Treatment Of Follicular Lymphoma Research Articles

A phase I trial of vaccination with lethally irradiated lymphoma cells admixed with granulocyte-macrophage colony-stimulating factor secreting K562 cells for the treatment of follicular lymphoma

Several vaccine strategies have been tested for the treatment of follicular lymphoma; however, none have proven successful. In a phase I dose-escalation protocol, we developed a vaccine consisting of lethally irradiated whole lymphoma cells admixed with K562 cells that constitutively secreted granulocyte-macrophage colony-stimulating factor (GM-K562)(ClinicalTrials.gov identifier: NCT00487305). Patients with grade 1, 2, or 3 A follicular lymphoma were divided into 2 study tiers based on prior treatment and received a maximum of 6 vaccines. Vaccines contained dose levels of 5 × 106 or 1 × 107 GM-K562 cells admixed with autologous tumor cells at doses ranging from 1 × 105 to 5 × 107.Correlative studies did not demonstrate a significant immune response as assessed by delayed-type hypersensitivity reactions, B and T cell subsets, and natural killer cell subsets. Future vaccine studies should focus on identifying lymphoma-specific immunogenic proteins and modifying the vaccine immune adjuvant.

Rituximab maintenance after bendamustine-based treatment for follicular lymphoma and mantle cell lymphoma may exert a negative influence on SARS-CoV-2 infection outcomes.

Not available.

The treatment of follicular lymphoma with CD19-directed chimeric antigen receptor T-cell therapy.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Significant unmet need remains for patients with relapsed/refractory FL after ≥3 lines of prior therapy. While recent advancements have likely improved the survival of patients with FL, most patients will eventually relapse. The treatment of patients with FL after multiple relapses or those with refractory disease has historically led to lower overall response rates (ORR) and shorter progression-free survival (PFS) with each subsequent line of therapy. New treatments with high ORR and durable PFS are needed in this setting, particularly in patients that progress within 2 years of first line chemoimmunotherapy (POD24) and/or those refractory chemoimmunotherapy. Chimeric antigen receptor T-cell therapies targeting the B-cell antigen CD-19 have shown to be an efficacious treatment option for both heavily pretreated patients and/or patients with refractory FL, resulting in a high ORR and durable remissions.

The Reduction of CD4+ T Lymphocytes after the Treatment of Follicular Lymphoma with the Bendamustine Containing Regimen May Predict the Occurrence of Infection and Efficacy

To investigate the effectiveness, safety, and related prognostic factors of the treatment of follicular lymphoma (FL) with a regimen containing Bendamustine. The clinical data of 129 FL patients who were treated with Bendamustine containing regimen were collected from January 1,2020 to October 30,2022 in the Hematology Department of Lianyungang Second People's Hospital and Jiangsu Provincial People's Hospital. The patients were divided into three groups: Bendamustine plus Rituximab (BR), Bendamustine plus Obinutuzumab (GB), Rituximab + Cyclophosphamide + Epirubicin / Doxorubicin + Vindesine + Prednisone (R-CHOP). The efficacy, safety and related prognostic factors of the treatment of FL with a regimen based on Bendamustine were retrospectively analyzed. The ORR was 98% for the BR group, 94% for the GB group, and 72.3% for the R-CHOP group, while the CR rate was 61.2%,70% and 40.4%, respectively. The ORR and CR rates of the R-CHOP group were statistically different from those of the BR group and GB group (P < 0.05). The 3-year PFS rate of the BR group, GB group, and R-CHOP group was 89.6%, 90.9%, 48.9%, respectively. There was a statistically significant difference in 3-year PFS between the R-CHOP group, BR group, and GB group (P < 0.05), while there was no statistically significant difference in 3-year OS（P ＞0.05）. Hematological adverse reactions were mainly bone marrow suppression. Lymphocytes and CD4+T lymphocytes decreased to the lowest level about 6 months after treatment, and the incidence of lymphopenia in BR group and GB group was higher than that in R-CHOP group, with a statistical difference (P < 0.05). The higher incidence of non-Hematological adverse reactions were pulmonary infection, EB virus infection, hepatitis B virus reactivation, and gastrointestinal reactions without statistical difference in 3 groups (P >0.05), and were all controllable. The Receiver operating characteristic of CD4+T lymphocyte count showed that AUC of BR group was 0.802, and the critical value was 258/uL; AUC of GB group was 0.754 with a critical value of 322/uL. The treatment of FL with the Bendamustine containing regimen has good efficacy and controllable adverse reactions, but lymphocytopenia was significant after treatment, and the curative efficacy in combination with various CD20 monoclonal antibodies was different. The lowest CD4+T lymphocyte count can be used as a predictive factor for the occurrence of infection and efficacy of the Bendamustine containing regimen for FL.

