First-line Follicular Lymphoma Research Articles

Preliminary Findings of a Phase Ib/II Trial Indicate Manageable Safety and Promising Efficacy for Mosunetuzumab in Combination with Lenalidomide (M+Len) in Previously Untreated (1L) Follicular Lymphoma (FL)

Background: First-line FL treatments typically include an anti-CD20 monoclonal antibody with alkylator-based chemotherapy. Despite encouraging efficacy, most patients (pts) eventually relapse; novel therapies that improve outcomes and prolong remission in 1L FL are needed. Also, chemotherapy-containing regimens may have substantial toxicities, emphasizing the need for new therapies with improved safety. Mosunetuzumab (M), a CD20xCD3 bispecific antibody that redirects T cells to eliminate malignant B cells, has shown manageable safety with high complete remission rates in pts with relapsed/refractory (R/R) FL after ≥2 prior lines of therapy (Budde et al. Lancet Oncol 2022). Lenalidomide (Len), a potent immunomodulatory agent, may have synergistic effects with M. Initial results from the CO41942 Phase Ib/II trial (NCT04246086) showed that M (intravenous) combined with Len had a manageable safety profile and encouraging chemotherapy-free anti-lymphoma activity in pts with R/R FL who had ≥1 prior line of therapy (Morschhauser et al. ASH 2021). We present preliminary safety, efficacy, and biomarker data from this ongoing trial of M (subcutaneous [SC]) combined with oral Len in pts with 1L FL who require systemic therapy. Methods: Pts with 1L FL requiring systemic therapy (investigator-assessed using GELF criteria) with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2 are included; target enrollment is 40 pts. Pts received 12 cycles of M+Len (cycle [C] 1, 21 days; C2-12, 28 days); in C1, 5mg of M was given on Day (D) 1, with the target dose (45mg) given on C1D8, C1D15, and on D1 of C2-12; Len (20mg) was given on D1-21 of C2-12 ( Figure A). Cytokine release syndrome (CRS) was reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Responses by PET-CT were investigator-assessed using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014). Flow cytometry (fluorescence-activated cell sorting) on whole blood was used to assess peripheral biomarkers. Results: At clinical cutoff date (CCOD; May 2, 2023), 37 pts were enrolled: 21 (56.8%) had been on the study for 0-3 months, 12 (32.4%) for 3-6 months, and 4 (10.8%) for 6-9 months. Median age was 62.0 (range 28-83) years and 20 (54.1%) pts were male. All pts had a baseline ECOG PS of ≤1; 32 (86.5%) had Ann Arbor stage III-IV; and 7 (18.9%), 13 (35.1%), and 17 (45.9%) had a FL International Prognostic Index score of 0-1 (low), 2 (intermediate), and 3-5 (high risk), respectively. All pts reported ≥1 treatment-emergent adverse event (TEAE); 12 (32.4%) had ≥1 serious TEAE. Two pts discontinued study treatment after the C1D15 dose, one pt due to uveitis and one pt due to tumor flare. TEAEs related to M or Len occurred in 36 (97.3%) and 29 (78.4%) pts, respectively. At least one Grade (Gr) 3-4 TEAE occurred in 16 (43.2%) pts, the most common being neutropenia (seven pts). No pts reported Gr 5 AEs. CRS occurred in 20 (54.1%) pts; all were Gr 1, except for one pt with Gr 2 CRS, and all events resolved (median CRS duration: 2 days [range 1-26]). CRS frequency was highest after C1D1 (32.4%), and steadily declined over subsequent days and cycles. No immune effector cell-associated neurotoxicity syndrome events were observed. To date, 27 pts were efficacy evaluable ( Figure B). Of 24 (88.9%) responders, 22 (81.5%) had a complete metabolic response (21 achieved by the first response assessment at end of C3), and two (7.4%) had a partial metabolic response. One pt (3.7%) had no response assessment by CCOD, and two (7.4%) had progressive disease but were recognized to have biopsy-proven transformed FL during C1 and C2. All responses were maintained at CCOD. Preliminary biomarker analyses of pt blood samples showed: increased CD69 and sustained HLA-DR expression in CD8 T cells, with modulation of CD8 subsets favoring central/effector memory phenotypes; sustained natural killer-cell activity; and minimal effects on CD4 T cells (except for lower PD-1 expression). Conclusions: This fixed-duration, chemotherapy-free M+Len regimen offers a convenient means for outpatient SC administration, and has a manageable early safety profile with promising anti-lymphoma activity in pts with 1L FL requiring systemic therapy, based on the preliminary data. Advancing M+Len into the first-line setting offers potential benefits in chemotherapy-naïve pts. Safety, efficacy, biomarker, and pharmacokinetic data from the complete cohort (40 pts) will be presented.

