Untreated Follicular Lymphoma Research Articles

IBCL-278 Epcoritamab With Rituximab + Lenalidomide (R2) in Previously Untreated (1L) Follicular Lymphoma (FL) and Epcoritamab Maintenance Therapy in FL: EPCORE NHL-2 Arms 6 and 7

IBCL-278 Epcoritamab With Rituximab + Lenalidomide (R2) in Previously Untreated (1L) Follicular Lymphoma (FL) and Epcoritamab Maintenance Therapy in FL: EPCORE NHL-2 Arms 6 and 7

Epcoritamab With Rituximab + Lenalidomide (R2) in Previously Untreated (1L) Follicular Lymphoma (FL) and Epcoritamab Maintenance Therapy in FL: EPCORE NHL-2 Arms 6 and 7

Epcoritamab With Rituximab + Lenalidomide (R2) in Previously Untreated (1L) Follicular Lymphoma (FL) and Epcoritamab Maintenance Therapy in FL: EPCORE NHL-2 Arms 6 and 7

Approach to Untreated Follicular Lymphoma, Where Are We Now and Future Directions

Approach to Untreated Follicular Lymphoma, Where Are We Now and Future Directions

Phase 3 trial evaluating the efficacy and safety of odronextamab versus investigator’s choice in previously untreated follicular lymphoma (OLYMPIA-1).

TPS7096 Background: Follicular lymphoma (FL) is an incurable disease in which patients will relapse despite the effectiveness of first-line (1L) rituximab-based chemoimmunotherapy (CIT), indicating the need for alternative 1L treatments that can deepen and prolong response. Odronextamab, an off-the-shelf, CD20×CD3 bispecific antibody, showed compelling efficacy and generally manageable safety as a monotherapy at 3L+ for patients with relapsed/refractory (R/R) FL in the Phase 2 ELM-2 study (Villasboas, et al. ASH 2023). Objective and complete response (CR) rates were 80% and 73%, respectively, median duration of response was 22.6 months, median progression-free survival (PFS) was 20.7 months, and median overall survival was not reached. The rate of treatment-related adverse events leading to treatment discontinuation was 7.8%. The activity of odronextamab monotherapy in this heavily pretreated R/R FL population, including among patients with rituximab-refractory disease, provides a strong rationale for developing odronextamab as a chemotherapy-free option that can improve long-term outcomes in 1L. Methods: OLYMPIA-1 (NCT06091254) is a Phase 3, randomized, open-label, multicenter study of odronextamab versus investigator’s choice of CIT (R-CHOP, R-CVP, or R-bendamustine) in patients with previously untreated FL. The study consists of Part 1 (safety run-in), followed by Part 2 (randomization). In Part 1, patients will receive six 21-day cycles (induction) of intravenous odronextamab, administered in a step-up regimen during Cycle (C) 1 to mitigate the risk of cytokine release syndrome, followed by full dose starting from C2. Patients with CR or partial response at the end of induction will receive 12 doses of odronextamab maintenance given Q8W. In Part 2, patients will be randomized 1:1 to receive induction of six cycles of odronextamab followed by odronextamab maintenance, or CIT followed by rituximab maintenance. Key inclusion criteria: aged ≥18 years; CD20+ FL Grade 1–3a, stage II bulky or stage III/IV; measurable disease; and ECOG performance status 0–2. Patients with central nervous system lymphoma or histological Grade 3b are excluded. The Part 2 primary endpoint is CR at 30 months (CR30) as assessed by independent central review. Key secondary endpoints include PFS, event-free survival, investigator-assessed CR30, and patient-reported outcomes. Biomarkers (including minimal residual disease by ctDNA) will be evaluated as exploratory endpoints. This trial is currently recruiting and is expected to enroll ~12–32 patients in Part 1 and ~446 patients in Part 2 at ~200 global sites. Clinical trial information: NCT06091254 .

Phase 3 trial evaluating the efficacy and safety of odronextamab plus chemotherapy versus rituximab plus chemotherapy in previously untreated follicular lymphoma (OLYMPIA-2).

TPS7099 Background: Odronextamab, an off-the-shelf, CD20×CD3 bispecific antibody, has shown compelling efficacy and generally manageable safety as monotherapy in patients with heavily pretreated relapsed/refractory (R/R) follicular lymphoma (FL), including those with rituximab-refractory disease (Villasboas et al. ASH 2023). In the Phase 2 ELM-2 study, odronextamab demonstrated objective and complete response (CR) rates of 80% and 73%, respectively, and median duration of response of 22.6 months; median overall survival was not reached. Treatment-related adverse events led to treatment discontinuation in 7.8% of patients. These encouraging results support an investigation into whether odronextamab plus chemotherapy is superior to the current FL first-line standard of care of rituximab plus chemotherapy. This study will also evaluate whether odronextamab maintenance is required to achieve progression-free survival (PFS), given the risks associated with sustained B-cell depletion. Methods: OLYMPIA-2 (NCT06097364) is a Phase 3, randomized, open-label, multicenter study of odronextamab plus chemotherapy (Odro-CHOP/Odro-CVP) versus R-CHOP/R-CVP in patients with previously untreated FL. The study consists of Part 1A (dose escalation), Part 1B (dose optimization), and Part 2 (randomization). In Part 1, patients will receive six 21-day cycles (induction) of Odro-CHOP, in which intravenous odronextamab will be administered in a step-up regimen starting on Cycle (C) 1 Day (D) 8 to mitigate the risk of cytokine release syndrome, followed by full dose starting from C2D8. Patients with CR or partial response at the end of induction will receive 12 doses of odronextamab maintenance given Q8W. In Part 2, patients will be randomized 1:1:1 to receive induction of 6 cycles of Odro-CHOP/Odro-CVP with no maintenance (Arm A), Odro-CHOP/Odro-CVP followed by odronextamab maintenance (Arm B), or R-CHOP/R-CVP followed by rituximab maintenance (Arm C). Key inclusion criteria: aged ≥18 years; CD20+ FL Grade 1–3a, stage II bulky or stage III/IV; measurable disease; and ECOG performance status 0–2. Part 1: patients with FL that is R/R (Part 1A only) or previously untreated with Follicular Lymphoma International Prognostic Index-1 (FLIPI-1) score 3–5. Part 2: previously untreated patients with FLIPI-1 score 0–5. Patients with central nervous system lymphoma or histological Grade 3b are excluded. The Part 2 primary endpoint is CR rate at 30 months (CR30) by independent central review. Key secondary endpoints include PFS, event-free survival, investigator-assessed CR30, and patient-reported outcomes. Biomarkers (including minimal residual disease by ctDNA) will be evaluated as exploratory endpoints. This trial is currently recruiting and is expected to enroll up to 64 patients in Part 1 and ~669 patients in Part 2 at ~200 global sites. Clinical trial information: NCT06097364 .

