Advanced Stage Follicular Lymphoma Research Articles

In the SARS-CoV-2 era, do we need to be afraid of obinutuzumab?

In their paper, Pinto etal. report findings from the Italian URBAN study; an ambispective, observational, multicentre study evaluating the safety and efficacy of obinutuzumab-based therapy for advanced stage follicular lymphoma (FL) in routine practice. The URBAN substudy reported here examined severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outcomes in 299 patients with treatment-naïve advanced stage FL, treated with obinutuzumab-based chemoimmunotherapy and maintenance. The study began enrolling in September 2019, continuing enrolment throughout the pandemic, with cut-off for the current analysis of 31 January 2022; thus, it provides unique insights into various pandemic phases, including the impact of administration of SARS-CoV-2 vaccination. Commentary on: Pinto etal. Exposure to obinutuzumab does not affect outcomes of SARS-CoV-2 infection in vaccinated patients with newly diagnosed advanced-stage follicular lymphoma. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19661.

Proteomic Profiling Identifies Predictive Signatures for Progression Risk in Patients with Advanced-Stage Follicular Lymphoma.

Background: Follicular lymphoma (FL) is characterized by an indolent nature and generally favorable prognosis, yet poses a particular clinical challenge, since disease progression is observed in a notable subset of patients. Currently, it is not possible to anticipate which patients will be at risk of progression, highlighting the need for reliable predictive biomarkers that can be detected early in the disease. Methods: We applied tandem-mass-tag labelled nano-liquid chromatography tandem mass spectrometry (nLC-MS/MS) on 48 diagnostic formalin-fixed, paraffin-embedded tumor samples from patients with advanced-stage FL. Of these, 17 experienced subsequent progression (subsequently-progressing, sp-FL) while 31 did not (non-progressing, np-FL). Results: We identified 99 proteins that were significantly differentially expressed between sp-FL samples and np-FL samples (p < 0.05; log2-fold changes between 0.2 and -1.3). Based on this subset of proteins, we classified patients into high-risk and low-risk subgroups using unsupervised machine learning techniques. Pathway analyses of the identified proteins revealed aberrancies within the immune system and cellular energy metabolism. In addition, two proteins were selected for immunohistochemical evaluation, namely stimulator of interferon genes 1 (STING1) and isocitrate dehydrogenase 2 (IDH2). Notably, IDH2 retained significantly lower expression levels in sp-FL samples compared with np-FL samples (p = 0.034). Low IDH2 expression correlated with shorter progression-free survival (PFS, p = 0.020). Conclusions: This study provides evidence for some of the biological mechanisms likely to be involved in FL progression and, importantly, identifies potential predictive biomarkers for improvement of risk stratification up-front at time of FL diagnosis.

Vaginal involvement as a rare extranodal manifestation in advanced-stage follicular lymphoma: a case report and literature review.

Apart from bone marrow involvement, extranodal involvement of follicular lymphoma (FL) is rare. Gynecologic FL is seldom reported, among which the vagina is the rarest involved site. No vaginal involvement in advanced-staged FL was reported before. Here, we report a case of FL with systemic involvement including the vagina.

Diagnosis, management and follow-up of follicular lymphoma: a consensus practice statement from the Australasian Lymphoma Alliance.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma subtype, accounting for 15-20% of all lymphoma diagnoses. Although typically slow-growing and responsive to frontline therapies, advanced-stage FL remains incurable with current treatments and typically follows a chronic relapsing/remitting course with increasingly shorter responses to subsequent lines of therapy. Outcomes are highly variable; some patients experience prolonged first remissions that may approximate a 'functional cure'. By contrast, a significant minority of patients experience disease progression shortly after frontline treatment resulting in high rates of lymphoma-related mortality. Reflecting on the heterogeneous natural history of FL, clinical practice varies widely, particularly in controversial areas, including appropriate disease staging, selection of management strategies and duration of clinical follow-up. This position statement presents an evidence-based synthesis of the literature for application in Australasian practice.

First-line treatment of follicular lymphoma (FL) with golcadamide, rituximab +/- nivolumab: An umbrella randomised phase 2 investigator-led study.

