Kridel, Robert

Abstract A short diagnosis-to-treatment interval independently predicts inferior outcomes in follicular lymphoma. Using international discovery and validation cohorts, we demonstrate its prognostic value beyond established prognostic indices, with implications for risk stratification, clinical trial design, and interpretation.

Background and Significance When patients (pts) with follicular lymphoma (FL) present with a high tumor burden, they require systemic treatment with rituximab (R) in combination with chemotherapy (chemo). Given the known cumulative toxicities of chemotherapy and the older age of pts at the time of diagnosis, novel chemo-free treatment approaches are desired by pts as well as physicians. R-lenalidomide (R-Len), a chemo-free alternative to R-based chemoimmunotherapy, has recently been listed as a chemo-free option in the National Comprehensive Cancer Network® (NCCN) guidelines. Golcadomide (GOLCA) is a potential first-in-class oral cereblon E3 ligase modulator (CELMoD™) agent purposefully designed for the treatment of lymphoma. GOLCA co-opts cereblon to induce targeted degradation of the transcription factors Ikaros/Aiolos, inducing deep, rapid, and extensive tumor killing, independent of cell of origin, and enhanced immunostimulatory activity. Compared with immunomodulatory (IMiD) agents like lenalidomide, GOLCA more efficiently drives the cereblon complex to the closed active state resulting in more potent degradation (Watson ER et al, Science 2022), which is expected to translate into improved clinical benefit. In addition, the phase 1/2 study CC-99282-NHL-001 showed that GOLCA alone or in combination with R (GOLCA-R) was well tolerated and showed promising activity in pts with heavily pre-treated relapsed/refractory (R/R) FL, including in those with prior Len-based therapies and/or T cell-redirecting therapies (Chavez et al, EHA 2024). Based on this, GOLSEEK-2 (NCT06425302) is a randomized phase 2 trial assessing the efficacy and safety of GOLCA-R as a chemo-free option in pts with newly diagnosed advanced-stage FL. Study Design and Methods After a screening period of ≤ 5 weeks, approximately 90 pts with newly diagnosed advanced-stage FL will be randomized 1:1:1 between GOLCA plus rituximab at a dose of 0.2 mg or 0.4 mg once daily from day 1 to 14 every 28 days for 12 cycles or investigator's choice R-chemo (R-CHOP or R-bendamustine). R maintenance could be considered (as per pt and physician decision) for pts who achieve a partial response or better after completion of initial therapy for up to one year in GOLCA-R arms and up to one and a half years in the R-chemo arm. Pts with histologically confirmed diagnosis of grade 1, 2, 3a FL, or classic FL according to WHO classification would be eligible for the study. Other key inclusion criteria include no prior systemic treatment for FL, stage II-IV disease, the requirement for treatment as per investigator's judgment, and measurable disease as defined by Lugano 2014 criteria. Key exclusion criteria include other lymphoma subtypes, clinical evidence of transformed lymphoma, and documented or suspected central nervous system involvement. The primary endpoint is complete metabolic response (CMR) during the GOLCA plus rituximab combination treatment period, assessed by the investigator and based on Lugano 2014 Response Criteria. Secondary endpoints include progression-free survival, overall survival, overall response rate, duration of response, complete response rate at 30 months, CMR rate at 6 months and 12 months, and safety outcomes.

