Therapy For Follicular Lymphoma Research Articles

In pursuit of a functional cure for follicular lymphoma.

We are now a quarter of a century after the transformative impact of rituximab in improving overall survival for patients with follicular lymphoma. With a burgeoning array of effective immunochemotherapy approaches, we can now frame many patients' expectations of longevity and a "functional cure," with survival estimates for many newly diagnosed patients comparable to age- and gender-matched populations. We highlight not just heterogeneity in disease but also in patients, which influences therapeutic decision-making in an immunochemotherapy era where progression-free survival advances are associated with efficacy-toxicity trade-offs, and no clear overall survival advantage is associated with any specific regimen. We provide the metrics that assist, prognostication both at diagnosis and after initial therapy, but we also highlight the limited long-term follow-up in institutional, population, and clinical trial data sets to inform our survival estimates. Nonetheless, the data are sufficient to empower us to reframe more optimistic conversations with our patients and the lymphoma community, discussions that engender hope and planning for a life lived long, and well, after therapy for follicular lymphoma.

Comparative Analysis of Bispecific Antibodies and CAR T-Cell Therapy in Follicular Lymphoma.

The treatment landscape for relapsed/refractory follicular lymphoma (RR-FL) is marked by a pivotal debate between chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies (BsAbs). While both CAR-T therapy and BsAbs target similar immunobiology and molecular markers, their efficacy comparisons are hindered by the lack of direct clinical trial comparisons. Key trials, such as the ZUMA-5 study, underscore axicabtagene ciloleucel (axi-cel)'s efficacy in treating RR-FL, achieving a 79% complete response rate with a median duration of response exceeding 3 years. Similarly, lisocabtagene maraleucel (liso-cel) in the TRANSCEND FL study reports a 94% complete response rate, emphasizing robust outcomes in heavily pretreated patients. Among BsAbs, mosunetuzumab showed promise in the GO29781 trial, with a 62% overall response rate in heavily pretreated RR-FL patients. Thus, CAR-T therapy offers potential curative benefits with a single infusion. However, its efficacy is tempered by significant adverse events such as cytokine release syndrome (CRS), neurotoxicity, and cytopenias, requiring specialized management and patient monitoring. In contrast, BsAbs provide a more tolerable treatment option counterbalancing by lower response rates and frequent dosing requirements. Personalized treatment strategies are crucial because of these distinct efficacy and safety profiles. When considering cost-effectiveness, both therapies need to be evaluated in the context of their clinical outcomes and quality of life improvements. Cost-effectiveness considerations are essential; while CAR-T therapies incur higher initial costs, their potential for long-term remission may mitigate expenses associated with repeated treatments or hospitalizations. Future research into resistance mechanisms and optimal therapeutic sequencing will further refine RR-FL management strategies.

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

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

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

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

Results from the follicular lymphoma (FL) outcomes in patients (pts) with relapsed/refractory (R/R) disease treated with systemic therapy in a real-world assessment (FLORA) study.

7076 Background: Odronextamab, an off-the-shelf CD20×CD3 bispecific antibody, has shown compelling efficacy (objective response rate [ORR] 80%, complete response [CR] rate 73%) and a generally manageable safety profile in pts with heavily pretreated R/R FL in the single-arm ELM-2 trial (NCT03888105; Villasboas, et al. ASH 2023). We evaluated outcomes in pts with R/R FL treated with currently available third-line or later (3L+) therapies in a real-world setting (FLORA; NCT05338879) to better evaluate the results from ELM-2 in the absence of a randomized control arm. This is the first real-world study in 3L+ FL that evaluated scans from 100% of the cohort. Methods: FLORA is a multicenter, retrospective, observational study, using electronic medical record or research databases, of pts with R/R FL who have received ≥2 prior lines of therapy (LoTs; including an anti-CD20 and an alkylator) and initiated 3L+ systemic therapy for FL between January 1, 2015 and December 31, 2020. After applying similar eligibility criteria to those in the ELM-2 trial, inverse-probability of treatment weighting (IPTW) was used to balance key prognostic characteristics between the trial and the real-world cohorts. Pts were followed from the start of qualifying LoT until death, end of study (December 31, 2021), or lost to follow-up, whichever occurred first. The primary endpoint was ORR assessed by independent central review (ICR). Secondary endpoints included ICR-assessed CR rate, disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS) (see Bachy, et al. ASH 2022). Results: Pts in FLORA (N=100) generally had less severe disease than trial pts prior to IPTW. The most commonly used regimens were chemotherapy + anti-CD20, chemotherapy alone, and anti-CD20 + immunomodulatory agent. The IPTW cohort had a median age of 61 y, 59% POD24, 56% high FLIPI, 60% chemo-immuno refractory, 73% refractory to last LoT, and median (range) prior LoT: 3 (2–8). In the IPTW cohort, ORR was 52%, CR 31%, and DCR 62%. Median PFS (mPFS) was 11.5 mo, median OS was 26.1 mo, and median DOR (mDOR; responders in IPTW cohort: n=54) was 28.2 mo. Given the lack of regular scans in routine practice (37% of responders did not have any subsequent ICR assessment after CR/PR), sensitivity analysis that considered subsequent treatment as a progression event resulted in shorter mDOR (8.1 mo) and mPFS (7.2 mo). Conclusions: Pts in the FLORA study had markedly lower response rates than those in the R/R FL cohort of ELM-2. This study also showed that most pts still received an anti-CD20–based regimen in 3L+ in routine practice, highlighting the need for treatment options with different mechanisms of action that provide deep and durable responses and improve outcomes in this pt population. Clinical trial information: NCT05338879 .

