Citations

Abstract Background Single-agent R is a common 1st-line therapy for patients (pts) with FL, especially those with low-tumor burden advanced stage disease or comorbidities. EO is a therapeutic vaccine generated from non-self-protein sequences from gut bacteria, including 4 HLA-A2 CD8 T cell epitopes that mimic B cell-specific markers: CD20, CD22, CD37 and BAFF-receptor. EO also contains a CD4 helper epitope UCP2. EO expands pre-existing memory CD8 T cells recognizing non-self-protein sequences from gut bacteria which can cross-react with B cell antigens on tumor cells. The aim adding EO to R is to safely increase the depth and duration of responses. Methods Cohort 3 (C3) of trial EONHL1-20/SIDNEY includes pts with HLA-A2 and previously untreated low-tumor burden (GELF) FL grade 1-3A in need of treatment (per pt/treating physician). Pts receive EO (300μg/peptide) SC with adjuvant Montanide, q2 weeks (w) x 4, then q4w for a total of 12 doses, combined with R starting at w7 (375 mg/m2 IV q1w x4, then q8w x4). For immune responses blood mononuclear cells were assayed by flow cytometry and EO-mimic or B cell peptide specific tetramers without in vitro stimulation. The primary objective is to assess safety; secondary objectives include EO immunogenicity and preliminary efficacy. Results As of July 2025, the 6 planned pts had started EO. Median age was 66 years (range 46-73); 5 ECOG 0/1 ECOG 1; 1 Ann Arbor stage III/5 stage IV; FLIPI low risk 2/intermediate 2/high 2; FLIPI-2 low risk 2/intermediate 4. At median follow-up 10.6 months (mo) 4 pts completed and 2 are ongoing on EO. Median treatment duration was 43 w (range 2-43). Best response by Lugano in the 6 pts included 4 complete (CR) and 2 partial responses (PR). Median time to PR/CR was 17.1 w (range 6.0-18.0). Currently there is only 1 (not yet confirmed) progression at 20.5 mo. All 5 immune response evaluable pts had expansion of CD8 T cells specific for EO mimic and B cell target peptides during treatment; 4 of 5 had detectable expansions at w5 (1st testing time). Currently, the longest tested immune response is at w65 and positive for both EO mimic and B cell target peptides. Expanded specific CD8 T cells had a memory phenotype predominantly composed of effector memory (TEM) cells but also including central memory (TCM) and terminally differentiated effector memory CD8 T (TEMRA) cells. Across the 5 pts, the medians of max % (sum of specific CD8 T cells targeting either the 4 EO mimic peptides or the 4 B cell antigen epitopes at a specific timepoint) among all peripheral CD8 T cells were 0.71% (range 0.19-3.97) for EO mimic and 0.33% (0.20-1.30) for B cell target peptides. The most common EO-related adverse events (AEs) were local administration site reactions (erythema, pain, induration). These included Gr (Grade) 1 reactions in 3 pts, Gr 2 in 1 pt, and Gr 3 in 1 pt; latter being ulceration with EO-interruption at w10.1, and in context of a strong immune response against EO mimic [3.97% of all peripheral CD8 T cells at w5] and B cell target [1.30%] peptides, and CR from w16.7. Other EO related AEs were Gr 1 lymph node pain (1 pt), and related to both EO and R were Gr 2 urticaria (1 pt) and Gr 1 fatigue (1 pt). Only R related were Gr 2 infusion related reaction (3 pts), Gr 2 enterocolitis infection (1 pt), and in 1 pt each Gr 1 flushing, anemia, headache and diarrhea. There were no further Gr 3-4 AE and no death on treatment/follow-up. Complete B cell depletion was seen in 5 pts tested at w18 (R added w7); no recovery in the range of w30-65. Only 3 infections were reported, per above enterocolitis, and 2 cases of COVID-19 both resolved without sequalae. ConclusionsThe combination of EO with R has a predictable and manageable safety profile, with EO only adding local administration site reactions to the well-known R safety profile. In this feasibility cohort all evaluable pts developed a specific immune response against EO and B cell targets, and a Lugano objective response. The combination of EO and R is feasible and can be evaluated in further trials. Updated results will be presented at the meeting.