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 .

First-line (1L) treatment of follicular lymphoma (FL) with atezolizumab and obinutuzumab (A+O) +/- radiotherapy (RT): Results from the FLUORO study.

7070 Background: Standard 1L immunochemotherapy in FL is highly effective but not without significant toxicity. Up to 75% of FL patients (pts) have grade 3-5 adverse events (AEs), primarily infection and myelosuppression. More tolerable approaches are needed. PD1/PDL1 inhibitors are active in FL. A+O yield responses in 57% of rituximab-refractory FL pts (Palomba 2017). Our phase 2 study of 1L nivolumab + rituximab in FL yielded 92% overall response rate (ORR), (54% Complete Response (CR)). Toxicity compared favourably with chemotherapy: 41% grade 3-5 AEs (Hawkes 2021). FL is sensitive to low dose RT, with proven abscopal effects, is safe and synergistic with PDL1i (Hawkes 2023), potentially improving treatment efficacy with minimal extra toxicity. This investigator-led, multicentre PET-adapted phase 2 trial assessed A+O +/- RT efficacy for treatment-naïve FL. Methods: ‘FLUORO’ (NCT03245021) is an open-label, multi-centre, phase 2, Simon’s 2-stage study of A+O+/-RT (N = 46; 15 in initial cohort). Key eligibility were stage II-IV grade 1-3A FL requiring therapy; ECOG ≤2; adequate organ function. All pts received 6 cycles (C) of A 1200mg + O 1000mg IV 3-weekly (plus O on C1, days 8 &amp; 15). Pts with &lt; CR on PET post C2 had RT (4Gy) to residual PET-avid disease. Pts with CR or PR(partial response) received 12 cycles 8-weekly maintenance O. Primary endpoint (EP) was CR rate with &lt;5/15 CR deemed futile in 1st stage. Secondary EP included ORR, Progression-free survival (PFS), overall survival (OS) and AEs. Exploratory EP included biomarker studies and PET radiomics. Results: 16 pts were enrolled from 08/2021-10/2022, 1 pt was replaced due to Grade(G) 4 infusion reaction to O requiring cessation. Baseline characteristics included median age 53y (range 33-79), stage IV disease in 81%, B symptoms in 12.5%, 44% had FLIPI &gt;2. Primary EP was met, with CR at end of induction in 13/15 (87%) evaluable pts (ORR 100%). 12 pts (80%) required RT. 2 pts (13%) discontinued due to progressive disease (Table). AEs were mostly G1-2; fatigue 44%, constipation 31%, nausea 25%. fever 25%, abdominal pain 18.6%. SAEs were reported in 7/16 (44%) pts, including grade 3 infections: COVID19 12%, upper respiratory tract 12%, urinary tract 6.2%. Median follow-up is 24m (range 16-28) and ongoing, 16m PFS &amp; OS is 87% &amp; 100%. Biomarker analysis is ongoing. Conclusions: Atezolizumab +Obinutuzumab +/- PET-adapted 4Gy RT yielded high complete response rates with low toxicity in treatment-naïve FL. CR threshold to proceed to stage 2 was met, however was not deemed commercially viable. Clinical trial information: NCT04962126 .[Table: see text]

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]

Incidence of any infections and SARS-CoV-2 infections in patients receiving treatment for follicular lymphoma and diffuse large B-cell lymphoma: Real-world evidence from a large US national claims database.