Abstract Background: CD20 antibody plus alkylator and/or anthracycline based immunochemotherapy (IC) is a standard frontline therapy for patients with follicular lymphoma (FL) with 10-year event-free survival (EFS) and overall survival (OS) rates of approximately 50% and 80% respectively in long-term follow-up of clinical trials. Currently available clinical prognostic indices for FL have been designed using PFS and OS endpoints. Early events, commonly defined as progression of disease within 24 months (POD24) or early transformation to a more aggressive histology, are associated with inferior outcomes and increased risk of death due to refractory FL. Timely identification of the minority of patients with elevated mortality risk might enhance clinical management and research strategies. The FLIPI24 Consortium was created to develop a clinical prognostic index using early events as the primary endpoint. We report the outcomes for the pooled cohort and investigate the implications of therapy patterns on potential model development. Methods: Individual patient data were pooled and harmonized from 11 prospective observational cohorts from Europe, North America, and Australia. Patients who were diagnosed with grades 1-3A FL and initiated frontline IC were eligible. EFS was defined as time from start of IC to progression, relapse, retreatment (2nd line), histologic transformation, or death due to any cause. Early events were defined using status at 24 months from start of IC. OS was defined as time from start of IC to death due to any cause. Kaplan Meier curves and Cox proportional hazards models were used to evaluate outcomes by clinical features and therapy types. Results: 9006 patients were abstracted and harmonized, 6111 patients initiated frontline IC between 2002 and 2018 and were included in this analysis. Median age at diagnosis was 61 years (IQR 52-69) and 50% were male. Complete FLIPI data were available in 5637 patients (92%) and 46%, 32%, and 22% were low, intermediate, and high risk, respectively. IC type was 3079 R-CHOP or like (50%) , 1529 R-CVP or like (25%), 918 R-bendamustine (B-R) or like (15%), and 585 fludarabine or other alkylator based IC (10%); 3187 received CD20 antibody maintenance (52%). Patients receiving R-CHOP were younger, more frequently grade 3A, and more frequently had elevated LDH; differences in other characteristics by IC type were not clinically meaningful. At median follow-up of 42 months (IQR 17-72), 2647 patients (43%) had an event (any) and 1494 patients (25%) died. Median survival after an early (non-death) event was 49 months (95% CI: 41-58); 5-year OS was 46% (95% CI: 43-49) compared to 89% (95% CI: 88-90) in patients without POD24. Across all IC types, EFS estimates at 2 and 10 years from start of IC were 80% (95% CI:79-81) and 49% (95% CI:48-51) and OS estimates were 92% (95% CI: 91-92) and 70% (95% CI: 69-72), respectively. FLIPI was highly associated with both EFS (c-statistic=0.61) and OS (c-statistic=0.65) from the initiation of IC (both p<0.0001). There were significant differences in EFS and OS by IC type (both p<0.0001) and use of maintenance was associated with prolonged EFS in landmark analyses at both 6 and 12 months from initiation of IC (both p<0.0001). Treatment patterns changed significantly over the study timeframe. Use of B-R and/or maintenance increased to 30% and 70% respectively in N=2937 patients treated in 2010-2018 (Era2) compared to <1% and 40% respectively in N=3174 patients treated 2002-2009 (Era1). EFS was significantly higher for Era2 compared to Era1 (HR=0.77, 95% CI: 0.71-0.83), which remained significant after adjustment for FLIPI (EFS HR=0.82, 95% CI: 0.76-0.89). However, the association between treatment eras and overall survival was weaker (HR=0.89, 95% CI: 0.79-0.99) and not significant after adjusting for baseline FLIPI (OS HR=0.99, 95% CI: 0.88-1.10). Conclusion: EFS and OS from this large pooled analysis of observational cohorts is similar to long-term follow-up of randomized clinical trials in the IC era and support the use of these data for model development. Modeling efforts for early events should adjust for initial IC selection and use of maintenance therapy. Utilization of bendamustine and/or maintenance therapy increased over the study timeframe from 2002-2018, and Era2 was associated with improved EFS but not OS. This cohort provides comprehensive and robust observational data to define clinical predictors in IC treated patients. Figure 1 Figure 1. Disclosures Maurer: Genentech: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Flowers: Janssen: Research Funding; Takeda: Research Funding; National Cancer Institute: Research Funding; Biopharma: Consultancy; BeiGene: Consultancy; Amgen: Research Funding; Celgene: Consultancy, Research Funding; Xencor: Research Funding; Acerta: Research Funding; Bayer: Consultancy, Research Funding; Sanofi: Research