Abstract Background: Acute myeloid leukemia (AML) with TP53 alteration (TP53alt), including deletion (TP53del) detected by cytogenetics (CG) (karyotype, FISH, or genomic microarray) and/or TP53 mutation (TP53mut) identified by next-generation sequencing, is associated with poor prognosis. However, a subset of patients may achieve long-term survival after allogeneic hematopoietic cell transplantation (allo-HCT). Patient-, disease-, and transplant-related variables may inform risk stratification and improve treatment decision-making in this high-risk population. We used the CIBMTR registry to investigate outcomes of patients with TP53alt AML undergoing allo-HCT. Methods: We included adult patients with 2017 ELN adverse-risk AML who underwent first allo-HCT between 2013–2019 and had available CG and molecular data. TP53del was centrally reviewed by expert cytogeneticist. Patients were stratified into three TP53alt groups: Group 1 (TP53mut+/ TP53del+), Group 2 (TP53mut −/ TP53del+), and Group 3 (TP53mut+/ TP53del −). The control group comprised patients with 2017 ELN adverse-risk AML negative for both TP53mut and TP53del. Patients from embargoed centers, lacking consent or comprehensive research data, or missing CG and molecular information were excluded. Results: Of 6,474 patients with adverse-risk AML, 703 patients with TP53alt met inclusion criteria: Group 1 (n=203), Group 2 (n=271), Group 3 (n=229). The control group included 2,763 patients. Median age was 58 years (44% ≥60); 44% were female; 16% had Karnofsky score <90, and 52% had HCT-CI ≥3. Secondary AML was more frequent in TP53alt groups (32%, 27%, 27%) versus control (21%) (p<.01). Complex and monosomal karyotypes were most common in Group 1 (61%), followed by Group 2 (54%), Group 3 (31%), and control (6%), p<.01. More patients in Groups 1 and 2 (28% each) underwent HCT in primary induction failure/relapse (PIF/Rel) versus Group 3 (19%) and control (19%), p<.01. Median time from diagnosis to transplant was 5 months (1-331). Donor type was matched related in 23%, matched or mismatched unrelated in 50%, haploidentical in 18%, and umbilical cord blood in 7%. Conditioning intensity was myeloablative (MA) in 51%; reduced-intensity (RIC) in 36% , and 13% non-MA (NMA). Post-transplant cyclophosphamide (PTCy) was used in 27%; and in vivo T-cell depletion (ATG or alemtuzumab) in 26%. After median follow-up of 66 months (3-130), 5-yr OS was 18% (Group 1), 18% (Group 2), 35% (Group 3) vs 46% in controls (p<0.001). 5-yr LFS was 14%, 15%, and 28%, respectively, vs 38% (p<0.001). 5-yr CIR was 69%, 66%, and 52% vs 43% (p<0.001). Transplant-related mortality (TRM) was similar across groups (1-year: 12–16%). On multivariate analysis, compared with controls, TP53del (with or without TP53mut) was independently associated with higher relapse risk: Group 1 HR 1.97, Group 2 HR 1.91, Group 3 HR 1.45 (all p<0.001). These findings translated into inferior OS (HR 1.94, 1.87, and 1.45, respectively, p<0.001). PIF/Rel and CR2+ were also associated with worse survival (HR 2.58 (p<0.001) and 1.18 (p<0.001, respectively). No significant difference was observed between MA and RIC for relapse, while non-myeloablative regimens (HR 1.65; p<0.001) were associated with higher CIR. In vivo T-cell depletion increased relapse risk (HR 1.22; p=0.004). TRM was not influenced by TP53alt status; it was impacted by age, KPS, time from diagnosis to HCT, and GVHD prophylaxis regiment (non-PTCy). Conclusions: This large, registry-based study with long term median follow-up showed that among patients with adverse-risk AML, TP53alt is a strong independent predictor of poor post-HCT outcomes in AML, particularly when TP53del is present. Patients with TP53del , with or without concurrent TP53mut, experienced the worst outcomes, followed by those with isolated TP53mut. Despite the limitations of registry data including lack of information on timing of TP53mut, variant allele frequency (VAF), number of mutations, or accurate information on measurable residual disease (MRD), these findings reinforce the adverse prognostic impact of TP53alt and support its inclusion in risk stratification frameworks. While some patients with TP53alt —particularly those with isolated mutations—may benefit from allo-HCT, relapse remains the dominant cause of failure. Future studies incorporating TP53 functional status, VAF, clonal architecture, specific CG, MRD, and novel transplant approaches are warranted.