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.

Фолликулярная лимфома 1–3А цитологического типа с наличием или отсутствием t(14;18)(q32;q21): прогноз, выбор противоопухолевой терапии и ее результаты

Aim. To determine the prognostic value of t(14;18)(q32;q21) in follicular lymphoma (FL) of grades 1–3А, to assess the chemotherapy efficacy in “t(14;18)+ FL” and “t(14;18)– FL” patients, and to analyze the cases of ineffective therapy.
 Materials & Methods. The retrospective/prospective study carried out at the National Research Center for Hematology in the period of 2001–2022 enrolled 362 patients with newly diagnosed FL of grades 1–3А. Their risk stratification was based on predictive models FLIPI and PPI3 (Personalized Predictive Index[1]). The patients were 30–81 years of age (median 52 years). There were 225 women and 137 men. They received the following regimens: R-B (n = 80), R-CHOP (n = 189), R-CHOP (4 cycles) + R-DHAP (2 cycles) (n = 28), and R-CHOP (4 cycles) + R-DHAP (2 cycles) + auto-HSCT in the first-line therapy (n = 65). For 2 years, maintenance rituximab therapy was administered to all the enrolled patients, whichever drug chemotherapy they received. Standard cytogenetic analysis and FISH were carried out in 265/362 (73 %) patients.
 Results. Patients were divided into two comparable groups: “t(14;18)+ FL” (n = 196) and “t(14;18)– FL” (n = 69). Patients without cytogenetics/FISH (n = 97) were excluded from the analysis. In patients without t(14;18), poor prognostic factors, such as grade 3А (p = 0.003) and Ki-67 > 35 % (p = 0.001), were identified significantly more often, and also high PPI3 risk was reported (p = 0.008). No differences (p = 0.84) were detected during FLIPI risk stratification of patients. Bone marrow lesions were observed significantly more often in “t(14;18)+ FL” compared to “t(14;18)– FL” (p = 0.002). The chemotherapy outcomes, such as 2-year EFS and OS, appeared to be considerably worse in “t(14;18)– FL” compared to “t(14;18)+ FL” patients.
 Conclusion. The group of FL patients with t(14;18) appeared to be most numerous and more prognostically favorable. Immunochemotherapy regimens R-B and R-CHOP are more justified in the first-line therapy of FL with low PPI3 risk. Therapy outcomes were comparable in efficacy. In intermediate and high PPI3 risk FL patients with t(14;18), the most effective first-line therapy was the one with consistent administration of R-CHOP, R-DHAP, and auto-HSCT. Based on the results of this study, FL of grades 1–3А without t(14;18) can well be considered to be a prognostically unfavorable variant of this malignant lymphoid tumor. The rate of early relapses/progression after the standard immunochemotherapy (R-B and R-CHOP), according to our data, is 60 %. In patients with newly diagnosed FL who received consistent administration of R-CHOP, R-DHAP, and auto-HSCT in the first-line therapy, this rate drops to 30 %. Our results clearly indicate the need for new FL treatment approaches.

Unraveling the complexity of follicular lymphoma: insights and innovations.