Identification of High-Risk Population in First-Line Follicular Lymphoma at Screening with a Next Generation Sequencing (NGS) Assay Using Plasma Circulating Tumor DNA (ctDNA): Initial Data from Gallium

Background Follicular lymphoma (FL) is an indolent disease with favorable outcome in patients (pt) treated with antibody-based immunochemotherapy. However, ca. 15% of the pt population experience disease relapse within 24 months or transformation to a more aggressive disease, representing a population with high unmet medical need. Available clinicogenetic risk scores show suboptimal performance for predicting early disease progression (Jurinovic, Blood 2016). Here we evaluated ctDNA at screening as a novel tool to identify high risk pt populations. Material and Methods Pre-treatment plasma samples from 221 selected pts diagnosed with advanced stage or bulky FL in need of systematic treatment from the GALLIUM trial (NCT 01332968) were analyzed. Pts were selected to be evenly distributed among chemo/antibody groups (50 Rituximab (R) -Bendamustine (Benda), 63 R-CHOP/CVP, 50 Gazyva (G) -Benda, 58 G-CHOP/CVP). Within each treatment group, 25 to 28 cases with good responses (progression-free survival (PFS) > 5 years) and 25 to 31 cases with early progression or transformation to an aggressive disease (median PFS: 352 days and 91.6% of these cases progressed within 24 months) were selected. Targeted NGS was performed using a modified version of the AVENIO ctDNA analysis workflow (Roche; Research Use Only) based on the previously described CAPP-Seq workflow (Kurtz, J Clin Oncol 2018). The targeted NGS panel was designed to cover ~314 kb in or near 466 genes associated with NHL. Potential germline derived variants were filtered out using a publicly available database and panel specific blacklist filtering; additionally, variants with allelic frequency (AF) >20% were excluded. ctDNA was quantified as mutant molecules per milliliter-of-plasma (MMPM) based on single nucleotide variants (SNV) in the sequenced genomic regions. The association of PFS with this classifier was evaluated by Kaplan-Meier methods and Cox proportional hazards model, and an optimal cut-off for MMPM high vs low was determined by using maximally selected rank statistics, validated by 10-fold cross validation. Results We detected a median of 107 (range 0-554) SNV at a median deduplicated depth of 3766x. A strong correlation between ctDNA at screening, measured as MMPM, and clinical prognostic markers was observed; higher levels of MMPM were associated with larger sum of the product of the diameters (SPD) (Mann-Whitney-U (MWU) P < 0.0001), higher FLIPI2 scores (MWU P < 0.0001) and m7-FLIPI (MWU P = 0.0001). Pts with long PFS had a significantly (MWU P < 0.0001) lower median MMPM (59.9) than those who progressed early (276.5). Using an optimal cut-off to predict pts at risk of early progression, MMPM high cases (n=96) showed significantly more total SNVs compared to MMPM low cases (n=125) (MWU P < 0.0001). MMPM high vs low was a stronger marker for PFS (cross-validated log-rank P < 0.0001; HR [95% CI] = 2.4 [1.6,3.5]) versus FLIPI2 (log-rank P = 0.0063; HR [95% CI] = 1.7 [1.2,2.4]) or tumor burden measured as SPD (log-rank P = 0.0009; HR [95% CI] = 1.9 [1.3,2.8]). In a multivariate Cox model, the association of high MMPM and worse PFS was still significant after correction for FLIPI2, SPD and m7-FLIPI, indicating that MMPM has an independent prognostic value (log-rank P < 0.0001; HR [95% CI] = 2.42 [1.6,3.8]) (Figure 1). Consistent with previous reports (Jurinovic, ASH 2021), also in this selected cohort m7-FLIPI was prognostic for CHOP/CVP (log-rank P = 0.0061; HR [95% CI] = 2.2 [1.2,3.8]) but not for Benda (log-rank P = 0.2274; HR [95% CI] = 1.5 [0.76,3.0]). Notably, the prognostic value of ctDNA at screening using MMPM was observed for both CHOP/CVP (log-rank P < 0.0001; HR [95% CI] = 2.9 [1.7,5.0]), and Benda (log-rank P < 0.0001; HR [95% CI] = 2.9 [1.7,5.1]). Conclusion Measurements of ctDNA at screening showed promising results as a biomarker to predict high risk populations for early treatment failure in untreated FL. MMPM at baseline, quantified using the AVENIO NHL assay, showed an independent prognostic value compared to FLIPI 2, m7-FLIPI and SPD. Notably, while known clinicogenetic risk scores had a prognostic value limited to CHOP/CVP regimen (Jurinovic, ASH 2019, Bolen, Blood 2021), MMPM prognostic value was maintained on CHOP/CVP and Benda chemotherapy. Overall, these initial results warrant additional analysis to investigate the value of the ctDNA as a treatment agnostic stratification tool for clinical research.

