Follicular Lymphoma International Prognostic Index Research Articles

Progression-free survival after front line, second line and third line in patients with follicular lymphoma treated in clinical practice.

The modern-day therapeutic landscape for follicular lymphoma (FL) includes a number of highly effective therapies. We set out to determine progression-free survival (PFS) after front line, second line, and third line of therapy on the basis of relevant biological characteristics and therapeutic choices. Patients (n = 743, 51% females, median 60 years old) diagnosed with grade 1-2 FL between 1997 and 2016 in nine institutions were included. The median PFS1, PFS2, and PFS3 were 8.1 years (95% confidence interval [CI]: 7-9.3 years), 4.2 years (95% CI: 2.8-5.6 years) and 2.2 years (95% CI 1.7-2.8 years). We found longer PFS1 for (1) females, (2) younger age, (3) lower-risk follicular lymphoma international prognostic index (FLIPI), (4) standard intensity (over low intensity) regimens and (5) immunochemotherapy strategies and (6) maintenance rituximab. We found a shorter PFS2 for patients who received front-line immunochemotherapy. Older age at diagnosis correlated with a shorter PFS3. Intensity of front-line chemotherapy, maintenance, or POD24 status did not correlate with PFS2 or PFS3 in this dataset. With current immunochemotherapy strategies, the natural course of FL is characterized by shorter-lasting remissions after each relapse. It will be interesting to see whether new therapies can alter this pattern.

Polatuzumab vedotin, venetoclax, and an anti-CD20 monoclonal antibody in relapsed/refractory B-cell non-Hodgkin lymphoma.

The Phase 2 portion of this study evaluated safety and efficacy of polatuzumab vedotin 1.8 mg/kg and venetoclax 800 mg, plus fixed-dose obinutuzumab 1000 mg or rituximab 375 mg/m2 in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), respectively. Patients with complete response (CR) or partial response (PR)/stable disease (FL) or CR/PR (DLBCL) at end of induction (EOI; six 21-day cycles) received post-induction therapy with venetoclax and obinutuzumab or rituximab, respectively. Primary endpoint was CR rate at EOI. Safety-evaluable populations included 74 patients (FL cohort; median age 64 years; progression of disease within 24 months on first-line treatment, 25.7%; FL International Prognostic Index 3-5, 54.1%; ≥2 previous therapies, 74.3%) and 57 patients (DLBCL cohort; median age 65 years; International Prognostic Index 3-5, 54.4%; ≥2 previous therapies, 77.2%). The most common non-hematologic adverse events (mostly Grades 1-2) in the FL and DLBCL cohorts were diarrhea (55.4% and 47.4%, respectively) and nausea (47.3% and 36.8%); neutropenia was the most common Grades 3-4 toxicity (39.2% and 52.6%). Efficacy-evaluable populations included patients treated at the recommended Phase 2 dose (FL, n = 49; DLBCL, n = 48). CR rates at EOI were 59.2% (FL) and 31.3% (DLBCL); median progression-free survival was 22.8 months (95% confidence interval [CI], 14.5-not evaluable) and 4.6 months (95% CI, 3.6-8.1), respectively. Polatuzumab vedotin plus venetoclax and obinutuzumab/rituximab had acceptable safety in patients with R/R FL or DLBCL, with promising response rates in R/R FL, including high-risk patients.

Prognostic relevance of circulating lymphoma cells at diagnosis in newly diagnosed follicular lymphoma patients.

Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma. Circulating lymphoma (CL) cells can be seen at diagnosis in some FL patients, however, previous studies evaluating this have shown mixed results. Therefore, we sought to evaluate the impact of CL at diagnosis on outcomes in patients with newly diagnosed FL using data from a single center. Patients were divided into CL+ and CL- based on immunophenotyping via peripheral blood (PB) flow cytometry. CL was defined as detectable clonally restricted B-cells that matched the actual or expected B-cell immunophenotype of FL. The primary endpoint was progression-free survival (PFS) after first-line treatment and secondary endpoints included overall response rate (ORR), overall survival (OS), diagnosis to treatment interval (DTI), progression of disease within 2years of diagnosis (POD24), and cumulative incidence of transformation between the two groups. Among the 541 patients with FL, 204 had PB flow cytometry performed at diagnosis, and after excluding patients not meeting the eligibility criteria, 147 cases remained with 24 (16%) CL+ at diagnosis. Patients in the CL+ group were younger (53 vs. 58years, p=0.02), had more extranodal involvement (83% vs. 44%, p<0.01), follicular lymphoma international prognostic index 3-5 (55% vs. 31%, p=0.01), and a higher proportion received first-line immunochemotherapy (75% vs. 43%, p=0.01) compared to the CL-group. The median PFS was not significantly different between CL+ (6.27years, 95% CI=3.61-NR) and CL- (6.61years, 95% CI=5.10-9.82) cohorts regardless of the first-line treatment or level of absolute PB CL cells. There was no significant difference in ORR, median OS, DTI, POD24, and cumulative incidence of transformation between the two groups. In our study, we found that the presence of CL cells at diagnosis in FL in the contemporary era did not impact outcomes and survival.

Characteristics and prognostic value of gut microbiota in follicular lymphoma.

The pathogenesis and progression of follicular lymphoma (FL) depends on immune evasion mechanisms. The gut microbiota has been reported to be associated with the development and outcome of several human diseases by modulating host immunity. Thus, the present study investigated the characteristics and prognostic value of the gut microbiota in FL. Fecal samples from treatment-naïve patients with FL (n=28) and healthy controls (n=18) were prospectively collected. The gut microbiota diversity and composition were examined by 16S ribosomal RNA sequencing. The results demonstrated that patients with FL had distinct microbiota compositions. The relative abundance of the Ruminococcaceae family was significantly increased in patients with FL (P=0.01). Furthermore, a high level of Ruminococcus was identified as a strong indicator of tumor burden (P=0.001), and was related to the FL International Prognostic Index score and serum lactate dehydrogenase levels. The present results indicated an association between the gut microbiota and FL prognosis. Findings from the present study may provide a rational foundation for further investigation of the role of gut microbiota in lymphoma management.

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.