This review discusses multiple aspects of follicular lymphoma (FL), including etiology, treatment challenges, and future perspectives. First, we delve into the etiology of FL, which involves a variety of pathogenic mechanisms such as gene mutations, chromosomal abnormalities, immune escape, immune system dysregulation, familial inheritance, and environmental factors. These mechanisms provide the context for understanding the diversity and complexity of FL. Second, we discuss the challenges faced when treating FL, particularly treatment resistance. Therapeutic resistance is a common problem in treatment, but by delving into the mechanisms of resistance, scientists have looked for strategies to combat it, including developing new drugs, improving treatments, and exploring combination therapy strategies. We also emphasize the breakthroughs in molecular biology, especially the study of targeting the BCL2 gene, which provides a new direction for targeted therapy in FL. Immunotherapy, small molecule targeted drugs, and individualized treatment strategies are also promising for the future treatment of FL. Finally, we look to the future, including research on therapeutic resistance, in-depth studies of genetics and gene expression, applications of gene editing and precision medicine, and clinical trials of new treatments. These lines of research offer additional opportunities for treating FL, and despite the challenges, the future is promising. This literature review provides comprehensive and integrated information for the in-depth understanding of FL and relevant treatment approaches.

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 & 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.

High-dose chemotherapy with transplantation of autologous hematopoietic stem cells in the first line of follicular lymphoma therapy

Introduction. The follicular lymphoma (FL) is the most common indolent lymphatic tumor with high sensitivity to immunochemotherapy un most cases. Although overall survival (OS) is generally long, the disease is characterized by multiple relapses. High-dose chemotherapy (HDCT) with transplantation of autologous hematopoietic stem cells (auto-HSCT) is used for recurrent FL. Aim: to evaluate the efficacy and safety of HDCT with aHSCT in the first line of FL therapy; identify risk factors for disease progression and refractoriness. Material and methods. A prospective single-center study (conducted from May 2015 to January 2023) included 35 patients aged 18–65 years (median 43) with PL 1–3A grade t(14;18)+ with stages III–IV or stage II with bulky, having at least one criterion for the need to start therapy (according to GELF). Patients were treated according to the FL-2015 protocol: 4 R-CHOP, 2 R-DHAP and BeEAM with auto-HSCT. The primary endpoint was the rate of overall response (OR) and/or complete remission (CR) at the end of chemotherapy. Secondary end points were 3-year survival rates: OS, relapse-free survival (RFS), progression-free survival (PFS), and event-free survival (EFS). Minimal residual disease (MRD) in blood and/or bone marrow was assessed by PCR based on immunoglobulin heavy chain (IGH) gene rearrangements and/or BCL2::IGH rearrangements. Statistical analysis (by intent to treat) was performed on January 12, 2023. Results. 86 % of patients had stage IV tumor and 79 % had 3–5 FLIPI factors. After the end of treatment, OR and PR were 90 % and 90 %, the incidence of POD24 was 3 %. After the end of induction (4 courses of R-CHOP), MRD-negativity was achieved in 77 % and 53 % of patients as determined by PCR-IGH and BCL2::IGH. After the full completion of the FL-2015 protocol, MRD was not detected in 96 % of patients (according to PCR-IGH). Three-year overall survival, disease-free survival, progression-free survival and event-free survival were respectively: 90 %, 90 %, 95 % and 85 % (with the same standarderror of 9 %) at a median follow-up (by inverse Kaplan-Meier estimate) of 19 months (range: from 1 to 91 months) There were no deaths due to early toxicity within 100 days of auto-HSCT. Prognostically unfavorable independent statistically significant (р < 0.01; Wald test; hazard ratio > 1) predictors of progression and refractoriness according to the results of multivariate analysis using the Fine-Grey competing risk model (р = 0.052 for the model) were: bone marrow disease, ECOG high risk, patient age > 50 years, stage 4 disease, elevated serum lactate dehydrogenase and B-symptoms. Conclusion. The use of HDCT with auto-HSCT in the first line in patients with FL is highly effective and can significantly reduce the incidence of POD24 and early mortality from the tumor. The study is ongoing.

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.

Real-World Patterns of Care and Financial Burden of Patients with Follicular Lymphoma in the United States