Abstract Introduction There is currently no standard-of-care for patients (pts) who cannot tolerate full dose anthracycline regimens in frontline large B-cell lymphoma (LBCL). R-miniCHOP is a commonly used regimen that provides curative intent treatment with manageable toxicity. Despite this, lymphoma and treatment-related mortality are the leading causes of death in these pts. Additionally, many pts may not be eligible to receive R-miniCHOP due to comorbidity or frailty. There are limited clinical trial and real-world data focused on this population. Methods Pts with LBCL age 18 years (yrs) and older were identified from the Lymphoma Epidemiology of Outcomes (LEO) cohort, a prospective study of newly diagnosed pts with non-Hodgkin lymphoma enrolled from 2015-2020 at 8 academic medical centers in the US. Pts with LBCL were included in this analysis if they had received R-miniCHOP or a regimen that did not include an anthracycline (nonAC). NonAC regimens included R-CVP, BR, rituximab, radiation and lenalidomide and rituximab. Pts completed the Vulnerable Elders Survey (VES-13) and were considered vulnerable if they had a score >3. Event-free survival (EFS) was defined as the time from start of treatment until progression/relapse, retreatment, or death due to any cause; EFS at 24 months (EFS24) was a secondary endpoint. Overall survival (OS) was defined as the time from start of treatment until death due to any cause. EFS and OS for R-miniCHOP and non-IC groups, as well as vulnerable and not vulnerable by VES-13 were estimated using Cox models. Results A total of 190 pts received R-miniCHOP (N=139) or nonAC (N=51). R-miniCHOP-treated pts were older (median 82 vs 72 yrs) and more commonly female (55% vs 35%). The majority in both groups (86% vs 78%) received their treatment at a LEO center and did not receive therapy on a clinical trial (89% vs 100%). Most pts receiving R-miniCHOP had high-intermediate (32%) or high (30%) international prognostic index (IPI) score, while both high-intermediate (22%) and high (20%) IPI were lower in the nonAC-treated pts. Cell of origin was determined by immunohistochemistry as available clinically, with GCB 42% vs 31%, non-GCB 32% vs 29%, and not done/unknown 26% vs 39% in R-miniCHOP vs nonAC pts. Double-hit status by FISH was known in 115 pts and was positive in 13% of R-miniCHOP pts and 10% of nonAC pts. The diagnosis-to-treatment interval (DTI) was ≤14 days in 30% of R-miniCHOP pts and 24% of nonAC pts. Of pts who had a VES-13 score (N=119), vulnerable status trended higher in the R-miniCHOP (66%) vs the non-IC group (50%; p=0.15). With a median follow-up of 50.5 months, the median EFS was 37.1 months and median OS was 50.0 months. R-miniCHOP, compared with non-IC, was associated with improved EFS (unadjusted HR=0.54, 95% CI 0.36-0.81; p=0.003) and OS (unadjusted HR=0.58, 95% CI 0.38-0.88; p=0.011). When adjusted for age, IPI, LBCL subtype (diffuse large B-cell lymphoma, not otherwise specified vs other), DTI and VES-13, R-miniCHOP was strongly associated with improved EFS (HR=0.26, 95% CI 0.14-0.50; p<0.001) and OS (adjusted HR=0.29, 95% CI 0.15-0.57; p<0.001). EFS24 rate was 56% in all pts and was superior in pts treated with R-miniCHOP vs non-IC (62.7% vs 34.1%; p=0.001). In the R-miniCHOP group, vulnerable status (adjusted for IPI) was associated with inferior OS (HR=2.22, 95% CI 1.09-4.50; p=0.028) and trended towards inferior EFS (HR=1.76, 95% CI 0.93-3.32; p=0.083). In a competing-risk cumulative-incidence analysis, lymphoma was the leading cause of death for pts receiving R-miniCHOP at 2 (0.16, 95% CI 0.11-0.24) and 5 (0.20, 95% CI 0.14-0.28) yrs, as well as for those receiving non-IC at 2 (0.35, 95% CI 0.24-0.53) and 5 (0.38, 95% CI 0.26-0.56) yrs. Treatment-related mortality was similar in both groups. In the R-miniCHOP group, the 2-yr (0.20 vs 0.03) and 5-yr (0.20 vs 0.11) lymphoma-related mortality was higher in pts who were vulnerable vs not by VES-13, while there were no differences for mortality due to therapy or other causes by vulnerable status. Conclusions These data support R-miniCHOP as a curative regimen in older and frail pts with the majority achieving EFS24. R-miniCHOP compared to non-IC use is strongly associated with improved EFS and OS when adjusted for disease and patient related variables. Within the R-miniCHOP group, vulnerable status is associated with inferior OS. Additional research efforts are needed to optimize outcomes for this group of pts.