Epcoritamab with rituximab + lenalidomide (R2) in previously untreated (1L) follicular lymphoma (FL) and epcoritamab maintenance in FL: EPCORE NHL-2 arms 6 and 7.

Epcoritamab with rituximab + lenalidomide (R²) in previously untreated (1L) follicular lymphoma (FL) and epcoritamab maintenance in FL: EPCORE NHL-2 arms 6 and 7.

EPCORE FL-2: Phase 3 trial of epcoritamab with rituximab and lenalidomide (R2) vs chemoimmunotherapy or R2 in previously untreated follicular lymphoma.

TPS7084 Background: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Most patients with advanced-stage FL in need of systemic therapy are treated with an anti-CD20 monoclonal antibody (eg, rituximab [R] or obinutuzumab [G]) with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] or bendamustine [benda]). Recent studies have shown R plus lenalidomide (R2) is a potent FL treatment in the 1L and relapsed or refractory (R/R) settings and is a promising backbone for combination therapies. Epcoritamab, a subcutaneous CD3xCD20 bispecific antibody, received breakthrough therapy designation by the FDA for R/R FL after ≥2 lines of systemic therapy. In the phase 1/2 trial (NCT04663347), epcoritamab plus R2 demonstrated high complete response (CR) rates in the 1L and R/R settings. The objective of this trial is to evaluate the safety and efficacy of 1L epcoritamab plus R2 vs CIT in patients with FL. Methods: EPCORE FL-2 (NCT06191744) is a global, randomized, open-label phase 3 trial. Eligible adult patients must have CD20+ histologically confirmed classic FL (previously grade 1–3A), stage III or IV disease (or bulky stage II), and in need of systemic treatment by meeting GELF criteria. Approximately 1080 patients will be randomized to 3 treatment arms (Table). Patients achieving CR or PR upon 6 cycles will move to epcoritamab on day 1 of cycles 7–12 (28-day cycles) and 13–21 (56-day cycles). After 120 weeks of treatment, patients will be followed for progression and survival. Dual primary endpoints will be CR rate at 30 months and progression-free survival in arm A vs arm B. Key secondary efficacy endpoints include overall survival, minimal residual disease negativity, and changes in patient-reported outcomes on the physical functioning scale of the European Organization for Research and Treatment of Cancer Quality of Life-C30 Questionnaire from baseline to week 25. Safety endpoints include incidence and severity of adverse events (AEs), including AEs of special interest (cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, and clinical tumor lysis syndrome). The study is open for enrollment. Clinical trial information: NCT06191744 . [Table: see text]

Analyzing the risk factors for disease progression within 2years and histological transformation in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone as first-line treatment: A 15-year follow-up of patients with advanced follicular lymphoma in JCOG0203.

Follicular lymphoma (FL) is an indolent lymphoma that becomes aggressive due to histological transformation (HT), leading to reduced survival. Patients with FL have different clinical courses and various treatment options. Some patients exhibit shorter survival and experience disease progression within 24months of diagnosis/treatment (POD24); the optimal treatment remains an unmet needs. Thus, identifying factors that predict shorter survival is essential to stratify treatment and prolong the survival of patients with FL. To analyze risk factors for POD24 and HT in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line treatment, we performed this post-hoc analysis of patients with advanced indolent B-cell lymphoma in a randomized clinical trial wherein six cycles of R-CHOP were administered every 2-3weeks. The primary analysis showed no differences in outcomes, which enabled the analysis of 248 patients with FL, assigned to two arms. All histopathological specimens from the 300 enrolled patients were reviewed by three expert hematopathologists. Multivariable analysis implicated Follicular Lymphoma International Prognostic Index (FLIPI) intermediate (odds ratio [OR] 2.531, 95% confidence interval [CI] 0.676-9.466) and high- (OR 2.236, 95% CI 0.160-31.226) risks, B symptoms (OR 2.091, 95% CI 0.747-5.851), and grade 3A (G3A) (OR 1.833, 95% CI 0.634-5.299) as risk factors for POD24. Furthermore, multivariable analysis through a median follow-up of 15.9years implicated G3A (OR 2.628, 95% CI 0.806-8.575) and high-risk FLIPI (OR 4.401, 95% CI 0.186-104.377) as risk factors for HT. However, an analysis limited to the first 10years revealed that the prognostic factors elucidated from the longer-term analysis had a greater impact on HT. G3A and high-risk FLIPI may independently predict POD24 and HT, thereby informing treatment stratification of patients with untreated advanced-stage FL in future trials, particularly to address the unmet needs of patients with POD24.

Comparing R-Bendamustine vs. R-CHOP Plus Maintenance Therapy as First-Line Systemic Treatment in Follicular Lymphoma: A Multicenter Retrospective GELTAMO Study.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and R-bendamustine (R-B) are the most common frontline treatment strategies for advanced-stage follicular lymphoma (FL). After R-CHOP induction therapy, using rituximab for maintenance therapy notably improves outcomes; however, whether this can be achieved by using the same approach after R-B therapy is still being determined. This retrospective analysis compared 476 FL patients from 17 GELTAMO centers who received R-based regimens followed by rituximab maintenance therapy for untreated advanced-stage FL. The complete response rate at the end of induction was higher with R-B and relapses were more frequent with R-CHOP. During induction, cytopenias were significantly more frequent with R-CHOP and so was the use of colony-stimulating factors. During maintenance therapy, R-B showed more neutropenia and infectious toxicity. After a median follow-up of 81 months (95% CI: 77-86), the 6-year rates of progression-free survival (PFS) were 79% (95% CI: 72-86) for R-bendamustine vs. 67% (95% CI: 61-73) for R-CHOP (p = 0.046), and 6-year overall survival (OS) values were 91% (95% CI: 86-96) for R-B vs. 91% (95% CI: 87-94) for R-CHOP (p = 0.49). In conclusion, R-B followed by rituximab maintenance therapy in patients with previously untreated FL resulted in significantly longer PFS than R-CHOP, with older patients also benefiting from this treatment without further toxicity. Adverse events during maintenance were more frequent with R-B without impacting mortality.

