Search

Abstract: Tisagenlecleucel is approved for adults with relapsed/refractory (r/r) follicular lymphoma (FL) in the third- or later-line setting. The primary analysis (median follow-up, 17 months) of the phase 2 ELARA trial reported high response rates and excellent safety profile in patients with extensively pretreated r/r FL. Here, we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after median follow-up of 29 months (interquartile range, 22.2-37.7). As of 29 March 2022, 97 patients with r/r FL (grades 1-3A) received tisagenlecleucel infusion (0.6 × 108-6 × 108 chimeric antigen receptor-positive viable T cells). Bridging chemotherapy was allowed. Baseline clinical factors, tumor microenvironment, blood soluble factors, and circulating blood cells were correlated with clinical response. Cellular kinetics were assessed by quantitative polymerase chain reaction. Median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached. Estimated 24-month PFS, DOR, and OS rates in all patients were 57.4% (95% confidence interval [CI], 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2), respectively. Complete response rate and overall response rate were 68.1% (95% CI, 57.7-77.3) and 86.2% (95% CI, 77.5-92.4), respectively. No new safety signals or treatment-related deaths were reported. Low levels of tumor-infiltrating LAG3+CD3+ exhausted T cells and higher baseline levels of naïve CD8+ T cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA. This trial was registered at www.clinicaltrials.gov as #NCT03568461., (© 2024 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.)

Abstract: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Approval was supported by the phase 2, multicenter, single-arm ZUMA-5 study of axi-cel for patients with R/R indolent non-Hodgkin lymphoma (iNHL; N = 104), including FL and marginal zone lymphoma (MZL). In the primary analysis (median follow-up, 17.5 months), the overall response rate (ORR) was 92% (complete response rate, 74%). Here, we report long-term outcomes from ZUMA-5. Eligible patients with R/R iNHL after ≥2 lines of therapy underwent leukapheresis, followed by lymphodepleting chemotherapy and axi-cel infusion (2 × 106 CAR T cells per kg). The primary end point was ORR, assessed in this analysis by investigators in all enrolled patients (intent-to-treat). After median follow-up of 41.7 months in FL (n = 127) and 31.8 months in MZL (n = 31), ORR was comparable with that of the primary analysis (FL, 94%; MZL, 77%). Median progression-free survival was 40.2 months in FL and not reached in MZL. Medians of overall survival were not reached in either disease type. Grade ≥3 adverse events of interest that occurred after the prior analyses were largely in recently treated patients. Clinical and pharmacokinetic outcomes correlated negatively with recent exposure to bendamustine and high metabolic tumor volume. After 3 years of follow-up in ZUMA-5, axi-cel demonstrated continued durable responses, with very few relapses beyond 2 years, and manageable safety in patients with R/R iNHL. The ZUMA-5 study was registered at www.clinicaltrials.gov as #NCT03105336., (© 2024 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.)