The clinical features, survival analysis, and geriatric assessment of 85 patients with follicular lymphoma: a single-center study

Objective: To retrospectively analyze the clinical characteristics and prognosis of 85 newly diagnosed patients with follicular lymphoma (FL), as well as the prognostic value of comprehensive geriatric assessment (CGA) in patients with FL aged ≥ 60 years old. Methods: The clinical data and prognosis of 85 newly diagnosed FL patients admitted from August 2011 to June 2022 were collected. The clinical features, laboratory indicators, therapeutic efficacy, survival and prognostic factors of patients were statistically analyzed, and the prognosis of patients was stratified using various geriatric assessment tools. Results: ① The patients with FL were mostly middle-aged and older, with a median age of 59 (20-87) years, including 41 patients (48.2%) aged ≥60 years. The ratio of male to female was 1∶1.36. Overall, 77.6% of the patients were diagnosed with Ann Arbor stage Ⅲ-Ⅳ, and 17 cases (20.0%) were accompanied by B symptoms. Bone marrow involvement was the most common (34.1%). ②Overall, 71 patients received immunochemotherapy. The overall response rate was 86.6%, and the complete recovery rate was 47.1% of 68 evaluated patients. Disease progression or relapse in the first 2 years was observed in 23.9% of the patient. Overall, 14.1% of the patients died during follow-up. ③Of the 56 patients receiving R-CHOP-like therapies, the 3-year and 5-year progression-free survival (PFS) rates were 85.2% and 72.8%, respectively, and the 3-year and 5-year overall survival (OS) rates were 95.9% and 88.8%, respectively. The univariate analysis showed that age ≥60 years old (HR=3.430, 95% CI 1.256-9.371, P=0.016), B symptoms (HR=5.030, 95% CI 1.903-13.294, P=0.016), Prognostic Nutritional Index (PNI) <45.25 (HR=3.478, 95% CI 1.299-9.310, P=0.013), Follicular Lymphoma International Prognostic Index (FLIPI) high-risk (HR=2.918, 95% CI 1.074-7.928, P=0.036), and PRIMA-prognostic index (PRIMA-PI) high-risk (HR=2.745, 95% CI 1.057-7.129, P=0.038) significantly predicted PFS. Moreover, age ≥60 years old and B symptoms were independent risk factors for PFS. Progression of disease within 24 months (POD24) significantly predicted OS in the univariate analysis. Conclusions: FL is more common among middle-aged and older women. Age, B symptoms, PNI score, FLIPI high-risk, PRIMA-PI high-risk, and POD24 influenced PFS and OS. The CGA can be used for treatment selection and risk prognostication in older patients with FL.

High Ki67 Index Is Associated with Shorter Progression Free Survival in Follicular Lymphoma Patients Treated with Frontline Immunochemotherapy

Introduction The Follicular Lymphoma International Prognostic Index (FLIPI) is a commonly used prognostic tool in follicular lymphoma (FL). However, there is a need for better risk stratification to predict risk of progression after frontline chemoimmunotherapy. Ki67 proliferation index has prognostic value in many lymphomas and is widely available in clinical laboratories. However, the impact of Ki67 on outcomes in FL have not been conclusive. Studies have been limited by the method of quantifying Ki67 (entire specimen or intrafollicular [IF]), heterogeneous treatments, or small single institution studies. Moreover, the impact of Ki67 on predicting disease progression at 24 months (POD24) is unknown. We sought to study the predictive value of Ki67 on PFS in FL treated with Bendamustine Rituximab (BR) or RCHOP with or without Rituximab maintenance (RM) as first line therapy at 2 tertiary care centers. Methods This study was conducted with approval by the Wake Forest University Health Sciences IRB. We retrospectively analyzed 122 patients with FL (grade 1-3A) from 2010 to 2021 at Atrium Health (AH) Levine Cancer Institute (n=72) and AH Wake Forest Baptist Medical Center (n=50) who underwent first line therapy with BR or RCHOP and had tissue/slides available for analysis. Clinical data was collected through electronic medical record review. Archival slides and paraffin-embedded blocks were retrieved. Ki67 immunohistochemistry (IHC) (SP6, Cell Marque, Rocklin, CA), was performed if it was not available from the original work-up (8 cases). CD21 IHC (1F8, Dako, Denmark) was performed in select cases to confirm the presence of follicles in order to assess IF Ki67. Diagnosis, grade, and Ki67 stains were evaluated by 2 hematopathologists. The IF Ki67 index was determined by visual estimate to the nearest 10%. All cases with scores between 20-40% were re-reviewed to achieve a consensus score. Ki67 controls were exchanged between the two centers to ensure equivalent staining. Comparisons of patient characteristics were done by Kruskal-Wallis test for continuous variables (age) or Chi-square tests (categorical variables). Survival analysis was performed using Kaplan-Meier estimation and log-rank testing. Cox proportional hazards modeling was used for multivariable progression free survival (PFS) analysis. Results The clinical and pathologic characteristics are shown in Table 1. No differences in demographics [age, stage, cytologic grade, FLIPI, IF Ki67 status (&amp;lt;30 or ≥30) and treatment selection] were seen between the two centers. 100 cases were grade 1-2 (82.0%) and 22 were grade 3A (18.0%). Consistent with expected treatment patterns in FL, more patients were treated with BR (70.5%) compared to RCHOP (29.5%) and RCHOP was more frequently used in grade 3A compared to grade 1-2 FL patients. As expected, low FLIPI score (0-1) was associated with favorable PFS (P=0.02, Figure 1A), but not OS. However, treatment regimen (BR vs RCHOP), use of RM, and cytologic grade (grade 1-2 vs 3A) were not associated with PFS or OS. The IF Ki67 index was elevated (≥30%) in 46 cases (38%) and high IF Ki67 was associated with shorter PFS (P=0.002, Figure 1B), but was not associated with OS (P=0.11). When stratified by treatment regimen and IF Ki67, these results were maintained ( Figure 1C). There was no association between FLIPI and IF Ki67 (P=0.10). In a multivariable regression analysis, IF Ki67 ≥30 was associated with a significantly higher risk of progression (HR= 2.3, 95% CI 1.3 to 4, P=0.005) after accounting for the effect of FLIPI. In an exploratory analysis, a FLIPI/Ki67 (FKi) score was devised in which one point was given for either FLIPI ≥ 2 or IF Ki67 ≥ 30% giving a possible score of 0, 1 or 2. The FKi score was associated with PFS (P=0.0005, Figure 1D). Moreover, IF Ki67 ≥ 30 was associated with a higher risk of POD 24 (P=0.037). FLIPI ≥2 was also associated with POD24 (P=0.005). Conclusion Intrafollicular Ki67 ≥ 30% predicts for increased risk of progression independent of FLIPI in patients with FL treated with frontline immunochemotherapy. Addition of Ki67 to FLIPI is strongly associated with PFS in FL. Ki67 stains were done over an 11 year period in different laboratories, demonstrating the wide applicability and robustness of the Ki67 IHC technique. Larger studies incorporating IF Ki67 in risk stratification models are warranted in FL.