Introduction: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma and accounts for nearly a quarter of cases. As a heterogenous disease with an estimated 20% having progression of disease within 24 months of first FL therapy, FL often quickly becomes relapsed or refractory (R/R) to current therapy. The objective of this study was to evaluate the real-world treatment patterns, time to next treatment, and associated costs and healthcare resource utilization (HCRU) in patients with FL in the United States. Methods: A retrospective observational study was conducted using an integrated real-world database including linked data from the Symphony Integrated Dataverse (IDV ®), electronic medical records, specialty pharmacy, and in-office dispensing datasets. Patients were included in the study if they were ≥ 18 years old and initiated a first-line (1L), second-line (2L), third-line (3L), or fourth-line (4L) of therapy for FL between 1/1/2019 and 12/31/2022. Patients were categorized by line of therapy into non-mutually exclusive cohorts based on the date of initiation of their treatment regimen. Each line of therapy cohort was followed for a minimum of 90 days through lost to follow-up or end of the study period (3/31/2023). Patients were also required to have continuous pre-index enrollment of 365 days to record baseline comorbidities. Demographics, clinical characteristics, and treatment regimens were examined for each line of therapy cohort. Within each line of therapy, patients were categorized into 6 mutually exclusive subgroups based on their treatment regimens: bendamustine + rituximab (BR), rituximab monotherapy (R-mono), cyclophosphamide, doxorubicin, prednisone, rituximab + vincristine (R-CHOP), bendamustine + obinutuzumab (BO), lenalidomide + rituximab (R2), and other treatments for all other regimens. Advancement to the next line of therapy, treatment regimen distribution, and switching for each cohort and subgroup were evaluated during the follow-up period. Treatment duration, time to next treatment (TTNT), HCRU and pharmacy costs were measured for each cohort and treatment regimen during the follow-up period. HCRU included outpatient visits and hospital claims, reported as per patient per month (PPPM) over the time on each treatment regimen. Results: The study population included 9,579 patients initiating 1L, and then 3,061, 952 and 263 patients who received 2L, 3L, and 4L, respectively. The median follow-up was 719 days (1L), 652 days (2L), 578 days (3L), and 468 (4L). Mean age at index was similar across treatment lines, ranging from 66.7 years (1L) to 67.9 years (4L). Males represented a little under half (47.3%) in 1L cohort but increased slightly with subsequent lines (49.3%, 2L; 54.9%, 3L; 70% 4L). The most common baseline comorbidities across treatment lines were hypertension (1L=35.2%; 2L=32.3%; 3L=29.8%; and 4L=28.1%) and gastrointestinal disease (1L=23.9%; 2L=22.2%; 3L=22.2%; and 4L=22.1%). Across all treatment lines, R-mono was the most common regimen (1L=34.1%; 2L=29.0%; 3L=23.8%; and 4L=18.6%) followed by BR (1L=32.8%; 2L=17.3%; 3L=12.0%; and 4L=11.4%), and R-CHOP (1L=14.5%; 2L=12.8%; 3L=10.1%; and 4L=9.5%). Median TTNT across all regimens was 417 days (159, 691) in 1L, 444.5 days (225, 661) in 2L, 414 days (174, 784) in 3L, and 382.5 days (200.5, 599.5) in 4L (Figure 1). Mean (standard deviation; SD) of all-cause outpatient visits PPPM were 5.99 (4.86) in 1L, 6.06 (5.42) in 2L, 6.27 (6.04) in 3L, and 6.25 (5.95) in 4L. Mean (SD) of FL-specific outpatient visits PPPM were 4.59 (4.00) in 1L, 4.49 (4.31) in 2L, 4.57 (4.93) in 3L, and 4.42 (4.65) in 4L. The mean all-cause hospitalizations PPPM were 0.35 (1.72) in 1L, 0.79 (3.36) in 2L, 1.94 (6.29) in 3L, and 1.85 (5.00) in 4L. The mean FL-related hospitalizations PPPM were 0.13 (0.76) in 1L, 0.18 (1.02) in 2L, 0.36 (1.56) in 3L, and 0.45 (2.12) in 4L (Figure 2). Average pharmacy costs PPPM increased from $1,033 ($3,963.8) in 1L to $2,166.6 ($6,001.1) in 2L, and $2,943.7 ($6,413.1) to $3,374.1 ($7,361.3) in 3L and 4L, respectively. Conclusions: Real-world treatment patterns for patients with FL were shown to be mostly consistent with clinical guidelines. This study highlighted that TTNT decreased while hospitalizations and pharmacy costs increased as line of therapy progressed, suggesting high financial burden and unmet need for better treatment options for R/R FL patients.

Mosunetuzumab and the emerging role of T-cell-engaging therapy in follicular lymphoma.

Follicular lymphoma (FL) is the most common indolent lymphoma. Since the advent of rituximab, FL has seen a progressive improvement in patient prognosis. While chemotherapy combined with an anti-CD20 monoclonal antibody remains standard first-line therapy, most patients will relapse and require subsequent therapy. T-cell-redirecting therapies can be very potent and are transforming the therapeutic landscape in the relapsed and refractory (R/R) setting. T-cell-dependent bispecific antibodies, of which mosunetuzumab is the first to be approved for R/R FL, are proving to be a highly effective, 'off-the-shelf' option with manageable toxicities. This review covers approved treatments for R/R FL and focuses on preclinical and clinical data available for mosunetuzumab (Lunsumio™), with the goal of determining its role in the treatment of R/R FL.