Funding; 4D: Research Funding; Adaptimmune: Research Funding; Allogene: Research Funding; EMD: Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Kite: Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Denovo: Consultancy; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Genmab: Consultancy; Epizyme, Inc.: Consultancy; Novartis: Research Funding; Nektar: Research Funding; Morphosys: Research Funding; Iovance: Research Funding; Spectrum: Consultancy; Pfizer: Research Funding; Ziopharm: Research Funding; Guardant: Research Funding; Eastern Cooperative Oncology Group: Research Funding; SeaGen: Consultancy; Pharmacyclics/Janssen: Consultancy; Genentech/Roche: Consultancy, Research Funding; Pharmacyclics: Research Funding. Villa: Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; NanoString Technologies: Honoraria. Weibull: Jansen-Cilag: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support. Ghesquieres: Janssen: Honoraria; Mundipharma: Consultancy, Honoraria; Roche: Consultancy; Celgene: Consultancy, Honoraria; Gilead Science: Consultancy, Honoraria. Kridel: Gilead Sciences: Research Funding. Gandhi: Janssen: Research Funding; Novartis: Honoraria. Cheah: Celgene: Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: advisory; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; AstraZeneca: Consultancy, Honoraria, Other: advisory; AbbVie: Research Funding; Beigene: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory; Gilead: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding. Hawkes: Gilead: Membership on an entity's Board of Directors or advisory committees; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Antigene: Membership on an entity's Board of Directors or advisory committees; Regeneron: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; Specialised Therapeutics: Consultancy; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Seymour: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Freeman: Amgen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria, Speakers Bureau; Incyte: Honoraria; Abbvie: Honoraria; Teva: Research Funding; Roche: Research Funding; Janssen: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau. Clausen: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Gilead: Consultancy, Other: Travel expences 15th ICML ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wahlin: Gilead Sciences: Research Funding; Roche: Consultancy, Research Funding. Link: Novartis, Jannsen: Research Funding; Genentech/Roche: Consultancy, Research Funding; MEI: Consultancy. Ekstroem Smedby: Janssen Cilag: Research Funding; Takeda: Consultancy. Sehn: Genmab: Consultancy; Novartis: Consultancy; Debiopharm: Consultancy. Trněný: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Celgene: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. El-Galaly: ROCHE Ltd: Ended employment in the past 24 months; Abbvie: Other: Speakers fee. Cerhan: Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; Regeneron Genetics Center: Other: Research Collaboration; Genentech: Research Funding; NanoString: Research Funding.

Abstract Introduction : Follicular lymphoma (FL) remains an incurable malignancy as patients eventually experience progressive disease. A subset of patients is at risk of early lymphoma-related mortality due to histological transformation (TFL) to aggressive lymphoma (2-3% of patients per year) or early progression after immuno-chemotherapy, each of which leads to shortened survival. Mutations associated with transformation and/or early progression have been reported in the literature (e.g. CDKN2A, TP53, B2M) and the m7-FLIPI clinico-genetic risk model defines a high-risk patient group with poor failure-free survival after first-line treatment. However, the current knowledge of genetic alterations underlying transformation and/or early progression is inadequate to explain the majority of transformed cases and accurately predict early progressive disease. Materials and Methods: We performed targeted capture-based sequencing of 94 genes in a large cohort of fresh-frozen and formalin-fixed and paraffin-embedded patient specimens (402 samples in total). This cohort comprised 277 samples from 159 patients that experienced transformation (including 128 samples at T1 (the time of FL) and 149 samples at T2 (the time of transformation) with 118 paired biopsies) and 125 samples from 125 patients (pre-treatment samples only) presenting with either early progression within 2.5 years after starting immunochemotherapy (n=41) or late or never progression for at least 5 years after starting immunochemotherapy or observation (n=84). Mutations were called using MutationSeq and putative single nucleotide polymorphisms were filtered out using either matching germline samples (n=84) or dbSNP (v147). Bayesian proportion tests were used to compare the prevalence of gene mutations between groups. Results : We first