Evaluating the impact of eligibility criteria in first-line clinical trials for follicular lymphoma: a MER/LEO cohort analysis

AbstractCancer 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.

End of induction positron emission tomography complete response (PET-CR) as a surrogate for progression-free survival in previously untreated follicular lymphoma.

Progression-free survival (PFS) has been the regulatory primary end-point for recent phase III trials in first-line follicular lymphoma (FL), but requires prolonged follow-up. Complete response (CR) at 30months after initiation of induction treatment was validated as surrogate end-point for PFS. Our objective was to further evaluate surrogacy of CR measured by [18 F] fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at the end of induction (EoI). Individual patient data were analysed from 1505 patients from five randomized trials. Trial-level surrogacy examining the association between treatment effects on EoI-PET-CR and PFS was evaluated using linear regression ( ) and bivariate Copula ( ) models. Although EoI-PET-CR strongly predicted PFS at a prognostic level, the trial-level assessment did not show strong correlation ( , confidence interval [CI]: 0.20-0.88; , CI: 0.0-0.82). The high uncertainty in estimation was possibly due to the small number of trials and the population of patients with available PET data. Maintenance therapy affecting PFS beyond induction treatment, but not EoI-PET-CR end-point, may have distorted the association between treatment effects. However, there will probably be a number of additional trials approaching completion with available PET response data. Refined evaluation of PET-CR based surrogate end-points is still warranted.

Evaluation of Eligibility Criteria in First-Line Clinical Trials for Follicular Lymphoma: A MER/LEO Database Analysis

Evaluation of Eligibility Criteria in First-Line Clinical Trials for Follicular Lymphoma: A MER/LEO Database Analysis

Early Relapse in First-Line Follicular Lymphoma: A Review of the Clinical Implications and Available Mitigation and Management Strategies.

Chemoimmunotherapy with rituximab (R-chemo) or obinutuzumab (G-chemo) is standard of care for patients with previously untreated symptomatic or high-tumor-burden follicular lymphoma. Median progression-free survival (PFS) with R-chemo plus R maintenance exceeds 10 years, and G-chemo plus G maintenance improves PFS relative to the corresponding R-containing regimen. Despite these positive results, a sizable proportion of patients continue to progress during or shortly after initial treatment. While no single definition of early relapse has been established, progression of disease within 24 months of initial treatment (POD24) is now widely accepted as a critical adverse prognostic factor. Multiple studies have shown increased mortality risk in patients with POD24 versus those without POD24. Unfortunately, tools for the assessment of POD24 risk are suboptimal, and it is not currently possible in clinical practice to identify individual patients who are at increased risk for early relapse. Treatment strategies for patients with POD24 are not well defined. G-chemo regimens appear to reduce the risk of POD24 relative to R-chemo regimens, although the impact on survival outcomes remains unclear. Beyond standard therapy, autologous stem cell transplant and emerging treatment modalities, such as bispecific antibodies and chimeric antigen receptor T-cells, may have a role in future management. Until standard treatments are defined, mitigating the risk of early relapse with effective up-front treatment remains the priority.

Rituximab Maintenance Versus Observation After Immunochemotherapy (R-CHOP, R-MCP, and R-FCM) in Untreated Follicular Lymphoma Patients: A Randomized Trial of the Ostdeutsche Studiengruppe Hämatologie und Onkologie and the German Low-Grade Lymphoma Study Group.