Targeted Therapy in Follicular Lymphoma: Towards a Chemotherapy-Free Approach.

The treatment of follicular lymphoma (FL) has previously centered on chemoimmunotherapy, which can be disadvantageous due to patient intolerance, cumulative toxicities, and disease refractoriness. Targeted therapies can produce deep responses and improve progression-free and overall survival with more tolerable adverse event profiles. We summarize the current literature and key clinical trials regarding targeted therapies in follicular lymphoma both in the front-line and in the relapsed-refractory setting. Targeted therapies studied in FL include immune modulators, anti-CD20 antibodies, Bruton's tyrosine kinase (BTK) inhibitors, enhancers of zeste homolog 2 (EZH2) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, and B-cell lymphoma 2 (BCL-2) inhibitors. Chimeric antigen receptor (CAR-T) therapy and bispecific T-cell engager (BiTE) therapies also show promise in monotherapy and in combination with targeted therapies. These therapies exhibit high overall response rates and substantial progression-free survival and overall survival, even in high-risk patients or patients previously refractory to chemotherapy or rituximab. Adverse events vary substantially but are generally manageable and compare favorably to the cumulative toxicities of chemotherapy. Targeted therapies represent a paradigm shift in the treatment of FL. Further studies are needed to directly compare these targeted therapies and their combinations, as well as to investigate biomarkers predictive of response.

Personalised therapy in follicular lymphoma - is the dial turning?

Follicular lymphoma is the most common indolent lymphoma accounting for approximately 20%-25% of all new non-Hodgkin lymphoma diagnoses in western countries. Whilst outcomes are mostly favorable, the spectrum of clinical phenotypes includes high-risk groups with significantly inferior outcomes. This review discusses recent updates in risk stratification and treatment approaches from upfront treatment for limited and advanced stage follicular lymphoma to the growing options for relapsed, refractory disease with perspectives on how to approach this from a personalized lens. Notable gaps remain on how one can precisely and prospectively select optimal treatment for patients based on varying risks, with an anticipation that an increased understanding of the biology of these different phenotypes and increasing refinement of imaging- and biomarker-based tools will, in time, allow these gaps to be closed.

Rituximab versus obinutuzumab-based first-line chemoimmunotherapy for follicular lymphoma-a real-world multicenter retrospective cohort study.

The GALLIUM study showed a progression-free survival advantage of 7% in favor of obinutuzumab vs. rituximab-based immunochemotherapies as first-line therapy in follicular lymphoma (FL) patients. Yet, the toxicity appears to be increased with obinutuzumab-based therapy. This is a multicenter retrospective-cohort study including adult FL patients comparing the toxicity of first-line rituximab vs. obinutuzumab-based chemo-immunotherapies (R and O groups, respectively). We compared the best standard-of-care therapy used per time period, before and after obinutuzumab approval. The primary outcome was any infection during induction and 6months post-induction. Secondary outcomes included rates of febrile neutropenia, severe and fatal infections, other adverse events, and all-cause mortality. Outcomes were compared between groups.A total of 156 patients were included in the analysis, 78 patients per group. Most patients received bendamustine (59%) or CHOP (31.4%) as adjacent chemotherapy. Half of the patients received growth-factor prophylaxis. Overall, 69 patients (44.2%) experienced infections, and a total of 106 infectious episodes were recorded. Patients in the R and O groups had similar rates of any infection (44.8% and 43.5%, p = 1), severe infections (43.3% vs. 47.8%, p = 0.844), febrile neutropenia (15% vs. 19.6%, p = 0.606), and treatment discontinuation, as well as similar types of infections. No covariate was associated with infection in multivariable analysis. No statistically significant difference was evident in adverse events of grades 3-5 (76.9% vs. 82%, p = 0.427). To conclude, in this largest real-life study of first-line treated FL patients comparing R- to O-based therapy, we did not observe any difference in toxicity during the induction and 6months post-induction period.