Pirtobrutinib, a Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Relapsed/Refractory Follicular Lymphoma: Results from the Phase 1/2 BRUIN Study

Background: Follicular lymphoma (FL) is a chronic and incurable disease requiring multiple lines of therapy for patients (pts) with relapsed/refractory (R/R) disease. Covalent Bruton tyrosine kinase inhibitors (cBTKi) have transformed the management of select B-cell malignancies, in particular chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). However, despite the transformative impact in CLL and MCL, the efficacy of single-agent cBTKi has been limited in pts with R/R FL, with an overall response rate (ORR) of 20.9% to 37.5% (Gopal et al, J Clin Oncol, 2018; Bartlett et al, Blood, 2018). Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, inhibits both wildtype and C481-mutant BTK with equal low nM potency and has a favorable oral pharmacology that enables continuous BTK inhibition throughout the once-daily dosing interval. Pirtobrutinib has demonstrated promising efficacy and tolerability in pts with poor-prognosis B-cell malignancies following prior therapy, including cBTKi. Here, we report the safety and efficacy of pirtobrutinib in a cohort of pts with R/R FL from the BRUIN study (NCT03740529). Methods: Pts with previously treated B-cell malignancies were eligible for treatment with pirtobrutinib monotherapy in either the dose escalation or expansion portion of the multicenter phase 1/2 BRUIN study. FL diagnosis required pathologic review of an adequate biopsy. Key endpoints included investigator-assessed ORR per Lugano 2014 criteria, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. A data cutoff date of 05 May 2023 was utilized. Results: Among the 48 pts with FL, 45 (94%) pts received the recommended phase 2 dose of pirtobrutinib (200 mg once daily) as their starting dose. Pts had a median age of 64.5 years (range, 37.0-85.0), were mostly male (60%, n=29), and had a median of 3 (range, 1-12) prior lines of therapy. Most pts (81%, n=39) had Ann Arbor stage III/IV disease. The Follicular Lymphoma International Prognostic Index (FLIPI) risk was low (0-1) in 9 (19%) pts, intermediate (2) in 13 (27%) pts, high (3-5) in 23 (48%) pts, and missing in 3 (6%) pts. Overall, 43 (90%) pts had received chemotherapy plus an anti-CD20 antibody, 17 (35%) pts had received a PI3K inhibitor, 14 (29%) pts had received lenalidomide, 6 (13%) pts had received an autologous stem cell transplant, and 4 (8%) pts had received CAR T-cell therapy. Of the 4 (8%) pts who had received a prior cBTKi, 3 discontinued due to disease progression and 1 discontinued for intolerance. The ORR was 50.0% (95% confidence interval [CI], 35.2-64.8), including 7 (14.6%) complete responses and 17 (35.4%) partial responses (Figure). An additional 12 (25.0%) pts had stable disease. Among 4 pts who had received prior cBTKi, 3 achieved partial response and 1 had stable disease. With a median follow-up of 18.4 months (interquartile range, 10.1-21.0) among 24 responding pts, median DoR was 5.5 months (95% CI, 3.7-not estimable [NE]), and the 18-month estimated DoR rate was 41.0% (95% CI, 20.1-60.9). Median PFS was 5.8 months (95% CI, 3.8-8.1), and the 18-month estimated PFS rate was 32.3% (95% CI, 19.1-46.2). Median OS was NE, and the 18-month estimated OS rate was 78.3% (95% CI, 62.1-88.1). The efficacy outcomes by FLIPI risk category are presented in the Table. The median time on treatment was 7.6 months (range, 0.6-42.2), with 14 (29.2%) pts still receiving pirtobrutinib. The most frequent treatment-emergent adverse events (TEAEs), regardless of attribution, were diarrhea (29.2%, n=14), fatigue (25.0%, n=12), and nausea (22.9%, n=11). TEAEs of hemorrhage/hematoma (6.3%, n=3), hypertension (4.2%, n=2), and atrial fibrillation/flutter (2.1%, n=1) were infrequent. The most frequent grade ≥3 TEAEs were infection (18.8%, n=9) and neutropenia/neutrophil count decreased (14.6%, n=7). Only 1 (2.1%) pt had a treatment-related adverse event (rash) that led to pirtobrutinib discontinuation. Conclusions: In this cohort of heavily pre-treated pts with R/R FL, pirtobrutinib showed potential efficacy and was well tolerated, including in pts with high risk FLIPI.

Integrative Genomic and Transcriptomic Analysis Reveals Genetic Alterations Associated with the Early Progression of Follicular Lymphoma

Background Follicular lymphoma (FL), the most common indolent lymphoma, is a clinically and genetically heterogeneous disease. However, the prognostic value of driver gene mutations and copy number alterations has not been systematically assessed. Patients and Methods Here, we analyzed clinical-biological features of 415 FL patients to identify variables associated with disease within 24 months of first-line therapy (POD24). In addition, we applied whole exome sequencing (WES) to identify genomic alterations that predict POD24 based on 102 FL patients. Furthermore, we characterized the cellular and molecular heterogeneity within and across patients through bulk RNA sequencing and single-cell RNA sequencing. ResultsPOD24 occurred in 21% of evaluable FL patients. To further examine the effect of POD24 on OS, we used a 24-month landmark approach for Kaplan-Meier curve analysis. As expected, POD24 was related to poor OS, and the 3- and 5-year survival probabilities of patients in whom the disease progressed within the first 24 months were 89.2% (95% CI, 84.5-93.9) and 78.6% (95% CI, 70.4-86.8), respectively, compared with 98.5% (95% CI, 97.8-99.2) and 96.2% (95% CI, 95.0-97.4) in patients who were progression free at 24 months, respectively. Moreover, patients without progression at 24 months were more likely to exhibit a CR to front-line treatment (54% vs. 35%, P = 0.001) compared to the POD24 cohort. Patients with B symptoms, elevated lactate dehydrogenase and β2-microglobulin levels, unfavorable baseline haemoglobin levels, advanced stage, and high-risk FL International Prognostic Index (FLIPI) scores had an increased risk of POD24, with FLIPI being the most important factor in logistic regression. HIST1H1D, known as a driver mutation, was correlated with POD24. Gains of 6q22.2 ( HIST1H1D) and 18q21.33 ( BCL2) and loss of 1p36.13 ( NBPF1) predicted POD24 independent of FLIPI. Integration of the four variants led to the identification of 76% of POD24 patients. Gene expression profiling of FL samples showed that the POD24 cohort was significantly enriched in the inflammatory response (mediated by interferon and tumor necrosis factor), cell cycle regulation (transcription, replication and proliferation) sets and PI3K-AKT-mTOR signaling. This result was further validated with transcriptome-wide information provided by RNA-seq at single-cell resolution. ConclusionOur study, performed on a large cohort of FL patients, highlights the importance of distinctive genetic alterations and gene expression relevant to disease diagnosis and early progression.