Background: We investigated the prognostic value of baseline positron emission tomography (PET) parameters for patients with treatment-naïve follicular lymphoma (FL) in the phase III RELEVANCE trial, comparing the immunomodulatory combination of lenalidomide and rituximab (R 2 ) versus R-chemotherapy (R-chemo), with both regimens followed by R maintenance therapy., Patients and Methods: Baseline characteristics of the entire PET-evaluable population (n = 406/1032) were well balanced between treatment arms. The maximal standard uptake value (SUV max ) and the standardized maximal distance between tow lesions (SD max ) were extracted, the standardized distance between two lesions the furthest apart, were extracted. The total metabolic tumor volume (TMTV) was computed using the 41% SUV max method., Results: With a median follow-up of 6.5 years, the 6-year progression-free survival (PFS) was 57.8%, the median TMTV was 284 cm 3 , SUV max was 11.3 and SD max was 0.32 m -1 , with no significant difference between arms. High TMTV (>510 cm 3 ) and FLIPI were associated with an inferior PFS (P = 0.013 and P = 0.006, respectively), whereas SUV max and SD max were not (P = 0.08 and P = 0.12, respectively). In multivariable analysis, follicular lymphoma international prognostic index (FLIPI) and TMTV remained significantly associated with PFS (P = 0.0119 and P = 0.0379, respectively). These two adverse factors combined stratified the overall population into three risk groups: patients with no risk factors (40%), with one factor (44%), or with both (16%), with a 6-year PFS of 67.7%, 54.5%, and 41.0%, respectively. No significant interaction between treatment arms and TMTV or FLIPI (P = 0.31 or P = 0.59, respectively) was observed. The high-risk group (high TMTV and FLIPI 3-5) had a similar PFS in both arms (P = 0.45) with a median PFS of 68.4% in the R-chemo arm versus 71.4% in the R 2 arm., Conclusions: Baseline TMTV is predictive of PFS, independently of FLIPI, in patients with advanced FL even in the context of antibody maintenance., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Purpose: Rituximab improves progression-free survival (PFS) and time to next treatment (TTNT) when compared with the watch and wait strategy for patients with low-tumor burden follicular lymphoma (FL). Prolonged rituximab maintenance did not prolong TTNT, whereas it raises concerns about resources use and patient adhesion. Our aim was then to investigate the use of short rituximab maintenance using the subcutaneous (SC) route in patients with low-tumor burden FL., Methods: Patients with histologically confirmed CD20 + low-tumor burden FL were randomly assigned to receive either rituximab, 375 mg/m 2 once daily on D1, D8, D15, and D22, intravenous route (IV, control arm), or rituximab, 375 mg/m 2 , on day 1 (D1), IV followed by rituximab 1,400 mg total dose, SC once daily on D8, D15, and D22, with maintenance at months 3 (M3), M5, M7, and M9 (experimental arm). The primary end point was PFS. Secondary end points included safety, overall response rates, TTNT, and overall survival (OS)., Results: Two hundred two patients with low-tumor burden FL were randomly assigned to the experimental (n = 100) or control arm (n = 102). The primary end point was met: the 4-year PFS was 58.1% (95% CI, 47.5 to 67.4) and 41.2% (95% CI, 30.6 to 51.6) in experimental and control arms, respectively (hazard ratio, 0.585 [0.393 to 0.871]; P = .0076). Complete response (CR) rates were 59.0% (95% CI, 48.7 to 68.7) in the experimental arm and 36.3% (95% CI, 27.0 to 46.4) in the control arm ( P = .001). TTNT and OS were not significantly different. CR was associated with longer PFS and TTNT. High rituximab exposure during the first three months was independently associated with higher CR, PFS, and TTNT., Conclusion: SC rituximab improves PFS for patients with low-tumor burden FL when used in induction followed by short maintenance. High rituximab exposure during the first 3 months after treatment initiation is, however, the only parameter influencing patient outcomes.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The RELEVANCE trial (ClinicalTrials.gov identifier: NCT01650701) showed that lenalidomide plus rituximab (R 2 ) provided similar efficacy to rituximab plus chemotherapy (R-chemo) in patients with advanced-stage, previously untreated follicular lymphoma (FL). We report the second interim analysis of the RELEVANCE trial after 6 years of follow-up. Patients with previously untreated grade 1-3a FL were assigned 1:1 to R 2 or R-chemo, followed by rituximab maintenance. Coprimary end points were complete response (confirmed/unconfirmed) at week 120 and progression-free survival (PFS). At median follow-up of 72 months, 6-year PFS was 60% and 59% for R 2 and R-chemo, respectively (hazard ratio = 1.03 [95% CI, 0.84 to 1.27]). Six-year overall survival was estimated to be 89% in both groups. Median PFS and overall survival were not reached in either group. Overall response after progression was 61% and 59%, and 5-year estimated survival rate after progression was 69% and 74% in the R 2 and R-chemo groups, respectively. The transformation rate per year in the R 2 and R-chemo groups was 0.68% and 0.45%, and secondary primary malignancies occurred in 11% and 13% ( P = .34), respectively. No new safety signals were observed. R 2 continues to demonstrate comparable, durable efficacy and safety versus R-chemo in previously untreated patients with FL and provides an acceptable chemo-free alternative.