e19061 Background: Non-Hodgkin’s lymphoma is a heterogeneous group of conditions, including the indolent subtype follicular lymphoma (FL) and the aggressive subtype diffuse large B-cell lymphoma (DLBCL). Infections associated with NHL are a major concern due to effects of the underlying disease and its treatment and have been reported to increase with increasing lines of therapy (LoT). However, the risk of infections overall and SARS-COV-2 infections specifically is not well characterized in patients who have received multiple LoTs. The goal of the study was to estimate the exposure-adjusted incidence rates (EAIR) of infections during the COVID-19 pandemic by type, severity and LoT received in patients treated for FL or DLBCL in the real-world setting. Methods: We identified patients in the Optum Clinformatics claims data from October 1, 2015, to June 30, 2023. Patients were aged ≥18 years, enrolled continuously for 365 days before index (start of LoT), and had ≥2 ICD-10 diagnosis codes for FL or DLBCL in the 365 days before index. The EAIR (per 100 person-years, PY) was estimated for infections by type (any infections and SARS-COV-2 [after 1/1/2020]), severity (hospitalized or fatal hospitalizations), and number of LoTs received. Results: A total of 4,799, 1,025 and 510 FL patients were included in the 1L (1 LoT), 2L, and 3L+ cohorts, respectively. The EAIR of infections resulting in hospitalization in 1L, 2L, and 3L+ cohorts were 20.6 (95% confidence interval (CI): 19.0-22.3), 30.2 (25.5-35.9), and 44.2 (35.4-55.3) per 100-PY for any infection; and 4.6 (4.0-5.4), 4.4 (3.0-6.5) and 8.3 (5.3-13.2) per 100-PY for SARS-COV-2 infections, respectively. The EAIR of fatal hospitalizations were 4.0 (3.4-4.8), 8.6 (6.4-11.5), and 13.9 (9.7-20.0) per 100-PY for any infection; and 1.3 (1.0-1.7), 1.6 (0.8-3.0), and 4.1 (2.2-7.9) per 100-PY for SARS-COV-2 infections. A total of 8,058, 2,114 and 977 DLBCL patients were included in 1L, 2L, and 3L+ cohorts, respectively. The EAIR of infections resulting in hospitalization in 1L, 2L, and 3L+ cohorts were 64.2 (60.7-67.8), 85.2 (76.9-94.3), and 113.4 (98.4-130.7) per 100-PY for any infection; and 6.3 (5.5-7.2), 7.3 (5.6-9.6), and 15.1 (11.3-20.2) per 100-PY for SARS-COV-2 infections respectively. The EAIR of fatal hospitalizations were 12.0 (10.8-13.3), 23.0 (19.5-27.1), and 27.8 (22.1-34.9) per 100-PY for any infection; and 1.6 (1.2-2.1), 2.7 (1.7-4.2), and 4.8 (2.9-8.0) per 100-PY for SARS-COV-2 infections in 1L, 2L and 3L+ cohorts, respectively. Conclusions: This real-world analysis demonstrated substantial morbidity and mortality associated with overall and SARS-COV-2 infections among NHL patients, with a higher incidence in DLBCL compared to FL, and with increasing LoTs.

Identification and Functional Investigation of Hub Genes Associated with Follicular Lymphoma.

Follicular lymphoma (FL), the most common type of indolent lymphoma, originates from germinal center B cells within the lymphoid follicle. However, the underlying mechanisms of this disease remain unclear. This study aimed to identify the potential hub genes for FL and evaluate their functional roles in clinical applications. Microarray data and clinical characteristics of patients with FL were obtained from the Gene Expression Omnibus database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were employed to explore hub genes for FL. Functional enrichment analysis was performed to investigate the potential roles of these hub genes in FL. Mendelian randomization (MR) analysis was performed to verify the causal effect of the top genes on FL risk. In addition, gene set enrichment analysis (GSEA) and immune cell analysis were performed to elucidate the involved mechanisms of the crucial genes in FL. A total of 1363 differentially expressed genes and 157 central genes were identified by differential expression analysis and WGCNA, respectively, resulting in 117 overlapping genes considered as hub genes for FL. Functional enrichment analysis revealed significant correlations between immune-related pathways and FL. MR analysis revealed a significant association only between zeta chain of T-cell receptor-associated protein kinase 70 (ZAP70) and FL risk, with no significance observed for the other top genes. GSEA and immune cell analysis suggested that ZAP70 may be involved in the development and progression of FL through immune-related pathways. By integrating bioinformatics and MR analyses, ZAP70 was successfully identified and validated as a promising FL biomarker. Functional investigations indicated a significant correlation between immune-related pathways and FL. These findings have important implications for the identification of targets for the diagnosis and treatment of FL and provide valuable insights into the molecular mechanisms underlying FL.