Development and Validation of a Machine-Learning Model to Predict POD24 Risk of Follicular Lymphoma

Background: Disease progression or relapse within 24 months after starting treatment (POD24) has been considered as an independent unfavorable factor in follicular lymphoma (FL). This study was to explore the discriminative accuracy of a machine learning-based (ML) model within different ethnic groups for identifying FL1-3a patients at higher risk for POD24. Methods: 1938 FL1-3a patients were enrolled from a Chinese multicenter cohort and randomly subdivided into a training cohort and an internal validation cohort. An external validation cohort included 1145 patients from the GALLIUM Study within different ethnicity. Univariable regression analysis with backward selection for inclusion of predictor variables and nonlinear analysis based on the XGBoost algorithm were used to develop a ML model for predicting POD24. For internal and external validation, the time-dependent area under the receiver operating characteristic curve (AUROC) was used to investigate the model's predictive performance, compared with established traditional models such as Follicular Lymphoma International Prognostic Index (FLIPI), FLIPI-2 and PRIMA-PI. The calibration and clinical usefulness of the ML model were evaluated using calibration plots and decision curve analyses, respectively. Results: During the follow-up period, 383 (19.7%) and 405 (36.3%) of patients who experienced POD24 were identified in the Chinese cohort and the GALLIUM Study, respectively. In the training cohort, important features of POD24 based on the XGBoost algorithm were ranked by SHAP analysis. Increased lymphocyte-to-monocyte ratio (LMR&amp;gt;10) ranked first (scoring 2), followed by elevated lactate dehydrogenase (LDH), hemogolobin reduction (HGB&amp;lt;12g/dl), elevated beta-2 microglobulin (B2-MG), higher maximum standardized uptake value (SUVmax&amp;gt;10), and 4 or more involved lymph nodes (each scoring 1) were incorporated into the new ML model, referred to as FLIPI-C. The new model performed well in predicting PFS as well as OS, and stratified patients into low- (0-3) and high-risk groups (4-7). In internal validation, FLIPI-C demonstrated a higher AUROC of 0.764 (95%CI:0.721-0.806) for POD24 prediction compared with 0.648 (95%CI: 0.599-0.696) of FLIPI, 0.706 (95%CI: 0.658-0.754) of FLIPI-2 and 0.716 (95%CI: 0.669-0.763) of PRIMA-PI. In external validation with GALLIUM Study, FLIPI-C demonstrated a higher AUROC of 0.701 (95%CI: 0.659-0.741) for POD24 prediction compared with 0.578 (95%CI: 0.531-0.625) of FLIPI, 0.600 (95%CI: 0.554-0.645) of FLIPI-2 and 0.593 (95%CI: 0.547-0.639) of PRIMA-PI. In addtion, the FLIPI-C model had adequate calibration with similar predicted and observed risk of POD24. In decision curve analysis, FLIPI-C yielded improved net benefits compared with FLIPI, FLIPI-2 and PRIMA-PI. Conclusions: TheFLIPI-C model generated using a machine learning approach exhibited greater discriminative accuracy than prior established traditional models for predicting POD24 and is valuable for treatment selection and prognostic assessment of FL.

Key Prognostic Factors in Patients with Relapsed/Refractory Follicular Lymphoma: An Evidence Based Systematic Literature and Medical Review

Introduction: A multi-center multi-country retrospective cohort study (FLORA [NCT05338879]), using real-world data (RWD) from electronic medical records (EMRs) and research databases, for patients with relapsed/refractory follicular lymphoma grade 1-3a (r/r FL) treated with standard of care is being conducted to contextualize treatment outcomes in a single-arm trial. A systematic literature review (SLR) was carried out to identify baseline prognostic factors that will be evaluated for imbalances between cohorts in the single-arm trial and RWD study. This SLR was followed by an evidence-based clinical expert review and ranking of prognostic variables in order of importance for the FLORA study as described herein. Methods: The approach and methods of the SLR (International Prospective Register of Systematic Reviews [PROSPERO] CRD42022307561) were informed by guidelines set forth by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins et. al. 2021) and PRISMA (Page et. al. BMJ 2021) and described previously (Hampp et. al. ISPOR 2023). Following the conduct of the SLR, the identified potential prognostic variables were evaluated by the FLORA study team to remove treatment-specific and outcome variables, determine their availability in the single-arm trial and FLORA RWD study, and develop a questionnaire. In the questionnaire, prognostic variables were grouped by type of variable - clinical, laboratory data, or treatment characteristic. Each prognostic variable was reviewed by an international panel consisting of 3 clinical experts in the field of lymphoma who categorized the prognostic impact on treatment response and survival on a 5-point scale ranging from “Very high importance” to “Not important”. The clinicians were asked to consider possible correlation among the variables, possible effect modifiers, specific variable definitions (e.g., chemoresistant), and whether there were any other prognostically important variables not captured in the questionnaire. For each variable the clinical experts categorized the availability within routine care on a 3-point scale ranging from “Readily available” to “Limited availability”. The results of the 3 expert completed questionnaires were reviewed and the top 10 highest ranking variables were determined by summing the clinicians' categorization of prognostic impact and considering variable availability in the event of a tie. Individual interviews with each clinical expert were held to clarify variables and definitions, discuss discrepant categorization, and rank the prognostic variables from 1-10. Following the 3 interviews, the ranking of each variable was summed across the 3 experts to determine the final ranking. Results: Across the 13 studies included, the SLR identified 28 prognostic factors, including patient demographics and clinical characteristics, disease and treatment characteristics, and laboratory data. Seven clinical outcomes with statistically significant associations were identified (most commonly, overall survival [OS], progression-free survival [PFS], and relapse/progression). No additional prognostic factors were identified by the clinical experts. The final ranked list of the 10 most important prognostic variables in descending order of importance includes: progression of disease within 2 years (POD24), chemo-immunorefractory/chemoresistant, refractory to last line of therapy (LoT), number of prior LoTs, serum lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group (ECOG) performance status, Follicular Lymphoma International Prognostic Index (FLIPI), age at start of LoT, Ann Arbor disease stage, and refractory to rituximab. Conclusion: SLR-based identification of prognostic factors combined with expert clinical review provides an unbiased evaluation and ranking of the level of evidence to assist in selecting prognostic factors to collect for the FLORA real-world cohort study. The appropriate selection of prognostic factors is critical for valid outcome estimation. These factors will be used for the evaluation of balance with the single-arm trial and for adjustment in a propensity score model. With this approach, the prognostic factors are chosen a priori to enable balancing of baseline covariates prior to outcome estimation.