Obinutuzumab and lenalidomide (referred to as the GALEN combination) is an active immunomodulatory combination with a manageable safety profile in multiple types of lymphoma. We report efficacy and safety results for the phase 2 GALEN study in previously untreated patients with advanced follicular lymphoma (FL). Eligible patients aged ≥18 years had an Eastern Cooperative Oncology Group performance status ≤2 and high-tumor burden, grade 1 to 3a FL. Induction treatment was obinutuzumab (1000 mg IV, days 8, 15, and 22, cycle 1; day 1, cycles 2-6) plus lenalidomide (20 mg/d, days 1-21, cycle 1; days 2-22, cycles 2-6) for six 28-day cycles. Maintenance included obinutuzumab (1000 mg every 2 cycles) plus lenalidomide (10 mg, days 2-22) for ≤12 cycles (year 1) followed by obinutuzumab (1000 mg every 56 days) for 6 cycles (year 2). The primary end point was complete response rate (CRR) after induction per the 1999 International Working Group criteria. From October 2015 to February 2017, a total of 100 patients were enrolled. CRR after induction was 47%, and the overall response rate (ORR) was 92%. Post hoc analyses per the 2014 Lugano classification, including patients with missing bone marrow assessments, identified an additional 13 patients fulfilling CRR criteria, resulting in a complete metabolic response of 80% and an ORR of 94%. At a median follow-up of 3.7 years, 3-year progression-free survival and overall survival were 82% and 94%, respectively. The most common adverse event was neutropenia (48% any grade; 47% grade ≥3). Only 2% of patients presented with febrile neutropenia; others were mainly grade ≤2. No other specific grade ≥3 toxicity occurred at a frequency >3%. Overall, these results showed promising clinical efficacy for the chemotherapy-free GALEN backbone in previously untreated patients with high tumor burden FL. Except for neutropenia, the safety profile of the combination is remarkable. The study was registered at clinicaltrials.gov as #NCT01582776., (© 2022 by The American Society of Hematology.)

Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor-T cell therapy with clinically meaningful outcomes demonstrated in patients with relapsed/refractory (r/r) B-cell lymphoma. In a previous pilot study of tisagenlecleucel in r/r follicular lymphoma (FL), 71% of patients achieved a complete response (CR). Here we report the primary, prespecified interim analysis of the ELARA phase 2 multinational trial of tisagenlecleucel in adults with r/r FL after two or more treatment lines or who relapsed after autologous stem cell transplant (no. NCT03568461). The primary endpoint was CR rate (CRR). Secondary endpoints included overall response rate (ORR), duration of response, progression-free survival, overall survival, pharmacokinetics and safety. As of 29 March 2021, 97/98 enrolled patients received tisagenlecleucel (median follow-up, 16.59 months; interquartile range, 13.8-20.21). The primary endpoint was met. In the efficacy set (n = 94), CRR was 69.1% (95% confidence interval, 58.8-78.3) and ORR 86.2% (95% confidence interval, 77.5-92.4). Within 8 weeks of infusion, rates of cytokine release syndrome were 48.5% (grade ≥3, 0%), neurological events 37.1% (grade ≥3, 3%) and immune effector cell-associated neurotoxicity syndrome (ICANS) 4.1% (grade ≥3, 1%) in the safety set (n = 97), with no treatment-related deaths. Tisagenlecleucel is safe and effective in extensively pretreated r/r FL, including in high-risk patients., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Follicular lymphoma and classic Hodgkin lymphoma can be associated in composite and/or sequential lymphomas. Common IGH and BCL2 rearrangements have already been identified between both contingents of these entities, but mutation profiles have not yet been investigated. The main objective of this study was to analyze the transdifferentiation process that may occur between Hodgkin and follicular contingents in sequential and composite lymphomas to better characterize these entities. From 2004 to 2020, a retrospective multicentric study was performed, including 9 composite and 13 sequential lymphomas. Clinical data were retrospectively collected. Fluorescent in situ hybridization of BCL2 and BCL6 rearrangements, polymerase chain reaction of IGH and IGK rearrangements, next-generation sequencing of IGK rearrangement, and targeted next-generation sequencing (TNGS) on a panel of genes frequently mutated in lymphomas were performed on each contingent of composite and sequential lymphomas. For TNGS, each contingent was isolated by laser capture microdissection. Clinical presentation and evolution were more aggressive in sequential than composite lymphomas. By fluorescent in situ hybridization, common rearrangements of BCL6 and BCL2 were identified between both contingents. Similarly, a common clonal relationship was established by evaluating IGH and IGK rearrangement by polymerase chain reaction or next-generation sequencing. By TNGS, the same pathogenic variants were identified in both contingents in the following genes: CREBBP, KMT2D, BCL2, EP300, SF3B1, SOCS1, ARID1A, and BCOR. Specific pathogenic variants for each contingent were also identified: XPO1 for Hodgkin lymphoma contingent and FOXO1, TNFRSF14 for follicular lymphoma contingent. This study reinforces the hypothesis of a transdifferentiation process between Hodgkin and follicular contingent of sequential/composite lymphomas., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Follicular lymphomas (FLs) with MYC rearrangements (MYC-R) and extra copies of MYC (MYC-EC) are rare and the prognosis impact is uncertain. We conducted a retrospective study including 321 FL patients, among whom 259 (81%) had no 8q24 alterations and 62 (19%) were assigned to 8qAlt. Forty-five cases were classified as MYC-EC and six as MYC-R. MYC-R patients were significantly older (P = 0·008), had higher follicular lymphoma international prognostic index (FLIPI) stage (P = 0·05) and β2-microglobulin (β2m; P = 0·05). Among patients treated with immuno-chemotherapy, four presented a MYC-R and 25 a MYC-EC. Univariate analysis showed the absence of significant difference between MYC-EC and normal MYC (MYC-NL) regarding progression-free survival (PFS; HR1·3; 95% CI [0·4-1·6]) and specific overall survival (SOS; HR 1·6; 95% CI [0·4-5·7]). Those results were compared to data from the PRIMA trial. This confirmed that MYC-EC had no impact on PFS (P = 0·86) or SOS (P = 0·9). Conversely, MYC-R was associated with a trend to inferior outcome regarding PFS (HR : 6·1; 95% CI [2·2-17·1]; P = 0·00026), lymphoma-related death (SOS; HR 13·6; 95% CI [2·9-65]; P = 0·00014) and risk of transformation (transformation-free survival (TFS); HR 82·7; 95% CI [14·8-463·4]; P < 0·0001). In conclusion, MYC-EC has no prognostic impact in FL but MYC-R FL tended to be associated with an increased risk of transformation and poorer outcome., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Follicular lymphoma (FL) is one of the most common subtypes of non-Hodgkin lymphoma worldwide. Improved survival outcomes with rituximab-based therapy in clinical trials led to the establishment of rituximab-based immunochemotherapy as standard of care for first-line (1L) treatment of FL. In the GALLIUM trial, obinutuzumab-based immunochemotherapy demonstrated improved progression-free survival (PFS), prolonged time-to-next antilymphoma treatment (TTNT) and comparable overall survival (OS) compared with rituximab-based immunochemotherapy as 1L treatment for FL. Using GALLIUM as an example, this article aims to explain how improved outcomes in 1L treatment of FL have changed the landscape for the design and interpretation of future trials. As approved therapies for 1L FL already achieve good responses, it is becoming more difficult to design trials that demonstrate further treatment benefits with the currently accepted primary endpoints. New endpoints are needed to reflect the long remission times, low relapse rates, and impact of subsequent therapies in FL. PFS is used as a primary efficacy endpoint in registrational clinical trials for indolent malignancies like FL, where improvement in OS is not always observed due to the large number of patients and long study duration required to demonstrate a clear survival benefit. However, there are limitations to using PFS as the primary endpoint. Other potential endpoints, including TTNT, progression of disease within 2 years, response rate, and minimal residual disease status are explored., (© 2021. The Author(s).)