TPS7092 Background: The most common therapy FL pts receive remains chemotherapy which yields high efficacy but also significant toxicity.(Marcus 2017, Rummel 2013). FL pts are largely aged over 65 and may require treatment multiple times over their disease course thus novel regimens which enhance efficacy and minimise toxicity are highly desirable. FL patient (pt) outcomes are influenced by tumor microenvironment composition and manipulation with immunotherapy. Ikaros and Aiolos, key cell development and homeostasis transcription factors are upregulated in FL. Cereblon-modulating compounds (CELMoDs) such as golcadomide (G) promote degradation of these with demonstrated efficacy alone or with rituximab (R) in FL (responses-ORR- upto 75% in heavily pre-treated FL pts) (Morschhauser 2018, Michot 2021). We reported favourable efficacy of nivolumab (N) a PD1 inhibitor plus R in 1L treatment of FL (ORR 92% complete response CR 54%). (Hawkes 2021).This study (‘TOP-FLOR’; NCT05788081) builds on these findings and potential immunomodulatory synergy to explore the efficacy and safety of R + G, a novel CELMoD +/- N in treatment-naïve advanced stage FL pts. Methods: This is an open label multicentre umbrella Bayesian Optimal randomised Phase 2 trial (n=40). Eligibility includes: age &gt;18 years, treatment-naïve, stage II-IV, low grade FL, ECOG 0-2. Pts from 5 Australian sites are randomised 1:1 to receive 8 cycles of R-G +/-N 8 cycles of 28 days (D) each as follows: Arm A; R 375 mg/m2 IV D1 + G 0.4 mg orally D1- 14; Arm B; R-G as above +N 480mg IV D1. All pts in partial response (PR) or CR post cycle 8 receive 8 doses of 12-weekly R maintenance. The primary endpoint (EP) is CR rate post induction in the absence of prohibitive toxicity (CTCAE V5.0). Secondary EP are overall toxicity, ORR (as per Lugano criteria), time to treatment failure, progression free survival, overall survival. Exploratory EP include: pt reported outcomes, PET radiomics, laboratory biomarkers. Study assessments include safety assessments every cycle until D28 post final study drug delivery. Response assessments (PET/CT), pt reported outcomes &amp; biomarker bloods are performed at baseline, post cycles 2, 5 &amp; 8, then 6 monthly during R maintenance. Futility analysis occurs after 11 pts are recruited to each arm with &lt; 7 pts achieve the primary EP. Treatment arms will not be formally compared. Kaplan-Meier analysis will be used to report survival probabilities. This trial received IRB approval on 14 July 2023 (HREC/88597/Austin-2023). To date 15 pts have been randomised. Clinical trial information: NCT05788081 .

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.

Treatment of follicular lymphoma with a focus on radiotherapy

PurposeTo describe the overall treatment patterns of follicular lymphoma (FL) in a single tertiary institution, with a focus on the outcomes of radiotherapy treatment in this group of patients. Methods and materialsRetrospective analysis on 177 patients with FL registered from 1996 to 2011 and followed up to October 2017. Diagnosis was confirmed by histology and staging by clinical examination and imaging with positron emission tomography (PET) or computed tomography (CT) scan. Demographics, clinicopathological characteristics, treatment details and clinical outcomes were reviewed. ResultsFifty-five patients (31%) had early stage and 122 (69%) had advanced stage FL. Median follow-up was 7 years and 7.5 years for early and advanced FL respectively. For advanced stage, median overall survival (OS) was 12.9 years, 5-year and 10-year OS were 77% and 63%, and 5-year and 10-yr PFS were 57% and 40% respectively. In multivariable model, moderate FLIPI, palliative RT and anti-CD20 targeted therapy were significantly associated with OS when comparing with those with high FLIPI score, no RT and no anti-CD20 targeted therapy respectively. For early stage, median OS has not reached, 5-year and 10-year OS were 79% and 74% and 5-year and 10-year progression free survival (PFS) were 64% and 52% respectively. Stage 2 non-contiguous disease had significantly poorer survival than stage 1 patients in multivariable (HR 8.19, 95%CI 1.86 – 35.98) analysis. Overall, 49 of 177 patients (27.7%) had any form of radiotherapy as part of their treatment for FL. There were no in-field alone relapses seen in all cases treated with RT. 10% in early FL had G3-4 acute toxicities with RT whilst there was no G3-4 late toxicities. In advanced FL, there were no G3-4 acute toxicities with consolidation RT and 1 G3 with salvage RT. ConclusionFL has effective response rates to RT both in early and advanced FL. We demonstrated that: 1) stage 2 disease has poorer outcomes than stage 1 disease with stage 2 non-contiguous disease having the poorest outcomes, indicating the need for more aggressive treatment strategies for this group of patients; 2) there were no in-field alone relapses seen in all cases treated with RT; 3) overall, there is a general under-utilization of RT concurring with the literature. New prospective studies are therefore warranted to shed light on improving the utility of RT for patients with FL. With advances in molecular medicine, imaging and treatment approaches, there is potential for better stratification of different patient groups for more localized versus systemic treatments.

Phased Variants Allow Robust Profiling of Circulating Tumor DNA in Untreated Follicular Lymphomas