Abstract Introduction LINVO, a human B-cell maturation antigen (BCMA)xCD3 bispecific antibody, was recently approved for triple-class exposed (TCE) RRMM after ≥3 prior therapies (EU) or ≥4 prior lines of therapy (US), demonstrating high efficacy and a generally manageable safety profile. Combining LINVO with an anti-CD38 mAb, such as DARA or ISA, may provide additional benefit to pts with RRMM. Here we report pooled safety and efficacy results from the LINVO + DARA and LINVO + ISA cohorts during the dose-finding portion of the Phase 1b LINKER-MM2 trial (NCT05137054). Methods Eligible pts were aged ≥18 years with RRMM that progressed after ≥3 lines of therapy (LoTs), or ≥2 LoTs if TCE or double-class refractory (immunomodulatory drug [IMiD] + proteasome inhibitor [PI]). Prior treatment (tx) with DARA or ISA was allowed if previously tolerated and ≥6 months (mos) or ≥3 mos washout, respectively, had elapsed since last exposure. Tx began with LINVO monotherapy (Cycle [C]0; 28-day cycle) consisting of 2 step-up doses (5 mg, 25 mg) and 2 full doses (dose level [DL]1 100 mg; DL1b 150 mg; DL2 200 mg) before standard dosing of DARA or ISA was added at C1. LINVO was given once weekly in C1–3 and once every 2 weeks in C4+. At the end of 2024, dosing once every 4 weeks was implemented after C6 if a very good partial response or better (≥VGPR) was achieved. Dexamethasone premedication was required during the first 2 cycles and then given per label for DARA or ISA. Primary endpoints: dose-limiting toxicities (DLTs) and tx-emergent adverse events (TEAEs). Key secondary endpoints: overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and rate of minimal residual disease (MRD) negativity. The analyses reported here combine the LINVO + DARA and LINVO + ISA cohorts. Results As of May 7, 2025, 42 pts were enrolled. All pts were included in the safety analysis set: DL1 (DARA, n=12; ISA, n=6), DL1b (n=6; n=10), or DL2 (n=8; n=0); 37 were included in the efficacy analysis set: DL1 (DARA, n=11; ISA, n=5), DL1b (n=5; n=9), or DL2 (n=7; n=0). At baseline, all pts had received ≥1 PI (refractory to ≥1 PI: 76%) or ≥1 IMiD (refractory to ≥1 IMiD: 86%), and 21 pts (50%) had received prior DARA or ISA (refractory to DARA or ISA: 33% [DARA, n=4; ISA, n=10]). Median number of prior LoTs was 3 (range 2–8), including 50% of pts with TCE and 21% with triple-class refractory disease. Median age was 68 years (range 42–86); male, 57%; ISS stage III at study entry, 12%; high-risk cytogenetics, 31%; bone marrow plasma cells ≥50%, 31%; and soft tissue plasmacytomas, 33% (extramedullary, 12%). Median follow-up duration was 14.8 mos for DL1 (DARA 21.3; ISA 11.3), 7.6 mos for DL1b (DARA 13.5; ISA 5.2), and 5.9 mos for DL2 (all DARA), with 44%, 50%, and 63% of pts still receiving tx, respectively. The most common TEAEs were anemia (any grade [Gr] 48%; Gr 3/4 26%), neutropenia (41%; 41%), diarrhea (38%; 2%), and thrombocytopenia (38%; 17%). Cytokine release syndrome was reported in 33% of pts (all Gr 1/2 events except 1 Gr 3 event during the step-up period that fully resolved). No pts experienced immune effector cell-associated neurotoxicity syndrome (ICANS). Infections were reported in 32 pts (any Gr 76%; Gr ≥3 40%), and 3 resulted in death (1 tx related: cytomegalovirus [CMV] pneumonia; 2 tx unrelated: C. diff colitis and lower respiratory infection). One DLT was observed at DL1b in the ISA cohort (Gr 3 Epstein–Barr virus pharyngitis) and 1 was observed at DL2 in the DARA cohort (Gr 5 CMV pneumonia). Among efficacy evaluable pts, ORR was 75% at DL1 (12/16; ≥VGPR rate 75%), 93% at DL1b (13/14; ≥VGPR rate 57%), and 86% at DL2 (6/7; ≥VGPR rate 86%). Of 10 MRD-evaluable pts, all were MRD negative (<10−5by clonoSEQ or EuroFlow). The 12-mo DOR rate was 79% (95% confidence interval [CI] 52–92; median DOR not reached) and 12-mo PFS rate was 73% (95% CI 53–86; median PFS not reached). Pharmacokinetic analyses showed LINVO concentrations were not affected by the addition of DARA or ISA. ConclusionsIn pts with heavily pretreated RRMM, half of whom had prior anti-CD38 mAb exposure, the combination of LINVO and DARA or ISA was feasible, inducing a high rate of deep and durable responses, and exhibiting a safety profile similar to that reported for each individual drug. These preliminary data support continued development of LINVO plus an anti-CD38 mAb for the tx of pts with MM.