Neoantigen landscape supports feasibility of personalized cancer vaccine for follicular lymphoma

AbstractPersonalized cancer vaccines designed to target neoantigens represent a promising new treatment paradigm in oncology. In contrast to classical idiotype vaccines, we hypothesized that “polyvalent” vaccines could be engineered for the personalized treatment of follicular lymphoma (FL) using neoantigen discovery by combined whole-exome sequencing (WES) and RNA sequencing (RNA-seq). Fifty-eight tumor samples from 57 patients with FL underwent WES and RNA-seq. Somatic and B-cell clonotype neoantigens were predicted and filtered to identify high-quality neoantigens. B-cell clonality was determined by the alignment of B-cell receptor (BCR) CDR3 regions from RNA-seq data, grouping at the protein level, and comparison with the BCR repertoire from healthy individuals using RNA-seq data. An average of 52 somatic mutations per patient (range, 2-172) were identified, and ≥2 (median, 15) high-quality neoantigens were predicted for 56 of 58 FL samples. The predicted neoantigen peptides were composed of missense mutations (77%), indels (9%), gene fusions (3%), and BCR sequences (11%). Building off of these preclinical analyses, we initiated a pilot clinical trial using personalized neoantigen vaccination combined with PD-1 blockade in patients with relapsed or refractory FL (#NCT03121677). Synthetic long peptide vaccines targeting predicted high-quality neoantigens were successfully synthesized for and administered to all 4 patients enrolled. Initial results demonstrate feasibility, safety, and potential immunologic and clinical responses. Our study suggests that a genomics-driven personalized cancer vaccine strategy is feasible for patients with FL, and this may overcome prior challenges in the field. This trial was registered at www.ClinicalTrials.gov as #NCT03121677.

Follicular lymphoma treatment decisions: put GELF on the shelf?

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Recent advances in understanding the biology of follicular lymphoma.

Follicular lymphoma (FL), the most common indolent B-cell lymphoma, develops over decades before manifesting as overt disease. BCL2 overexpression by t(14;18) confers a survival advantage to B cells during the germinal center reaction, and abnormalities in epigenetic modifier genes lead to desynchronization of gene expression changes in germinal center B cells. Studies in mouse models have shown that BCL2 overexpression and epigenetic deregulation in B cells cooperatively promote lymphomagenesis. The immune microenvironment also plays an essential role in the biology of FL, and many molecular prognostic indicators based on the immune microenvironment have been proposed. However, high-risk gene signatures do not appear to be consistent between patients receiving different chemotherapies. FL cells frequently carry N-linked glycosylation motifs within the immunoglobulin gene, leading to chronic activation of the B-cell receptor (BCR). Recent evidence suggests that this chronic BCR signaling drives FL polarization toward a dark-zone phenotype and promotes clonal evolution. Since both epigenetic and post-transcriptional modifications of B cells have been implicated in the early stage of FL development, it may be possible to use novel non-chemotherapeutic approaches that interfere with the immunobiology in treatment or early prevention of FL.

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.&#x0D; Materials &amp; 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.&#x0D; 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 &gt; 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.&#x0D; 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.

