, respectively (hazard ratio [HR], 0.81; 95% CI, 0.56 to 1.16; P = .256). For 117 patients who received Id vaccine (n = 76) or control (n = 41), median DFS after randomization was 44.2 months for Id-vaccine arm versus 30.6 months for control arm (HR, 0.62; 95% CI, 0.39 to 0.99; P = .047) at median follow-up of 56.6 months (range, 12.6 to 89.3 months). In an unplanned subgroup analysis, median DFS was significantly prolonged for patients receiving IgM-Id (52.9 v 28.7 months; P = .001) but not IgG-Id vaccine (35.1 v 32.4 months; P = .807) compared with isotype-matched control-treated patients., Conclusion: Vaccination with patient-specific hybridoma-derived Id vaccine after chemotherapy-induced CR/CRu may prolong DFS in patients with FL. Vaccine isotype may affect clinical outcome and explain differing results between this and other controlled Id-vaccine trials.

Follicular lymphoma is an indolent lymphoma associated with a relapsing course. Immunization with tumor B cell idiotype (Id; a unique variable region of surface B cell immunoglobulin) may induce humoral and cellular immune response against the tumor. Based on promising results from early phase clinical trials with Id vaccine, three Phase III trials were initiated, which, despite failing to meet their primary end points, still provided a glimmer of optimism. This article describes the clinical development of the Id vaccine against follicular lymphoma, outlines the outcomes of clinical trials and delineates the future prospects for the integration of the idiotype vaccine into follicular lymphoma treatment.