Abstract Background: For LS-DLBCL, clinical trials (FLYER, LYSA/GOELAMS 02-03, LYSA LNH09-1B, S1001) have shown that 4 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP4) without radiation (RT) leads to durable remissions in >90% of cases. However, only patients (pts) with non-bulky disease and/or international prognostic index (IPI) of 0 and complete metabolic response (CMR) on interim positron emission tomography (PET) scan, if performed, were eligible for RCHOP4 alone in these studies. Outcomes in trial-ineligible LS-DLBCL and the appropriate real-world candidates for RCHOP4 are still undefined. Methods: We conducted a multicenter retrospective study of adult pts with stage I/II DLBCL of any tumor bulk, IPI and with or without B-symptoms diagnosed after 2011 and treated with RCHOP4 +/- 2 cycles R from 21 U.S. centers. Pts with PMBCL, PTLD or receiving non-standard dose RCHOP for cycle (C) 1 or planned consolidative RT were excluded. The primary endpoint was PFS from C1 by Kaplan-Meier method, not counting indolent lymphoma relapse. Event free survival (EFS) was time to next therapy without progression (including unplanned RT for non-CR), progression or death. A competing risks analysis of non-relapse mortality (NRM) vs. DLBCL progression was performed. Results: The characteristics of the 428 pts were: median age 60 (18-88), 60% male, 11% Hispanic and 4% non-Hispanic Black, 62% stage I, 15% elevated LDH, 3% ECOG PS>1, 5% tumor bulk >7cm, 9% had B-symptoms and median Charlson Comorbidity Index (CCI) was 4 (2-12). IPI was 0, 1 and 2-3 in 42%, 46% and 12% and stage-modified IPI (smIPI) was 0, 1, 2 and 3-4 in 25%, 48%, 21% and 6% of pts. 66% had nodal (59% head/neck, 11% pelvic, 9% multiple above diaphragm, 7% abdominal) and 46% extranodal sites (37% head/neck, 20% gastric/intestinal, 9% spleen, 8% skin/soft tissue); 6% had transformed/concurrent FL/MZL or grade 3B FL, 33% (138/408) were non-GCB cell of origin (COO), 25% (90/357) double expressor (DEL) and 0.5% (2/379) double-hit. 13% had completely resected disease, 97% staging PET and 47% bone marrow biopsy. Median diagnosis to treatment interval was 30 days (IQR 20-43), 6% had dose reductions after C1, 77% had an interim PET (iPET) after C2 (33%) or C3 (67%), 15% received 2 additional cycles R and 4% CNS prophylaxis. CMR rates by iPET were 83% after C2 and 94% after C3, and 95% by end-of-treatment PET. iPET PMR was more likely if smIPI>2 or bulky disease. Median follow-up time was 2.7 years. There were 32 progression events: 14 occurred at the primary site and 17 at distant sites (1 unknown), and 12 occurred after 2 years. Another 11 pts received unplanned RT after RCHOP4 for non-CR. There were 24 deaths, 12 without prior progression. Cause of death was DLBCL in 7 and non-DLBCL in 17 cases (6 infection, 2 ILD, 2 heart failure, 2 second cancer, 1 seizure, 4 unknown). EFS, PFS and OS rates were 88%, 90% and 96% at 3 years. By univariable Cox regression, Black race, elevated LDH, smIPI>2, DEL, increasing CCI, multiple subdiaphragmatic nodal sites and iPET PMR were associated with worse PFS. Non-significant variables of note included COO, extranodal sites, complete resection, missing bone marrow biopsy, missing iPET and additional cycles R. By multivariable analysis (including age>60, stage, ECOG PS>1, elevated LDH, bulky disease, CCI, B-symptoms and DEL), ECOG PS>1 (HR 3.95 p=0.050), CCI (HR 1.29 p=0.003) and DEL (HR 2.02 p=0.069) were associated with worse PFS. Cumulative incidence of DLBCL progression and NRM were 8% and 2% at 3 years. Competing risk analysis by univariable models found that age>60, ECOG PS>1, smIPI>2, elevated LDH, CCI and bulky disease were associated with NRM, while DEL and B-symptoms were associated with DLBCL progression.Conclusion: Presented is the largest retrospective cohort of LS-DLBCL treated uniformly with RCHOP4 to date. Despite modest follow-up time and lack of an “intention-to-treat“ population, this study shows that abbreviated RCHOP4 leads to excellent outcomes in the real-world, albeit with continuous risk of late relapse. smIPI risk factors were associated with worse PFS, though this may in part be driven by risk of non-lymphoma death. As pts with advanced age, poor performance status or comorbidities may benefit from reduced treatment exposure, RCHOP4 should still be considered for these and other “trial-ineligible” pts, particularly if other high-risk features (iPET PMR, DEL or B-symptoms) are absent.

Abstract Introduction Approximately 40% of patients with DLBCL will experience relapse after initial treatment with standard-of-care chemo-immunotherapy. Effective treatment options are limited for patients who experience first-line treatment failure, particularly for those with R/R disease following CAR T-cell therapy or those not able to receive CAR T-cell therapy (Sehn et al, N Engl J Med. 2021). GOLCA is a potential, first-in-class, oral CELMoD agent designed for the treatment of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA drives the closed, active conformation of cereblon to induce rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing (agnostic of cell of origin) and immunomodulatory activity. In the two-part, multicenter, first-in-human Phase 1/2 study (CC-99282-NHL-001; NCT03930953), GOLCA was well tolerated and effective in patients with R/R DLBCL (Bachy et al, ICML 