Определение соматических мутаций в гене EZH2 и оценка их прогностической значимости при фолликулярной лимфоме 1–3А цитологического типа

Aim. To determine the incidence and prognostic value of mutations in exon 16 of EZH2 as well as those of polymorphism с.1582-21А&gt;G (rs2072407) in EZH2 in patients with follicular lymphoma (FL) grades 1–3А in relation to morphologic and cytogenetic tumor characteristics.&#x0D; Materials &amp; Methods. The prospective cohort study conducted by the National Research Center for Hematology from January 2017 to April 2021 enrolled 80 patients with newly diagnosed FL grades 1/2 and 3А. The median follow-up was 53 months. Molecular and cytogenetic analyses were based on biopsy samples of lymph nodes obtained before chemotherapy. The mutation status of exon 16 in EZH2 and the presence of intronic polymorphism rs2072407 in EZH2 were examined by Sanger sequencing method. Translocation t(14;18)(q32;q21) was detected by karyotyping or FISH.&#x0D; Results. Mutations in exon 16 of EZH2 (mutEZH2) were identified in 10/80 (13 %) patients. All patients showed missense mutation in codon 646 of EZH2. Translocation t(14;18) was detected in 45/80 (56 %) cases. Poor outcome in the cohort with no t(14;18) was observed 3 times more often than in the group of patients with t(14;18) (p = 0.0001). The presence of t(14;18) was associated with favorable prognosis irrespective of either the mutation status of exon 16 in EZH2 or the FL grade. The analysis of the polymorphism rs2072407 status yielded the following genotypes: AA in 24 % (n = 19), AG in 42 % (n = 34), and GG in 34 % (n = 27) of cases. The variants АА and AG were associated with higher risk of death (hazard ratio 2.9; 95% confidence interval 1.2–10.6; p = 0.01), whereas the genotype GG was associated with wtEZH2 (10 % vs. 37 %) and favorable prognosis (p = 0.065).&#x0D; Conclusion. Significant biological markers for favorable prognosis in FL appeared to be the presence of t(14;18)(q32;q21) and GG genotype of polymorphism rs2072407 in EZH2. The previously identified prognostic factors (grade 3А, bulky tumor lesions &gt; 6 cm, Ki-67 &gt; 35 %, and a short interval between symptom onset and chemotherapy start) were incorporated into a new unified personalized predictive (index PPI) FL model by supplementing it with two additional biological markers: the presence of t(14;18)(q32;q21) and GG genotype of polymorphism rs2072407. This approach may increase the prognostic value of the new personalized design which will provide the basis for risk-adapted algorithms for FL treatment.

A miniaturized mode-of-action profiling platform enables high throughput characterization of the molecular and cellular dynamics of EZH2 inhibition

The market approval of Tazemetostat (TAZVERIK) for the treatment of follicular lymphoma and epithelioid sarcoma has established “enhancer of zeste homolog 2” (EZH2) as therapeutic target in oncology. Despite their structural similarities and common mode of inhibition, Tazemetostat and other EZH2 inhibitors display differentiated pharmacological profiles based on their target residence time. Here we established high throughput screening methods based on time-resolved fluorescence energy transfer, scintillation proximity and high content analysis microscopy to quantify the biochemical and cellular binding of a chemically diverse collection of EZH2 inhibitors. These assays allowed to further characterize the interplay between EZH2 allosteric modulation by methylated histone tails (H3K27me3) and inhibitor binding, and to evaluate the impact of EZH2’s clinically relevant mutant Y641N on drug target residence times. While all compounds in this study exhibited slower off-rates, those with clinical candidate status display significantly slower target residence times in wild type EZH2 and disease-related mutants. These inhibitors interact in a more entropy-driven fashion and show the most persistent effects in cellular washout and antiproliferative efficacy experiments. Our work provides mechanistic insights for the largest cohort of EZH2 inhibitors reported to date, demonstrating that—among several other binding parameters—target residence time is the best predictor of cellular efficacy.

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.

Gene targeted and immune therapies for nodal and gastrointestinal follicular lymphomas.