Dual Immune Checkpoint Agents in Combination with Rituximab for Patients with Relapsed or Refractory Follicular Lymphoma

Background: Follicular lymphoma (FL) is an inherently immunosensitive cancer. While PD-1 blockade was associated with a low objective response rate (ORR) in FL, some durable responses were seen. Manipulation of other checkpoint pathways, like 4-1BB, have shown promising activity (Gopal, CCR 2020) and OX40 stimulation may enhance activity of other immunotherapies. We therefore conducted a multi-cohort phase 1b trial testing different combinations of immune checkpoint therapy targeting 4-1BB (utomilumab), OX-40 (PF-04518600), and PD-L1 (avelumab) all in combination with rituximab (R) among patients (pts) with relapsed/refractory (R/R) FL. Methods: Adult pts with R/R grade 1-3a FL who had received ≥ 1 prior therapies (including a CD20 monoclonal antibody) were enrolled. All pts had measurable disease and required therapy based on modified GELF criteria. Pts in need of urgent cytoreductive therapy were excluded. Pts were enrolled onto 2 of 3 planned cohorts (A1 - R, utomilumab, avelumab; A2 - PF-04518600 +/- R, utomilumab). The trial was closed early when development of utomilumab and PF-04518600 was halted by Pfizer. Enrollment ended before dose expansion was completed for cohorts A1 and A2 and before enrollment began for a 3rd cohort (R, avelumab, PF-04518600). Each cohort began with a dose escalation stage (using a standard 3+3 design) followed by a dose expansion stage at the recommended phase 2 dose (RP2D) (15 pts). Treatment consisted of six 28-day cycles for both cohorts (see table for dose levels and dosing details). The co-primary endpoints were RP2D and complete response rate (CRR), assessed using 2014 Lugano criteria. Peripheral blood, stool samples, and tissue biopsies were collected for correlative studies. Results: 24 pts were enrolled at 4 centers, including 1 pt who was initially treated on cohort A2 (with R + PF-04518600), ended treatment due to progression, and then enrolled on cohort A1. In total, 16 pts were treated on cohort A1 and 9 on cohort A2. The median age was 58 (42-76). Pts had received a median of 2 (1-9) prior therapies. 11 pts (46%) had progression within 24 months of initial therapy (POD24). At trial entry, 6 pts (25%) were R-refractory, defined as no response to last R-containing regimen or progression ≤6 months after last R dose. The highest planned dose level (dose level 2) was selected as the RP2D for cohorts A1 and A2. There were no treatment discontinuations due to adverse events (AEs) and no treatment-related deaths. 1 dose-limiting toxicity (grade 3 gastric obstruction, unrelated to study treatment) was observed for a pt in cohort A1. In total, 19/25 (76%) pts had at least 1 treatment-related (tr)AE of any grade, including 7 (28%) pts with grade 3 trAEs. Typical immune-related AEs were not observed. The most common trAEs of any grade were fatigue (24%) and infusion reaction (20%). Grade 3 trAEs included neutropenia in 2 pts (8%), and hypertension, hypertriglyceridemia, hypophosphatemia, lymphopenia, COVID infection, and thromboembolic event in 1 pt each (4%). In cohort A1, the ORR and CRR were 44% and 19%, respectively. Among 10 pts treated at the RP2D, the ORR and CRR were 50% and 30%, respectively. ORRs were observed in 2/5 POD24 pts and 1/4 R-refractory pts in cohort A1. In cohort A2, no responses were observed. After a median follow-up of 16 months, the median progression-free survivals in cohorts A1 and A2 were 7.0 and 3.2 months (m), respectively. The median duration of response in A1 was 9.7m. The 18m overall survivals in cohorts A1 and A2 were 81% and 100%, respectively. We performed 16S ribosomal RNA sequencing of pre- and on-treatment stool samples from pts in cohort A1 and found a positive association between abundance of Akkermansia and ORR to study therapy (p<0.001). Other correlative studies including multiplex immunofluorescence and single-cell analyses (assessing serial biopsy samples) are ongoing. Conclusions: We observed clinical activity with the combination of utomilumab, avelumab, and R, supporting a possible role for 4-1BB agonist therapy in FL. In contrast, our limited results do not support a role for OX40 targeting in this disease. Correlatives studies are ongoing which may shed further light on predictors of response. Interestingly, we found an association between Akkermansia and response, which has been reported in checkpoint blockade studies in solid tumors and supports the hypothesis that the microbiome impacts response to immunotherapies in lymphomas. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Obinutuzumab Versus Rituximab Based First-Line Chemoimmunotherapy for Follicular Lymphoma - a Real-World Multicenter Retrospective Cohort Study