An Externally Controlled Trial to Indirectly Compare Tazemetostat Plus Lenalidomide and Rituximab Versus Lenalidomide and Rituximab after at Least One Prior Systemic Therapy in Patients with Refractory and Relapsed Follicular Lymphoma

BACKGROUND: Follicular lymphoma (FL) is an indolent, incurable lymphoma with a heterogeneous clinical course characterized by multiple relapses. Recent data indicate a potential synergism between tazemetostat and lenalidomide and an additive effect with rituximab, offering a clinical rationale for this as a combination strategy (Batlevi, Blood 2022). SYMPHONY-1 Phase 1b, Stage 1 (EZH-302; NCT04224493) is an open-label, single-arm, safety run-in trial to evaluate the safety and tolerability of tazemetostat combined with lenalidomide plus rituximab (R2). This study indirectly compares the efficacy results of the SYMPHONY-1 Phase 1b single arm trial with an external control arm (ECA) derived from the Flatiron Health Research Database (FHRD), consisting of real-world FL patients treated with R2 after receiving ≥1 prior systemic therapy. METHODS: This study utilized individual patient data from SYMPHONY-1 based on a data cutoff date of July 10, 2023, and the FHRD, a large database of electronic health records from oncology practices in the United States, including data through December 31, 2022. The treatment arm consisted of patients enrolled in the safety run-in portion of SYMPHONY-1 treated with a combination of tazemetostat plus R2, followed from enrollment to the data cutoff date. The ECA was constructed by applying eligibility criteria adapted from SYMPHONY-1 to real-world patients from the FHRD treated with R2 in second line (2L); patients were followed from the start date of the earliest eligible line of therapy (LOT) to the end of the patient's record. The primary endpoint was objective response rate (ORR), defined as the proportion of patients who achieved a complete or partial response. In SYMPHONY-1, ORR was assessed by an independent review committee according to the 2014 Lugano Classification. In the ECA, real-world ORR (rwORR) was determined by the treating clinician's interpretation of change in disease burden. The analysis set included patients from the treatment arm with ≥1 evaluable response assessment and patients from the ECA with ≥1 radiographic assessment documented in the FHRD. The statistical analysis used propensity score weighting (PSW) to adjust the distribution of seven prespecified baseline patient characteristics of the ECA to align with the treatment arm. These characteristics were age, Eastern Cooperative Oncology Group Performance Status, disease grade at diagnosis, progression of disease within 24 months (POD24) from diagnosis, lactate dehydrogenase (LDH) &amp;gt; upper limit of normal (ULN), size of the largest node, and Follicular Lymphoma International Prognostic Index (FLIPI) risk group. An impute-then-exclude multiple imputation strategy was used to handle missing data for variables required in the eligibility criteria and PSW. The primary endpoint was indirectly compared by estimating the difference between the ORR of the treatment arm and rwORR of the balanced ECA on each imputed dataset, and the associated standard errors were approximated using bootstrapping. Rubin's rules were applied to combine the results into a single estimate with a 95% confidence interval and corresponding two-sided p-value. RESULTS: The primary analysis compared 42 patients in the treatment arm from SYMPHONY-1 and a median of 36 patients (range: 34 to 38) in the ECA among 815 total patients in the FHRD across ten imputed datasets. The unweighted analysis found an ORR of 95.2% in the treatment arm and 75.7% in the ECA, resulting in a difference of 19.6% (95% confidence interval [CI]: 3.6-35.5) (Table 2). After PSW, the distribution of baseline characteristics for the ECA was comparable with the treatment arm (all standardized mean differences &amp;lt; 0.16), and the median effective sample size was reduced to 12.7 (range: 4.9 to 19.1) (Table 1). ORR was 95.2% in the treatment arm and 77.9% in the ECA, resulting in a difference of 17.3% (95% CI: -17.5-52.1; two-sided P = 0.16) (Table 2). CONCLUSIONS: This ECA study found that patients treated with tazemetostat combined with R2 were estimated to have a higher ORR than those treated with R2, though inference is limited due to small sample sizes. These findings help contextualize the SYMPHONY-1 Phase 1b single-arm trial results and combination potential of tazemetostat plus R2. There is a randomized Phase 3 confirmatory trial underway to confirm the clinical benefit of tazemetostat plus R2 (SYMPHONY-1 Stage 2, NCT04224493).

Long-Term Efficacy of a 6-Month Regimen of Rituximab and Lenalidomide in Follicular Lymphoma Patients in Need of First Therapy: Updated Analysis of the SAKK 35/10 Randomized Trial

Background:The Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) conducted the SAKK 35/10 randomized phase-2 trial (NCT0137605) to compare the effectiveness of rituximab (R) alone versus R combined with lenalidomide (L) as the initial treatment for symptomatic follicular lymphoma (FL). The primary endpoint analysis, which demonstrated higher complete remission (CR) rates with the combination therapy, was previously reported (Zucca et al. Blood 2019). This report provides a long-term analysis of time-to-event endpoints with a median follow-up of approximately 10 years. Methods:A total of 154 eligible patients with untreated grade 1 to 3a FL requiring systemic therapy were centrally randomized to receive either R monotherapy (375 mg/m2 IV on day 1 of weeks 1-4 and repeated during weeks 12-15 for responding patients) or R+L. In the combination arm, R was administered at the same schedule as the monotherapy, while L was taken orally at a daily dose of 15 mg, starting 14 days before the first R administration, and continued until 14 days after the last R administration, for a total of 18 weeks. Random assignment to treatment arms was stratified based on histological grade (1-2 vs 3a), bulky disease (&amp;lt;6 vs ≥6 cm), Follicular Lymphoma International Prognostic Index (FLIPI) score (1-2 vs ≥3), and centre, using the minimization method. The sample size was determined to detect a 20% increase in the CR/CRu rate with 90% power, using a one-sided Z-test with a false positive rate of 10% to compare the two treatment arms. The assessed endpoints, including progression-free survival (PFS), time to next anti-lymphoma treatment (TTNT), duration of CR/CRu (DoR), and overall survival (OS), were defined according to NCI international standardized criteria (Cheson et al. J Clin Oncol 1999). Results:Seventy-seven patients (median age 63 years, 52% with stage IV and 47% with poor-risk FLIPI score) were assigned to the single-agent rituximab arm, and 77 patients (median age 61 years, 48% with stage IV and 47% with poor-risk FLIPI score) were assigned to the combination arm. The results for the primary endpoint were consistent with the positive initial analysis. At a median follow-up of 9.5 years, the overall survival was similar in both arms (77% vs. 78% at 10 years, p=0.881). However, significant, and sustained improvements were seen in all other time-to-event endpoints. Patients in the R+L arm had a longer PFS (median, 9.3 vs. 2.3 years; HR=0.58, 95% CI: 0.37-0.89; p=0.013) and TTNT (median, not reached vs. 2.1 years; HR=0.43, 95% CI: 0.27-0.67; p&amp;lt;0.001). DoR with R+L was also longer (median not reached vs 3.2 years with R only; HR=0.42, 95% CI: 0.21-0.86; p=0.014) and with over 60% of responders still in first remission at 10 years. The improved outcomes with R+L were not associated with unexpected toxicity. Grade ≥3 adverse events were more common with the combination regimen (56% vs. 22% of patients), with grade 3-4 neutropenia in 23% of patients receiving R+L and in 7% of those receiving R alone. Fatigue, diarrhea, and skin rash were more frequent with R+L, but mostly of grade 1-2 (grade 3 occurred in ≤ 5% in both arms, and no grade 4 was reported). The side effects were manageable, and there were no treatment-related deaths in either arm. Two cases of biopsy-proven into diffuse large B-cell lymphoma were reported in the R+L arm, and two cases of Hodgkin lymphoma were described in the R arm. Although their causal relationship with treatment is not completely clear, the number of second solid cancers was significantly higher in the R+L arm. Two cases of prostate cancer, two lung adenocarcinomas (one in situ), one small cell lung carcinoma, one rectal cancer, and four skin cancers (three squamous cell and one basal cell), were observed in the R+L arm, while only one solid tumor (prostate cancer) occurred in the R arm (p=0.09). Only one patient died of a second solid cancer (small cell lung carcinoma in the R+L arm). The rate of POD24 was 29% in the R+L arm vs. 34% in the R-arm (p=0.483). Conclusions:The long-term results of the SAKK 35/10 trial demonstrated a durable benefit for the R+L combination compared to R alone. Notably, the adopted R+L schedule is considerably shorter than the standard R2 regimen (18 vs. 120 weeks). This provides a promising alternative when treatment is required but durable immunosuppression is undesirable.

Estimation of Relapsed/Refractory Follicular Lymphoma Patients on Therapy in the United States

Background: Follicular lymphoma (FL) represents approximately 20-25% of non-Hodgkin lymphomas (NHL). In contrast to patients with more aggressive NHL, patients with FL have a heterogenous course of disease in which some can spend extended periods in an initial watch-and-wait state and/or within a single line of treatment. As such, these patients may have multiple relapses and a variety of clinical features that may impact disease course (eg, double-refractory disease, increased Follicular Lymphoma International Prognostic Index (FLIPI) scores, high Ann Arbor disease stage, older age, etc.). The objective of this study was to estimate the number of treated patients with FL in each line of therapy (LOT) to better understand the proportion with relapsed or refractory (R/R) disease in the US while accounting for distributions of LOTs within a baseline prevalent population and annual trends in treatment initiation by LOT. Methods: Two companion models were developed from a US perspective: 1) an epidemiologic model that utilized FL incidence and survival data from the Surveillance, Epidemiology, and End Results (SEER) program to project the size of the prevalent population; and 2) a state-transition model describing the proportion of patients with FL initiating treatment and time on treatment by line of therapy. Within the state-transition model, hypothetical incident cohorts were simulated annually to follow FL treatment patterns and survival trajectories until a “steady-state” was reached regarding the distribution of LOTs in the prevalent population. Model inputs were based on data from published literature. Several published sources were identified regarding estimates of treatment rates by line of therapy, with base-case values based on physician survey: 51% for first LOT, 32% for second LOT, and 31% for third and successive LOTs. This distribution was then applied to a baseline prevalent population and subsequent incident cohorts were modeled annually over a 3-year time horizon. Results: In 2022, the estimated FL prevalent population in the US was 154,922. Over a subsequent 3-year period combining the prevalent patients with newly incident patients, the model projected 10,399 patients initiating first-line treatment, 3197 initiating second-line treatment, and 975 initiating third-line treatment. Conclusions: While incidence of FL initial diagnosis in the US is well reported, there are limited data describing prevalence or population makeup with respect to LOT. While many patients can benefit from long remissions after first-line therapy, a portion of patients experience R/R disease and require further treatment. Estimation of the R/R FL population can support with planning of treatment needs as novel therapies emerge in the US.

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.

Matching-Adjusted Indirect Comparison (MAIC) of Efficacy and Safety of Lisocabtagene Maraleucel (liso-cel) and Mosunetuzumab for the Treatment (Tx) of Third Line or Later (3L+) Relapsed or Refractory (R/R) Follicular Lymphoma (FL)

Background:The tx landscape of R/R FL is evolving with the availability of anti-CD19 chimeric antigen receptor (CAR) T cell therapies and CD20xCD3 bispecific T-cell-engaging monoclonal antibodies (mAb). Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell therapy which recently reported a positive benefit-risk tx profile for the 3L+ tx of patients with R/R FL (Morschhauser F, et al. ICML 2023; LBA4). Mosunetuzumab, a CD20xCD3 bispecific T-cell-engaging mAb, is approved for the tx of R/R FL after 2 or more lines of therapy (LOT). In the absence of head-to-head data, we conducted an unanchored MAIC to compare the efficacy and safety of liso-cel and mosunetuzumab for the 3L+ tx of patients with R/R FL. Methods: Unanchored MAICs were used to estimate population-adjusted relative tx effects between individual patient-level data from TRANSCEND FL (NCT04245839; data as of January 27, 2023; median follow-up of 19.3 months) and aggregate data from GO29781 (NCT02500407; data as of August 27, 2021; median follow-up of 18.3 months; N = 90). For TRANSCEND FL, the leukapheresed (intention to treat [ITT]) set (N = 114) was used for primary comparisons of efficacy endpoints: Progression-free survival (PFS), objective response rate, and complete response rate (all per independent review committee assessment). Overall survival was not analyzed due to the low rate of events. The treated efficacy set (n = 101) was used for a sensitivity analysis of efficacy comparisons. The treated set (n = 107) was used for comparisons of safety endpoints: cytokine release syndrome (CRS), neurological events (NEs), serious infections, and use of corticosteroids or tocilizumab for CRS. Baseline characteristics and outcome measures in TRANSCEND FL were redefined to align with those reported in GO29781. Data from TRANSCEND FL were weighted using a method-of-moments propensity score model to match the marginal distribution (ie, mean, variance) of clinical factors among patients from GO29781. A panel of expert clinicians selected and ranked tx effect modifiers separately for efficacy and safety endpoints. For efficacy, factors adjusted for included number of prior systemic LOTs, progression of disease ≤ 24 months from initiation of immunochemotherapy, bulky disease at screening, FL International Prognostic Index risk factor, refractory to last therapy, double refractory to an anti-CD20 antibody and alkylating agent, ECOG PS at screening, sex, and prior autologous HSCT. For safety, factors adjusted for included age, bulky disease at screening, refractory to last therapy, number of prior systemic LOTs, ECOG PS at screening, Ann Arbor stage, and sex. Hazard ratios (HR) were used to compare PFS, and odds ratios (OR) were used for response rates and safety outcomes. Results: After adjusting for all available factors, when compared with mosunetuzumab, liso-cel was associated with higher objective response rate (OR, 3.78 [95% CI, 1.48‒9.67]), and complete response rate (OR, 6.46 [2.85‒14.65]), and improved PFS (HR, 0.28 [0.16‒0.49]) based on an effective sample size (ESS) of 71.4 (Figure). Results were consistent across all scenario analyses, including unadjusted comparisons and sensitivity analyses using the treated efficacy set for TRANSCEND FL. Although liso-cel was associated with higher incidence of any-grade CRS (OR, 1.86 [1.01‒3.43]) and any-grade NEs (OR, 2.16 [0.72‒6.44]), it demonstrated a lower incidence of grade ≥ 3 CRS (OR, 0.45 [0.04‒5.13]) and grade 3-4 serious infections (OR, 0.35 [0.12‒1.03]) based on an ESS of 81.9 compared with mosunetuzumab. Furthermore, liso-cel was associated with reduced use of corticosteroids for CRS management (OR, 0.14 [0.03‒0.65]), while the use of tocilizumab was higher in patients treated with liso-cel (OR, 2.27 [0.86‒5.99]). Conclusions: In this MAIC, liso-cel was associated with improved efficacy compared with mosunetuzumab. Liso-cel had a lower incidence of grade ≥ 3 CRS, grade 3-4 serious infections, and steroid use for management of CRS; however, liso-cel exhibited higher incidence of any-grade CRS, any-grade NEs, and tocilizumab use for CRS management. Safety comparisons were confounded by preventative use of corticosteroids in all patients in GO29781 and definition differences, most notably for NEs. These findings highlight a potential positive benefit-risk profile of liso-cel over mosunetuzumab as a 3L+ tx option for R/R FL.

TRANSCEND FL: Phase 2 Study Primary Analysis of Lisocabtagene Maraleucel as Second-Line Therapy in Patients with High-Risk Relapsed or Refractory Follicular Lymphoma

Background: Results with CD19-directed CAR T cell therapy in patients (pts) with second-line (2L) R/R follicular lymphoma (FL) and high-risk features, such as progression of disease within 24 months (POD24) from diagnosis or double refractory to anti-CD20 antibody plus alkylator, have not been previously reported. TRANSCEND FL (NCT04245839), a global, phase 2, open-label, single-arm, multicohort, pivotal study, assessed efficacy and safety of the anti-CD19 CAR T cell therapy lisocabtagene maraleucel (liso-cel) in pts with second line or later (2L+) R/R indolent NHL. Some data from the primary analysis were previously reported, including safety in 2L+ R/R FL, and focused on efficacy in third line or later R/R FL (Morschhauser F, et al. Hematol Oncol 2023;41[S2]:877‒880). Here, we report primary analysis results in the cohort of pts with 2L high-risk R/R FL. Methods: Eligible pts in the 2L R/R FL cohort had biopsy-confirmed FL before enrollment and must have had POD24 with treatment ≤ 6 months from original FL diagnosis and/or must have had high tumor burden as defined by modified Groupe d'Etude des Lymphomes Folliculaires (mGELF) criteria. All pts received 1 prior combination systemic therapy with an anti-CD20 antibody and alkylator. Eligible pts received liso-cel (100 × 10 6 CAR + T cells) after lymphodepleting chemotherapy (LDC). Bridging therapy was allowed with reconfirmation of PET-positive disease before LDC. The primary endpoint was ORR per independent review committee (IRC) by PET/CT using Lugano 2014 criteria. Secondary endpoints included CR rate, duration of response (DOR), PFS, OS, safety, and cellular kinetics. Pharmacodynamic endpoints were exploratory. Results: At data cutoff (January 27, 2023), 23 of 25 leukapheresed pts received liso-cel and were evaluable for safety and efficacy per IRC; 1 received nonconforming product and 1 reached CR after bridging therapy and no longer met eligibility criteria. Median (range) age was 53 y (34-69), 74% had stage III/IV disease, and 35% were high-risk per FL International Prognostic Index (FLIPI). Sixty-five percent of pts had POD24 from initiation of first-line combination chemoimmunotherapy (52% had POD24 from diagnosis), 70% met mGELF criteria (mGELF only, 48%; mGELF and POD24 from diagnosis, 22%), and 48% were double refractory to anti-CD20 antibody plus alkylator. Median (range) on-study follow-up was 18.1 months (1.0-26.8). In efficacy-evaluable pts, the ORR and CR rate were both 95.7% (95% CI, 78.1-99.9; 1-sided P &amp;lt; 0.0001; Table). With a median follow-up of 16.8 months and 17.8 months, respectively, median DOR and PFS were not reached; 12-month DOR and PFS were 89.8% and 91.3%, respectively. The most common grade (gr) ≥ 3 treatment-emergent AEs (TEAE) were cytopenias; neutropenia was most frequent (52%). Cytokine release syndrome (CRS) occurred in 12 (52%) pts (no gr ≥ 3). Median (range) time to onset and resolution of CRS was 6 days (2-9) and 3 days (2-7), respectively. Neurological events (NE) occurred in 4 (17%) pts, with 1 (4%) gr 3 and no gr 4-5 (Table). Median (range) time to onset and resolution of NEs was 8.5 days (6-11) and 2.5 days (1-4), respectively. Three (13%) pts received tocilizumab/steroids for CRS/NEs. Prolonged cytopenia (gr ≥ 3 laboratory values at Day 29) occurred in 3 (13%) pts; all recovered to gr ≤ 2 by Day 90. No gr ≥ 3 infections were reported. One TEAE death occurred in the context of IRC-assessed disease progression due to gr 5 macrophage activation syndrome (MAS). Liso-cel showed rapid expansion with median (range) time to maximum transgene levels of 10 days (7-11). Persistence of liso-cel transgene was detected up to Month 12 in 5 of 18 (28%) pts. B-cell aplasia (&amp;lt; 3% CD19 + B cells in peripheral blood lymphocytes) after liso-cel infusion was rapid and maintained in ≥ 95% of pts through Month 2. Conclusions: This is the first report of outcomes in 2L high-risk R/R FL with CD19-directed CAR T cell therapy. In this population, liso-cel achieved very high CR rates (22 of 23 pts); deep and durable remissions, with follow-up ongoing; and a favorable safety profile with low rates of severe (gr ≥ 3) CRS, NEs, and prolonged cytopenia, and no severe infections. These data support liso-cel as a potential new treatment option in pts with 2L R/R FL at high-risk for treatment failure.

