Follicular Lymphoma

P1, N=18, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=40 --> 18

P2, N=37, Recruiting, David Bond, MD | Trial primary completion date: Dec 2024 --> Dec 2025

P1, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting

Notably, a reduction in CD4 + T cells, predominantly contributing to treatment-related T-cell reduction, was only observed in patients undergoing Bendamustine-based regimens...Overall, FL patients demonstrated compromised T-cell immunity, with a lower CD4 + T cell count at diagnosis correlating with treatment response and early progression. Therefore, monitoring CD4 + T cells at diagnosis might reflect immune status and aid in stratifying FL patients.

Here, we review FoxO1's roles across B cell and myeloid malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and multiple myeloma (MM). We also discuss preclinical evidence for FoxO1 targeting by currently available inhibitors (AS1708727, AS1842856, cpd10).

P1, N=154, Completed, Xencor, Inc. | Active, not recruiting --> Completed | N=270 --> 154 | Trial completion date: Jan 2025 --> Apr 2024 | Trial primary completion date: Oct 2024 --> Apr 2024

Six weeks later, while receiving the CD20-directed immunotherapies glofitamab and obinutuzumab, another bone marrow biopsy revealed eradication of the B-ALL and new involvement by pure erythroid leukemia (PEL). This patient's B-ALL lacked an IGH::BCL2 fusion resulting from t(14; 18), suggesting it did not arise through transformation of his prior FL/DLBCL. Instead, the B-ALL was likely caused by his extensive exposure to genotoxic chemotherapy drugs – including alkylating agents – for his preceding lymphomas. The shared cytogenetic and molecular features between this patient's B-ALL and PEL imply they are clonally related.

Our NGS testing found tier 1 or 2 variants in the majority of cases, supporting its use in the clinical setting. Additionally, a subset of variants identified with the pan-Heme list likely represents mutations of clonal hematopoiesis of indeterminate potential, which could be removed with a more lymphoma-specific gene list. Given these findings, and a growing number of targets in indolent B cell lymphomas, future studies focusing on evaluation of a lymphoma-specific gene list is of interest for clinical validation and implementation.

P1, N=0, Withdrawn, University Health Network, Toronto | N=40 --> 0 | Recruiting --> Withdrawn

P1, N=16, Active, not recruiting, Sana Biotechnology | Recruiting --> Active, not recruiting | N=57 --> 16 | Trial completion date: Dec 2027 --> Nov 2038 | Trial primary completion date: Dec 2026 --> Nov 2025

P=N/A, N=45, Not yet recruiting, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

P2, N=170, Not yet recruiting, Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

P2, N=164, Recruiting, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

P1/2, N=80, Recruiting, Beijing Tiantan Hospital, Capital Medical University; Hyperway Pharmaceutical Co.,Ltd.

P1/2, N=112, Recruiting, Shanghai AbelZeta Ltd. | Phase classification: P1b/2 --> P1/2 | N=72 --> 112 | Trial completion date: Mar 2027 --> Dec 2027 | Trial primary completion date: Mar 2027 --> Oct 2025

Our single center analysis confirmed AITL as the most common variant of nTFHL. AITL and non-AITL appear similar regarding clinical presentation, molecular profile, and outcomes. DNMT3A adversely impact outcomes, as previously reported.

Updated long-term follow-up from the ELARA trial continues to demonstrate robust durable responses >4 years post infusion, alongside a favorable safety profile. Correlative analyses suggest that most baseline high-risk disease characteristics (double-refractory disease, bulky disease, POD24, and high FLIPI) are not associated with inferior efficacy following tisagenlecleucel infusion in pts with r/r FL. Furthermore, high frequencies of MRD-negative status were achieved in a subset of evaluable pts.

After transformation, tFL samples showed a reduction in T follicular helper cells (p=0.008) and an increase in immunosuppressive M2-like macrophages and neutrophils (p<0.001 and p=0.028, respectively). By elucidating the distinct molecular and immune landscapes of FL at the time of diagnosis and transformation, this study underscores the importance of immune microenvironment in FL transformation and patient outcome.

These findings underscore the significance of pre-treatment systemic inflammation (e.g. serum TNFa levels), product T cell phenotype, TMTV, CAR T-cell expansion, tumor IFN signaling and FLIPI as independent factors associated with clinical outcomes in patients with r/r FL treated with axi-cel. These results offer insights into mechanisms of resistance and toxicity, risk stratification, combination therapy and development of next-generation CAR-T therapy for patients with r/r FL.

Three pts were unevaluable for progression at 2y due to non-progression events including a second malignancy, sudden death, and hemolytic anemia requiring rituximab... Circulating tumor DNA is detectable in baseline plasma of >90% pts with untreated FL. Quantitative ctDNA levels correlate with both FLIPI and TMTV and are associated with earlier need for treatment. Serial ctDNA monitoring shows fluctuating levels that correlate with tumor burden on CT which provides a non-invasive method to monitor disease.