Introduction - The recent GALLIUM study showed an advantage of 7% in progression free survival in favor of obinutuzumab (G) vs. rituximab (R) based immunochemotherapies as first line therapy in follicular lymphoma (FL) patients. Yet, the toxicity appears to be increased with obinutuzumab based therapy. Methods - To assess for toxicity we compared treatment for FL in the era before the approval of obinutuzumab by the Israeli health authorities on 1/1/2018 (rituximab-based therapy) to the era post approval (obinutuzumab-based therapy). This is a multicenter retrospective cohort study comprising five medical centers in Israel. All adult FL patients treated with first line chemo-immunotherapy were included. Comparison of G vs. R based chemo-immunotherapy was performed in order to assess real life toxicity profile between the two anti-CD20 monoclonal antibodies (R- and G-groups). Primary outcome was any infection recorded during the induction and 6 months post induction period. Secondary outcomes included rates of febrile neutropenia, severe infections defined as grade 3-4 infections, infections requiring intravenous (IV) antibiotics, life threatening infections or fatal infections, as well as rates of other non-hematological and hematological toxicities and treatment discontinuation. Response rates at the end of induction therapy were also recorded. Results - A total of 156 patients, treated between 1/1/2016-1/1/2019, were included in the analysis - 78 patients in each group. Most patients received bendamustine (n= 92, 59%) or CHOP (n=49, 31.4%) as the adjacent chemotherapy regimen. Baseline characteristics of patients were comparable between groups, apart from a higher incidence of diabetes mellitus and hypertension in the R-group. Any infection occurred in 69 patients (44.2%) of the cohort, and a total of 106 infectious episodes were recorded. Patients in the R- and G-groups had similar rates of any infection (44.8% and 43.5%, p=1), severe infections (43.3% vs. 47.8%, p=0.844), febrile neutropenia (15% vs. 19.6%, p=0.606) and treatment discontinuation (14.1% vs. 19.2%). Characteristics of the 106 infection episodes according to the R- versus G- groups are described in Table 1. Most other adverse events recorded, including hematological and non-hematological toxicities, were also comparable between groups, apart from higher rates of nausea and vomiting (30.7% vs. 11.5%, p=0.029) and fever from a non-infectious origin (32% vs. 10%, p=0.032) in the R-group. Overall, no statistically significant difference was evident in adverse events of grades 3 to 5 (hematological and non-hematological) between R and G-based treatments (76.9% vs. 82%, p=0.427) nor in complete remission rates at the end of induction therapy (79.5% vs. 84.6%, p=0.147). Baseline factors significantly associated with any infection in univariate analysis included female gender, chronic obstructive pulmonary disease, use of GCSF prophylaxis, elevated LDH, beta2 microglobulin and lower levels of hemoglobin before `treatment commencement. None of the parameters was found to be significantly associated with any infection in multivariable analysis, albeit gender and LDH values had a trend towards significance. Conclusions - In this first and largest real-life study of first line treated patients with follicular lymphoma, we did not observe excess toxicity with G- compared to R- based therapy during the induction and 6 months post induction period. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase 3 Trial of Subcutaneous Epcoritamab in Combination with Rituximab and Lenalidomide (R2) Vs R2 Among Patients with Relapsed or Refractory Follicular Lymphoma (EPCORE FL-1)

Background: Follicular lymphoma (FL) is the most common 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 R2. However, advanced stage FL remains incurable and new treatment options for relapsed or refractory (R/R) disease are needed. Epcoritamab is a subcutaneously administered, bispecific antibody that binds CD3 on T lymphocytes and CD20 on B-cells, inducing 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 the complete response (CR) rate was 50%. In the ongoing phase 1b/2 trial evaluating epcoritamab and R2 among 28 evaluable patients with R/R FL (EPCORE NHL-2 arm 2; NCT04663347), ORR was 100%, with a complete metabolic response observed in 96%. Most cytokine release syndrome (CRS) events were of low grade (grade 1, 30%; grade 2, 13%; grade 3, 7%) and occurred in cycle 1; all CRS events resolved with standard management. These encouraging data, as well as the distinct mechanisms of action of epcoritamab and R2, support evaluation of this combination for its potential to improve clinical outcomes in patients with R/R FL. The phase 3 trial described herein was designed to evaluate epcoritamab in combination with R2 vs R2 alone in patients with R/R FL with at least 1 prior line of therapy. 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 R2 vs R2 alone in adults with histologically confirmed grades 1 to 3a R/R FL after at least 1 prior line of systemic anti-lymphoma therapy, including an anti-CD20 monoclonal antibody (not including prior radiotherapy). Other key eligibility criteria include Eastern Cooperative Oncology Group performance status 0 to 2, fluorodeoxyglucose positron emission tomography-avid disease, and at least 1 measurable disease site. Lenalidomide-refractory FL is excluded. Approximately 642 patients will be randomized in a 1:1:1 ratio to receive alternative full doses of epcoritamab in combination with R2 or R2 alone (Figure). Epcoritamab will be subcutaneously administered using a step-up dosing regimen followed by a full dose of epcoritamab in cycle 1 (28 days/cycle). Full doses of epcoritamab will be administered weekly in cycle 2 and monthly in cycles 3 and beyond. Patients will receive up to 12 cycles of treatment and will be assessed for disease progression per the 2014 Lugano criteria. Primary endpoint is progression-free survival (PFS) as assessed by blinded independent review committee (IRC). Secondary efficacy endpoints include response rates (per Lugano criteria by IRC), overall survival and minimal residual disease negativity. Other efficacy endpoints include duration of response, duration of complete response, 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. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Final Analysis of JCOG0203 for Advanced-Stage Indolent B-Cell Lymphoma 15 Years after the End of Enrollment: Pooled Analysis of Arms a and B for Follicular Lymphoma