The German study groups, the German Low-Grade Lymphoma Study Group (GLSG) and Ostdeutsche Studiengruppe Hämatologie und Onkologie (OSHO), initiated in 2007 a double randomized trial to investigate efficacy and safety of rituximab maintenance versus observation in remission after randomly assigned induction treatment in the first-line follicular lymphoma. Previously untreated patients with stage II–IV follicular lymphoma in need of therapy were randomized to receive 6 cycles of R-CHOP, R-MCP, or R-FCM. Responding patients were subsequently randomized to 2 years rituximab maintenance or observation, stratified by type of immunochemotherapy, quality of remission, and Follicular Lymphoma International Prognostic Index (FLIPI). Recruitment was stopped in 2011 after the PRIMA results had been published. Median age of the 206 recruited patients was 66 years (range, 24–86), and (FLIPI) was low in 13%, intermediate in 28%, and high in 60%. High and comparable overall response rates were observed after R-CHOP (88%), R-MCP (89%), and R-FCM (91%). Rituximab maintenance substantially prolonged progression-free survival (PFS) in comparison to observation in remission (hazard ratio 0.39, P = 0.0064). In the rituximab maintenance group, the 3-year PFS was 89% compared with 69% in the observation group. No differences in overall survival were observed for maintenance vs. observation (hazard ratio 1.04, 95% confidence interval 0.32–3.43, P = 0.95). In this randomized trial, 2 years of rituximab maintenance was associated with significantly prolonged PFS in comparison to observation after response to first-line immunochemotherapy in follicular lymphoma. Our data represent an independent confirmation of the PRIMA trial results.(Clinical Trial EudraCT Number: 2005-005473-29, 2006-09-26)

Four Versus Two Years of Rituximab Maintenance (R-maintenance) Following Bendamustine Plus Rituximab (B-R): Initial Results of a Prospective, Randomized Multicenter Phase 3 Study in First-Line Follicular Lymphoma (the StiL NHL7-2008 MAINTAIN study)

Background: R-maintenance for 2 years is part of a standard treatment approach for previously untreated follicular lymphoma. In this study we compared the efficacy and safety of 4 versus 2 years of R-maintenance following first-line treatment with B-R.Methods: Patients included in the study were required to have stage II (bulky disease >7 cm), III, or IV disease. Patients were treated with up to 6 cycles of B-R plus 2 additional cycles of Rituximab. All responding patients received 2 years R-maintenance (375 mg/m2 every 2 months). Patients who tolerated treatment for the entire 2 years and who were still in remission hereafter were subsequently randomized to 2 more years of R-maintenance or observation. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rates, overall survival (OS), and toxicity.Results: A total of 612 patients with follicular lymphoma were enrolled in the study. Of enrolled patients, 555 were evaluable for response and 497 (90%) responded to B-R induction, with 181 patients (33%) achieving a complete remission. A total of 261 patients discontinued treatment during induction or the first 2 years of R-maintenance. The most frequent reasons for discontinuation included progression in 85 of 261 pts (33%), patient's or doctor's choice in 55 pts (21%), toxicity or infections in 29 pts (11%), Rituximab intolerance in 14 pts (5%), or death in 11 pts (4%) with a median age of 70 years and 5 pts who died from infections. Of 351 patients randomized to 2-years or 4-years of R-maintenance, 350 were evaluable (n = 172 and n = 178, respectively). The median age was 60 years and patient characteristics were comparable between groups. The median observation time was 36 months following randomization. Median PFS and OS have not yet been reached in either arm. PFS appears superior with 4 years versus 2 years of R-maintenance with a hazard ratio (HR) of 0.63 (95% CI 0.36-1.11; fig. 1). There was no difference in OS between groups. One patient died from a progressive multifocal leukoencephalopathy (PML, randomized to 4 years of Rituximab). A historical comparison for PFS between responding patients given 2 years of R-maintenance in this MAINTAIN trial and subjects from the former StiL NHL1 study (B-R versus CHOP-R) who received B-R only appears to favor R-maintenance with a HR of 0.78 (95% CI 0.54-1.04). Data analysis is ongoing and updated results will be presented at the ASH meeting.Conclusions: Results at the time of this analysis appear to favor 4-years over 2-years of R-maintenance and 2-years over observation compared to a historical control. Further analysis including the updated dataset will be presented at the ASH meeting and should provide more definitive evidence regarding the benefit of prolonged R-maintenance. [Display omitted] DisclosuresRummel:Roche: Honoraria, Other: PrefMab is sponsored by F. Hoffmann-La Roche Ltd. Third-party Medical Writing assistance, under the direction of Mathias Rummel, was provided by Lynda McEvoy of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd, Research Funding. Buske:Hexal: Honoraria; Celltrion, Inc.: Consultancy, Honoraria; Pfizer: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Balser:Sanofi-Aventis: Other: Travel support; IOMEDICO: Other: Travel support. Behringer:Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Dürig:Lead Discovery Center: Research Funding. Maschmeyer:Gilead: Honoraria; Pfizer: Honoraria, Travel support; Merck-Serono: Honoraria; Celgene: Honoraria; Bristol-Meyers Squibb: Honoraria; Basilea: Honoraria; Janssen-Cilag: Honoraria; Astellas: Honoraria; AstraZeneca: Honoraria; Boehringer-Ingelheim: Honoraria; Amgen: Honoraria; Bristol-Meyers Squibb: Other: Travel support. Schliesser:Bayer: Equity Ownership; Roche: Equity Ownership. Burchardt:Celgene: Honoraria; Roche: Honoraria; CSL: Honoraria; Medac: Honoraria. Barth:Celegene: Honoraria; CSL: Honoraria, Other: Travel support; BMS: Honoraria; Hexal: Honoraria; Johnson & Johnson: Honoraria; Medac: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Roche: Honoraria; Takeda: Honoraria; Gilead: Other: Travel support; Amgen: Other: Travel support. Greil:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Novartis, Celgene: Research Funding; Takeda: Honoraria, Research Funding; BMS, Amgen: Honoraria.