Minimal Residual Disease Status Predicts Outcome in Patients With Previously Untreated Follicular Lymphoma: A Prospective Analysis of the Phase III GALLIUM Study.

We report an analysis of minimal residual/detectable disease (MRD) as a predictor of outcome in previously untreated patients with follicular lymphoma (FL) from the randomized, multicenter GALLIUM (ClinicalTrials.gov identifier: NCT01332968) trial. Patients received induction with obinutuzumab (G) or rituximab (R) plus bendamustine, or cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or cyclophosphamide, vincristine, prednisone (CVP) chemotherapy, followed by maintenance with the same antibody in responders. MRD status was assessed at predefined time points (mid-induction [MI], end of induction [EOI], and at 4-6 monthly intervals during maintenance and follow-up). Patients with evaluable biomarker data at diagnosis were included in the survival analysis. MRD positivity was associated with inferior progression-free survival (PFS) at MI (hazard ratio [HR], 3.03 [95% CI, 2.07 to 4.45]; P < .0001) and EOI (HR, 2.25 [95% CI, 1.53 to 3.32]; P < .0001). MRD response was higher after G- versus R-chemotherapy at MI (94.2% v 88.9%; P = .013) and at EOI (93.1% v 86.7%; P = .0077). Late responders (MI-positive/EOI-negative) had a significantly poorer PFS than early responders (MI-negative/EOI-negative; HR, 3.11 [95% CI, 1.75 to 5.52]; P = .00011). The smallest proportion of MRD positivity was observed in patients receiving bendamustine at MI (4.8% v 16.0% in those receiving CHOP; P < .0001). G appeared to compensate for less effective chemotherapy regimens, with similar MRD response rates observed across the G-chemo groups. During the maintenance period, more patients treated with R than with G were MRD-positive (R-CHOP, 20.7% v G-CHOP, 7.0%; R-CVP, 21.7% v G-CVP, 9.4%). Throughout maintenance, MRD positivity was associated with clinical relapse. MRD status can determine outcome after induction and during maintenance, and MRD negativity is a prerequisite for long-term disease control in FL. The higher MRD responses after G- versus R-based treatment confirm more effective tumor cell clearance.

Maintenance and consolidation strategies for patients with untreated advanced follicular lymphoma: A systematic review and network meta-analysis of randomized trials.

The emergence of novel and efficient antibody maintenance approaches has provided more options for post-induction treatment of advanced follicular lymphoma (FL), and further comparisons are required to determine the most clinically beneficial regimen. The authors conducted a systematic review and meta-analysis to evaluate the maintenance or consolidation strategy. The authors performed two independent searches in PubMed, Web of Science, the Cochrane library databases, Scopus, and Embase for randomized controlled trials (RCTs) evaluating maintenance or consolidation therapy in untreated FL patients. Extracted data included the clinical characteristics, treatment regimen, progression-free survival (PFS), overall survival (OS), and adverse effects. They then pooled the data and used a Bayesian random-effects model to combine direct comparisons with indirect evidence. The authors screened 1515 records and identified 13 eligible RCTs that assessed nine different regimens in 5681 advanced FL patients. Reconstructed individual survival data presented that obinutuzumab had the highest effect sizes and certainty of the evidence for PFS (hazard ratio, 0.43; 95% confidence interval, 0.22-0.79) and tolerability compared with observation. However, no benefit was observed in patients according to the OS, regardless of which regimen was taken. Considering other regimens, although an extended course of rituximab maintenance and consolidation therapies presented PFS benefits compared with standard rituximab maintenance, they were also associated with higher toxicity. Although obinutuzumab and rituximab maintenance treatment improved PFS significantly, its clinical benefit requires further validation in larger populations. Furthermore, because few trials informed each treatment comparison, research is needed to refine the understanding of this complex and rapidly evolving treatment landscape.

Imaging Mass Cytometry Reveals a Highly Heterogenous Cell Makeup of the Follicular Lymphoma Tumour Microenvironment