Real-World Response Rates across Lines of Therapy Among Patients with Relapsed/Refractory Follicular Lymphoma

Background: Follicular lymphoma (FL) is the most common indolent subtype of non-Hodgkin lymphoma. Despite the generally indolent nature of the condition, there are subgroups of FL patients who may not have an indolent experience, with their disease not responding to multiple lines of therapy. Thus, optimization of novel therapy could improve patient outcomes. This analysis examined treatment patterns, overall response rates (ORR), and complete response (CR) rates by line of therapy (LOT) in relapsed/refractory (R/R) FL in third-line or later (3L+) therapy. Methods: This retrospective observational study was conducted using the COTA database, comprising electronic health records (EHR) from academic (50%) and community (50%) practices in the US. Adults with a confirmed diagnosis of FL, with 3L+ therapy initiation in 2010 or later, at least 3 months of follow-up, and any response assessment after 3L initiation were included. LOTs eligible for inclusion met the following conditions: treatment with an anti-CD20, alkylating agent, or lenalidomide, and no investigational drug in the selected LOT. In addition, patients with only 3L had that line selected; patients with more than 1 eligible LOT had only 1 LOT randomly selected for the analysis. Outcomes were assessed by FL International Prognostic Index (FLIPI), double refractory (DR) status, and type of therapy. DR status was defined as being refractory (disease progression or initiation of a new LOT in &amp;lt;6 months) to an anti-CD20 monoclonal antibody therapy and an alkylating agent. Chemoimmunotherapy (CIT) regimens included obinutuzumab/rituximab + bendamustine (OB/BR), rituximab/obinutuzumab+cyclophosphamide, doxorubicin, vincristine, and prednisolone (R/O+CHOP), R/O+CVP, R/O+other alkylating agent, and R/O+fludarabine and cyclophosphamide (FC). Novel therapies included lenalidomide + rituximab (R 2), phosphatidylinositol-3-kinase (PI3K) inhibitors, and chimeric antigen receptor T-cell therapy (CAR T). The proportion of patients with CR (as retrieved from clinician documentation in EHR) as the physician-reported response within each LOT was calculated. ORR was calculated as the proportion of patients with a CR or PR. Response rates were reported by LOT (3L, 4L, 5L+) and stratified by patient age (&amp;lt;65 vs ≥65 years), FLIPI score (low/intermediate vs high), and DR (not DR vs DR). Results: Overall, 240 patients with R/R 3L+ FL were included: 3L (n=140), 4L (n=55), and 5L+ (n=45). At 3L initiation, median age was 66 years and most patients were male (58.8%), White (89.6%), and had FL grade 1/2 (72.5%); 47.9% of patients were DR, 22.9% had novel therapy use, and 51.3% had CIT use. A total of 152 patients had FLIPI scores available, 38.2% of whom had high-risk scores at 3L initiation. Among all R/R 3L+ FL patients, ORR was 67.9%, with CR in 30.4% ( Figure 1). Response rates decreased across LOTs for both ORR (3L: 72.9%; 4L: 65.5%; 5L+: 55.6%) and CR (3L: 35.0%; 4L: 30.9%; 5L+: 15.6%) ( Figure 2). ORR was higher among all R/R 3L+ FL patients &amp;lt;65 years vs ≥65 years (75.5% vs 62.3%), as was CR rate (36.3% vs 26.1%). Among the subset of R/R 3L+ FL patients with a FLIPI score, those with low/intermediate risk vs high risk had a greater ORR (78.7% vs 58.6%) and CR rate (36.2% vs 20.7%). ORR was also higher for R/R 3L+ patients without DR status vs with DR status (73.0% vs 63.2%), as was CR rate (37.4% vs 24.0%). Patients receiving novel therapy 3L+ had an ORR of 70.9% and a CR rate of 27.3%. Among R/R 3L+ FL patients, more LOTs of CIT were associated with decreased response rates; patients with CIT in 1 LOT vs CIT in &amp;gt;2 LOTs had greater ORR (76.4% vs 69.2%) and CR rate (37.4% vs 26.9%). Conclusions: This analysis provides granular details on patients with R/R FL with poor prognosis. Patients with FL who progress to later LOTs have worsening response rates. This analysis included more patients with later LOTs than previously published reports, providing additional insight into response rates as treatment progresses. Lower response rates were observed among patients ≥65 years, those with a high-risk FLIPI score, and those with DR status. The high utilization of CIT in later LOTs, despite suboptimal response rates, especially among subgroups of patients with FL who may not have indolent experience of the disease, underlines the need for efficacious alternative therapies in patients with R/R 3L+ FL.

Metabolic bulk volume from FDG PET as an independent predictor of progression-free survival in follicular lymphoma.

Total metabolic tumor volume (TMTV) in 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) predicts patient outcome in follicular lymphoma (FL); however, it requires laborious segmentation of all lesions. We investigated the prognostic value of the metabolic bulk volume (MBV) obtained from the single largest lesion. Pretreatment FDG PET/computed tomography (CT) scans of 201 patients were analyzed for TMTV and MBV using a 41% maximum standardized uptake value (SUVmax) threshold. During a median follow-up of 3.2 years, 54 events, including 14 deaths, occurred. Optimal cut-offs were 121.1 cm3 for TMTV and 24.8 cm3 for MBV. Univariable predictors of progression-free survival (PFS) included a high Follicular Lymphoma International Prognostic Index 2 (FLIPI2) score, TMTV, and MBV. In the multivariable analysis, high TMTV and MBV were independent predictors of worse PFS (P =0.015 and 0.033). Furthermore, in a sub-group with FLIP2 scores of 0-2 (n = 132), high MBV could identify patients with worse PFS (P = 0.007). . Readily measurable MBV is useful for stratifying risk in FL patients.

Metabolic tumor volume predicts outcome in patients with advanced stage follicular lymphoma from the RELEVANCE trial

We investigated the prognostic value of baseline positron emission tomography (PET) parameters for patients with treatment-naïve follicular lymphoma (FL) in the phase III RELEVANCE trial, comparing the immunomodulatory combination of lenalidomide and rituximab (R2) versus R-chemotherapy (R-chemo), with both regimens followed by R maintenance therapy. Baseline characteristics of the entire PET-evaluable population (n= 406/1032) were well balanced between treatment arms. The maximal standard uptake value (SUVmax) and the standardized maximal distance between tow lesions (SDmax) were extracted, the standardized distance between two lesions the furthest apart, were extracted. The total metabolic tumor volume (TMTV) was computed using the 41% SUVmax method. With a median follow-up of 6.5 years, the 6-year progression-free survival (PFS) was 57.8%, the median TMTV was 284 cm3, SUVmax was 11.3 and SDmax was 0.32 m-1, with no significant difference between arms. High TMTV (>510 cm3) and FLIPI were associated with an inferior PFS (P= 0.013 and P= 0.006, respectively), whereas SUVmax and SDmax were not (P= 0.08 and P= 0.12, respectively). In multivariable analysis, follicular lymphoma international prognostic index (FLIPI) and TMTV remained significantly associated with PFS (P= 0.0119 and P= 0.0379, respectively). These two adverse factors combined stratified the overall population into three risk groups: patients with no risk factors (40%), with one factor (44%), or with both (16%), with a 6-year PFS of 67.7%, 54.5%, and 41.0%, respectively. No significant interaction between treatment arms and TMTV or FLIPI (P=0.31 or P= 0.59, respectively) was observed. The high-risk group (high TMTV and FLIPI 3-5) had a similar PFS in both arms (P= 0.45) with a median PFS of 68.4% in the R-chemo arm versus 71.4% in the R2 arm. Baseline TMTV is predictive of PFS, independently of FLIPI, in patients with advanced FL even in the context of antibody maintenance.