compared T1 (n=128) and T2 (n=149) samples from 159 patients experiencing transformation. Eleven genes were more commonly altered in transformed lymphoma. These included genes that had previously been associated with transformation, such as TP53, B2M, MYC and EBF1, as well as genes that have not yet been implicated as contributing to this process, for example EZH2, CCND3, PIM1 and ITPKB. Moreover, mutations in GNA13, S1PR2 and P2RY8, that have been implicated in dissemination of germinal centre B cells, were enriched in T2 samples. In addition, cell-of-origin classification was available for 108 of the TFL cases with DLBCL histology, 18 and 90 of which were of the ABC and GCB subtype, respectively. Although the number of ABC-TFL cases was small, we observed higher percentages of BCL10 (16% versus 1%, Fisher P=0.004), CD79B (22% versus 4%, Fisher P=0.005) and MYD88 mutations (28% versus 9%, P=0.006) in ABC-TFL than in GCB-TFL, suggesting that B-cell receptor signaling and NF-κB signaling are important contributors to the ABC phenotype in TFL. Next, we assessed the association of gene mutations with patient outcomes contrasting early progressers (n=41) and late or non-progressers (n=84). Eleven genes were mutated more commonly in early progressers than in late progressers, including KMT2C, TP53, BTG1, MKI67, XBP1 and SOCS1. Overall, 32 out of 41 early progressers (78%) had mutations in at least one of the 11 early progression-associated genes, but none of the individual early progression-associated genes were mutated at a frequency > 22%. Thus, early progression appears to be related to relatively infrequent genetic alterations. None of the early progression-associated gene mutations form part of the m7-FLIPI outcome predictor. Furthermore, in our cohort that was enriched for clinical extremes, the m7-FLIPI was similarly associated with early progression when compared to the FLIPI but it was not superior, having higher specificity (89% versus 76%), but lower sensitivity (36% versus 63%). Conclusions: We found novel associations of gene mutations with transformation and showed that TFL is molecularly heterogeneous, with the ABC subtype being characterized by differential gene mutation when compared to the GCB subtype. With regards to progressive disease after immuno-chemotherapy, our approach identified early progression as a distinct clinico-genetic disease category that is imperfectly captured by traditional prognostic tools. Disclosures Connors: Seattle Genetics: Research Funding; Bristol Myers Squib: Research Funding; F Hoffmann-La Roche: Research Funding; NanoString Technologies: Research Funding; Millennium Takeda: Research Funding. Scott:NanoString Technologies: Patents & Royalties: named inventor on a patent for molecular subtyping of DLBCL that has been licensed to NanoString Technologies.

Abstract Although recent advances in molecular genetics have enabled improved risk classification of follicular lymphoma (FL) using, for example, the m7-FLIPI score, the impact on treatment has been limited. We aimed to assess the prognostic significance of copy-number aberrations (CNAs) and copy-neutral loss of heterozygosity (cnLOH) identified by chromosome genomic-array testing (CGAT) at FL diagnosis using prospectively collected clinical trial specimens from 255 patients enrolled in the SWOG study S0016. The impact of genomic aberrations was assessed for early progression (progressed or died within 2 years after registration), progression-free survival (PFS), and overall survival (OS). We showed that increased genomic complexity (ie, the total number of aberration calls) was associated with poor outcome in FL. Certain chromosome arms were critical for clinical outcome. Prognostic CNAs/cnLOH were identified: whereas early progression was correlated with 2p gain (P = .007; odds ratio [OR] = 2.55 [1.29, 5.03]) and 2p cnLOH (P = .005; OR = 10.9 [2.08, 57.2]), 2p gain specifically encompassing VRK2 and FANCL predicted PFS (P = .01; hazard ratio = 1.80 [1.14, 2.68]) as well as OS (P = .005; 2.40 [1.30, 4.40]); CDKN2A/B (9p) deletion correlated with worse PFS (P = .004, 3.50 [1.51, 8.28]); whereas CREBBP (16p) (P < .001; 6.70 [2.52, 17.58]) and TP53 (17p) (P < .001; 3.90 [1.85, 8.31]) deletion predicted worse OS. An independent cohort from the m7-FLIPI study was explored, and the prognostic significance of aberration count, and TP53 and CDKN2A/B deletion were further validated. In conclusion, assessing genomic aberrations at FL diagnosis with CGAT improves risk stratification independent of known clinical parameters, and provides a framework for development of future rational targeted therapies.

Key Points The posttreatment end point progression of FL within 24 months (POD24) is strongly associated with OS. A pretreatment clinicogenetic risk model (m7-FLIPI) predicts POD24 and OS and identifies the smallest subgroup with highest unmet need.