Muñoz, Javier

Abstract The benefit of rituximab maintenance after first-line (1L) bendamustine-rituximab (BR) in patients with mantle cell lymphoma (MCL) remains uncertain, with inconsistent results from the phase 2 MAINTAIN trial and several retrospective studies. We conducted a large retrospective study at 27 US and Canadian academic centers to examine the benefit of rituximab maintenance after BR. A total of 911 patients received 1L BR between 2010 and 2020, and 703 had an objective response and no evidence of disease progression at the 3-month post-BR landmark. Among those, 394 (56%) received rituximab maintenance and 309 (44%) did not, with largely similar baseline patient and disease characteristics. In the landmark analysis, rituximab maintenance was associated with improved event-free survival (EFS; median, 49.9 vs 29.7 months; P< .001) as well as overall survival (OS; median, 109.5 vs 74.2 months; P< .001). The EFS and OS benefits were observed across most of the subgroups. EFS and OS differences were statistically significant in those who achieved a complete response to 1L BR (n = 590; median EFS, 62.7 vs 31.1 months [P< .001]; median OS, 136.1 vs 75.3 months [P< .001]), but the analysis among those who achieved a partial response to 1L BR was limited by the small sample size. These results provide additional evidence for the survival benefit of rituximab maintenance after BR in MCL and support its use in clinical trial design and routine practice.

Abstract Introduction While outcomes in patients with R/R FL have improved with T-cell–redirecting treatments (e.g. CAR T-cell therapy, bispecific antibodies), there remains an unmet need for safe, efficacious, and more convenient chemotherapy-free treatment options (Caridà et al, Eur J Haematol. 2025). 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 FL (Cordoba et al, ICML 2025, #441). Here, we provide longer follow-up in patients with R/R FL from Part B of the study. Methods Patients with R/R FL with ≥ 2 prior lines of therapy (≥ 1 in Part B if prior anti-CD20 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 72 patients with R/R FL were enrolled: 12 in Part A (GOLCA monotherapy) and 60 in Part B Cohort D (22 received GOLCA 0.2 mg + R; 38 received GOLCA 0.4 mg + R). Patients were heavily pre-treated. Median number of prior treatments was 4.5 (range, 2–6) in Part A and 3 (range, 1–12) in Part B Cohort D. Approximately one-third of the treated patients were exposed to prior T-cell–redirecting therapy, approximately one-third had prior lenalidomide (len) exposure, and approximately one-third were refractory to the last regimen received. At the time of data cutoff, in Part A, 4 patients completed 2 years of GOLCA, remaining in remission at last follow-up; 8 discontinued due to PD. In Part B Cohort D, 41% of patients treated with 0.2 mg and 63% with 0.4 mg were ongoing. PD was the most common reason for discontinuation. In the safety evaluable population (n = 60; GOLCA 0.2 or 0.4 mg + R), neutropenia, an on-target side effect of GOLCA, was the most common grade 3/4 treatment-emergent adverse event (TEAE) and occurred in 65% of patients, followed by anemia (13%) and febrile neutropenia (8%). Serious AEs related to GOLCA occurred in 22% of patients, most commonly infections (17%) and febrile neutropenia (7%); pulmonary embolism occurred in 1 patient with 0.2 mg. The most common causes of GOLCA interruption in the overall safety population were infections (32%) and neutropenia (18%). Dose reductions were mostly due to neutropenia (10%) and febrile neutropenia (5%). No discontinuations or deaths occurred from GOLCA-related TEAEs. Non-hematologic TEAEs were infrequent and mostly low grade, with the most common being gastrointestinal disorders (7%). In the efficacy evaluable patients (n = 56; GOLCA 0.2 or 0.4 mg + R) at a median follow-up of 10.8 months, the overall response rate (ORR) was 89% (complete response rate [CRR], 61%). With 0.2 mg, ORR was 81% (CRR, 43%) and with 0.4 mg, ORR was 94% (CRR, 71%). In the 0.4-mg group, responses were consistent in high-risk subsets, including patients with prior len (ORR, 100%; CRR, 73%) and/or T-cell–redirecting therapy (ORR, 91%; CRR, 64%). With GOLCA 0.4 mg, 10 patients had response lasting > 12 months, including 5 with prior T-cell–redirecting therapy and 6 with prior len. Conclusions With additional follow-up, GOLCA + R continued to show promising efficacy with durable responses and no new safety signals. A higher ORR/CRR and similar tolerability were observed with GOLCA 0.4 mg + R vs GOLCA 0.2 mg + R, including in patients with prior len-based and/or T-cell–redirecting treatment. These data support continued development of GOLCA 0.4 mg + R as a fixed-duration, chemotherapy-free, outpatient option in the ongoing Phase 3 GOLSEEK-4 study in 2L+ FL (NCT06911502).