Background: In the absence of tumor tissue, several studies have shown the utility of plasma cell-free DNA (cfDNA) for blood based noninvasive genotyping of diverse human tumors, including aggressive lymphomas. However, it remains unclear whether these same cfDNA advantages also apply to follicular lymphoma (FL), and if they could inform noninvasive minimal residual disease (MRD) monitoring in the context of modern regimens inducing deep FL remissions. Here, we address these questions in previously untreated patients with FL receiving standard first-line (1L) therapy, using Phased Variant Enrichment and Detection Sequencing (PhasED-Seq, Kurtz et al 2021, Nat Biotech) to monitor ctDNA and MRD. Methods: We profiled 298 samples from 61 patients with FL, including archival formalin fixed paraffin embedded (FFPE) tumor tissues, and serial blood samples before, during, and following 1L therapy. All patients were treatment-naive, with most (75%) presenting with advanced stage FL. Induction regimens primarily comprised Bendamustine/Rituximab (66%) and R-CHOP (26%). At a median follow-up of 23 months from start of 1L therapy, 80% of patients were alive and progression free, while 11% experienced progression within 24 months (POD24). MRD was analyzed by PhasED-Seq (Foresight Diagnostics). Phased variants (PVs) were genotyped either using baseline blood plasma, or alternatively from FFPE tumor tissue; matched leukocytes were used as a source of constitutional DNA to censor germline variants and clonal hematopoiesis of indeterminate potential (CHIP). Baseline PV genotypes from each baseline source were then used to longitudinally assess MRD serially during 1L therapy. Blood timepoints included baseline (pre-treatment), Cycle 2 Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, at End of Induction (EOI), and serially thereafter. Levels of ctDNA were compared to known FL prognostic factors, including radiographic responses, POD24, and progression-free survival (PFS). Results: PVs were successfully identified from tumor FFPE samples in all patients (61/61), enabling ctDNA MRD assessment by PhasED-Seq. The median number of PVs identified was 530 (IQR 285-1152). Prior to therapy, ctDNA was detectable in 94% of cases (57/61). The median tumor fraction in baseline plasma was 0.28%, significantly lower than pretreatment ctDNA levels in diffuse large B-cell lymphoma (DLBCL) (DLBCL median = 6.1%, Roschewski, ASH 2022, P&amp;lt;0.0001 for FL vs DLBCL). Median pre-treatment ctDNA levels were significantly higher in advanced stage disease (stage I/II, 0.04%, stage III/IV, 0.53%, P=0.006), and correlated with FLIPI risk scores (P=0.04). We next tested whether adequate PVs can be directly identified from plasma without need for tumor tissue to allow MRD surveillance. Despite lower baseline ctDNA levels in FL, a sufficient number of PVs were identified directly in plasma to enable disease monitoring in 75% of cases (45/61). Moreover, ctDNA levels were highly correlated, regardless of the baseline sample used to identify PVs (i.e., tumor versus pretreatment plasma, Spearman rho=0.92, P&amp;lt;0.0001, Fig 1a). Despite high genotypic concordance of tumor vs plasma, we observed significant tumor heterogeneity across compartments with variable rates of concordance between specific mutated genes (Fig 1b). We next assessed the prognostic performance of ctDNA MRD to predict clinical outcomes. ctDNA levels prior to treatment were not significantly prognostic for time to progression. In contrast, in patients with ctDNA MRD assessed after two cycles of therapy (i.e., at C3D1), detection of residual ctDNA was significantly associated with inferior time to progression (log-rank P=0.03 HR = 8.9). Finally, we assessed the feasibility of serial ctDNA surveillance during radiographic remission. In patients with subsequent clinical relapse of disease, we detected reemergence of detectable MRD over two years prior to clinical disease progression. Conclusions: Circulating tumor DNA analysis with PhasED-Seq is feasible in FL, with baseline ctDNA levels significantly lower than those observed in DLBCL. In cases without tissue samples available, plasma DNA can frequently be used as a surrogate for tissue samples. ctDNA detection during treatment is strongly associated with eventual treatment responses, and serial disease surveillance with ctDNA can anticipate clinical relapse.

Evaluation of the m7-FLIPI in Patients with Follicular Lymphoma: FOXO1 Mutational Status May be a Predictive Marker of Early Progression and Long-Term Outcome