Follicular lymphoma (FL) is the most common indolent B-cell lymphoma (BCL) globally. Recently, its incidence has increased in Europe, the United States, and Asia, with the number of gastrointestinal FL cases expected to increase. Genetic abnormalities related to t(14;18) translocation, BCL2 overexpression, NF-κB pathway-related factors, histone acetylases, and histone methyltransferases cause FL and enhance its proliferation. Meanwhile, microRNAs are commonly used in diagnosing FL and predicting patient prognosis. Many clinical trials on novel therapeutics targeting these genetic abnormalities and immunomodulatory mechanisms have been conducted, resulting in a marked improvement in therapeutic outcomes for FL. Although developing these innovative therapeutic agents targeting specific genetic mutations and immune pathways has provided hope for curative options, FL treatment has become more complex, requiring combinatorial therapeutic regimens. However, optimal treatment combinations have not yet been achieved, highlighting the importance of a complete under-standing regarding the pathogenesis of gastrointestinal FL. Accordingly, this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations. Moreover, the results of clinical trials are summarized, with a particular focus on treating nodal and gastrointestinal FLs.

Patterns of Care and Resource Use Among Elderly Relapsed/Refractory Follicular Lymphoma Patients: US Medicare Claims Analysis

Background: Follicular lymphoma (FL)is the second most common type of non-Hodgkin lymphoma (NHL) and most common indolent NHL. Rituximab-based chemotherapy is highly effective and considered the mainstay first-line (1L) treatment for FL, though many patients relapse and continue through successive lines of therapy. These relapsed/refractory (R/R) patients experience worse outcomes and represent an unmet need for more effective treatment approaches. This study examined treatment patterns, health care resource utilization (HCRU), and costs among R/R FL patients initiating third line (3L) therapy between 2011 and 2020. Methods: This retrospective, observational study used Center for Medicare and Medicaid fee-for-service Medicare data. The sample included treated patients with FL (identified via 1 inpatient or 2 outpatient claims) aged ≥66 years who initiated 1, 2, and 3L therapy between January 1, 2011, and December 31, 2020. Patients were required to have continuous coverage in the 12 months pre-FL diagnosis and 3 months post-diagnosis and were followed until discontinuation of enrollment or death. Line of therapy (LoT) was calculated until the end of treatment, death, or transformation to diffuse large B-cell lymphoma. Outcomes included patient characteristics, treatment patterns, health care costs and HCRU. R esults: This analysis identified 8737 1L, 1847 2L, and 410 3L treated FL patients. Median age at the start of each LoT was 75 years at 1L, 77 at 2L, and 79 at 3L. Of R/R FL patients initiating 3L, the most common baseline Charlson comorbidities included diabetes without chronic complications (23%), chronic pulmonary disease (22%) and renal disease (20%), 32% were defined as having progression of disease within 2 years of 1L (POD24), and 30% were defined as double refractory to both an anti-CD20 agent and an alkylating agent. Treatment utilization rates were similar across LoTs; the most used regimens were rituximab/obinutuzumab (R/O) (used 35% of the time in 1L, 33% in 2L, and 31% in 3L) and bendamustine + R/O (39% in 1L, 33% in 2L, and 21% in 3L). Mean duration of 1L treatment was longer for patients who only initiated 1L (10.1 months) vs. those with R/R FL who went on to initiate 2L and 3L (7.5 and 7.4 months, respectively). As R/R FL patients who initiated 3L moved through LoTs, increases were observed in the number of patients with at least 1 inpatient admission (17% in 1L and 31% in 3L) and with at least 1 emergency room visit (27% in 1L and 41% in 3L). Mean total all-cause costs per-member per-month (PMPM) also increased with each subsequent LoT ($15,917 in 1L, $17,767 in 2L, and $18,266 in 3L). In addition, mean total all-cause costs of R/R FL patients defined as POD24 and double refractory were higher in 3L; $20,172 PMPM and $21,724 PMPM, respectively). Conclusions: In this elderly R/R FL population, similar therapies were used across multiple LoTs. With each subsequent LoT, treatment duration shortened and notably, costs and HCRU increased. Additionally, patients defined as POD24 and double-refractory experienced higher costs. This research highlights a substantial unmet need in R/R FL for novel therapeutic options that can provide better outcomes and reduce HCRU.

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

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