Abstract The treatment patterns and clinical outcomes for patients experiencing progression of disease (POD) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) mantle cell lymphoma (MCL) are undefined. We identified all patients who received CD19-directed CAR T-cell therapy for R/R MCL therapy across 15 international centers, and studied those experiencing POD post–CAR T-cell therapy in detail. We extracted clinical/treatment/pathologic variables, and associated these features with survival outcomes. In total, 384 patients received CAR T-cell therapy, and 135 (35%) experienced POD. POD occurred at a median of 6 months following CAR T-cell therapy infusion, and most (64%) patients with POD had complete response as best response to CAR T-cell therapy. Tumor features at POD included blastoid/pleomorphic morphology in 29 of 78 (37%) patients, and TP53 mutation in 21 of 41 (51%) patients. Following POD, 17 patients received no further therapy, 13 underwent local therapy, and 105 received systemic therapy. The most common first-line systemic therapies were chemo(immuno)therapy (22 patients; overall response rate [ORR], 40%), pirtobrutinib (17 patients; ORR, 36%), and bispecific antibodies (13 patients; ORR, 67%). Among patients experiencing POD, the median progression-free survival and overall survival (OS) were 2.5 months and 5.4 months, respectively, from POD. Lack of response to CAR T-cell therapy and short time from CAR T-cell therapy infusion to POD (<3 vs 3-6 vs >6 months), among other factors, were associated with inferior OS after POD. In conclusion, we confirm the challenging prognosis for patients experiencing POD following CD19 CAR T-cell therapy for R/R MCL, and establish a benchmark for future investigations in this patient population.

Introduction: GOLCA is a potential first-in-class CELMoDTM agent for the treatment of lymphoma, purposefully designed to target the proteins Ikaros/Aiolos to produce dual immunomodulatory and anti-tumor activity, with preferential distribution to lymphoid organs. Pharmacodynamic data in pts with R/R FL show that, combined with RTX, the immunomodulatory effects of GOLCA are significantly increased (Chavez et al, EHA 2024, #1132). GOLCA as monotherapy (mono) and + RTX has been shown to be well-tolerated and effective in pts with R/R DLBCL (Chavez et al, ASH 2023, #4496) and R/R FL (Chavez et al, EHA 2024, #1132). Here, we report 30 mo follow up of pts with R/R FL who received GOLCA mono, and updated safety/efficacy of GOLCA + RTX from the ongoing Phase 1/2 CC-99282-NHL-001 study (NCT03930953). Methods: Pts with R/R FL with ≥ 2 prior lines of therapy (L) received GOLCA mono at different dosing schedules during part A (dose exploration) and GOLCA ± RTX at 0.2 mg or 0.4 mg days (d) 1-14 every 28 d (q28d) in part B (dose expansion). Total treatment duration with GOLCA was up to 2 years or until progressive disease or unacceptable toxicity, whichever occurred first. The efficacy-evaluable population consisted of pts completing ≥ 1 cycle of GOLCA and having baseline tumor assessment and ≥ 1 post-baseline tumor assessment or clinical progression or disease-related death. Results: As of May 31, 2024, 63 pts with R/R FL have enrolled: GOLCA mono (n = 19) at various dosing schedules and GOLCA + RTX at 0.2 mg (n = 22) or 0.4 mg (n = 22) on d1-14 q28d schedule. The median time from diagnosis to first dose of GOLCA was 68 mo (range, 23-136) and 59 mo (range, 15-309) in GOLCA mono and + RTX cohorts, respectively. The median number of prior therapies received was 4 (range, 2-11), and 3 (range, 1-12) in GOLCA mono and + RTX cohorts, respectively. In the GOLCA mono and + RTX cohorts, 9/19 (47%) and 13/43 (30%) pts had received prior lenalidomide (len)-based therapy, with 5/9 and 7/13 having len-refractory disease, respectively. In the GOLCA + RTX cohort, 10/43 (23%) had prior CAR T cell therapy and 6/43 (14%) had prior anti-CD20xCD3 bispecific antibody with or without CAR T cell therapy. In the GOLCA + RTX-treated safety population (n = 43), the incidence of treatment emergent adverse events (TEAEs) was similar across 0.2 and 0.4 mg dose levels (DL). The most frequent grade (G) 3+ TEAEs were neutropenia (44%) and anemia (12%). The incidence of febrile neutropenia was 7%. Serious adverse events occurred in 30% of pts, with febrile neutropenia and pneumonia being the most common, in 2 pts (5%) each, as well as pulmonary embolism in 1 pt. Neutropenia led to GOLCA dose interruption in 4 pts (9%) and dose reduction in 1 pt (2%). No pts discontinued treatment because of GOLCA-related TEAEs. Non-hematological TEAEs (e.g., GI toxicity, rash, fatigue) were all low-grade (except 1 pt with G3 fatigue). There were no new safety signals identified for GOLCA mono (part A) at the 30-mo follow up period. In the efficacy-evaluable population, at a median follow up of 6 mo (range 3-18), the ORR and CRR in the GOLCA + RTX cohort (n = 29) were 57% and 29% at 0.2 mg dose (n = 14) and 93% and 67% at 0.4 mg dose (n = 15), respectively. The median time to response was 2 mo (first response assessment). At the 0.4 mg DL of GOLCA + RTX, consistent responses were seen in pts at 2L/3L and 4L+, including in those with prior exposure to len-based therapies and/or T-cell-redirecting therapy. At the 0.4 mg DL, 12/14 (86%) pts remained in response at the time of data cut-off. In pts receiving GOLCA mono across different dose schedules in part A (n = 12), ORR and CRR were 67% and 42%, respectively. Responses were durable, with median DOR of 22 mo (range, 2-51) at a median follow up of 30 mo. 33% of pts (4/12) have completed 2 yrs of protocol defined GOLCA treatment and remain in response at the 1 yr post-treatment follow-up period, without requiring any intervening treatment. Conclusions: GOLCA 0.4 mg + RTX was well tolerated and highly active in heavily pre-treated pts with R/R FL, including those with prior exposure to len-based therapies and/or T-cell-redirecting therapies. Treatment with fixed-duration GOLCA mono led to durable responses including a subset of pts remaining treatment free, without progression at extended follow up. These data further support development of GOLCA + RTX as a fixed-duration, chemotherapy-free, outpatient treatment option in pts with R/R FL, and also pts with newly diagnosed advanced stage FL (NCT06425302).