DISCUSSION In pts with follicular lymphoma (FL) who received chemoimmunotherapy (CIT) as first-line treatment, progression of disease within 24 months of diagnosis (POD24) was associated with increased risk of death (Casulo, 2015). A clinicogenetic risk model that includes the mutation status of 7 genes ( EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), FLIPI and ECOG, known as the m7-FLIPI, was shown to improve risk stratification in frontline pts with advanced stage FL treated with CIT (Pastore, 2015), as well as predict POD24 after first-line CIT (Jurinovic, 2016). With the hypothesis that there are distinguishing features in the mutational landscape between pts with FL who experience POD24 vs those who don't, we evaluated the prognostic utility of the m7-FLIPI and its components in a retrospective series. MSK-IMPACT Heme (Ptashkin, 2019) is a 468 targeted gene panel that includes the 7 genes required to calculate the m7-FLIPI. We identified all pts with FL, grade 1-3A, who had IMPACT testing, excluding pts with FL grade IIIB, mixed histology, or de novo transformation at diagnosis (n = 295). Three pts were excluded for inadequate clinical data (n = 292). The m7-FLIPI was calculated as previously described. Progression-free survival (PFS) was calculated from date of diagnosis till date of progression after first-line treatment, death, or censored at date of last follow-up. Overall survival (OS) was calculated from date of diagnosis till death or censored at date of last follow-up. Cox proportional hazard models were used to compare differences in survival and the Fisher's exact test for categorical variables in SAS 9.4. A cohort of 292 pts was analyzed. Genomic alterations were identified in the 7 genes . Median age of diagnosis was 57 years (range 26-92) with a slight male predominance (53%). The median follow-up was 5.2 years (95% CI, 4.6-5.7). Initial treatment included monoclonal antibody + chemotherapy (57%), single-agent rituximab (17%), chemotherapy (2%), radiotherapy alone (8%), and other treatments (5%). Thirty-four pts (12%) were never treated. Out of 292 pts, 86 (29%) were high-risk by FLIPI and 42 (14%) were high-risk m7-FLIPI. Forty-four out of 86 pts with high-risk FLIPI (51%) were reclassified as low-risk by the m7-FLIPI. High-risk FLIPI was associated with shorter PFS (HR 1.54, 95% CI 1.12 - 2.11, p = 0.0085) and OS (HR 3.73, 95% CI 1.74 - 7.98, p = 0.0007). High-risk m7-FLIPI was associated with shorter PFS (HR 1.55, 95% CI 1.05 - 2.28, p = 0.027) but not OS (HR 2.09, 95% CI 0.92 - 4.76, p = 0.08). C-statistics showed that m7-FLIPI did not outperform FLIPI alone as a prognostic tool for PFS (FLIPI c-statistic = 0.55, 95% CI 0.51 - 0.59; m7-FLIPI c-statistic = 0.53, 95% CI 0.50 - 0.56) or OS (FLIPI c-statistic = 0.68, 95% CI 0.58 - 0.78; m7-FLIPI c-statistic = 0.55, 95% CI 0.47 - 0.63). Mutations in ARID1A as a single factor were associated with shorter PFS (HR 1.52, 95% CI 1.01-2.29, p=0.047), but this association did not remain significant after adjusting for FLIPI and ECOG (HR 1.49, 95% CI 0.97-2.28, p=0.07). Mutations in FOXO1 were associated with shorter PFS (HR 1.48, 95% CI 1.00-2.19, p=0.049) and OS (HR 2.65, 95% CI 1.21-5.79, p=0.015) as a single factor. This association remained significant after adjusting for FLIPI and ECOG: PFS (HR 1.60, 95% CI 1.08-2.37, p=0.020) and OS (HR 2.65, 95% CI 1.21-5.83, p=0.015; Table 1). High-risk m7-FLIPI and FLIPI pts were not more significantly likely to experience POD24, OR 1.44, 95% CI 0.73-2.83, p=0.37 for m7-FLIPI and 1.48, 95% CI 0.87-2.51, p=0.17 for FLIPI. Pts with mutated FOXO1 were more likely to experience POD24, OR 2.47, 95% CI 1.29-4.71, p=0.008. The m7-FLIPI neither improved risk stratification compared to FLIPI nor did it predict POD24 in this series. Mutations in FOXO1 were associated with shorter PFS and OS independent of FLIPI and ECOG. Pts with mutated FOXO1 were enriched among those with POD24, suggesting that FOXO1 mutation may be a predictive marker for early failure of first-line treatment and death, including pts not fulfilling the POD24 criteria. Similar negative impact of FOXO1 was reported in a comprehensive genomic analysis of FL (Mozas, 2023). Both series are limited by patient numbers. Additional efforts to confirm this observation may be useful for understanding the mechanisms behind the prognostic effect of POD24 on survival and improving long-term outcome in this high-risk FL group.

EPCORE FL-1: Phase 3 Trial of Subcutaneous Epcoritamab with Rituximab and Lenalidomide (R 2) Vs R 2 Alone in Patients with Relapsed or Refractory Follicular Lymphoma

Background: Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma (NHL). Several treatment options are approved by the US Food and Drug Administration for second- or later-line FL therapy, including rituximab + lenalidomide (R 2). However, advanced-stage FL remains incurable and new treatment options for relapsed or refractory (R/R) disease are needed. Epcoritamab, a subcutaneously administered, bispecific antibody that binds CD3 on T lymphocytes and CD20 on B cells, induces potent and selective T-cell-mediated killing of malignant CD20 + B cells (van der Horst et al, Blood Cancer J 2021). In the first-in-human, phase 1/2 EPCORE NHL-1 trial (NCT03625037) in heavily pretreated patients with B-cell NHL (N=68), epcoritamab showed manageable safety and promising single-agent anti-tumor activity (Hutchings et al, Lancet 2021). Among 10 patients with R/R FL, objective response rate (ORR) was 90% (95% CI: 55-100) and complete response (CR) rate was 50%. In the ongoing phase 1b/2 trial evaluating epcoritamab + R 2 for R/R FL (EPCORE NHL-2 arms 2a and 2b; NCT04663347), ORR was 98% among 104 efficacy-evaluable patients, with a complete metabolic response in 87%. Most cytokine release syndrome (CRS) events were low grade (n=111; grade 1-2, 46%; grade 3, 2%) and occurred in cycle 1; all CRS events resolved with routine management. These encouraging data, and the distinct mechanisms of action of epcoritamab and R 2, support ongoing evaluation of this combination for its potential to improve clinical outcomes in patients with R/R FL. The phase 3 EPCORE FL-1 trial was designed to evaluate epcoritamab in combination with R 2 vs R 2 alone in patients with R/R FL with ≥1 prior line of anti-lymphoma therapy. We present an updated protocol, reflecting recent developments and revisions implemented in this study. Study Design and Methods: EPCORE FL-1 (NCT05409066) is a global, randomized, open-label, multicenter phase 3 trial designed to evaluate efficacy and safety of epcoritamab in combination with R 2 vs R 2 alone in patients with R/R FL. Adult patients must have histologically confirmed classic FL (previously grades 1 to 3a FL) stage II, III, or IV with a CD20 + tumor on a representative biopsy based on local pathology report and no evidence of histologic transformation. Patients must have R/R disease after ≥1 prior anti-lymphoma regimen that contained an anti-CD20 monoclonal antibody in combination with chemotherapy; patients receiving only prior anti-CD20 monoclonal antibody monotherapy and/or radiation are not eligible. Other key eligibility criteria include Eastern Cooperative Oncology Group performance status 0 to 2, fluorodeoxyglucose positron emission tomography-avid disease, and ≥1 measurable disease site per Lugano 2014 criteria. Lenalidomide-refractory FL (best response to lenalidomide of stable or progressive disease or progressive disease within 6 months of completion of lenalidomide) is excluded. Approximately 520 patients will be enrolled and randomized 1:1 to receive a full dose of epcoritamab in combination with R 2 or R 2 alone ( Figure); the trial is currently enrolling in 2 arms, Arms A &amp; C. Based on emerging safety and efficacy data, Arm B has been closed to enrollment and the recommended dose of epcoritamab in combination with R 2 is 48 mg. Epcoritamab will be subcutaneously administered using a step-up dosing regimen to full dose in cycle 1 (28 days/cycle). Full dose of epcoritamab will be administered weekly in cycles 2-3 and monthly from cycle 4 onward for up to 12 cycles of treatment. Patients will be serially assessed for disease progression at prespecified intervals. The primary endpoint is progression-free survival assessed by independent review committee (IRC) per Lugano criteria. Key secondary efficacy endpoints include CR rate (by IRC per Lugano criteria), overall survival, and minimal residual disease negativity. Other efficacy endpoints include best overall response, duration of response, duration of complete response, time to progression, event-free survival, time to next anti-lymphoma treatment, and patient-reported outcomes. Safety endpoints include incidence and severity of treatment-emergent adverse events and adverse events of special interest. Exploratory endpoints include assessments of pharmacodynamic and pharmacokinetic data. The study opened for enrollment in 2022 in North America, South America, Europe, Africa, Asia, and Australia.

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.

Minimal Residual Disease (MRD) Status Predicts Outcomes in Patients with Follicular Lymphoma (FL) Treated with Chemo-Immunotherapy on SWOG S0016

Background. FL is associated with a heterogeneous clinical course, and currently available prognostic indicators are unable to reliably separate patients who exhibit early therapy resistance (POD24, defined as progression within 24 months from diagnosis) from those who achieve “functional cure” following initial therapy. NGS methods developed in recent years enabled quantification of MRD. The ClonoSeq assay (Adaptive Biotechnology, Inc.) has been FDA-cleared to track MRD in several hematologic malignancies. Here we demonstrate that MRD analysis by ClonoSeq assay predicts outcomes in a prospective cohort of patients with advanced stage FL enrolled on SWOG S0016 clinical trial. Methods. SWOG S0016 was a phase III randomized study that compared the safety and efficacy of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with CHOP-RIT (CHOP + I 133-tositumomab) in patients with FL. Between 2001 and 2008, 531 patients with previously untreated advanced-stage FL (bulky stage II, III-IV) of any pathologic grade were randomly assigned to receive 6 cycles of R-CHOP or CHOP-RIT. We used high-throughput sequencing (HTS) of the IGH and IGK/L loci (ClonoSeq assay) from tumor biopsy specimenstaken prior to treatment to define CDR3 rearrangements that tag the tumor. Subsequently, 1-year bone marrow specimens were screened for residual disease. The baseline dominant clone was defined as ≥10 estimated number of genomes (ENG) and comprised ≥5% of the library. MRD-positive state (MRDp) was defined as a minimum Hamming distance (HD) ≤6 in a patient's post-library (in any clone also detected in a pre-library) and conserved pre-existing SHM (if HD&amp;gt;0). Undetectable MRD (MRDu, at &amp;lt;10 -4) was defined as CRD3 HD&amp;gt;6 in a post-library with a depth &amp;gt;10,000 ENG. Five-year progression-free survival was the primary endpoint (PFS; defined as the time from registration to the first observation of progression or death due to any cause). Landmark analysis was defined at 1 year after registration and used for imputing the 5-year PFS and OS. Overall survival (OS) was defined as the time from registration to date of death due to any cause or last follow-up. PFS and OS estimates and 95% confidence interval were calculated using the Kaplan-Meier method and compared for MRDp and MRDu disease using two-sided log-rank test. HR and 95% CI were calculated using Cox regression model. Results. Tumor biopsy tissue was available for 189 patients. Of these, 24 patients were not evaluable (16 did not consent for banking, 6 were ineligible and 4 had an early event). In 36 patients, pre-libraries did not yield a trackable clone. In total, MRD status could not be ascertained in 47 patients due to absence of a clear trackable clone in either pre- or post-library, contributing to a 28.8% failure rate. Of 116 patients which yielded a trackable clone in both libraries, 83 were MRDu and 33 were MRDp. Baseline characteristics (age, sex, race, β2M, B symptoms, bulky disease, grade 3, stage, and FLIPI risk) were similar between MRDp and MRDu patients; however, MRDp patients were more likely to exhibit morphologic baseline bone marrow involvement by FL (82% vs. 55%, p=0.01). The estimated 5-year PFS was 72% in MRDu patients and 30% in MRD+ patients (Figure); 10-year PFS was 56% and 17%, correspondingly. Meanwhile, 5-year OS was not different (96% for MRDu, 81% for MRD+, p=0.91). Patients with MRDu had a significantly higher best overall response rate than MRDp patients (96% vs 79%, p=0.005), but complete response (CR) rates were similar (41% vs. 30.3%). Patients who received CHOP-RIT had better PFS regardless of MRD status (HR=0.48, p=0.01 for MRDu; HR=0.38, p=0.02 for MRDp), while OS was not statistically different. Five-year PFS was superior in patients who achieved MRDu (75% for CR and 70% for PR) compared with MRDp patients, regardless of response (34%). Patients who had MRDp status had a significantly increased risk of experiencing POD24 relative to MRDu patients (RR=6.5, 95% CI 3.0-14.0; p&amp;lt;0.0001). Conclusion. Here we for the first time demonstrate that MRDu status, as assessed by Clonoseq, predicts improved 5- and 10-year PFS in patients with FL initially treated with chemoimmunotherapy. MRD+ status in the bone marrow at a 1-year timepoint was associated with POD24. Despite a relatively high failure rate to detect trackable sequences using current technology (~29%), MRD assessment by NGS is a promising prognostic tool in FL. *co-senior authors

Trial in Progress: Treatment of Newly-Diagnosed Follicular Lymphoma with Celmod BMS-986369, Rituximab +/- Nivolumab: An Umbrella Phase II Investigator-Initiated Study

Background: Follicular lymphoma (FL) outcomes are influenced by tumour microenvironment composition and manipulation. As patients (pts) with FL are predominantely aged over 65 and may require treatment multiple times over their disease course, novel regimens which maintain or enhance efficacy and minimise toxicity are highly desirable. We have previously reported favourable efficacy and safety of nivolumab plus rituximab as a 1 st line treatment in advanced-stage, grade 1-3A treatment naïve FL, (ORR 92%; CR 54%; toxicity grade 3 or higher in 41%) in an investigator-led trial. 1-3 Oral cereblon-modulating (CELMoD) compounds have shown substantial efficacy alone or in combination with rituximab in both treatment naive and relapsed/refractory FL. 4,5 CELMoDs co-opt cereblon to promote degradation of key transcription factors in cell development and homeostasis, including Ikaros and Aiolos, which are upregulated in FL. 6 Additionally, they act as immunomodulatory agents and augment immune host response. The novel CELMoD, BMS-986369 (golcadomide), demonstrated enhanced antiproliferative and apoptotic activity in pre-clinical studies, with ORR of up to 75% following monotherapy doses of 0.4mg or higher in heavily pre-treated FL pts. 7-10 Our follow-on study (‘TOP-FLOR’; NCT05788081) builds on these findings and potential immunomodulatory synergy to explore the efficacy and safety of BMS-986369 with rituximab +/-nivolumab in treatment-naïve advanced stage FL pts. Study Design and methods: This is an open label multicentre umbrella Bayesian Optimal randomised Phase II trial. The study will randomise up to 40 eligible pts 1:1 to receive rituximab, BMS986369 +/- nivolumab (20 per arm) from 5 Australian sites. Eligibility includes pts aged &amp;gt;18 years, with previously-untreated, stage II-IV, grade 1-3A FL with performance status of 0-1 who require systemic therapy. Treatment consists of 8 cycles (28 days each) of BMS-986369 0.4 mg po daily on days 1- 14 plus rituximab 375 mg/m2 IV day 1 in Arm A; BMS-986369, rituximab as above plus nivolumab 480mg IV day 1 in Arm B. All pts in partial or complete response at end of induction receive 12-weekly rituximab maintenance (8 doses). The primary endpoint will be CR rate in the absence of prohibitive toxicity in accordance with CTCAE V5.0 after eight cycles of rituximab, BMS-986369 +/-nivolumab. Secondary endpoints include: Overall toxicity, response rate (according to modified Lugano criteria), time to treatment failure, progression-free survival and overall survival. Exploratory endpoints include: pt reported outcomes as measured by EORTC-QLQ-c30 and FACT-Lym, PET radiomics and tissue, blood and stool immune and genomic biomarkers. Study assessments include: PET/CT, biomarker blood collection and pt reported outcome measures performed at baseline, post cycle 2, 5 and 8, then 6 monthly on maintenance therapy. Response assessment according to modified Lugano criteria. Safety assessments prior to each cycle until 28 days after the final study drug is administered using CTCAEv5.0. Interim assessment of the primary endpoint will be conducted for 11 pts in each arm, arms will be closed for futility if fewer than 7 pts achieve the primary endpoint. Treatment arms will not be formally compared. Survival probabilities will be reported using Kaplan-Meier analysis. Status: This trial received IRB approval on 14 July 2023 (HREC/88597/Austin-2023) at Austin Health, Heidelberg, Australia. Funding: This trial is supported by an investigator-sponsored research grant from Bristol-Myers Squibb. Nivolumab and BMS 989369 supplied by Bristol-Myers Squibb.

Safety and Efficacy of Parsaclisib in Combination with Rituximab in Patients with Previously Untreated Indolent B-Cell Lymphoma: Primary Analysis from a Phase 2 Study (REPLY)

Background: Advanced-stage follicular lymphoma (FL) and marginal zone lymphoma (MZL) represent incurable indolent B-cell lymphomas and perplex elders mainly. Chemoimmunotherapy can induce durable remissions; however, the side effects of chemotherapy remain a major source of concern for patients. Parsaclisib, a next-generation PI3K inhibitor, has demonstrated significant clinical activity in refractory or relapsed indolent B-cell lymphomas, including FL and MZL. This study investigated the efficacy and safety of a chemo-free regimen in patients with FL and MZL tumors. Here, we present preliminary results from a response-adapted study utilizing parsaclisib and rituximab as frontline therapy for FL and MZL (NCT05073250). Methods: Eligible patients aged ≥18 years with previously untreated indolent B-cell non-Hodgkin lymphoma (NHL) of either FL grade 1-3a or MZL and stage III-IV disease (Patients with stage I-II FL and MZL who have received radiation therapy and subsequently relapsed were also eligible) were included in the study. Patients with active HIV, CMV, Hepatitis B or C infections, and autoimmune conditions requiring therapy were excluded. Patients received 6 28-day cycles of parsaclisib at a daily dose of 20mg during the first two cycles, followed by a reduced dose of 2.5mg daily for the subsequent four cycles; rituximab was administered at 375mg/m 2 weekly for 4 weeks, and then on day 1 of each cycle. All patients received PCP prophylaxis. Baseline FDG-PET and CT scans were performed, and additional scans were conducted after cycles 3 and 6 to assess treatment response. Patients achieving complete response (CR) after the 6 cycles discontinued therapy, while patients with partial response (PR) received another 6 cycles of the combination therapy. Non-responding patients were offered standard chemotherapy. The primary endpoint of the study is the overall rate of complete response (CR), with secondary endpoints including safety, objective response rate (ORR), duration of CR, and progression-free survival (PFS). Results: As of the data cut-off on July 20, 10 patients were enrolled, with a median follow-up time of 10.2 months, and 7 patients were eligible for response evaluation. The median age of patients was 47 years (range 35-52), and three were older than 60. Fifty percent (5/10) of the patients were Follicular Lymphoma (FL), while the remaining 50% were the extra-nodal MZL of mucosa-associated lymphoid tissue. Three patients had bone marrow involvement, and one had C-MYC/BCL-2 double expression. The Complete Response (CR) rate was 71.4%, with the FL cohort showing a CR rate of 75% (3/4) and the MZL cohort showing a CR rate of 66.7% (2/3). The Overall Response Rate (ORR) was 85.7% (6/7, with 3 cases in FL and 3 cases in MZL). The median duration of CR was 3.9 months (range 0.6-7.7), and the median Progression-Free Survival (PFS) was not reached. Five patients are still receiving treatment, two patients who completed treatment were followed up and remained in sustained complete remission. Among the 10 treated patients, treatment-emergent adverse events (TEAEs) occurred in 60% (n=6), and no serious adverse events (SAEs) were observed. The most common TEAEs were infusion reaction (40%, rituximab-related), neutropenia (30%), anemia (30%), and total cholesterol elevation (30%). Only one patient experienced grade 3 neutropenia, no grade 4-5 TEAEs occurred. Two patients experienced delayed medication due to COVID-19 infection. Conclusion: The combination of parsaclisib with rituximab showed a deep and durable response, with a favorable safety profile and generally good tolerability in patients with previously untreated indolent B-Cell Lymphoma.

Obinutuzumab, Lenalidomide and Venetoclax in Patients with Treatment-Naïve Advanced-Stage Follicular Lymphoma: First Results of the Investigator-Initiated Phase Ib/II, Multicenter Leverage Study

Background Follicular lymphoma (FL) is the most common indolent lymphoma. The most widely used initial treatment is chemo-immunotherapy, however conventional cytotoxic agents may result in acute and late toxicities which can be problematic. There is a need for active novel treatment approaches with more favorable safety profiles. Methods We designed a phase Ib/II study of obinutuzumab, lenalidomide and venetoclax in patients with treatment-naïve follicular lymphoma. Key inclusion criteria included non-contiguous or bulky stage II-IV disease, meeting GELF criteria for treatment, adequate organ function and performance status. Treatment was divided into 2 phases, induction (6 x 28-day cycles) and maintenance (12 x 56-day cycles). During induction, patients received fixed doses of obinutuzumab (1000mg D1, 8, 15 cycle 1; D1 of C2-6) and lenalidomide 20mg days 1-21 from C2-6. Venetoclax was given from C1-6 and the dose was escalated, according to a 3+3 design with 4 dose levels (DL) tested: DL 1: 400mg daily D1-10, DL 2: 800mg D1-10, DL 3: 400mg D1-28 and DL 4: 800mg D1-28. After 6 cycles, patients who attained complete response (CR) received obinutuzumab maintenance (1000mg every 8 weeks for 2 years). Patients who attained partial response received a further 6 cycles of lenalidomide (10mg D1-28) and venetoclax (at the same dose given in induction) in addition to the obinutuzumab maintenance. Patients who experienced SD discontinued study in favour of alternate therapy. The primary endpoint of phase Ib was recommended phase II dose (RP2D). The primary endpoint of phase II was intention to treat CR rate by investigator assessment at end of induction by Lugano 2014. Key secondary endpoints included safety, objective response rate (ORR), progression free survival (PFS), overall survival and quality of life. This interim analysis focuses on the RP2D, safety and preliminary efficacy data. Results As of 13 Mar 2023, 36 patients have been enrolled of whom 26 completed end of induction phase and are included in this interim analysis. Eighteen patients were treated in dose escalation (3, 6, 3 and 6 at dose levels 1-4, respectively) and 18 in expansion phase. The baseline characteristics are summarized in Table 1. The median relative dose intensity was &amp;gt;90% for all 3 agents. One dose limiting toxicity (DLT) occurred (grade 3 ALT elevation possibly related to venetoclax on C1D1, which resolved within 48 hours) and no maximum tolerated dose was reached. Dose level 4 (venetoclax 800mg daily D1-28) was the RP2D. The only grade≥3 AEs to occur in more than two patients were neutropenia (65%), without febrile neutropenia. The most common any grade AEs were nausea (50%), diarrhea (46%), maculopapular rash (31%), thrombocytopenia (27%), fatigue (23%) and constipation (23%). One patient developed biochemical TLS. 7 patients prematurely discontinued study treatment due to progressive disease (PD) in 2, and 1 case of each DLT, COVID-19, grade≥3 cytopenias lasting &amp;gt;28 days, upper respiratory infection and development of a second malignancy requiring systemic therapy. At the end of induction, the CR and ORR were 81% and 92%, respectively. The 2 PD events were both found at the end of induction restaging, and biopsy revealed histologic transformation to diffuse large B-cell lymphoma. Updated data (including PFS) will be presented at the meeting. Conclusion The combination of obinutuzumab, lenalidomide and venetoclax is a highly active and safe combination in patients with treatment-naïve high tumor burden FL. No unexpected safety signals were identified. Enrolment to phase II is ongoing at 4 Australian sites. This trial is registered at clinicaltrials.gov (NCT03980171)

Time to Lymphoma Treatment within 24 Months in Watchful Waiting Follicular Lymphoma Defines Patients at High Risk for Progression: A Multicenter Analysis

Purpose Follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease, watch and wait (W&amp;W) remains a management therapeutic option in patients with advanced-stage, low-tumor-burden and asymptomatic FL in the rituximab era. We continue to use Groupe d'Etudes des Lymphomes Folliculaires criteria for active disease to initiate therapy. We sought to understand whether time to lymphoma treatment (TLT) after diagnosis in patients who managed by W&amp;W was a factor affecting survival outcomes in FL. Patients and Methods Between 2008 and 2022, 411 FL patients from 16 institutions in China were managed by W&amp;W strategy, and their TLT was retrospectively evaluated. Patients were further divided into training and validation Cohorts. Logistic regression was used to identify and incorporate independent predictors of early TLT into a model with variable scoring. Model performance was evaluated through the area under the receiver operating characteristic curve (AUC) and goodness-of-fit statistics. Results After a median follow-up of 46 months, 35 percent of W&amp;W patients experience TLT within 24 months (TLT24) after diagnosis, and the 5-year progression free survival (PFS) rate was significantly lower than that of patients who were treatment-free at 24 months (62.3% vs. 89.5%). In multivariable analysis, five clinical factors were identified as independent predictors of TLT24: stage III-IV, β 2 microglobulin ≥ 3mg/L, lymphocyte-to-monocyte ratio＜3.8, bone marrow involved and spleen enlargement. We calculated risk scores (TLT24PI) for each patient and defined three risk groups: low (0-1 points), intermediate (2 points), or high (3-5 points). Its AUC for TLT24 was 0.761 (95% CI, 0.698 - 0.823) in the development cohort and 0.761 (95% CI, 0.698 - 0.823) in the validation cohort. Risk groups were also associated with PFS ( P&amp;lt;0.001). Conclusion In patients with FL who initially managed by W&amp;W, TLT within 24 months after diagnosis was associated with poor outcomes. We developed a multivariable model that incorporates clinical and laboratory factors to identify patients at high risk for TLT24, which may be useful to identify candidates for early interventional treatment.

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.

Recent Updates on Diagnosis and Treatment of Follicular Lymphoma

Follicular lymphoma (FL) is the third most common subtype of non-Hodgkin lymphoma in Korea. Patients with FL generally present with asymptomatic lymphadenopathy, which may wax and wane for years and have indolent disease course. Most patients with FL have advanced-stage disease at diagnosis and less than 20% of patients with FL have stage I/II disease. Radiation therapy is generally accepted with the treatment of choice for limited-stage FL and results in 60-80% of 10-year overall survival rates. Patients with advanced-stage FL do not require an immediate treatment unless they have symptomatic disease, compromised end organ function, B symptoms, or cytopenia. The initial treatment of advanced-stage FL recommends rituximab-containing immunochemotherapy followed by 2 years of maintenance with rituximab, or bendamustine plus rituximab is a preferred choice because of superior progression-free survival with less toxicity than other rituximab-containing immunochemotherapy. For patients with relapsed or refractory FL, there are many options ranging from anti-CD20 monoclonal antibody alone to a combination with lenalidomide and chemotherapy or autologous stem cell transplantation. In addition, the novel approaches for relapsed or refractory FL have been applied with phosphoinositide 3-kinase inhibitor, Bruton’s tyrosine kinase inhibitor, enhancer of zeste homolog 2 inhibitor, anti-CD19 chimeric antigen receptor T-cell therapy and bispecific antibodies.