2025, #148). Here, we provide longer follow-up in patients with R/R DLBCL from Part B of the study. Methods Patients with R/R DLBCL and disease progression after ≥ 2 lines of therapy or transplant-ineligible patients after ≥ 1 line of therapy were included in the study. Patients received GOLCA monotherapy orally, once daily at different dosing schedules in Part A. In Part B, GOLCA was dosed at 0.2 or 0.4 mg (14 days on/14 days off) ± R. Total GOLCA treatment duration was up to 2 years or until progressive disease (PD)/unacceptable toxicity. Primary objectives included safety and recommended Phase 2 dose determination. Results As of April 3, 2025, a total of 77 patients with R/R DLBCL were enrolled in Part B Cohort C (GOLCA 0.2 mg + R, n = 39; GOLCA 0.4 mg + R, n = 38). Median age was 66 years (range, 20–86). Patients were heavily pre-treated; median number of prior treatments was 4 (range, 1–11), 55% of pts had prior CAR T-cell therapy, 38% had prior bispecific antibody treatment, and 44% were refractory to last treatment. Ten patients (13%) were ongoing, 4 completed 2 y of treatment, and 63 (82%) had discontinued treatment, mostly due to PD (n = 48 [62%]). The most common any-grade (G) treatment-emergent adverse events (AEs) in the 0.2- and 0.4-mg cohorts, respectively, were neutropenia (54% and 84%), an on-target side effect of GOLCA, and anemia (44% and 45%). G3/4 neutropenia was reported in 49% of patients with 0.2 mg and 79% with 0.4 mg, and febrile neutropenia (FN) in 5% and 16%, respectively. Granulocyte colony-stimulating factor was used in 81% and 88% of patients with neutropenia and 50% and 100% of patients with FN in the 0.2-mg and 0.4-mg cohorts. Dose interruptions (mainly due to infections/neutropenia) occurred in 49% and 53% of patients and discontinuations due to AEs occurred in 10% and 3% with 0.2 and 0.4 mg. One G5 pneumonia was considered related to study treatment (0.2 mg). The median follow-up was 11.8 months (range, 3.1–35.1) with 0.2 mg and 16.2 months (range, 3.8–31.4) with 0.4 mg. The overall response rate (ORR) in efficacy evaluable patients was 34% (complete response rate [CRR], 20%) with 0.2 mg (n = 35) and 58% with 0.4 mg (n = 36), including a CRR of 44% with this dose. In patients with prior T-cell–redirecting treatment, the ORR was 33% (CRR, 22%) with 0.2 mg (n = 18) and 56% (CRR, 38%) with 0.4 mg (n = 16). Seven of 35 (0.2 mg) and 14 of 36 (0.4 mg) patients experienced durable response > 12 months. The median time to response with both 0.2 and 0.4 mg was 1.8 months. In patients with durable responses (remained in response [CR or partial response] for more than two consecutive efficacy assessments) to GOLCA, circulating tumor DNA reduction from baseline continues to deepen over time. Response was similar across clones/tumor variants. Conclusions With additional follow-up, GOLCA + R continued to demonstrate a predictable and manageable safety profile, with no new safety signals observed at longer follow-up. Durable responses were shown in heavily pretreated patients with R/R DLBCL, including those with prior T-cell–redirecting therapy. GOLCA + R induced a decrease in circulating tumor DNA across tumor variants. These data support the ongoing development of GOLCA + R in patients with R/R non-Hodgkin lymphoma.

Abstract Marginal zone lymphoma (MZL) is an uncommon non-Hodgkin B-cell lymphoma accounting for 7-10% of lymphoma diagnoses. Extranodal MZL (EMZL) of mucosa-associated lymphoid tissue (MALT) is the most common subtype (61%) of MZL. While the mutational landscape, chromosomal aberrations and transcriptome of nodal and splenic MZL have been extensively evaluated, the mutational landscape of EMZL has only been evaluated in a small number of patients and mainly by targeted sequencing. Consequently, the comprehensive genomic landscape of EMZL remains largely uncharacterized. Herein, we performed whole exome sequencing followed by targeted sequencing of potential tumor driver genes, copy number and/or RNA transcriptome analyses in 165 patients with pretreatment EMZL tumors involving 16 anatomic locations. All samples were collected and underwent expert review as part of the Atlas of Blood Cancer Genomes consortium. The most common anatomic locations were ocular adnexa (OAMZL) (n=35), gastric (n=25, including 6 positive for Helicobacter pylori), salivary glands (n=25), and lungs (n=24). Using common criteria for variant mutation calling and significant focal copy number (CN), we identified 1218 variants (1030 missense and 188 truncation mutations) across 174 genes and 2837 CN focal alterations (1614 copy gains and 1223 copy number losses). Of these genes, 44 and 11 were mutated in >5% and >10% of specimens, respectively. We detected variants identified previously by targeted sequencing in EMZL from different locations (e.g. TNFAIP3 (A20) (12%), TBL1XR1 (13%), SPEN (10%), CARD11 (7%), TET2 (7%) and CREBBP (6%)). We detected mutations in KLF2 (10 mutations in 8 EMZL patients) and PTPRD (7 mutations in 7 EMZL patients) that were previously suggested to be specific for splenic and nodal MZL, respectively. We also detected variants not previously reported in EMZL, including a transcriptional factor ZEB2, LRP1B,and others. The most frequently mutated gene in our study (25% of tumors) was IGLL5. Some mutations were limited to specific locations (e.g. ZEB2 mutations seen exclusively