Optimal immunochemotherapy as first-line treatment for patients with follicular lymphoma (FL) remains undetermined. FL frequently relapses after frontline treatment; thus, fatal secondary malignancies (SMs) and treatment-related death, including death due to infection, which will be accumulated by subsequent treatments, should be avoided. To evaluate the cumulative incidence of SMs as well as histologic transformation (HT), a follow-up of more than 15 years is necessary. However, such data are available only in the pre-rituximab era by retrospective and single-institute studies. In addition, the real incidence of HT was probably underestimated in the studies that estimated only biopsy-proven cases. In JCOG0203, previously untreated patients with stage III/IV indolent B-cell lymphoma were randomly assigned to receive six cycles of R-CHOP (Arm A) or R-CHOP-14 (every 2 weeks with G-CSF, Arm B) without rituximab maintenance. All histopathological specimens were centrally reviewed by three hematopathologists. To evaluate long term follow-up data, analyses for overall survival (OS), progression-free survival (PFS), HT, SMs, and progression of disease within 24 months after treatment initiation (POD24) were performed. OS and PFS were calculated using Kaplan-Meier method. Hazard ratios (HRs) were estimated by proportional hazards model. Cumulative incidence function of HT and SM were estimated. Exploration of risk factors for frequency of HT and POD24 were conducted by logistic regression model. Between Sep 1, 2002 and Feb 28, 2007, 300 patients, including 248 with grade (G)1-3A FL, were enrolled from 44 centers. Nineteen (6.3%) patients were lost to follow-up. The 10- and 15-year OS of patients with FL in Arm A vs. Arm B was 83.8% vs. 85.3% and 76.4% vs. 75.9%, respectively. No protocol treatment-related death or fatal late infection was reported. Multivariable analysis for the 299 patients eligible for OS revealed that significant adverse prognostic factors were age ≥61 (HR=2.54, p<0.0001), male sex (HR=2.06, p=0.002), and ECOG PS ≥1 (HR=1.71, p=0.044). As both arms revealed similar outcomes, pooled analyses of Arms A and B were performed for FL. The incidence of HT, including biopsy-proven and clinically diagnosed HT, was 9.8% and 14.4% at 10 and 15 years after enrollment, respectively, and increased thereafter. Seventy-seven of 245 (31.4%) patients, excluding two who died and one lost to follow-up patients without POD24, experienced POD24. HT occurred in 19 of 76 (25.0%) patients. Multivariable analysis for POD24 identified high Follicular Lymphoma International Prognostic Index (FLIPI) score (Odds ratio (OR)=4.40) and G3A histology (OR=2.63) as risk factors for HT and intermediate (OR=2.53) and high (OR=2.24) FLIPI score, B symptoms (OR=2.09), and G3A (OR=1.83) as risk factors for POD24. Additional analysis suggested that, restricted to within a 10-year period, high FLIPI (OR=3.24, p=0.046) and G3A (OR=3.30, p=0.054) were more related to HT than in the whole study period in univariable analysis. The cumulative incidence of SMs increased after the 10-year follow-up. The incidence of solid tumors was 12.8% {10.6% (fatal [f], n=3/17 events) in Arm A vs. 15.0% (f, n=10/23 events) in Arm B} at 15 years, whereas that of hematologic malignancies was 3.7% {4.1% (f, n=2/5) in Arm A vs. 3.3% (f, n= 1/4) in Arm B}. These results are the longest follow-up data of more than 200 patients with FL homogeneously treated in a multicenter prospective trial. R-CHOP was safe and efficacious, reducing HT, without increasing fatal hematologic malignancies in the long-term and may, therefore, be a reasonable option as frontline therapy for advanced-stage FL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal