Follicular Lymphoma Patients Research Articles

Impact of the Immune Landscape in Follicular Lymphoma: Insights into Histological Transformation in the Rituximab Era.

Background: Follicular lymphoma (FL) presents significant clinical heterogeneity, with some patients experiencing transformation into an aggressive disease, a key contributor to FL-related mortality. Based on gene expression profiles, this study aimed to provide insights into immunological differences associated with transformation. Methods: Gene expression analysis using the NanoString nCounter Tumor Signaling 360 Panel was performed on diagnostic lymphoma samples from 70 FL patients diagnosed in the rituximab era, either non-transforming FL (nt-FL, n = 34) or subsequently transforming FL (st-FL, n = 36), with paired high-grade transformed FL (tFL, n = 36) samples available. In silico immunophenotyping was performed to infer immune cell infiltration using the CIBERSORTx algorithm. Results: The gene expression analysis revealed 164 significantly differentially expressed genes, distinguishing st-FL from nt-FL and generally presenting an upregulation of B cell-related genes (CD40, IRF4, RELB), immunosuppressive molecules (IL10, SOCS3), and immune checkpoint molecules (CD276, TIM3). Analysis of immune cell proportions indicated significant differences in infiltrates of M1-like macrophages (p = 0.007) and neutrophils (p = 0.012) in nt-FL versus st-FL samples. Transformation-free survival (TFS) was associated with high numbers of both these cellular subsets (p = 0.006 and 0 = 0.002, respectively). This was even more evident when combined with inferior TFS in lymphomas with high infiltrates of both cell types (p < 0.001). 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). Conclusion: 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.

Utilizing Clinical Transformation Criteria for Prognostic Stratification in Follicular Lymphoma Prior to Initial Immunochemotherapy.

Although the prognosis of follicular lymphoma (FL) has improved, some patients experience early disease progression, including progression of disease within 24 months (POD24). Histological transformation is a critical event in FL. However, the heterogeneity of FL tumors makes it challenging to diagnose transformation accurately. We retrospectively applied the clinical transformation criteria used for FL transformation assessments at relapse or disease progression to conduct transformation assessments before the initial immunochemotherapy. Sixty-six FL patients who first received immunochemotherapy between January 2009 and February 2023 at our institution were selected. Twenty-three were clinical-transformation-positive (CLT+). The progression-free survival (PFS) rate of the CLT+ patients was significantly lower than that of the clinical-transformation-negative (CLT-) patients. In the POD24 assessment subgroup, the CLT+ patients had a higher incidence of POD24 than the CLT- patients. There was no significant difference in PFS between the patients treated with CHOP-like regimens and those treated with bendamustine regimens. In the CHOP-like group, the CLT+ patients exhibited significantly lower PFS than the CLT- patients. In the bendamustine group, the clinical transformation did not affect PFS. Clinical transformation criteria may be useful for the prognostic stratification of FL prior to immunochemotherapy. Additionally, they may serve as predictors of POD24.

B-227 Customized molecular tests for minimal residual disease: a tool for therapeutic decisions in follicular lymphoma patients

Abstract Background Monitoring of minimal residual disease (MRD) is based on accurate laboratory tests which can recognize a small fraction of malignant cells that survived the course of treatment. Several studies of the B-non-Hodgkin lymphoma group have been presented that MRD positivity at the end of treatment is a negative prognostic index. Follicular lymphoma (FL) is a chronic indolent malignancy, which response highly to immuno-chemotherapy followed by prolonged remissions but with inevitable relapse in most patients. The GALLIUM study showed that immuno-chemotherapy combinations, 6 cycles of bendamustine-obinutuzumab (BO), is the most efficacious treatment, but with severe side effects .In addition, 90% of patients achieved negative MRD from peripheral blood (PB) or bone marrow (BM) after only 3 BO cycles. These findings raise the possibility for MRD based treatment approach, where the duration of chemotherapy could be decided according to MRD status at mid-induction (MI). Identification of a marker in the PB and/or BM of each FL patient which will be use to the design of a sensitive RQ-PCR test for MRD detection for follow-up. Methods Qualitative PCR for translocation 14:18 and for the VDJ rearrangement sequence of the immunoglobulin heavy chain was used for marker identification. MRD monitoring was done by RQ-PCR. MRD monitoring for VDJ was designed specifically to each patients based on his VDJ sequence. MRD was assessed on PB and BM at MI. Results Marker for monitoring was identified at 11/21 patients in this study. After 3 combined therapy cycles, 7 patients were found to have MRD negativity by RQ-PCR therefore continue with immuno-therapy only. MRD positivity was assessed in BM of 3 patients (0.11%, 0.022%, and 0.133%). These 3 patients continued with the combined therapy. RQ-PCR sensitivity was 10-4-10-5. Conclusions This study will reveal the ability to use sensitive and specific MRD that has to be designed for each patient according to his marker and enable the establishment of a treatment with a high safety profile for FL patients. Correlation between MRD status and clinical and safety parameters will be assessed at the end of the study, 30 months after the first treatment, taking into account MRD status from different time point of the follow-up period.

Outcomes for high-risk defining events in follicular lymphoma following frontline immunochemotherapy

Progression of follicular lymphoma (FL) or transformation (tFL) within 24 months of immunochemotherapy (ICT) represent high-risk defining events (HRDE) with poor overall survival (OS). We examined baseline clinical characteristics, imaging and outcomes for patients experiencing HRDE in an international retrospective cohort of newly diagnosed FL patients requiring ICT. We defined HRDE groups as: relapse or progression of FL within 24 months (FL24); Early TFL (transformation <24 months of ICT); Late TFL (transformation >24 months of ICT). 433 patients were categorised: reference FL n=352 (no HRDE), FL24 n=43, Early TFL n=29, or Late TFL n=9. Chemotherapy regimens included bendamustine (63%), CHOP (27%) or CVP (10%); 85% received rituximab/15% obinutuzumab and 48% received maintenance therapy. Compared to the reference FL group, OS from HRDE was inferior for FL24 (HR 3.93, 95% CI 2.14-7.23), Early TFL (HR 8.16, 95% CI 4.38-15.2) and Late TFL (HR 8.23, 95% CI 3.18-21.25). OS from HRDE was inferior for Early TFL compared to FL24 (HR 2.08, 95% CI 1.02-4.21). In multivariable analysis, baseline performance status, elevated lactate dehydrogenase, elevated beta-2-microglobulin and grade 3A were associated with Early TFL. Clinical characteristics were not able to differentiate Early TFL from FL24. Standardised uptake value max was higher in Early TFL but not FL24 compared to reference FL. Early TFL and FL24 represent different HRDEs in FL after ICT and are associated with inferior OS. Distinguishing between early TFL and FL24 is important for biomarker development, management and to develop and interpret clinical trials in this area of unmet need.

Maximum disease diameter is associated with outcomes in stage II follicular lymphoma treated with radiation therapy alone

PurposeThe optimal management of stage II follicular lymphoma (FL) is unclear. Radiation therapy (RT) alone has been the gold standard treatment, but a proportion of patients relapse. We sought to characterize outcomes and prognostic factors for stage II FL treated with RT alone to identify a high-risk subgroup of patients who may benefit from treatment intensification. MethodsThis was a population-based, province-wide, retrospective study. Included patients had grade 1–3A, non-mesenteric, stage IIA or IIAE FL diagnosed between 1986 and 2016 and treated with curative-intent (≥20 Gy) RT alone. Results102 patients were included. Median follow-up was 10.4 years (range, 0.3–22.3). Median age was 59 years (range, 33–86). Median greatest disease diameter was 3.6 cm (range, 1.5–11.5). Freedom from progression (FFP) was 60.3% at 5 years and 40.7% at 10 years. Overall survival (OS) was 89.2% at 5 years and 81.8% at 10 years. Greatest disease diameter of >3.6 cm was associated with inferior FFP (10-year FFP 34% vs. 47%, p = 0.013) on univariable analysis and inferior FFP (hazard ratio [HR] 1.87, p = 0.019) and inferior OS (HR 2.12, p = 0.027) on multivariable analysis (MVA). Older age was associated with inferior OS (HR 1.08, unit = 1 year, p < 0.001) on MVA. Conclusions40.7% of stage II FL patients treated with RT alone remained disease-free at 10 years. Greatest disease diameter >3.6 cm was associated with inferior FFP and OS, representing a novel prognostic indicator in this population that may help in the decision-making process on whether to complement RT with systemic therapy.

Impact of positive CD4 cells on event-free survival in follicular lymphoma patients.

Previous results about prognostic value of CD4+ T cells in follicular lymphoma (FL) remain controversial. Immunohistochemistry was used to examine expression of positive CD4 cells in 103 patients with FL 1-3A. Early failure was described as failing to achieve event-free survival (EFS) at 12 or 24 months. There were 49 (47.6%) male and 54 (52.4%) females, with a median age of 54 years. Compared to patients with <20% of positive CD4 cells, patients with ≥20% of positive CD4 cells exhibited a significant lower risk of early failure (2-year EFS rate: 56.7% vs 73.5%, p = 0.047). When patients were stratified based on positive CD4 cell combined with FLIPI, the median EFS (p = 0.002) and median OS (p = 0.007) were significantly different. This study demonstrated that higher expression of positive CD4 cells predicts lower risk of early failure in follicular lymphoma, and combination analysis of CD4 and FLIPI could better predict disease relapse and survival outcome.

805MO Real-world efficacy and safety of tisagenlecleucel (CTL019) for relapse or refractory follicular lymphoma patients included in the early access program through the French DESCAR-T registry

805MO Real-world efficacy and safety of tisagenlecleucel (CTL019) for relapse or refractory follicular lymphoma patients included in the early access program through the French DESCAR-T registry

Multi-omics profiling of longitudinal samples reveals early genomic changes in follicular lymphoma

Follicular lymphoma (FL) is the most common indolent type of B-cell non-Hodgkin lymphoma. Advances in treatment have improved overall survival, but early relapse or transformation to aggressive disease is associated with inferior outcome. To identify early genetic events and track tumor clonal evolution, we performed multi-omics analysis of 94 longitudinal biopsies from 44 FL patients; 22 with transformation (tFL) and 22 with relapse without transformation (nFL). Deep whole-exome sequencing confirmed recurrent mutations in genes encoding epigenetic regulators (CREBBP, KMT2D, EZH2, EP300), with similar mutational landscape in nFL and tFL patients. Calculation of genomic distances between longitudinal samples revealed complex evolutionary patterns in both subgroups. CREBBP and KMT2D mutations were identified as genetic events that occur early in the disease course, and cases with CREBBP KAT domain mutations had low risk of transformation. Gains in chromosomes 12 and 18 (TCF4), and loss in 6q were identified as early and stable copy number alterations. Identification of such early and stable genetic events may provide opportunities for early disease detection and disease monitoring. Integrative analysis revealed that tumors with EZH2 mutations exhibited reduced gene expression of numerous histone genes, including histone linker genes. This might contribute to the epigenetic dysregulation in FL.

CREBBP histone acetyltransferase domain mutations predict response to mTOR inhibition in relapsed/refractory follicular lymphoma.

Despite the clinical and molecular heterogeneity of follicular lymphoma (FL), there remains a lack of biomarker-directed therapeutic approaches in routine clinical practice, with the notable exception of the EZH2 inhibitor tazemetostat in EZH2-mutant FL. Here we examined whether gene mutation status predicts response to clinical mTOR inhibitors (mTORi) in FL, by performing targeted mutational profiling of biopsies from 21 relapsed/refractory FL patients treated with mTORi everolimus or temsirolimus within clinical trials. We observed an enrichment of mutations within the catalytic histone acetyltransferase (HAT) domain of CREBBP in mTORi-responders, and describe distinct transcriptional characteristics and co-occurring mutations of FL harbouring these mutations; reinforcing the growing appreciation of CREBBPHAT mutation as a key biological determinant and its promise as a therapeutic biomarker in FL.

High Risk of Transformation and Secondary Malignancies in Follicular Lymphoma Patients Treated With First-Line Bendamustine Rituximab and Rituximab Maintenance

High Risk of Transformation and Secondary Malignancies in Follicular Lymphoma Patients Treated With First-Line Bendamustine Rituximab and Rituximab Maintenance

IBCL-550 High Risk of Transformation and Secondary Malignancies in Follicular Lymphoma Patients Treated With First-line Bendamustine Rituximab and Rituximab Maintenance

IBCL-550 High Risk of Transformation and Secondary Malignancies in Follicular Lymphoma Patients Treated With First-line Bendamustine Rituximab and Rituximab Maintenance

Single gene mutations and prognosis in limited-stage follicular lymphoma treated with radiation therapy.

Radiotherapy is routinely used for management of limited-stage follicular lymphoma (FL), yet half of patients ultimately relapse. We hypothesized that the presence of specific gene mutations may predict outcomes. We performed targeted sequencing of a 69-gene panel in 117 limited-stage FL patients treated with radiotherapy and identified recurrently mutated genes. CREBBP was most frequently mutated, and mutated CREBBP was associated with inferior progression-free survival, though not after false discovery rate adjustment. This association failed to validate in an independent cohort. We conclude that recurrent gene mutations do not predict outcomes in this setting. Alternative biomarkers may offer better prognostic insight.

Abstract Mo027: Impact of Ventricular Arrhythmias On Outcomes of Patients with Follicular Lymphoma

Background: Follicular lymphoma (FL) is typically a slow-growing form of non-Hodgkin lymphoma (NHL) that arises from B-lymphocytes. Large-scale studies are lacking for the outcomes of patients with ventricular arrhythmias and FL. We retrospectively reviewed FL patients with ventricular tachycardia utilizing the National Inpatient Sample (NIS) database. Our analysis aimed to identify risk factors that worsen outcomes in patients with FL and ventricular arrhythmias and evaluate the impact of ventricular arrhythmias on in-hospital outcomes of patients with FL. Methods: Data were extracted from the National Inpatient Sample (NIS) 2016-2019 Database. The NIS was searched for hospitalizations for adult patients with FL as the principal discharge diagnosis with and without ventricular arrhythmias as a secondary diagnosis using ICD-10 codes. The primary outcome was inpatient mortality. Multivariate logistic and linear regression analysis was used accordingly to adjust for confounders. STATA software was used for analysis. Results: This study included 15,795 patients with FL of which 225 had ventricular arrhythmias. Patients with both FL and an associated ventricular arrhythmia had higher inpatient mortality (OR 5.44, CI 2.48-11.93, p&lt;0.0001), hospital length of stay (LOS) (+5.48 days, CI 3.27-7.68, p&lt;0.0001) and total hospital charges (TOTHCG) (+$109,117.3, CI $65,702.9- $152,531.7, p&lt;0.0001). In this patient population, the secondary analysis revealed that mortality was increased if patients had a cardiac arrest (OR 25.62, CI 1.36-484.48, p&lt;0.031). LOS was increased in the presence of an acute kidney injury (+0.34 days, 0.04-0.64, p&lt;0.026). Conclusions: Our study revealed that patients with FL and ventricular arrhythmias had increased mortality, hospital LOS, and TOTHCG, as well as much higher rates of complications, including cardiac arrest and acute kidney injury, compared to those without ventricular arrhythmias. Efforts to prevent, monitor, and aggressively manage ventricular arrhythmias in patients with FL will improve overall outcomes.

Exposure to obinutuzumab does not affect outcomes of SARS-CoV-2 infection in vaccinated patients with newly diagnosedadvanced-stage follicular lymphoma.

URBAN is a multicentric, ambispective study evaluating the effectiveness and safety of obinutuzumab-based immuno-chemotherapy and maintenance in patients with untreated advanced follicular lymphoma (FL). The study began before the COVID-19 emergency declaration in Italy. It is currently ongoing for follow-up, and the enrolment timeline encompassed different stages of the pandemic, various vaccination roll-out phases and prevalence of SARS-CoV-2 variants. Outcomes of interest of the present sub-analysis included SARS-CoV-2 infection rates and COVID-19-related hospitalizations/deaths. At data cut-off, 86 (28.8%) and 213 patients (71.2%) were treated before and during/after the COVID-19 outbreak respectively; 294 (98.3%) completed the induction, 31 (10.4%) completed maintenance and 170 (56.9%) were still on maintenance. Overall, 245 patients (81.9%) received at least one SARS-CoV-2 vaccine dose: 13.5%, 31.4% and 55.1% received one, two and three doses respectively. We observed a substantial decrease in COVID-19-related mortality rates in pre- versus post-vaccination phases, along with a reduction in COVID-19-related outcomes due to the shift from alpha/delta to omicron variant predominance. No differences emerged between patients given maintenance or not, although the schedule was modified in 65% of cases. To our knowledge, URBAN represents the largest dataset of COVID-19-related outcomes in FL patients extensively exposed to obinutuzumab. ClinicalTrials.gov identifier: NCT04034056.

Baseline 18F-FDG PET/CT may contribute to the determination of initial treatment strategy for newly diagnosed follicular lymphoma

Background“Watch-and-wait” approach is an important management option in asymptomatic follicular lymphoma (FL) patients with low tumor burden. Since most FL lesions are FDG-avid, we wonder if 18F-FDG PET/CT at baseline can help to better choose the patients who can benefit from early chemotherapy. This study aimed to investigate the prognostic value of baseline 18F-FDG PET/CT in newly diagnosed FL patients treated with either watch-and-wait approach or chemotherapy. ResultsPatients received chemotherapy as initial treatment had higher Ann Arbor stage, higher incidence of extranodal involvement and bulky disease, more involved lymph nodes larger than 3 cm, and higher SUVmax, MTV, and TLG than those managed with watch-and-wait approach (p < 0.05). The median PFS and TTNT in patients received chemotherapy and under watch-and-wait did not show significant difference, however patients with MTV<111.66 mL or TLG<141.50 SUVbw*mL had significantly longer PFS and TTNT than those patients with MTV≥111.66 mL or TLG≥141.50 SUVbw*mL (p < 0.05). Further analysis revealed that for patients with TLG≥141.50 SUVbw*mL or MTV≥111.66 mL, those who received chemotherapy as initial treatment had a significantly longer PFS and TTNT than those managed with initial watch-and-wait approach (p < 0.05). However, for patients with MTV<111.66 mL or TLG<141.50 SUVbw*mL in baseline PET/CT, there was no significant difference in PFS or TTNT between patients who received chemotherapy and those under watch-and-wait. ConclusionBaseline 18F-FDG PET/CT may provide prognostic value and help to improve the decision-making of initial treatment plans for newly diagnosed FL patients.

Impact of Primary Disease Site of Involvement by Early-Stage Follicular Lymphoma on Patient Outcomes

IntroductionFollicular lymphoma is a common non-Hodgkin lymphoma that can start in a diverse array of tissues throughout the body. While the majority of patients may be able to live many years with this disease, cure remains very difficult to achieve. ObjectiveWe sought to investigate the impact of follicular lymphoma primary disease site in early-stage disease on patient outcomes using a large national database. MethodsBaseline demographic and disease data for patients diagnosed with follicular lymphoma from 2000-2015 was identified and extracted from the NCI Surveillance, Epidemiology, and End Results (SEER) database. Primary disease sites were grouped into one of two cohorts: nodal disease (lymph nodes and spleen) and extranodal disease (everything else). Analysis was performed using summary statistics, Kaplan-Meier method, and Cox-proportional hazards models for univariate and multivariate analysis. ResultsA total of 13,400 patients were included in the final analysis and the majority were non-Hispanic white (81%), with stage I (63%), and nodal FL (79%). Median overall survival for nodal disease was 15.1 years [95% CI (14.6-15.6)] while median overall survival for extranodal disease was 15.8 years [95% CI (14.9-16.3)]. Overall survival was slightly better for patients with extranodal disease [HR = 0.89, 95% CI (0.84-0.96); p-value = 0.00012]. This finding remained consistent after controlling for age and race [HR = 0.84, 95% CI (0.79-0.90); p-value <0.0001]. ConclusionsThe primary site of involvement by early-stage follicular lymphoma may have an impact on patient outcomes and warrants further investigation.

Efficacy and safety of MIL62, a novel glycoengineered type Ⅱ anti-CD20 monoclonal antibody, combined with lenalidomide in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma: a multicentre, single-arm, phase 1b/2 trial

MIL62, a novel glycoengineered type Ⅱ anti-CD20 monoclonal antibody, with a nearly completely afucosylated N-glycans in Fc region, has demonstrated superior activity compared with rituximab and obinutuzumab invitro and invivo, respectively. This multicentre, single-arm, phase 1b/2 trial aimed to explore the efficacy, pharmacokinetics, and safety of MIL62 combined with lenalidomide in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or marginal zone lymphoma (MZL). Eligible patients included those who had histopathologically confirmed CD20 positive FL (grade 1-3a) or MZL and failed to be treated with rituximab. Patients received intravenously infused MIL62 1000mg (cycle 1: day 1, 15; cycles 2-8: day 1, cycles 10 and 12: day 1) combined with oral lenalidomide (once a day, days 2-22, the initial dose was 10mg, and the maximum dose was 20mg) for 12 cycles, 28 days as a cycle. The primary endpoint was objective response rate (ORR) assessed by investigator per Lugano 2014 criteria every 3 cycles. This study was registered in ClinicalTrials.gov (NCT04110301). Between November 22, 2019 and December 22, 2020, 54 patients were enrolled from 11 hospitals in China and received study treatment. Fifty patients were included in the efficacy analysis set, and 43 patients (86%, 95% CI: 73, 94) achieved objective response, meeting the pre-specified primary endpoint. Disease control rate was 96% (48/50, 95% CI: 86, 100), proportion of patients with duration of response (DoR) > 6 months was 77% (33/43). The median follow-up for survival was 12.3 months (IQR 12.0-12.6). The 1-year progression-free survival rate was 72% (95% CI: 57, 83), 9-month DoR rate was 74% (95% CI: 58, 85), and 1-year overall survival rate was 98% (95% CI: 85, 100). Most common TRAEs were neutropenia (93%, 50/54), leukopenia (85% 46/54), thrombocytopenia (61% 33/54), lymphopenia (32% 17/54), and alanine aminotransferase increased (20% 11/54). MIL62 combined with lenalidomide showed promising efficacy in patients with R/R FL and MZL. A multicentre, randomized, open-label, phase Ⅲ trial of MIL62 combined with lenalidomide versus lenalidomide in anti-CD20 monoclonal antibody refractory FL patients is ongoing (NCT04834024). Beijing Mabworks Biotech Co. Ltd, Beijing China and the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

Abstract PO-023: CD70 deregulation in follicular lymphoma at diagnosis is associated with relapse and opens new avenues for dual CD19-CD70 CAR-T therapy

Abstract Follicular lymphoma (FL) is the most common indolent B-cell lymphoma. Despite most patients achieve a complete response with first-line treatment, an important fraction of them relapse, which may worsen the prognosis and increase the risk of a histological transformation to aggressive lymphoma. Therefore, there is a need to better stratify the patients at the diagnosis and develop tailored therapies for high-risk patients. Here we have assessed the immune profile (Nanostring® nCounter) in FFPE-derived biopsies in a series of FL patients at diagnosis, homogenously treated with immunochemotherapy regimen (mostly R-CHOP), and followed-up at Hospital Clínic de Barcelona for more than 12 years. By comparing patients who experienced relapse (n=20) with those who did not relapse at any time (NR, n=12), we have found 31 differentially expressed genes, 25 of them up-regulated in the relapse group. Among them, we have further focused on the role of CD70 in FL pathogenesis. mRNA CD70 was higher in those patients who eventually relapsed and correlated with inferior PFS. Moreover, CD70high FL cases bear a limited number of recurrent somatic mutations. We next sought to determine the specific subpopulations expressing CD70 by multiplex immunofluorescence (Vectra Polaris). Interestingly, we have demonstrated it is mainly expressed in tumor cells correlating with inferior PFS. Moreover, a fraction of T cells from the tumor microenvironment also expresses CD70. Intriguingly, higher levels of CD70 were detected in both CD4+ and CD8+ T cells in the relapse group, including T regulatory and T follicular helper cells. CD70 interacts with CD27, its only known ligand, and can be mutually activated. While CD27 RNA levels did not change between groups, CD27 protein was increased in the B cell population in patients who eventually relapse and in TFH cells, while it was down-regulated in CD8+ and CD4+ T helper non-follicular cells. Furthermore, we found an association between the percentage of CD70+ cells within B cell population and CD70+ in CD4+ and CD8+ cells (R=0.51, p &amp;lt; 0.05). To investigate the role of CD70 in FL pathogenesis we generated two CD70 KO cell lines and FL patient derived cells (n=4) using CRISPR/Cas9 technique. By co-culturing T cells from healthy donors with CD70+ or CD70- FL cell lines, we observed CD70+ tumor cells promote CD70 expression in T cells. In primary samples, we have demonstrated that CD70-KO B cells exhibit reduced response to proliferative stimuli. Moreover, RNAseq analysis followed by GSEA pathway assignment indicated that CD70 expression was related to increased angiogenesis, glycolysis and hypoxia. Finally, to advance towards personalized therapies for this high-risk patient and taking advantage of our institution CAR-T program, we have generated a dual CD19-CD70 CAR-T combining an approved academic product, ARI-0001, and a truncated CD27 protein. Finally, we have demonstrated that this novel CAR-T is effective in both cell lines and ex vivo FL spheroids (PDLS, Dobaño-López, Blood Cancer J 2024), while in vivo studies are ongoing. Citation Format: Ferran Araujo-Ayala, Mireia Bachiller, Raluca Alexandru, Pablo Mozas, Salut Colell, María Villalba-Esparza, Judith Mateos-Jaimez, Ferran Nadeu, Andrea Rivero, Maria Ros, Cèlia Dobaño-López, Juan Garcia Valero, Neus Serrat, Marta Gimenez-Alejandre, Ariadna Giro, Daniel Hodson, Armando López-Guillermo, Elias Campo, Dolors Colomer, Alba Maiques-Diaz, José Ignacio Martín-Subero, Sílvia Beà, Laura Magnano, Sonia Guedan, Carlos E. de Andrea, Patricia Pérez-Galan. CD70 deregulation in follicular lymphoma at diagnosis is associated with relapse and opens new avenues for dual CD19-CD70 CAR-T therapy [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-023.

Abstract PR07: SETD1B mutations confer apoptosis resistance and BCL2 independence in B-cell lymphoma