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a therapeutic option for patients with relapsed follicular lymphoma (FL). The clinical characteristics and outcomes of FL relapse after ASCT in the rituximab era have not yet been fully elucidated. We retrospectively reviewed 414 FL patients treated with ASCT between 2000 and 2014 in four hematology departments. All patients received rituximab as a first-line treatment. We specifically analyzed the clinical characteristics, treatment strategies at relapse, and outcomes of 95 patients (23%) who relapsed after ASCT. The patients (median age, 57 y) received a median of two lines of therapy (range, 2-6) prior to ASCT, with 92% in complete response (CR) or partial response (PR) before ASCT. Histological transformation at relapse after ASCT was observed in 20% of the patients. Treatment at relapse after ASCT consisted of chemotherapy with or without rituximab (n = 45/90, 50%), targeted agents (18%), rituximab monotherapy (14%), or consolidation allogeneic transplantation after induction chemotherapy (12%) and radiotherapy (6%). After relapse, the median progression-free survival (PFS) and overall survival (OS) were 1 year (95% CI, 0.541-1.579) and 5.5 years (95% CI, 1.910-9.099), respectively. In the multivariate analysis, histological transformation (HT) was associated with OS (P = .044; HR 2.439; 95% CI, 1.025-5.806), and a high FLIPI score at relapse was associated with PFS (P = .028; HR 2.469; 95% CI, 1.104-5.521). This retrospective study showed that the period of PFS of patients who relapsed after ASCT is short. A biopsy should be performed for these patients to document the HT. Our results indicate that new treatment strategies will need to be developed for these patients., (© 2020 John Wiley & Sons Ltd.)

Purpose: The PRIMA study (ClinicalTrials.gov identifier: NCT00140582) established that 2 years of rituximab maintenance after first-line immunochemotherapy significantly improved progression-free survival (PFS) in patients with follicular lymphoma compared with observation. Here, we report the final PFS and overall survival (OS) results from the PRIMA study after 9 years of follow-up and provide a final overview of safety., Methods: Patients (> 18 years of age) with previously untreated high-tumor-burden follicular lymphoma were nonrandomly assigned to receive one of three immunochemotherapy induction regimens. Responding patients were randomly assigned (stratified by induction regimen, response to induction treatment, treatment center, and geographic region) 1:1 to receive 2 years of rituximab maintenance (375 mg/m 2 , once every 8 weeks), starting 8 weeks after the last induction treatment, or observation (no additional treatment). All patients in the extended follow-up provided their written informed consent (data cutoff: December 31, 2016)., Results: In total, 1,018 patients completed induction treatment and were randomly assigned to rituximab maintenance (n = 505) or observation (n = 513). Consent for the extended follow-up was provided by 607 patients (59.6%) of 1,018 (rituximab maintenance, n = 309; observation, n = 298). After data cutoff, median PFS was 10.5 years in the rituximab maintenance arm compared with 4.1 years in the observation arm (hazard ratio, 0.61; 95% CI, 0.52 to 0.73; P < .001). No OS difference was seen in patients randomly assigned to rituximab maintenance or observation (hazard ratio, 1.04; 95% CI, 0.77 to 1.40; P = .7948); 10-year OS estimates were approximately 80% in both study arms. No new safety signals were observed., Conclusion: Rituximab maintenance after induction immunochemotherapy provides a significant long-term PFS, but not OS, benefit over observation.

Purpose: Although the life expectancy of patients with follicular lymphoma (FL) has increased, little is known of their causes of death (CODs) in the rituximab era., Patients and Methods: We pooled two cohorts of newly diagnosed patients with FL grade 1-3A. Patients were enrolled between 2001 and 2013 in two French referral institutions (N = 734; median follow-up 89 months) and 2002 and 2012 in the University of Iowa and Mayo Clinic Specialized Program of Research Excellence (SPORE; N = 920; median follow-up 84 months). COD was classified as being a result of lymphoma, other malignancy, treatment related, or all other causes., Results: Ten-year overall survival was comparable in the French (80%) and US (77%) cohorts. We were able to classify COD in 248 (88%) of 283 decedents. In the overall cohort, lymphoma was the most common COD, with a cumulative incidence of 10.3% at 10 years, followed by treatment-related mortality (3.0%), other malignancy (2.9%), other causes (2.2%), and unknown (3.0%). The 10-year cumulative incidence of death as a result of lymphoma or treatment was higher than death as a result of all other causes for each age group (including patients ≥ 70 years of age at diagnosis [25.4% v 16.6%]) Follicular Lymphoma International Prognostic Index score 3 to 5 (27.4% v 5.2%), but not Follicular Lymphoma International Prognostic Index score 0 to 1 (4.0% v 3.7%); for patients who failed to achieve event-free survival within 24 months from diagnosis (36.1% v 7.0%), but not for patients who achieved event-free survival within 24 months of diagnosis (6.7% v 5.7%); and for patients with a history of transformed FL (45.9% v 4.7%), but not among patients without (8.1% v 6.2%). Overall, 77 of 140 deaths as a result of lymphoma occurred in patients whose FL transformed after diagnosis., Conclusion: Despite the improvement in overall survival in patients with FL in the rituximab era, their leading COD remains lymphoma, especially after disease transformation. Treatment-related mortality also represents a concern, which supports the need for less-toxic therapies.

In follicular lymphoma (FL), no prognostic index has been built based solely on a cohort of patients treated with initial immunochemotherapy. There is currently a need to define parsimonious clinical models for trial stratification and to add on biomolecular factors. Here, we confirmed the validity of both the follicular lymphoma international prognostic index (FLIPI) and the FLIPI2 in the large prospective PRIMA trial cohort of 1135 patients treated with initial R-chemotherapy ± R maintenance. Furthermore, we developed a new prognostic tool comprising only 2 simple parameters (bone marrow involvement and β 2 -microglobulin [β 2 m]) to predict progression-free survival (PFS). The final simplified score, called the PRIMA-PI (PRIMA-prognostic index), comprised 3 risk categories: high (β 2 m > 3 mg/L), low (β 2 m ≤ 3 mg/L without bone marrow involvement), and intermediate (β 2 m ≤ 3 mg/L with bone marrow involvement). Five-year PFS rates were 69%, 55%, and 37% in the low-, intermediate-, and high-risk groups, respectively ( P < .0001). In addition, achieving event-free survival (EFS) or not at 24 months (EFS24) was a strong posttreatment prognostic parameter for subsequent overall survival, and the PRIMA-PI was correlated with EFS24. The results were confirmed in a pooled external validation cohort of 479 patients from the FL2000 LYSA trial and the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence Molecular Epidemiology Resource. Five-year EFS in the validation cohort was 77%, 57%, and 44% in the PRIMA-PI low-, intermediate-, and high-risk groups, respectively ( P < .0001). The PRIMA-PI is a novel and easy-to-compute prognostic index for patients initially treated with immunochemotherapy. This could serve as a basis for building more sophisticated and integrated biomolecular scores., (© 2018 by The American Society of Hematology.)

Rituximab is used as a standard of care for follicular lymphoma and is usually administered intravenously. A novel subcutaneous formulation recently showed non-inferior efficacy with similar pharmacokinetic and safety profiles compared to intravenous rituximab in patients with follicular lymphoma. This new approach is promising in terms of comfort for patients and time-saving for hospital staff. To evaluate the real-life economic impact of subcutaneous rituximab as maintenance therapy in patients with follicular lymphoma in real life, we conducted a cost-consequence analysis from the hospital's point of view in three French teaching hospitals. Health-related quality of life (EQ-5D-3L) was investigated as well as patients' and nurses' perception. Compared to intravenous rituximab, subcutaneous administration showed an estimated cost-saving of €109.20 per patient per cycle (p < 0.001), 78.6% of which could be attributed to the rituximab cost. Health-related quality of life showed no significant difference between the two groups despite tendencies for greater pain in the subcutaneous group and greater anxiety in the intravenous group. Thus, subcutaneous rituximab had a favorable pharmacoeconomic profile, with clinical efficacy similar to that of intravenous rituximab. The subcutaneous form was preferred by almost all patients, but further consideration should be given to improve the patients' experience: a dedicated day unit with trained medical, nursing, and pharmaceutical staff could be helpful.

Relapse remains the most common cause of treatment failure in patients receiving autologous stem cell transplantation (ASCT) for follicular lymphoma (FL). The aim of this study was to evaluate the effect of adding radioimmunotherapy or rituximab (R) to BEAM (carmustine, etoposide, ara-c, melphalan) high-dose therapy for ASCT in patients with relapsed FL. Using the European Society for Blood and Marrow Transplantation registry, we conducted a cohort comparison of BEAM (n=1973), Zevalin-BEAM (Z-BEAM) (n=207) and R-BEAM (n=179) and also a matched-cohort analysis of BEAM vs Z-BEAM including 282 and 154 patients, respectively. BEAM, Z-BEAM and R-BEAM groups were well balanced for age, time from diagnosis to ASCT and disease status at ASCT. The cumulative incidences of relapse (IR) at 2 years were 34, 34 and 32% for Z-BEAM, R-BEAM and BEAM, respectively. By multivariate analysis, there were no significant differences with Z-BEAM or R-BEAM compared with BEAM for IR, non-relapse mortality, event-free survival or overall survival. With the caveat that the limitations of registry analyses have to be taken into account, this study does not support adding radioimmunotherapy or R to BEAM in ASCT for relapsed FL. However, we cannot rule out the existence a particular subset of patients who could benefit from Z-BEAM conditioning that cannot be identified in our series, and this should be tested in a randomized trial.

Recent advances in follicular lymphoma (FL) have resulted in prolongation of overall survival (OS). Here we assessed if early events as defined by event-free survival (EFS) at 12 and 24 months from diagnosis (EFS12/EFS24) can inform subsequent OS in FL. 920 newly diagnosed grade 1-3A FL patients enrolled on the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2012 were initially evaluated. EFS was defined as time from diagnosis to progression, relapse, re-treatment, or death due to any cause. OS was compared to age-and-sex-matched survival in the general US population using standardized mortality ratios (SMR) and 95% confidence intervals (CI). We used a cohort of 412 FL patients from two Lyon, France hospital registries for independent replication. Patients who failed to achieve EFS12 had poor subsequent OS (MER SMR = 3.72, 95%CI: 2.78-4.88; Lyon SMR = 8.74, 95%CI: 5.41-13.36). Conversely, patients achieving EFS12 had no added mortality beyond the background population (MER SMR = 0.73, 95%CI: 0.56-0.94, Lyon SMR = 1.02, 95%CI: 0.58-1.65). Patients with early events after immunochemotherapy had especially poor outcomes (EFS12 failure: MER SMR = 17.63, 95%CI:11.97-25.02, Lyon SMR = 19.10, 95%CI:9.86-33.36; EFS24 failure: MER SMR = 13.02, 95%CI:9.31-17.74, Lyon SMR = 7.22, 95%CI:4.13-11.74). In a combined dataset of all patients from both cohorts, baseline FLIPI was no longer informative in EFS12 achievers. Reassessment of patient status at 12 months from diagnosis in follicular lymphoma patients, or at 24 months in patients treated with immunochemotherapy, is a strong predictor of subsequent overall survival in FL. Early event status provides a simple, clinically relevant endpoint for studies assessing outcome in FL. Am. J. Hematol. 91:1096-1101, 2016. © 2016 Wiley Periodicals, Inc., Competing Interests: Declaration of Interests We declare no competing financial interests., (© 2016 Wiley Periodicals, Inc.)

An adverse prognostic impact of statin use in lymphoma was first suspected from in vitro data showing an impairment of anti-CD20 antibody binding. However, further clinical studies suggested an improved outcome associated with their use in hematological malignancies. In particular, a survival benefit was reported for patients with follicular lymphoma on statins. Our objective was to assess the outcome of follicular lymphoma patients treated in the PRIMA study with immunochemotherapy according to the use of statins. Among the 1,217 patients enrolled in the PRIMA study, 1,135 were included in the present study. Concomitant treatments at registration were available for all patients. Among those 1,135 patients, 119 were on statins (10.5%) at diagnosis. Adverse events frequencies, event-free survival (EFS), time to next lymphoma treatment (TTNLT), time to next chemotherapy (TTNCT), and overall survival (OS) were evaluated according to the use of statins. The rates of overall and specific cardiovascular adverse events between the two groups of patients were comparable both during induction and maintenance. Outcome in terms of response rates or EFS, TTNLT, TTNCT, and OS were similar regardless of the use of statins (P = 0.57, P = 0.85, P = 0.30, and P = 0.43, respectively) in univariate analysis and after further adjustments for potential confounding factors in multivariate analysis. In conclusion, statin use does not impact the prognosis of patients with follicular lymphoma treated with immunochemotherapy., (© 2016 Wiley Periodicals, Inc.)

The outcome of patients with follicular lymphoma (FL) has improved over the last two decades through the introduction of anti-CD20 monoclonal antibodies, usually used in combination with chemotherapy. However, patients with FL still experience multiple relapses, requiring several lines of treatment. Early toxicity of chemotherapy is a significant concern and as the life expectancy of patients with FL is increasing, late toxicities become an increasingly important concern. Progress made in understanding the biology of FL, especially dysregulation of intracellular pathways and immunological antitumor responses, recently allowed for the development of innovative chemo-free therapeutic approaches. In this report, different options such as new anti-CD20 antibodies, antibodies targeting other cell surface antigens, bi-specific antibodies, immunomodulation, idiotype vaccine and other targeted therapies are presented. The article also highlights how, although promising in early phase studies, the cost-effectiveness of new agents will have to be justified in Phase III trials. Furthermore, chemo-free regimen might not mean toxicity-free treatment and monitoring of early and late toxicities is required.