in gastric and salivary gland EMZL), while most were observed across all anatomic locations. There was no association between specific mutations and clonal IGHV, in contrast to previous reports. Using Enrichr tool, we observed enrichment of mutations in genes belonging to the B cell receptor activation, NOTCH signaling, Wnt-beta catenin signaling, NF-kB signaling , PI3K AKT signaling, DNA repair and other pathways. Chromosomal and copy number changes were also commonly observed including previously reported trisomy of chromosomes 3 and 18. Combining DNA mutations and CN alterations, the number of genetic lesions per tumor sample in the 174 mutated genes ranged from 0 to 95, with an average load of 17 lesions per case. RNA sequencing was successful in 159 EMZL tumors from 16 distinct anatomic locations. Unsupervised clustering using all genes with a median log2-normalized gene expression value greater than 5 and a standard deviation greater than 1 (1323 genes) demonstrated that the majority of gastric EMZL with and without H. pylori infections clustered together on 2 dendrograms as did most of the samples of OAMZL. Since the clustering could be forced by organ-specific and not tumor-specific gene expression, we next focused on the expression of the 345 genes from the LM22 matrix that passed our transcriptomic row filtering. Unsupervised clustering resulted in clustering of most gastric EMZL irrespective of H. pylori positivity together in the same dendrogram branch, accompanied by few additional EMZL from other anatomic locations. Most of the EMZL samples from other locations did not show preferential co-clustering together. On comparison of gene expression between gastric and OAMZL, there was enrichment of the B-cell receptor signaling pathway, B-cell activation, B-cell naïve and B-cell memory cells, B-cell proliferation and NF-kB signaling in the latter. Immune microenvironment analysis showed a statistically significant increase in resting mast cells and decrease in M1 macrophages in gastric EMZL and increase in regulatory T cells in salivary EMZL. The broad genomic studies reported here underscore the biological similarity of EMZL across anatomical sites with the potential exceptions of gastric EMZL (regardless of H. Pylori status). These data provide valuable genomic and transcriptomic resources to inform future diagnostic and therapeutic strategies.

Abstract Background: Multiple myeloma (MM) remains incurable, though key advances such as chimeric antigen receptor T-cells (CAR-T) and immunomodulatory agents, now evolving toward cereblon E3 ligase modulatory drugs (CELMoDs), have substantially improved the longevity and quality of life for patients (pts). Idecabtagene vicleucel (ide-cel) is a CAR-T targeting B-cell maturation antigen (BCMA), now US FDA-approved for pts who have received ≥2 prior lines of therapy including a proteasome inhibitor, immunomodulatory agent, and CD38 monoclonal antibody. Ide-cel was initially FDA-approved for ≥4 prior lines of therapy based on the KarMMa-1 study, which demonstrated a median progression-free survival (PFS) of 8.8 months across all cell doses and median overall survival (OS) of 19.4 months (Munshi et al., New Eng J Med 2021). Although promising, the fact that virtually all pts relapse post-ide-cel indicates that further progress is needed. To that end, iberdomide is an investigational CELMoD that in combination with dexamethasone has demonstrated a 30% response rate in early phase studies of triple class-refractory MM (Lonial et al., Lancet Haem 2022). Additionally, in laboratory-based correlative studies, iberdomide, at doses of ≤1 mg (well below the recommended phase 2 dose of 1.6 mg) was shown to augment immune function, including enhanced T-cell activation and cytotoxicity, and modulation of the cytokine milieu (Amatangelo et al., Cell Rep Med 2024). Iberdomide's combined properties of direct MM cytotoxicity and T-cell potentiation have clear, potential relevance to CAR-T clinically, providing the conceptual basis for the CADMIUM study (NCT06179888), exploring the effects of iberdomide as post-ide-cel maintenance therapy in MM. Study Design and Methods: This is a randomized phase II trial with a safety run-in to evaluate if treatment with iberdomide maintenance post-ide-cel can significantly improve PFS vs. standard of care (SOC) observation without therapy, in pts with relapsed/refractory MM with ≥4 prior lines of therapy, who have received ide-cel within 3 months of registration, and no evidence of MM progression or additional MM therapy since ide-cel. Pre-ide-cel iberdomide exposure is permissible but refractoriness is not. The safety run-in will confirm tolerability of the iberdomide dose to be carried forward, where doses to be tested include: iberdomide 1 mg orally on days 1-21 of a 28-day cycle (dose level 1; DL1) and iberdomide 0.7 mg on days 1-21 of a 28-day cycle (DL2). Dose-limiting toxicities (DLTs) include any of the following during the DLT period of a pt's first three months on iberdomide: prolonged Grade 3 non-hematologic toxicities, Grade 4 non-hematologic toxicities, prolonged Grade 4 neutropenia or thrombocytopenia, or any adverse event requiring iberdomide interruption for >4 weeks. Six pts will be enrolled onto DL1; if at most 1 of these pts has a DLT, DL1 will be carried forward to the randomized part of the