Abstract The translocation t(14;18) activates BCL2 and is considered the initiating genetic lesion in over ninety percent of follicular lymphomas (FL). Surprisingly, FL patients respond poorly to clinically approved inhibitor, venetoclax. The mechanisms underlying BCL2 independence in FL are poorly understood, and it has been speculated that epigenetic rewiring of cell death programs may play a role. We performed separate genome-wide CRISPR/Cas9 screens to explore the mechanisms of resistance to Venetoclax and an experimental MCL-1 inhibitor (S63845) and unveiled the histone lysine methyltransferase SETD1B (KMT2G) as an unexpected mechanism of resistance to both inhibitors in lymphoma. We show that mutations and deletions affecting SETD1B occur in 7% of FLs and 16% of diffuse large B cell lymphomas (DLBCL). In vivo, SETD1B acts as a tumor suppressor gene and cooperates with the related histone-lysine N-methyltransferase 2D (KMT2D) gene leading to a more aggressive disease presentation. This oncogenic cooperation is reflected in the genomes of human lymphoma, where SETD1B mutations typically co-occur with KMT2D mutations. Mechanistically, SETD1B is required to express pro-apoptotic BCL2 family proteins like BIM and BIK. Inhibitors of the KDM5 histone H3K4 de-methylase restore the expression of BIM and BIK, venetoclax sensitivity and lead to synergistic drug effects in SETD1B deficient lymphoma xenografts. Our results highlight a role for SETD1B in the epigenetic regulation of cell death proteins in B cell lymphomas, connecting the loss of SETD1B to lymphoma development and reduced sensitivity to venetoclax. Citation Format: Ana Portelinha, Shenqiu Wang, Sara Parsa, Man Jiang, Sagarajit Mohanty, Soumya Sharma, Neeraj Arya, Omid Tavana, Jiayu Wen, Jude Fitzgibbon, Ahmet Dogan, Ana Younes, Ari M. Melnick, Hans-Guido Wendel. SETD1B mutations confer apoptosis resistance and BCL2 independence in B-cell lymphoma [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PR07.

Matching-Adjusted Indirect Comparisons of Axicabtagene Ciloleucel to Mosunetuzumab for the Treatment of Relapsed/Refractory Follicular Lymphoma

Axicabtagene ciloleucel (axi-cel) was the first chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL) patients, while mosunetuzumab was the first bispecific monoclonal antibody approved in this population. In the absence of head-to-head evidence, this study sought to conduct a matching-adjusted indirect comparison (MAIC) to estimate the comparative efficacy and safety of these treatments in 3rd line or higher (3L+) FL. The evidence base consisted of individual patient data (IPD) of all enrolled patients, regardless of infusion status, from the single-arm axi-cel trial, ZUMA-5 (NCT03105336), and aggregate data from the mosunetuzumab FL trial (NCT02500407) from publications identified through a systematic review. Efficacy outcomes were progression-free survival (PFS), duration of response (DoR), objective response rate (ORR), complete response rate (CRR). Analyses used independent central review for both trials, where possible. Safety outcomes were cytokine release syndrome (CRS), neurological events (NE), and treatment-related adverse events (TRAEs). Unanchored MAICs were conducted to align ZUMA-5 to the patient characteristics of the mosunetuzumab trial. For each outcome, prognostic factors were identified a priori through quantitative analysis and clinical experts. For time-to-event outcomes, hazard ratios (HRs) were estimated using Cox regression using IPD from ZUMA-5 and pseudo-IPD extracted from Kaplan-Meier plots for mosunetuzumab. Patient characteristics were well-aligned between trials leading to large effective-sample sizes after matching, ranging from 93.4 to 115.5, for ZUMA-5 (n = 127). In comparisons to mosunetuzumab (n = 90), axi-cel was associated with improved PFS (HR: 0.39; 95% confidence interval [CI]: 0.24-0.62) and DoR (HR: 0.45; 95% CI: 0.27-0.76). Similarly, axi-cel led to higher ORR (OR: 3.87; 95% CI: 1.53-9.76) and CRR (OR: 2.80; 95% CI: 1.50-5.26). Although axi-cel was associated with a higher rate of all-grade CRS (OR: 5.54; 95% CI: 2.63-8.94) and NEs (OR: 3.54; 95% CI: 1.28-9.83), differences in grade ≥3 CRS and TRAEs were not statistically significant. Findings from this study show improved efficacy and more durable response for the treatment of 3L+ R/R FL with axi-cel relative to mosunetuzumab, with increased odds of all-grade CRS and NE, but not G3+ CRS and TRAEs.