With a 3-year follow-up, epcoritamab continued to show deep and durable responses, with more than half of complete responders remaining in remission at 3 years: median duration of CR, 36.1 mo. Sustained MRD negativity was observed. Long-term safety was consistent with prior reports.

With over 3 years of follow-up, single-agent epcoritamab demonstrated deep and durable responses and manageable side effects in CAR T–naive pts with R/R LBCL, as demonstrated by this subgroup analysis. Results were consistent with those seen in the overall EPCORE NHL-1 LBCL population, considering differences in baseline characteristics, and show that epcoritamab can be administered safely and effectively before or after CAR T for the treatment of R/R LBCL.

For patients (pts) with R/R FL, rituximab + lenalidomide (R2) is an approved and widely accepted regimen based on results from the AUGMENT trial (overall response rate [ORR], 78%; complete response [CR] rate, 34%; estimated 2-y progression-free survival [PFS], 58%). With more than 2 y of follow-up, fixed-duration epcoritamab + R2 continued to show deep and durable responses (CR rate, 87%; estimated 24-mo DOCR, 75%) in pts with R/R FL, irrespective of high-risk features. Considering limitations of cross-trial comparisons, these results (estimated 2-y PFS, 70%) compare favorably with those reported for R2 alone in the AUGMENT trial (estimated 2-y PFS, 58%). The depth of responses was underscored by MRD negativity in 88% of evaluable pts.

Median prior lines of therapy was 3 (range 2–12), 18 (38%) pts received prior lenalidomide–based therapy, 7 (15%) pts received prior chimeric antigen receptor T-cell therapy (CAR-T), and 4 (9%) received prior CD20 TCE therapy. AZD0486 offers high response rates in pts with R/R FL at target doses ≥2.4 mg. Responses were durable. 2SUD allows safe administration of the target dose up to at least 15 mg.

Results from the ongoing ATALANTA-1 study show a manageable overall safety profile, with low rates of Grade ≥3 CRS and ICANS and high antitumor activity in all NHL subtypes studied. GLPG5101, a fresh, stem-like, early memory CD19 CAR T-cell therapy manufactured using a rapid decentralized platform, showed robust in vivo expansion and durable persistence. Treatment with GLPG5101 led to promising efficacy and safety across indications in heavily pretreated pts with R/R NHL.

P2, N=39, Recruiting, University of Rochester | Trial completion date: Jul 2024 --> Jul 2026 | Trial primary completion date: Jul 2024 --> Jul 2026

P2, N=59, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

P1/2, N=24, Recruiting, Jonsson Comprehensive Cancer Center | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

P2, N=184, Recruiting, Genmab | Trial primary completion date: Aug 2027 --> May 2029

P2, N=622, Recruiting, Genmab | Trial completion date: Jun 2031 --> Nov 2032 | Trial primary completion date: Jun 2031 --> Nov 2032

Finally, all acute myeloid leukaemia (n = 52) and most T-cell non-Hodgkin lymphoma (n = 31/32) tested samples were negative for ROR1 via IHC. In conclusion, ROR1 shows a heterogeneous tumour cell expression profile across multiple leukaemias and lymphomas, making it a tumour target that would require different patient selection strategies to develop novel therapeutic modalities.

P=N/A, N=200, Recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

P1, N=133, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Jun 2040 --> Oct 2024

We will detail the diagnostic criteria for FL and emphasize the importance of genetic and mutational analyses in accurately characterizing and distinguishing FL subtypes. Furthermore, we will propose methodologies and best practices for the diagnostic work-up of FL to enhance diagnostic accuracy.

Our study confirms the close relationship between CD20 and EC. Anti-CD20 antibodies may exert a protective effect on EC and reduce the risk of EC morbidity, providing a reference for future clinical diagnosis and treatment. However, further clinical verification of our results is warranted.

P2, N=42, Active, not recruiting, University of Washington | Recruiting --> Active, not recruiting | Trial completion date: Dec 2025 --> Mar 2025 | Trial primary completion date: Dec 2025 --> Mar 2025

P1, N=165, Recruiting, AbbVie

P2, N=55, Not yet recruiting, Epizyme, Inc. | Trial completion date: Sep 2027 --> Apr 2029 | Trial primary completion date: Sep 2027 --> Apr 2029

GATA3 is a useful marker for differentiating CHL from B-cell non-Hodgkin lymphomas but its efficiency is limited in ALK (-) ALCL and mediastinal grey zone lymphomas. Due to the heterogeneous reaction diagnostic value is limited in core needle biopsies.

P1/2, N=50, Recruiting, University of Washington | Trial completion date: Mar 2030 --> Mar 2031 | Trial primary completion date: Mar 2025 --> Mar 2026

P1/2, N=18, Completed, University of Colorado, Denver | Active, not recruiting --> Completed

P1, N=78, Completed, Sanjay Mohan | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Sep 2024