The highly variable clinical course and response to treatment of follicular lymphoma (FL) is strongly influenced by the tumor microenvironment (TME). While both pro- and anti-tumor effects depend on cell-cell interactions within the TME, these mechanisms remain incompletely understood. Bulk (Dave et al. NEJM 2004) and single-cell RNA-seq studies have identified signatures associated with prognosis, e.g., ‘T cell depleted’ microenvironments that are linked with inferior clinical outcomes (Han et al. Blood Cancer Discov. 2022). While such research has shed light on the TME, single-cell studies often lack spatial context and conventional immunohistochemistry is limited by a low number of parameters. Imaging mass cytometry (IMC) allows multiplexed analysis of up to 40 markers in tissue simultaneously, offering a unique opportunity to study the spatial features of single cells within the TME, informing both disease biology and predictors of clinical outcome. To our knowledge, IMC has more commonly been applied to solid malignancies. FL presents unique challenges in this remit, such as its morphologic variability and phenotyping cells within highly structured, dense lymph-node tissue composed of inherent tight-knit microenvironments. To analyse FL tissue by IMC, we first optimized a 31-plex panel to identify key immune and non-immune lineages including tumor cells, T and NK cells, macrophages, fibroblasts, dendritic, endothelial and reticular cells. Additionally, we wished to identify functional states such as memory, effector or regulatory phenotypes in addition to other parameters including activation, exhaustion and proliferation. Formalin-fixed paraffin embedded (FFPE) biopsies from 100 untreated FL patients enrolled on the Gallium trial (NCT01332968) of frontline chemo-immunotherapy, were subjected to IMC. In total, 381 highly multiplexed images were acquired; 13 were excluded due to suboptimal image quality. Following image pre-processing and deep-learning based cell segmentation, we analysed &amp;gt;3.5 million cells across 368 high-dimensional images (mean=9659 cells, SD=4600). To effectively phenotype large numbers of cells, we constructed a workflow incorporating ‘ASTIR’ (Geuenich et al. Cell Syst. 2021) - a publicly available marker-based algorithm - and cell clustering to identify population subsets. We identified 95 cell populations including Lymphoma subsets (variable CD10, CD11c, CD80 expression), CD4+ and CD8+ T cell subsets (memory, naïve, exhausted etc) and a range of non-lymphoid cells including myeloid and stromal cells. Of particular interest, we found a CD4+ CD3+ PD1+ ICOS+ population which are likely T follicular helper cells (Tfh). On average, Tfh-like cells constitute 1.9% of cells per image (SD=3.1%), although we a found considerable range in their presence. Given previous associations with Tfh cells and FL prognosis we are investigating this variability in further detail. In addition, we have identified ~30 samples enriched for CD57+ T cells, a phenotype suggestive of functional senescence. Amongst substantial heterogeneity of identified cell phenotypes (Fig A), we have identified variable sample sets characterised by enrichment or depletion of i) Lymphoma vs. T-cells (Fig B) and ii) Macrophage vs. T-cell subsets, consistent with previous single cell studies. Here, we report the use of IMC to examine the TME of untreated FL, observing marked heterogeneity of cell phenotypes across FL. Future work seeks to examine prognostic associations between the frequency of cell subsets and their spatial interactions, with this clinically annotated dataset derived from the front-line GALLIUM study. This work will provide a detailed characterization of how the spatial context of FL TME influences disease behaviour, response to treatment and survival. Given the high-throughput and high-plex nature of this study, ultimately, we aim to distil this multitude of information into condensed biomarker(s), to provide potential insights into enhancing diagnostic and/or prognostic capabilities. Therefore, we aim to derive meaningful clinical correlates associated to outcome that can be ultimately translated into practice.

Addition of Acalabrutinib to Lenalidomide and Rituximab Induces High Complete Response Rates in Patients with Previously Untreated Follicular Lymphoma: Results of a Phase II Study

Background. We previously reported pro-tumoral macrophages may be associated with resistance to lenalidomide and rituximab (R 2) treatment in follicular lymphoma (FL) ( Marques-Piubelli, Blood Adv 2022). As pre-clinical studies suggest that BTK inhibition can mitigate the crosstalk between monocyte/macrophages and FL B cells, we hypothesized that acalabrutinib, a specific BTK inhibitor, may synergize with R 2 without increasing toxicity. In agreement with this, the combination of acalabrutinib and R 2 (aR 2) was shown to be safe and effective in patients with relapsed FL ( Strati P et al, ASH 2022). Here, we investigated the safety and efficacy of aR 2 in previously untreated FL patients and analyzed the biological effects of this combination on peripheral blood immune cells. Methods. This phase 2 single arm study (NCT04404088) was conducted between 09/2020 and 09/2021 (data cutoff 06/2023). Adult patients with previously untreated FL, grades 1 to 3A, stage 3-4, and meeting indication for treatment per GELF criteria were included. Treatment consisted of acalabrutinib lead-in at 100 mg PO twice a day for one 28-day cycle and continued for total of 13 cycles, lenalidomide 20 mg PO daily on days 1-21, during cycle 2-13, and rituximab 375 mg/m 2 IV weekly during cycle 2, and on day 1 of cycle 3-13. The primary endpoint was best complete response (CR) rate per Lugano 2014 criteria. Bulk RNA sequencing with deconvolution to characterize circulating immune cells was performed on peripheral blood collected at baseline, and on day 1 of cycles 2 and 6. Results. We enrolled and treated 24 patients. Baseline characteristics are shown in the Table. Median number of cycles was 13 (range, 6-13) and 15 (62.5%) patients experienced a cycle delay, due to COVID19 in 11 (46%) cases; 6 (25%) patients required dose reduction of lenalidomide, but none discontinued, and 2 (8%) required dose reduction of acalabrutinib and 1 discontinued. The most common (&amp;gt;5% of patients) grade 3-4 adverse events were neutropenia (58%), liver function test elevation (17%), infection (12.5%; 2 out of 3 related to COVID19), anemia (8%) and skin rash (8%). Best ORR was 100%, best CR rate was 92%, and median time to CR was 3 months ( Figure). After a median follow-up of 26.8 months (95% CI 24.6-29.6 months), 6 (25%) patients had disease progression, including 2 who transformed at 5 and 7 months. The 2-year PFS rate was 79.2% (95% CI, 64.5-97.2%). At data cutoff, 2 patients have died, 1 due to COVID19 (while in CR, at 14 months) and 1 due to transformed lymphoma (at 10 months). The 2-year OS rate was 91.7% (95% CI, 81.3-100%). While the frequency of circulating immune cells were unchanged after single agent acalabrutinib, its use associated with a significant decrease in the expression of VMO1 (FDR 0.001), a gene encoding for a protein expressed on extra-cellular exosomes derived from non-classical monocytes, and a significant increase in gene signatures of monocyte proliferation (p=0.01), TNF response (p=0.01), anti-viral (p=0.006) and anti-tumoral activity (p=0.009), consistent with the expected effect of BTK inhibition in monocytes. After 5 cycles of aR 2, we observed a decrease in the frequency of circulating B cells (p=0.003) and regulatory NK cells (p=0.01), and an increase in the frequency of circulating naive T cells (p=0.004), CD4+ T cells (p=0.005) and classical monocytes (p=0.003). Conclusion. Our results indicate that the addition of acalabrutinib to R 2 is a safe and effective frontline non-chemotherapy regimen for FL patients, resulting in high CR rates, and induces favorable biological changes in multiple circulating immune cells. Since CRs occurred early, the study has been amended to include 26 additional patients who will be treated with only 6 cycles of aR2.

Early Complete Responses with Mosunetuzumab Monotherapy in Treatment-Naïve Follicular and Marginal Zone Lymphomas with Only Low-Grade Cytokine Release Syndrome

Introduction Mosunetuzumab (mosun) is a CD20xCD3 bispecific antibody that has been FDA-approved for relapsed/refractory follicular lymphoma after two prior lines of therapy. Updated follow up of the pivotal study in relapsed/refractory patents (Sehn et al ICML 2023, median follow up 28.3 months) showed a CR rate of 60%. Among the patients in CR, 77% remained alive and progression free at 2 years. We hypothesized that mosun would be even more active in patients (pts) without prior lymphotoxic therapy. Therefore, we designed a response adapted study for pts with untreated follicular lymphoma (FL) and marginal zone lymphoma (MZL). Methods This is a single center, open label, investigator-initiated response-adapted clinical trial in untreated pts with FL or MZL with indication for treatment. Pts received subcutaneous mosunetuzumab monotherapy for 8 cycles (21 day cycle, Part A) employing step up dosing in cycle 1 (5 mg, 45 mg, 45 mg). Dexamethasone prophylaxis was administered through C2D1, and could be omitted after that for patients without CRS in the previous cycle. A PET/CT was performed after 8 cycles, and pts in CR were observed without further treatment. Pts with SD or PR could receive 6 cycles (21 day cycle, Part B) of polatuzumab vedotin and obinutuzumab, followed by an end of treatment (EOT) PET/CT. Total planned accrual is 42 pts. The primary endpoint is complete response (CR) rate. A pre-planned interim efficacy analysis is being reported after 20 enrolled pts. If 14 or fewer of the first 20 subjects do not achieve an objective response, the study will be suspended to enrollment. Additional planned safety analyses are in place with suspension rules to detect excessive G4 non-heme toxicity and G2+ CRS. Results 26 pts enrolled on study between March 24, 2022, and March 11, 2023, with 26 pts evaluable for safety, and 21 pts are evaluable for efficacy. Median age was 64 (42-83), including 16 (62%) age 60+. Histologies enrolled include G1-2 follicular lymphoma (19, 73%), G3A follicular lymphoma (4, 15%), and marginal zone lymphoma (3, 12%). The most common indication for treatment was symptomatic disease (19, 73%). All treatment was delivered as an outpatient. Three pts experienced a serious adverse event (one pt with G3 lung infection followed by G3 shingles, one pt observed overnight with G1 cytokine release syndrome, and one pt with a G2 URI). Other G3 non-lab AEs observed were diarrhea (1, 4%), syncope (1, 4%), and hypertension (1, 4%). Sixteen (62%) pts experienced G1 CRS, with no G2 or higher CRS observed or any grade ICANS observed. No pts required tocilizumab. All CRS events first occurred during cycle 1. Headache was common but low grade (G1 14, 54%, G2 1, 4%). Heme toxicity &amp;gt; G1 was uncommon, with G4 neutropenia (1, 4%), and G2+ thrombocytopenia (2, 8%). No G4 non-heme toxicity was observed. Nearly all pts (92%) experienced at least one injection site reaction, which were all G1 except a single pt with a G2 reaction. Seven (26%) pts experienced a treatment delay due to toxicity, primarily due to infection in 4 pts. Only one patient did not receive all doses of mosun - G3 ALT increase and prolonged G1 CRS led to discontinuation after cycle 1 (patient achieved CR). Twenty-one patients are efficacy evaluable, with an overall response rate (ORR) of 100%. Eighteen patients have completed mosun therapy, with an ORR and CR rate of 100% and 83%, respectively. Three patients proceeded to obinutuzumab and polatuzumab combination therapy, of whom two have completed all treatment (both converted to CR). All pts remain alive and progression-free. Updated data will be presented at the meeting. Conclusion Fixed duration mosun monotherapy achieves a high CR rate in untreated pts with follicular and marginal zone lymphoma with no G2+ CRS and no ICANS of any grade. Injection site reactions and headaches were common but reversible. Safety and efficacy has remained well within study suspension thresholds and accrual is ongoing to a goal of 42 total patients.

A Prospective Phase II Study of Radiotherapy Followed By Tiselizumab Combined with R-CHOP in the Untreated Follicular Lymphoma Patients with Bulky Disease in China

Background Follicular lymphoma (FL) is the second most common B cell lymphoma subtype and chemoimmunotherapy treatment is the standard therapy for patients with high tumor burden. Bulky disease was associated with shorter median PFS compared to non-bulky disease in FL patients. Radiation and anti-programmed death-1 (PD-1) monoclonal antibody are both effective in FL and also have a synergistic effect. We assessed the potential benefit of Tiselizumab (a humanized monoclonal antibody targeting PD-1), radiotherapy combined with RCHOP as first-line treatment in FL patients with bulky disease. Methods This was a single center, single arm, phase II study. Patients with previously untreated follicular lymphoma were enrolled from the department of lymphoma, Tianjin Medical University Cancer Institute and Hospital. The bulky disease was received radiation (dose:18～24Gy) before RCHOP. Patients began chemoimmunotherapy 1～2 weeks later than radiation. Treatment included Tiselizumab (200 mg iv d1) plus R-CHOP (rituximab 375 mg/m 2 intravenous [IV] day 2, cyclophosphamide 750 mg/m 2 IV day 3, doxorubicin 50 mg/m 2 IV day 3, vincristine 1.4 mg/m 2 [maximum 2.0 mg total] IV day 3, and prednisone 100 mg oral days 3-7, 21～28 days for one cycle ) for six cycles. Rituximab was given every 2 months to patients who were complete metabolic response /partial metabolic response（CMR/PMR）after first-line chemo until 2 years. Response was assessed by PET/CT scan after cycle 4 and cycle 6. The primary endpoint was complete response rate (CRR). R esults FromFebruary 2021 to June 2023, 6 patients were enrolled. 4 patients finished all 6 cycles treatment. 1 patient was dead because of COVID-19 who was PMR after 5 cycles treatment. The last one with CMR stopped chemotherapy because of COVID-19 and only received 4 cycles treatment. The median follow-up is 15 months. 5 patients achieved CMR in the mid-term evaluation and were still on remission in June 2023. The CRR was 83.3% and the overall response rate was 100%. The common adverse events were nausea, vomiting, bloating, loss of appetite, constipation, and diarrhea. The most common grade 3/4 adverse events were neutropenia (66.7% ), thrombocytopenia (16.7% ), and leukopenia (66.7% ). Conclusion Tiselizumab, radiotherapy combined with RCHOP is effective and tolerable in the untreated FL patients with bulky disease. More patients will be enrolled to estimate the efficacy and safety.

The Nature of High-Risk Defining Events in Follicular Lymphoma Determines Overall Survival

Background: A subset of follicular lymphoma (FL) patients will experience a ‘high-risk defining event’ (HRDE) that portends poor survival due to early progression of disease or transformation to diffuse large B cell lymphoma (TFL). Progression of disease within 24 months (POD24) from front-line immunochemotherapy (ICT) identifies patients with a subsequent five-year OS of 50% compared to a reference group of 90% (Casulo et al. JCO 2015). Although a robust surrogate endpoint for OS in clinical trials (Casulo et al. Blood 2022), it remains to be established if the OS of patents is influenced by the nature of the HRDE. In this study, we examined whether characteristics and clinical trajectory of those with relapsed/progressive FL is the same as that of patients experiencing TFL. Methods: We conducted an international retrospective analysis of newly diagnosed FL patients requiring treatment across 14 academic centres between 2002 and 2021 in the era of rituximab and PET-CT staging. Patients were included with grade 1-3A FL requiring first-line (1L) treatment (ICT, rituximab monotherapy or radiotherapy). We excluded patients with untreated FL, de novo TFL and those with &amp;lt;24 months follow up provided they did not experience a HRDE. Baseline clinical, imaging and laboratory values, treatment details and outcomes were collected. We defined HRDE groups as persistent (relapse or progression) FL within 24 months of 1L treatment (FL24), early TFL (&amp;lt;24 months of 1L treatment) or late TFL (&amp;gt;24 months of 1L treatment). Patients not experiencing a HRDE formed the FL reference group. Landmark overall survival (OS) analysis was performed by Cox regression using risk status as a time-varying covariate for time of HRDE. For the FL reference group, landmark was defined at 24 months after 1L treatment. Results: 501 patients met the inclusion criteria and were categorised as: reference FL (n=378), FL24 (n=50), early TFL (n=28), late TFL (n=15). 24 patients who died within 24 months of 1L treatment without documentation of preceding HRDE and were omitted. Median follow up for patients alive beyond 24 months was 5.1 years. Median age at diagnosis was 60 years, 91% had ECOG performance status 0-1 and 38% were high-risk (&amp;gt;3) FLIPI. 1L chemotherapy regimens included: bendamustine (59%), CHOP (24%), CVP (8%), other (9%); a majority received rituximab (80%) vs obinutuzumab (20%). Maintenance therapy was used in 54% of pts. Expectedly, those experiencing HRDE had an inferior OS compared to the reference group (HR 5.23, p&amp;lt;0.001)(Figure 1). However, among HRDE group, median OS significantly differed: early TFL patients (3.0 yrs) and FL24 (12.6yrs)(HR 2.27, p=0.02) (Table 1). There was no difference in OS after HRDE between early TFL and late TFL ( p=0.81). Biopsy was performed in 84% of TFL cases with no difference in OS between biopsy-proven vs clinically suspected cases ( p=0.23). Multivariate OS analysis assessing HRDE and treatment demonstrated no significant interaction between HRDE group and 1L chemotherapy ( p=0.52), monoclonal antibody ( p=0.29) or maintenance therapy ( p=0.27). Several established prognostic features at baseline were enriched in patients who went on to experience HRDE including: ECOG &amp;gt;1 ( p&amp;lt;0.001), raised LDH ( p&amp;lt;0.001), advanced-stage disease (( p&amp;lt;0.011) and high risk FLIPI ( p=0.005). Baseline FDG-PET was available in 259 patients. Adverse PET metrics were enriched in only early TFL, and not FL24 or late TFL patients, including high SUV max( p=0.009), total metabolic tumor volume ( p=0.015) and total lesional glycolysis ( p=0.01). Conclusions: HRDEs after 1L treatment are associated with inferior OS in FL compared with standard-risk patients. Unlike POD24, this study demonstrates disparate clinical outcomes between patients experiencing early progression with persistent FL and those experiencing TFL. Adverse metabolic characteristics on baseline FDG-PET also suggest biological distinction between HRDE subsets. These findings have important implications for epidemiological studies, biomarker development and clinical trials aiming to improve outcomes in this underserved high-risk FL cohort.

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.

Preliminary Analysis of an Ongoing Phase II Study of Response-Adapted Therapy with Copanlisib and Rituximab for Untreated Follicular Lymphoma

Introduction Frontline therapy for pts with follicular lymphoma (FL) is not based on the molecular profile of the tumor. The PI3K pathway is central to FL biology, but the molecular profile of tumors most sensitive to PI3K inhibition (PI3Ki) is unknown. Copanlisib inhibits both PI3Kα and δ isoforms, and we hypothesized that most pts with treatment naïve FL will have PI3Ki-sensitive tumors and durable complete responses (CRs) may be achievable with short durations of targeted therapy. A gene expression profiling (GEP) predictor utilizes a combination of the expression of 45 selected informative genes and an additional 19 housekeeping genes to identify FL pts at high-risk for early progression within 24 months (Wright et al. ASH Annual Meeting2022). We also hypothesized that copanlisib would induce durable CRs in high-risk pts by the GEP assay. Here, we report a preliminary analysis of an ongoing “window of opportunity” study of copanlisib followed by response-adapted copanlisib and rituximab in treatment-naïve pts with FL (NCT03789240). Methods Pts with untreated grade 1-2, 3A FL, ≥stage 2 are eligible if systemic therapy is indicated: symptoms, progressive lymphadenopathy, or organ compromise. Prior radiation is permitted. Eligibility includes age ≥18 and adequate organ function unless due to lymphoma. HIV, CMV, Hep B or C, and autoimmune conditions are excluded. Pts first receive copanlisib 60mg on days 1, 8, and 15 of a 28-day “window of opportunity” to explore the activity of copanlisib. Following the window, pts receive 6 cycles of copanlisib 60mg on days 1, 8, and 15 of a 28-day cycle along with rituximab 375mg weekly x 4 then on day 1 of each cycle and response is assessed with FDG-PET and CT scans. Pts without response after C6 are taken off study and those with a partial response (PR) can continue for an additional 6 cycles and then stop therapy. Pts who achieve a CR after 6 cycles stop therapy. No maintenance is given. Supportive care includesPCP prophylaxis. The primary endpoint is the CR rate with secondary endpoints of safety, duration of CR, and PFS. Exploratory objectives include identification of a predictive signature of PI3Ki response and the response rate in high-risk pts identified by the GEP assay. Results Twenty-eight pts have enrolled. Median age was 56y (range, 24-80). Seventeen (61%) and 12 (43%) pts had high-risk FLIPI and FLIPI-2 scores ≥3, respectively; 6 (21%) pts had Grade 3A FL, and 17 (61%) pts met two or more GELF criteria. After copanlisib monotherapy in the window, 27 (96%) pts had tumor reductions by CT with a median change of -38% (-62% to +16%) (Figure 1). Among 22 pts who completed 6 cycles, 21 (96%) responded, including 9 (41%) pts with PR and 12 (55%) pts with CR. Of 9 pts with PR who received an additional 6 cycles of therapy, only 1 (11%) converted to a CR bringing the overall CR rate to 59% (13/22 pts). After a median follow-up of 25.8 months, the 2-year PFS was 43.2% (95% CI, 20.7-64.0%). The median duration of CR was 29.7 months (95% CI, 6.3 months - not estimable) with 8 (62%) CRs ongoing (Figure 2). Toxicity was evaluated in 28 pts across 220 cycles. Most common were rash (64%), mucositis (50%), and nausea/vomiting (50%), all G1-2 except 1 (4%) pt with G3 mucositis. The most common ≥G3 toxicities were neutropenia and infections in 5 (18%) pts each. ≥G3 neutropenia occurred in 10 (5%) cycles, responded to therapy interruption and/or growth factors, and did not require dose reduction. Two (8%) pts had copanlisib dose reduced, 1 (4%) each due to rash and mucositis. Therapy was prematurely discontinued in 5 pts: 3 due to COVID-19, 1 for hepatotoxicity that resolved, and 1 due to infusion reaction to rituximab. Nine of 24 (38%) pts were poor risk by the GEP assay. Complete responses were observed in 71%, 67%, and 57% of pts categorized as high-risk by FLIPI, FLIPI-2, and GEP assay, respectively. The CR rate was not affected by bulky disease (any LN &amp;gt;7cm; p=1.00), high-risk FLIPI (p=0.19), high-risk FLIPI-2 (p=0.67), poor-risk GEP (p=1.00), or metabolic tumor volume (p=0.33). Conclusion Nearly all pts with treatment naïve FL have PI3Ki-responsive tumors, and the combination of copanlisib with rituximab achieved a CR rate of 59% at the end of induction therapy. The median duration of CR is nearly 30 months, including ongoing remissions without maintenance. CRs were observed in pts deemed high-risk by the GEP assay and FLIPI score. The safety profile is excellent, with mostly G1-2 toxicities manageable with supportive care.

Utility of Bone Marrow Biopsies for Basal Stratification and Response Assessment in a Large Series of Real Life Follicular Lymphoma Patients

Introduction: Bone marrow biopsies (BMB) are usually performed before/after therapy to confirm complete response (CR) in follicular lymphoma (FL) patients. Up to 60% of patients may have bone marrow infiltration, that can change Ann Arbor stage, assigning the highest disease stage. Also, BMB infiltration is included in several prognostic indexes such as FLIPI2 and PRIMA-PI. Persistence of bone marrow disease after treatment is associated with worse outcome. Aim: The main objective is to establish whether BMB adds value in assessing response or predicting progression-free survival (PFS) and overall survival (OS) in previously untreated FL subjects from a large, Spanish unicentric retrospective cohort. Results: From 2001-2022 we recorded data from 260 newly diagnosed FL grade 1-3A from Hospital 12 de Octubre.The median age at diagnosis was 64 years (range 27-90) and 34 patients (13%) had grade 3A FL. Most patients (67%) had advanced Ann-Arbor stage and 45,4% presented bone marrow infiltration (111/244). 104 (40%) patients were considered suitable for a watchful waiting policy; of them, 52 (50%) never required systemic treatment during follow-. 132 patients (61% of those receiving treatment) were treated with R-CHOP or R-CVP, 44 (21%) received R-bendamustine and 20 (10%) rituximab monotherapy. In 114 patients (55%) PET/CT was done at the moment of diagnosis and to evaluate the response after treatment. The other were evaluated by CT. Basal bone marrow biopsy was essential in the diagnostic of 3 patients that only presented FL in BM. In addition, BMB upgraded disease stage in 9 (3.7%) that presented &amp;lt;3 nodal areas involved, without other extranodal infiltration. Basal BMB positive was predictive of worse PFS and OS in univariate analysis (HR = 1.69; 95%CI 1.04-2.76 and HR = 1.98; 95%CI 1.10-3.60, respectively). Ten-years PFS was 72% in patients without BM involvement vs 51% in patients with BM infiltration (HR= 1.7, p=0.034) ( Figure 1) and, Ten-years OS was 82% vs 62%, respectively. In 82 of 104 patients (79%) with basal BM infiltration, a BMB was performed after finishing induction treatment. In the other 22 patients BMB was not performed because of evidence of progression (n=10) or because of unknown causes (n=12). 12 (15%) of 82 patients evaluated remained BMB positive by histology. Globally, and independent of the image response assessment, the reassessment of BM did not confer prognostic differences in patients in whom it was performed and in those who were not (p= 0.92). Nevertheless, patients with post-induction BM infiltration (n=12) showed worse outcomes than those without post-induction BM involvement (n=70) (HR=3.9, 95CI 1.8-8.5) ( Figure 2). Only 3 of 59 treated patients (5%) had positive baseline BMB, CR on imaging, and subsequent positive BMB, and therefore that affected response assessment. All 3 patients were evaluated by CT because they received treatment in 2004-2007. Of subjects with CR on imaging (n = 73), PFS and OS were not significantly different among those with negative BMB to confirm CR (n = 59) versus those without repeat BMB (n = 11); PFS: HR=1.12, 95%CI 0.38-3.31, p = 0.83; OS: HR=1.66 95%CI 0.46-6.07, p = 0.44) Conclusion: In a real-life study of newly diagnosed FL we conclude that BMB adds little value in the basal evaluation; with only 4.% of patients who were thought to have early stage disease before bone marrow evaluation. Besides, despite BM infiltration confers prognostic value, to date there are no differences in the management of these patients based on this finding. In relation to response assessment, BMB adds little value to response assessment. Only 3 patients (1.4%) in our series presented CR on imaging and BM infiltration postinduction. Moreover, none of them was evaluated by PET. With this data, we strongly recommend performing diagnostic BMB in FL in scenarios in which it may change management including confirmation of limited stage and assessment of cytopenias. Prospective studies are necessary to see its value during follow- up. Nevertheless, with new techniques as LiqBio MRD, removing this study from reassessment might be an option that would reduce patient discomfort and resource utilization.

Tazemetostat in Combination with R-CHOP in Patients with High-Risk, Frontline Follicular Lymphoma (Epi-RCHOP): A Phase II Study from the Lysa

Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies or with R/R FL who have no satisfactory alternative treatment options. We previously reported that the RP2D of TAZ in combination with R-CHOP was 800mg BID in the phase 1 part of Epi-RCHOP study (NCT02889523). Here, we report results of the phase 2 part evaluating TAZ with R-CHOP + rituximab maintenance in a cohort of previously untreated high-risk FL patients. Methods: patients were eligible if aged 18-80 years, had histologically confirmed FL grade 1-3A, high-risk FLIPI (score of 3-5) and were in need of treatment according to GELF criteria. Induction treatment consisted in 6 cycles of RCHOP every 21 days and TAZ 800mg BID every day, starting on day 2 of cycle 1, plus 2 additional 21 days cycles of rituximab+TAZ (cycle 7 and 8). Responses were assessed at end of induction (EOI), and responders then received maintenance 1 (TAZ 6 mo + rituximab 12 mo) and maintenance 2 (12 mo of rituximab alone).The primary efficacy endpoint was PET-based complete response rate based on local assessment at the end of induction or at permanent treatment discontinuation, as determined by Cheson IWG 2014 Lugano Classification (Deauville scale 1-3); in addition bone marrow biopsy (BMB) was mandatory at EOI if involved at baseline and complete metabolic response (CMR) patients with missing assessment at EOI classified as partial responders. Sample size calculation was made with the expectation of an increase of 13% in CR, with an H0 hypothesis of 67% and an H1 assumption of 80%, leading to a theorical sample size of 62 pts, assuming a drop out of 10%. Initial assumption was that CR rate should be &amp;gt;76.4% to consider the combination eligible for further clinical evaluation in high risk FL patients. Results: As of June 14, 2022, 62 patients were enrolled between Aug2020 and Apr2022 across 20 centers (including a drop-out of 12 patients, 70 were enrolled in France, 4 in Belgium). Disease characteristics included: males 61.3%, median age 64.5 years, FLIPI 3/4/5 in 61.3%/32.3%/6.5%, EZH2 mutated 17.3% (n=9/46 assessed had EZH2 mutation; 16 undertermined), BM involvement 68.3%, circulating FL cells in 21%, and increased LDH in 50%. Fifty eight (93%) patients completed induction and initiated maintenance 1, 44 (71%) initiated maintenance 2. Fourteen patients permanently discontinued treatment: 4 before EOI not related to PD (2 COVID19 disease, 1 late onset neutropenia and 1 stopped therapy but accepted FU), and 9 after EOI (5 PD, 2 COVID19 disease, 1 neutropenia, 1 paralytic ileus and 1 patient's refusal). At EOI, 79% (95%CI 66.8; 88.3%) achieved complete metabolic response (CMR) and 16.2% PMR for an overall metabolic response rate of 95.2%, however, according to the stringent protocol definition, 16 patients who achieved CMR had no BMB assessment at EOI and were downgraded to PR leading to 53.2% CR and 41.9% PR rate at EOI. Complete response rates were significantly higher in EZH2 mutants (8/9 CMR 88.9%) versus 17/37 (45.9%) in EZH2 wild-type (WT) patients (Fisher exact test p=0.027). Figure 1 shows the AEs reported by more than 10% of patients. The most common grade 3-4 TEAEs were neutropenia (53.2%, only 3.2% febrile), thrombocytopenia (17.7%), anemia (16.1%). Serious AEs occurred in 14 patients, the two most frequent being Covid19 disease (6.5%) and gastrointestinal hypomotility (6.5%). This latter AE was the most frequent non-hematologic event (40.3%), followed by peripheral neuropathy (35.5%). After amending vincristine dose (Oct2020), 30 digestive AEs were reported (16 related to TAZ, mostly grade 1-2, only 1 grade 3, no sequelae). No SPM was observed. With a median follow-up of 19 months, 7 relapses (5 EZH2 WT and 2 undetermined) including 5 needing subsequent treatment and 2 deaths occurred (1 Covid19 disease, 1 after PD). Median PFS and median DOR were not reached and appeared to be similar irrespective of EZH2 status, 18-months PFS and OS rates were 89.3% and 98.3% respectively. Conclusions: Although the primary endpoint was not met due to missing BM assessments, TAZ + RCHOP combination demonstrated a promising complete metabolic response rate of 79% in this high-risk frontline FL population, with a manageable safety profile, after vincristine dose was reduced.