Phase III Clinical Trials in First-Line Follicular Lymphoma: A Review of Their Design and Interpretation.

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.

Lenalidomide/rituximab induces high molecular response in untreated follicular lymphoma: LYSA ancillary RELEVANCE study

AbstractComplete molecular response (CMR) after first-line immunochemotherapy reflects treatment efficacy and may predict prognosis in patients with follicular lymphoma (FL). RELEVANCE is the first phase 3 trial comparing the chemotherapy-free regimen lenalidomide/rituximab (R2) vs rituximab/chemotherapy (R-Chemo) in previously untreated FL patients (ClinicalTrials.gov identifier: NCT01650701). The objective of the minimal residual disease (MRD) analysis was to determine the ability of a chemotherapy-free regimen to induce CMR. Of 440 French patients participating in the Lymphoma Study Association (LYSA) RELEVANCE MRD study, all 222 patients with a BIOMED-2–detectable BCL2-JH translocation at diagnosis were analyzed. MRD was quantified by droplet digital polymerase chain reaction with a sensitivity ≤10−4. At week 24 (end of induction treatment), 98% and 78% of patients achieved CMR in peripheral blood (PB) and bone marrow (BM), respectively. Achievement of CMR (in PB and/or BM) had a significant impact on progression-free survival (PFS), with 3-year PFS of 84% and 55% for patients with CMR and detectable MRD, respectively (P = .015). CMR at week 24 was reached more frequently in the R2 arm (105/117; 90%) than in the R-Chemo arm (70/90; 77%) (P = .022). The poor prognostic value in terms of PFS for the persistence of molecular disease was observed irrespective of treatment arm (interaction test, P = .31). In agreement with the clinical results of the RELEVANCE trial, our results show that R2 immunomodulatory treatment in first-line FL can achieve high rates of CMR.

The combination of ibrutinib and rituximab demonstrates activity in first-line follicular lymphoma.

SummaryThis phase 2 study evaluated the activity and safety of ibrutinib, a Bruton’s tyrosine kinase inhibitor, plus rituximab in adults with previously untreated follicular lymphoma. Patients received once‐daily ibrutinib 560 mg continuously plus once‐weekly rituximab 375 mg/m2 for 4 weeks beginning Week 1 (Arm 1, n = 60) or Week 9 (following an 8‐week ibrutinib lead‐in) to explore biomarkers (Arm 2, n = 20). The primary endpoint was the best overall response rate (ORR). The median age was 58 years; most had an Eastern Cooperative Oncology Group Performance Status of 0 (74%) and Stage III/IV disease (84%). At a median study follow‐up of 34 months in Arm 1 and 29 months in Arm 2, ORRs were 85% [95% confidence interval (CI) 73–93] and 75% (95% CI 51–91), respectively, with complete responses in 40% and 50%. The median duration of response was not reached in either arm; 30‐month progression‐free and overall survival rates were 67% and 97% (Arm 1) and 65% and 100% (Arm 2). The most common adverse events were fatigue, diarrhoea and nausea. Higher grade (Grade 3/4) haematological, haemorrhagic and cardiac events occurred infrequently. Ibrutinib plus rituximab was active and tolerable in first‐line follicular lymphoma.

