Citations

ABSTRACT Introduction Composite indolent B‐cell lymphomas may remain unrecognized when one component dominates the clinical presentation. Apparent relapse after therapy may, therefore, represent the emergence of a biologically distinct lymphoma rather than the recurrence of the original disease. Case Presentation An 82‐year‐old woman presented with systemic low‐grade B‐cell lymphoma that was most consistent with marginal zone lymphoma (MZL). Staging demonstrated peripheral blood involvement and multifocal FDG‐avid disease. Treatment with the CD20×CD3‐bispecific antibody mosunetuzumab resulted in complete metabolic remission. During surveillance, a new, isolated cervical lymph node developed despite sustained systemic response. Biopsy revealed follicular lymphoma (Grade 1–2) with a germinal center phenotype and a BCL2 rearrangement, findings discordant with recurrence of MZL. Retrospective review of the original specimen identified in situ follicular neoplasia within the initial biopsy. The disease course was, therefore, reinterpreted as a synchronous composite lymphoma in which treatment of the dominant MZL unmasked a previously clinically silent B‐cell neoplasm with follicular lineage. Local radiotherapy achieved remission of the follicular component. Conclusions New disease following treatment of an indolent lymphoma should not automatically be interpreted as relapse. Discordant clinical behavior, particularly focal progression after systemic response, warrants repeat biopsy and integrated pathologic reassessment. This case illustrates how therapy may reveal preexisting clonal heterogeneity and emphasizes the importance of temporality in distinguishing relapse from composite lymphoma. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission

e19046 Background: While outcomes in pts with R/R FL have improved with current SOC treatments (Tx), there remains a need for safe, efficacious, and convenient Tx options. GOLCA is a potential, first-in-class, oral CELMoD designed for Tx of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA induces rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing and immunomodulatory activity. GOLCA + R was well tolerated and effective in heavily pretreated pts in the two-part Ph 1/2 study, CC-99282-NHL-001. Here, we provide longer f/u in pts with R/R FL from Part B of the study. Methods: Pts with R/R FL with ≥2 prior lines of Tx (≥1 if prior anti-CD20 Tx) received GOLCA orally, once daily at 0.2 mg (n=22) or 0.4 mg (n=38) ± R for up to 2 y or until progressive disease (PD)/unacceptable toxicity. Primary endpoints included safety and RP2D determination; secondary endpoints are preliminary efficacy and PK. Results: As of September 15, 2025, 60 pts were enrolled. In 0.2 and 0.4 mg groups, median prior Tx lines were 3 and 3, 32% and 32% had prior lenalidomide (LEN), 27% and 29% had prior T-cell–redirecting Tx (CAR T and/or bispecific antibody) and 32% and 32% were refractory to last regimen. Tx is ongoing in 6 (27%) and 17 (45%) pts at 0.2 and 0.4 mg, respectively; discontinuations (d/c) were mostly due to PD. Neutropenia, an on-target side effect of GOLCA, was the most common grade 3/4 Tx-emergent adverse event (TEAE) occurring in 59% and 68% of pts at 0.2 and 0.4 mg, followed by anemia (9% and 16%) and febrile neutropenia (9% and 8%). Median time to resolution of neutropenia was 8 days. Dose reductions occurred in 14% and 37% of pts at 0.2 and 0.4 mg, most commonly due to neutropenia (5% and 21%) and febrile neutropenia (5% and 5%). No d/c or deaths were from GOLCA-related TEAEs. Non-hematologic TEAEs were infrequent and mostly low grade. In efficacy-evaluable pts (GOLCA 0.2 and 0.4 mg + R, n=22 and n=36), median f/u was 14.03 months (mo), overall response rate (ORR) was 77% (complete response rate [CRR], 41%) at 0.2 mg, and 97% (CRR, 78%) at 0.4 mg. In the 0.4 mg group, responses were consistent in high-risk subsets including pts with prior LEN (ORR, 100%; CRR, 75%) and/or T-cell–redirecting Tx (ORR, 91%; CRR, 64%). GOLCA 0.4 mg + R demonstrated durable responses (median DOR, 9.17 mo; 91% of pts who achieved a CR remained in CR at cutoff). Conclusions: With longer f/u, GOLCA + R demonstrated promising efficacy with durable responses and no new safety signals. The 0.4 mg group had higher ORR and CRR than 0.2 mg, including in pts with prior LEN-based and/or T-cell–redirecting Tx, with a manageable safety profile at both doses. The results support the development of GOLCA + R as a fixed-duration, chemotherapy-free outpatient Tx in the Ph 3 GOLSEEK-4 study in 2L+ FL (NCT06911502). Clinical trial information: NCT03930953 .