study. Otherwise, 6 pts will be enrolled onto DL2. The randomized part of the trial will randomize 60 pts 1:1 to either iberdomide or SOC observation without therapy. A 1-sided log-rank test with α=0.15 has 81% power to detect a true hazard ratio (iberdomide/SOC) of 0.55 or less, corresponding to an improvement in median PFS to 16 vs. 8.8 months with SOC. One interim analysis for futility is planned. Secondary outcomes include OS, best response by International Myeloma Working Group (IMWG) criteria, and deepening of response, particularly conversion to complete response with a bone marrow minimal disease-negative state by Adaptive clonoSEQ (sensitivity 1e-6). Robust correlative studies will include CAR-T persistence, assays of T- and other immune cell function, and pathological analyses of whether BCMA expression on MM cells (prior to enrollment or at relapse) or other markers predict clinical outcomes. Study status: To date, 12 pts have been screened, with 7 pts enrolled on study as part of the safety run-in (1 patient replaced). Enrollment data will be updated at presentation. Notably, an amendment is forthcoming which will enhance correlative studies and broaden eligibility criteria to include patients who have received ≥2 prior lines of therapy, conforming with ide-cel's current FDA label. Study COI: BMS is supporting correlative studies. Study Support: U10CA180821, U10CA180882; BMS; U10CA180868 (NRG Oncology); http://acknowledgements.alliancefound.org

PURPOSE STELLAR (ClinicalTrials.gov identifier: NCT02796261 ) was a phase III, randomized, open-label trial of eflornithine + lomustine versus lomustine monotherapy in patients with recurrent grade 3 astrocytoma. METHODS At trial initiation, eligibility criteria included: age ≥18 years, anaplastic astrocytoma (2016 WHO CNS Tumor classification [WHO CNS4]), first recurrence ≥6 months after radiation and temozolomide (TMZ), Karnofsky performance status ≥70, and no imaging findings consistent with grade 4 glioblastoma. Random assignment (1:1) was stratified by isocitrate dehydrogenase ( IDH ) mutation, age, resection extent, and geography. Patients received eflornithine (2.8 g/m 2 orally, every 8 hours [2 weeks on, 1 week off]) + lomustine (90 mg/m 2 orally, once every 6 weeks), or lomustine monotherapy (110 mg/m 2 once every 6 weeks). The primary end point was overall survival (OS). RESULTS Among 343 patients randomly assigned across 74 sites in eight countries, there was no difference in survival between eflornithine + lomustine and lomustine monotherapy (median OS 23.4 v 20.3 months, hazard ratio [HR], 0.94). Following changes in classification and grading in the 2021 WHO CNS5, a subset analysis of patients with IDH- mutant, grade 3 astrocytoma (n = 196), defined in 2024, before unblinding, showed clinically meaningful improvements in median OS with eflornithine + lomustine versus lomustine monotherapy (34.9 v 23.5 months, HR, 0.64) and median progression-free survival (PFS, 15.8 v 7.2 months, HR, 0.57). No differences were observed among patients with CNS grade 4 disease. Grade ≥3 treatment-emergent adverse events of relevance were related to reversible myelosuppression (eflornithine + lomustine 42% v lomustine monotherapy 29% of patients) and hearing impairment (24% v 0%). No new safety signals were identified. CONCLUSION Clinically meaningful improvements were observed; eflornithine + lomustine doubled PFS and improved OS in patients with recurrent IDH -mutant, grade 3 astrocytoma, but not grade 4 tumors, after prior radiotherapy and TMZ, consistent with its cytostatic mechanism of action.

Abstract Background Socioeconomic position (SEP) is a fundamental social determinant of health (SDoH) contributing to observed disparities in cancer and cardiovascular (CV) care among individuals with prostate cancer (PC). Understanding the influence of SEP on CV health is essential for addressing outcome inequities within this population. Methods We conducted a retrospective study utilizing Surveillance, Epidemiology, and End Results (SEER)-Medicare to evaluate CV outcomes in patients ≥65 years with PC from 2009 to 2017. We studied the impact of SEP on cardiovascular events (CVEs), cardiovascular mortality (CVm), PC-specific mortality (PCsm), and all-cause mortality. CVE, CVm, and PCsm were analyzed using competing risk models and all-cause mortality with Cox proportional hazards models. A subgroup analysis was performed in Non-Hispanic Black and Non-Hispanic White individuals. Results We included 141 242 patients of whom 76 844 were in high SEP areas (45.6%) and 64 398 in low SEP ones (54.4%). Both groups had a mean age of 72 years; patients in low SEP areas were 67.5% Non-Hispanic White, 34.4% having diabetes, 73.3% hypertension, and 67.7% dyslipidemia versus the high SEP group with 85.6% Non-Hispanic White, 30.4% diabetes, 69.9% hypertension, and 70.7% dyslipidemia. Patients in low SEP areas had higher risks of CVm (subdistribution hazard ratio [sHR] = 1.18, 95% CI = 1.12 to 1.25), PCsm (sHR = 1.12, 95% CI = 1.06 to 1.17), CVE (sHR = 1.07, 95% CI = 1.04 to 1.09), and all-cause mortality (HR 1.16, 95% CI = 1.13 to 1.20). Accentuated results were shown in the Non-Hispanic Black subgroup. Conclusion Adverse SEP plays a significant role in shaping outcomes among older patients with PC, contributing to elevated risks of adverse CV and survival outcomes.