Expectations and Experience: Optimising Efficacy and Maintaining Quality of Life in Follicular Lymphoma

Prof Salles provided an update on the ongoing first-line follicular lymphoma (FL) studies, demonstrating how analysis of the GALLIUM study data regarding the use of different chemotherapy backbones consistently showed the benefits of obinutuzumab (G) chemotherapy (G-chemo) versus rituximab (R) chemotherapy (R-chemo) in FL patients. An update from the PRIMA study showed that 10-year progression-free survival (PFS) was improved following the use of R maintenance compared with observation following induction. Prof Salles also provided an overview of the RELEVANCE study data, which showed that R plus lenalidomide was not superior to standard R-chemo for the treatment of first-line FL. Prof Seymour presented data showing that two-thirds of premature FL deaths occur in patients experiencing disease progression within 2 years of treatment, highlighting the need to identify patients at early risk of progression. Prof Seymour explored various prognostic and predictive tools that could be used to identify patients at high risk of death, but he noted that until these prognostic tools are available in the clinic, the high-risk population remains unidentifiable. Furthermore, the accuracy of these prognostic indices needs to be improved. Data analysis from the GALLIUM study showed that G-chemo decreased the risk of a disease progression event in the first 2 years by 46% compared to R-chemo. Prof Trotman explored the use of PET imaging and detection of minimal residual disease (MRD) to assess treatment outcomes. Prof Trotman showed that PET status at the end of induction is highly prognostic of the outcome. An exploratory analysis of the GALLIUM data showed that the application of the Lugano 2014 response criteria showed a rapid, deep separation of the PFS curves of patients achieving a complete metabolic response (CMR) versus those who did not. There was almost a 5-fold increase in risk of progression and in risk of death in patients failing to achieve CMR. An exploratory analysis of the MRD status of GALLIUM patients showed that a greater proportion of patients in the G-chemo arm achieved MRD-negative status at the end of induction (EOI). Interestingly, patients achieved similar MRD outcomes with G-chemo, regardless of chemotherapy backbone. Both PET and MRD status after induction were independently predictive of PFS. Dr Pettengell and Mr Bouguet discussed FL from both the clinician’s and the patient’s perspective, with a focus on health-related quality of life (HRQoL). They demonstrated how a marked decrease in HRQoL at progression highlights the importance of extending remission for FL patients. Dr Pettengell presented data from GALLIUM showing comparable quality of life for patients treated with either G-chemo or R-chemo. They also presented patient surveys showing that FL has a substantial physical and psychological impact on patients that both lasts beyond treatment and persists even during long-term remission.

Four versus Two Years of Rituximab Maintenance (R-Maintenance) Following Bendamustine Plus Rituximab (B-R): Results of a Prospective, Randomized Multicenter Phase 3 Study in First-Line Follicular Lymphoma (the StiL NHL7-2008 MAINTAIN Study)

Four versus Two Years of Rituximab Maintenance (R-Maintenance) Following Bendamustine Plus Rituximab (B-R): Results of a Prospective, Randomized Multicenter Phase 3 Study in First-Line Follicular Lymphoma (the StiL NHL7-2008 MAINTAIN Study)

Thirty-Month Complete Response as a Surrogate End Point in First-Line Follicular Lymphoma Therapy: An Individual Patient-Level Analysis of Multiple Randomized Trials.

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 (R2WLS) and bivariate copula (R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 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 R2WLS of 0.88 (95% CI, 0.77 to 0.96) and an R2Copula 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.

Prognostic value of circulating Bcl-2/IgH levels in patients with follicular lymphoma receiving first-line immunochemotherapy

AbstractBcl-2/IgH rearrangements can be quantified in follicular lymphoma (FL) from peripheral blood (PB) by polymerase chain reaction (PCR). The prognostic value of Bcl-2/IgH levels in FL remains controversial. We therefore prospectively studied PB Bcl-2/IgH levels from 173 first-line FL patients who were consecutively enrolled, randomized, and treated within the multicenter phase 3 clinical trial NHL1-2003 comparing bendamustine-rituximab (B-R) with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone. From April 2005 to August 2008, 783 pre- and posttreatment PB samples were quantified by quantitative PCR. At inclusion, 114 patients (66%) tested positive and 59 (34%) were negative for Bcl-2/IgH. High pretreatment Bcl-2/IgH levels had an adverse effect on progression-free survival (PFS) compared with intermediate or low levels (high vs intermediate: hazard [HR], 4.28; 95% confidence interval [CI], 1.70-10.77; P = .002; high vs low: HR, 3.02; 95% CI, 1.55-5.86; P = .001). No PFS difference between treatment arms was observed in Bcl-2/IgH-positive patients. A positive posttreatment Bcl-2/IgH status was associated with shorter PFS (8.7 months vs not reached; HR, 3.15; 95% CI, 1.51-6.58; P = .002). By multivariate analysis, the pretreatment Bcl-2/IgH level was the strongest predictor for PFS. Our data suggest that pre- and posttreatment Bcl-2/IgH levels from PB have significant prognostic value for PFS in FL patients receiving first-line immunochemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT00991211 and at the German Federal Institute for Drugs and Medical Devices as #BfArM-4021335.