Detection of MUM1+ cells in follicular lymphoma (FL) tissues was previously found to be associated with poor prognosis in a single report, whereas the usefulness of Ki-67 immunostaining remains debated. Our goal was to establish whether these markers have predictive value for patients with FL. We analyzed MUM1 and Ki-67 expression using immunohistochemistry in biopsy samples from 434 patients from the PRIMA randomized trial. The MUM1 prognostic value was then validated in a cohort of 138 patients from the FL2000 randomized trial, using the optimal cutoff value obtained from the PRIMA cohort. The surface of positive staining was quantified using computerized image analysis. In the PRIMA cohort, both high levels of MUM1 positivity (cutoff value of 0.80%) and high levels of Ki-67 positivity (cutoff value of 10.25%) were significantly associated with a shorter progression-free survival (PFS) (P = .004 and P = .007 for MUM1 and Ki-67, respectively). In a multivariate Cox proportional hazards regression model, only MUM1 retained a statistical significance (hazards ratio 1.56; 95% confidence interval, 1.02-2.37; P = .038) after adjustment for the maintenance arm of treatment and the follicular lymphoma international prognostic index score. In the FL2000 cohort, high levels of MUM1 positivity were significantly associated to a shorter PFS (P = .004) and to a trend toward a shorter overall survival (P = .043). This remained significant using a multivariate Cox regression model after adjustment for the follicular lymphoma international prognostic index and the treatment arm for PFS (P = .016). These results show that MUM1 is a strong and robust predictive immunohistochemical marker in patients with FL., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Anti-CD20-containing chemotherapy regimens have become the standard of care for patients with follicular lymphoma needing cytotoxic therapy. Four randomized trials demonstrated a clinical benefit for patients treated with rituximab. However, no long-term follow up (i.e. > 5 years) of these trials is yet available. Between May 2000 and May 2002, 358 newly diagnosed patients with high tumor burden follicular lymphoma were randomized to receive cyclophosphamide, adriamycin, etoposide and prednisolone plus interferon-α2a or a similar chemotherapy-based regimen plus rituximab, and outcome was up-dated. With a median follow up of 8.3 years, addition of rituximab remained significantly associated with prolonged event-free survival (primary end point) (P=0.0004) with a trend towards a benefit for overall survival (P=0.076). The Follicular Lymphoma International Prognostic Index score was strongly associated with outcome for both event-free and overall survival in univariate analysis and its prognostic value remained highly significant after adjusting for other significant covariates in multivariate models (P<0.0001 and P=0.001, respectively). Considering long-term toxicity, the addition of rituximab in the first-line setting was confirmed as safe with regards to development of secondary malignancies. Long-term follow up of patients with follicular lymphoma treated in the FL2000 study confirms the sustained clinical benefit of rituximab without long-term toxicity.

High-dose therapy followed by autologous stem cell transplantation is widely accepted as salvage therapy for patients with relapsed aggressive lymphoma. In the pre-rituximab era, autologous stem cell transplantation had also been increasingly applied as a consolidation treatment for patients with indolent lymphoma in second or subsequent remission whereas controversies have emerged concerning its role in first line therapy from several randomized trials. Broad development and amazing efficacy of monoclonal antibody-based combination therapies for de novo or relapsing follicular lymphoma patients render previous conclusions outdated and underline the critical need for further phase III trials. This review focuses on available data from pre-rituximab and rituximab eras to help clarifying the precise role and timing of autologous stem cell transplantation among the current armamentarium for follicular lymphoma treatment., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

PURPOSE First-line treatment for patients with newly diagnosed follicular lymphoma (FL) still remains debated, even in the rituximab-based combination therapy era. Few studies have addressed the question whether complete remission (CR) translates into better survival. The aim of this study was to assess the long-term follow-up of prospectively treated patients with FL and the potential correlation between response quality to first-line treatment and overall survival (OS). PATIENTS AND METHODS Data from 536 patients with FL with low (n = 193) or high (n = 343) tumor burden enrolled from October 1986 to May 1995 in the French and Belgian GELF86 studies were analyzed. Data from these trials have been previously reported for low-tumor burden and high-tumor burden patients. Results Median follow-up was 14.9 years, and median OS was 9.8 years. Treated patients who achieved a complete response (CR; n = 194; 45%) had a significant longer OS than those only reaching a partial response (PR; n = 168; 39%) throughout treatment (hazard ratio [HR], 0.55; 95% CI, 0.42 to 0.72; P < .001) in an univariate time-dependent Cox model. Similar findings were found when response to treatment (CR v PR) was adjusted for potentially confounding factors in a multivariate model (HR, 0.53; 95% CI, 0.38 to 0.73; P < .001). CONCLUSION These data provide a long follow-up of these patients' cohorts and indicate that a better response to first-line treatment translates into an improved survival for patients with FL. Therefore, response-adapted therapy aiming to achieve a CR should be considered as first-line treatment.