Introduction: GOLCA is a potential first-in-class oral cereblon E3 ligase modulator (CELMoD™) agent for non-Hodgkin lymphoma, purposefully designed to target Ikaros/Aiolos and have favorable pharmacokinetics, resulting in apoptotic and immunomodulatory activity with preferential distribution to lymphoid organs. CC-220-DLBCL-001 (NCT04884035) is an ongoing phase 1b, open-label, multicenter, dose-escalation/expansion trial to assess safety and preliminary 1L GOLCA + R-CHOP efficacy in a-BCL. Although longer follow-up is needed to assess durability of response, MRD negativity (MRD-) is an emerging endpoint in a-BCL. Achieving MRD- on and at end of treatment (EOT) can potentially predict clinical benefit. This study aimed to analyze circulating tumor DNA (ctDNA) kinetics of GOLCA + R-CHOP across the trial population and in defined patient (pt) segments-cell of origin (COO), high baseline ctDNA, and high-risk genomics-and to correlate MRD- with imaging and clinical outcomes. Methods: Eligible pts were ≥ 18 years of age with ECOG performance status ≤2, IPI 0-5 in Part 1 and 2-5 in Part 2, and untreated a-BCL with measurable disease. Pts were treated with GOLCA + R-CHOP for 6 x 21-day (D) cycles (C) or until disease progression/unacceptable toxicity/study withdrawal. Dose escalation phase GOLCA dose levels (DLs) were 0.2 mg D1-7 (DL-1), 0.4 mg D1-7 (DL1), or 0.4 mg D1-10 (DL2). During dose expansion, pts were randomized 1:1 to R-CHOP + GOLCA DL-1 or DL1. The primary endpoint was safety of GOLCA at DL1; efficacy was a secondary endpoint, ctDNA was an exploratory endpoint. ctDNA was analyzed using the PhasED-Seq assay (<10-6 sensitivity) at baseline, C2D1, C3D1, and EOT. MRD- was defined as the absence of detectable ctDNA on-treatment. Pretreatment biopsies were sequenced by whole genome sequencing (WGS) and whole transcriptome sequencing (WTS). Results: At data cutoff (June 3, 2024), the median follow-up was 14.3 months. One-year progression-free survival (PFS) was 85.3% at 0.4 mg and 77.3% at 0.2 mg. Rates of MRD- increased over time but were consistently higher at 0.4 vs 0.2 mg, with values of 44% (14/32) vs 29% (8/28) at C2D1; 63% (17/27) vs 54% (15/28) at C3D1, and 90% (26/29) vs 73% (19/26) at EOT, respectively. Interim MRD- at C3D1 strongly predicted EOT MRD-; all 0.4 mg pts and all but two 0.2 mg pts who were MRD- at C3D1 remained MRD- at EOT. In contrast, fold-changes from baseline ctDNA were similar between 0.4 mg and 0.2 mg. The early molecular response rate (≥102-fold drop from baseline at C2D1) was 81.2% (26/32) at 0.4 mg and 82.1% (23/28) at 0.2 mg. The major molecular response rate (≥102.5-fold drop from baseline at C3D1) was 88.9% (24/27) at 0.4 mg and 85.7% (24/28) at 0.2 mg. Across genetically defined pt segments, EOT MRD- at 0.4 mg was prevalent for both COO subtypes measured by the Hans algorithm: 94% (17/18) among germinal center B-cell (GCB) and 75% (6/8) among non-GCB pts. Of the 29 pts with baseline genomics, 13 were genomically high risk: p53 mutant (VAF >0.5), DZsig and/or A7 subtype. In these pts, EOT MRD- was 80% (4/5) at 0.4 mg but only 20% (1/5) at 0.2 mg. In high baseline ctDNA (>102.5 hGE/mL) pts who were high-risk for R-CHOP failure, EOT MRD- at 0.4 mg was 86.7% (13/15) vs 57.1% (8/14) at 0.2 mg. There was an association between high baseline ctDNA and lower PFS at 0.2 mg (HR, 4.56 [95% CI, 0.53-39.12]), but interestingly the association decreased at 0.4 mg (HR, 2.10 [95% CI, 0.19-23.5]). Combining both arms, MRD- at both C3D1 and EOT trends with improved PFS (C3D1: HR, 0.73 [95% CI, 0.2114-2.523]; EOT: HR, 0.53 [95% CI, 0.1103-2.592]); longer follow-up may be required to demonstrate significance. Conclusions: Interim and EOT levels of MRD- were higher at 0.4 mg vs 0.2 mg GOLCA, with a one-year PFS of 85.3% vs 77.3%, respectively. Although pt numbers were small, the data suggest that 0.4 mg is efficacious in high-risk ctDNA and high-genomic risk pts, independent of COO, and support the 0.4 mg GOLCA + R-CHOP regimen in the randomized phase 3 trial GOLSEEK-1. Interim MRD- may play a role in future adaptive trial designs.