Evaluation of complete response rate at 30 months (CR30) as a surrogate for progression-free survival (PFS) in first-line follicular lymphoma (FL) studies: Results from the prospectively specified Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) analysis with individual patient data (IPD) of 3,837 patients (pts).

8504 Background: Although PFS is the standard endpoint for new drug approvals in first-line FL, advances in efficacy (median PFS >7 y) coupled with the indolent nature of FL necessitate extended patient follow-up in clinical trials. The FLASH group conducted a meta-analysis to evaluate whether treatment effects on CR30, an earlier endpoint, could accurately predict treatment effects on PFS. Methods: Correlation of CR30 odds ratio (OR) with PFS hazard ratio (HR) was evaluated using both linear regression (R2WLS) and copula bivariate (R2Copula) models. Prespecified criteria for CR30 surrogacy required either R2WLS or R2Copula ≥ 0.80 with a lower bound of the 95% confidence interval (CI) > 0.60, with neither estimate < 0.70. The minimum CR30 difference to predict significant PFS difference was calculated. Results: Data from 13 randomized first-line trials (8 induction, 5 maintenance trials) with IPD for 3837 pts were included. The prespecified threshold for surrogacy was met: R2WLS of 0.88 (95% CI, 0.77-0.96...

A Phase Ib Study of Obinutuzumab Combined with Lenalidomide for Relapsed/Refractory Follicular B-Cell Lymphoma

BACKGROUND:Lenalidomide exerts anti-proliferative activity on lymphoma cells, enhances T- and NK-cell function, and improves ADCC. The combination of lenalidomide and rituximab (R2) has been shown to be synergistic in pre-clinical models and in patients with relapsed and first-line follicular lymphoma (FL). Obinutuzumab, a unique type II glycoengineered monoclonal anti-CD20 antibody with increased ADCC and increased direct cell death induction compared to rituximab, has shown promising efficacy in NHL. Combining obinutuzumab with lenalidomide might be even more efficient than R2 combination. In 2012, we started a phase Ib/II study to assess the safety and efficacy of this combination (ClinicalTrials.gov: NCT01582776, GALEN) for relapsed/refractory lymphoma patients. Here, we report the phase Ib part whose primary objective was to determine the maximum tolerated dose (MTD) of lenalidomide in combination with a fixed dose of obinutuzumab.METHODS:To identify the MTD of lenalidomide, four patient cohorts received escalating doses (10, 15, 20, and 25 mg) of daily oral lenalidomide on days 1-21 of a 28-day cycle for the first cycle and on days 2-22 of a 28-day cycle from cycles 2 to 6. Intravenous infusions of obinutuzumab at a flat dose of 1000mg were given on Days 8, 15, and 22 of the first cycle and at D1 of cycles 2 to 6 (total of 8 infusions). Steroid premedication was mandatory before first obinutuzumab infusion. All subjects were required to take daily aspirin (100 mg) for deep vein thrombosis (DVT) prophylaxis during study period. Subjects who were unable to tolerate aspirin and subjects with prior history of DVT or at high risk received low molecular weight heparin therapy or warfarin (coumadin) treatment. Dose was escalated in a 3+3 design based on dose limiting toxicity (DLT) assessment during cycle 1RESULTS:20 patients with FL ([10 mg: 7; 15 mg: 3; 20 mg: 6, 25 mg: 4] QD) were enrolled between Oct 2012 and Feb 2014 at 7 centers, 10 men/10 women, median age 64 (range, 39–80) years, 15 with Ann Arbor stage IV, median number of prior systemic therapies 2 (range, 1–5) and 8 were rituximab refractory. One patient was withdrawn before receiving any treatment due to neutropenia occurring at baseline screening. Median number of cycles was 6 (range, 1–6). We observed 163 AEs (87 grade 1; 53 grade 2; 21 grade 3; one grade 4 and one grade 5). The most common AEs (All grades, ≥20% patients) were neutropenia (10/19; 53%), constipation (10/19; 53%) asthenia (7/19; 37%), upper respiratory tract infection (7/19; 37%), rash/cutaneous eruption (5/19; 26%), cough (5/19; 26%), diarrhea (4/19 ; 26%) and fever (4/19, 21%). Grade (G) 3/4 AEs occurring in ≥2 patients only consisted in neutropenia (8/19; 42%). Infusion related reactions occurred in 3 patients and did not exceed grade 2. Four DLTs have occurred in 2 patients: one unexplained death (G5) at 10 mg in the setting of G3 worsening pleural effusion; another patient treated at 20 mg had G3 pulmonary infection with G3 hypokalemia, both deemed unrelated to study treatment. The MTD was not reached. Among 19 evaluable patients, 13 (68%) had an overall response according to Cheson 1999 criteria: 7 achieved CR, 3 CRu and 3 PR.CONCLUSION:Oral lenalidomide plus obinutuzumab is well tolerated and effective in patients with relapsed or refractory FL. Recommended dose of lenalidomide was established at 20mg based on the increased incidence of grade 3/4 neutropenia between cycle 2 and 6 at 25mg. The Phase II partis currently assessing theefficacy of lenalidomide (at 20 mg) in combination with obinutuzumab in 2 separate populations of patients: relapsed/refractory follicular lymphoma in one cohort and relapsed/refractory aggressive lymphoma (diffuse large B-cell lymphoma and mantle cell lymphoma) in another cohort. DisclosuresMorschhauser:Celgene: advisory boards, advisory boards Other, Honoraria; Genentech/roche: Honoraria, travel grants Other. Off Label Use: obinutuzumab and lenlidomide in relapsed follicular lymphoma. Salles:celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; roche: advisory boards, advisory boards Other, Honoraria, Research Funding. Le Gouill:Roche: Consultancy. Tilly:Roche/Genetech: advisory boards, advisory boards Other, Honoraria; Celgene: advisory boards Other, Honoraria. Cartron:roche: Consultancy, Honoraria; celgene: Honoraria.

Impact of the introduction of rituximab in first‐line follicular lymphoma: a retrospective study of 247 unselected patients referred to a single institution with a long‐term follow‐up

Rituximab was approved in France in 2004, following randomized trials that demonstrated efficacy in newly diagnosed high tumour burden follicular lymphoma (FL). This retrospective study compared the management and outcome of FL in unselected patients treated in a single institution before and after rituximab approval. Two hundred and forty-seven adult patients were referred with first-line FL between 1996 and 2010 and are included in this study. The 103 pre-rituximab patients comprising cohort 1 were diagnosed between January 1996 and December 2003; cohort 2 includes the 144 patients diagnosed after the approval of rituximab between January 2004 and December 2010. Baseline clinical and biological data, type of therapy, treatment response, progression-free survival (PFS) and overall survival (OS) rates were compared. There were no statistically significant differences between the two cohorts with respect to baseline clinical and disease characteristics, including FL International Prognostic Index score. The major difference between the two cohorts is the use of rituximab in first line. Seventy-one per cent of patients in cohort 2 received rituximab (19% alone, 52% with chemotherapy) versus 10% in cohort 1 (2% alone, 8% with chemotherapy; p < 0.0001). The objective response rate (ORR) was significantly higher for cohort 2 (ORR 84% compared with 72% for cohort 1; p = 0.03). The PFS and OS rates were also significantly better: 3-year PFS 72% [95% confidence interval (CI) 64-80%] versus 55% (95% CI 45-64%), p = 0.0039 and 3-year OS 98% (95% CI 94-99%) versus 83% (95% CI 74-90%), p = 0.0007. Effect of period of study is significant when using multivariate analysis on PFS and OS and lactate dehydrogenase level (PFS and OS) and age (OS). These data from everyday practice confirm the benefit for patients with FL treated in the last decade through availability of rituximab in first line used alone or in association with various chemotherapy regimens.

Maintenance therapy for low-grade lymphomas: has the time come?

The introduction of rituximab (MabThera, Rituxan) maintenance treatment has initiated a new era in the management of low-grade non-Hodgkin's lymphomas. Five randomized trials have recently reported on rituximab maintenance in the treatment of indolent non-Hodgkin's lymphomas. These trials enrolled patients with follicular, mantle cell and small lymphocytic non-Hodgkin's lymphomas, mostly in relapse. Patients responding to either rituximab monotherapy, chemotherapy alone or rituximab associated with chemotherapy were randomly assigned between observation and rituximab maintenance. Maintenance treatment significantly improved progression-free survival and response duration, and resulted in increased overall survival in two patients. In one trial, rituximab maintenance therapy produced significantly longer progression-free survival compared with rituximab retreatment at disease progression. Rituximab maintenance therapy has demonstrated an impact on survival in patients with follicular lymphoma. These data justify recommending rituximab maintenance for patients with relapsed follicular lymphoma. Further trials are needed to determine its efficacy in first-line follicular lymphoma and other histological subtypes. The optimal schedule of maintenance therapy has not been established. Although these trials did not report severe adverse drug reactions, information concerning long-term toxicity is scarce, and careful monitoring of patients is therefore recommended.