7062 Background: MCL is a rare and aggressive subtype of B-cell non-Hodgkin lymphoma that remains incurable. Bruton tyrosine kinase (BTK) inhibitors are an established standard of care for R/R MCL. However, comparative effectiveness data for different BTK inhibitors for R/R MCL are limited. This study evaluated the real-world effectiveness of zanu and acala in US patients with R/R MCL based on overall survival (OS) and time to next treatment (TTNT). Methods: A retrospective cohort study was conducted using Komodo health administrative claims data. Eligible patients were adults (aged ≥18 years) with ≥2 MCL diagnoses and continuous enrollment or activities within 1 year prior to and 3 months following the index date. Patients were required to initiate monotherapy with zanu (index period: November 2019 to August 2025) or acala (index period: October 2017 to August 2025) as a second-line or later (2L+) treatment, with index date defined as the first observed claim for zanu or acala. Patients with evidence of clinical trial participation, end stage renal disease or prior stem cell transplant were excluded. Outcomes included OS (time from index date to all-cause mortality) and TTNT (time from index date to subsequent therapy with an allowable gap of 120 days). If an outcome was not observed, patients were censored at the date of last activity or enrollment end date. Survival analyses were conducted using Kaplan-Meier estimates and Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) was adjusted for age, sex, US region, treatment initiation year and Charlson Comorbidity Index (CCI). Results: In total, 2219 patients (zanu, n=931; acala, n=1288) were eligible and included in the study. The mean age was higher in the zanu (72.3 years; SD, 9.4) vs acala cohort (71.4 years; SD, 9.7). Most patients were male (zanu, 71%; acala, 75%), non-Hispanic white (zanu, 73%; acala, 74%), and the mean CCI was 3.5 (SD, 3.2) and 3.6 (SD, 3.1) in the zanu and acala cohorts, respectively. Median follow-up was 14.8 and 18.2 months in zanu and acala cohorts, respectively. Median TTNT was 26.7 months for zanu and 20.8 months for acala. Median OS was not reached for zanu and was 60.6 months for acala. In the unadjusted model, zanu had a longer TTNT (HR, 0.86; 95% CI, 0.76-0.97; P =.012) and OS (HR, 0.74; 95% CI, 0.62-0.88; P <.001). After IPTW adjustment, TTNT and OS favored zanu treatment (TTNT: IPTW-adjusted HR, 0.86; 95% CI, 0.76-0.98; P =.025; OS: IPTW-adjusted HR, 0.81; 95% CI, 0.68-0.98; P =.03). Conclusions: In this real-world analysis of US health claims data, zanu monotherapy demonstrated significantly longer TTNT and improved OS compared with acala in patients receiving 2L+ therapy for MCL. These findings support zanu as an effective BTK inhibitor for R/R MCL.

CD19-directed chimeric antigen receptor (CAR) T-cell therapies have been instrumental in improving outcomes of refractory or relapsed B-cell malignancies. However, there have been safety concerns due to recent reports of second primary malignancies (SPMs) related to CAR T-cell therapies. We reviewed articles from Embase, PubMed, and Cochrane Library records and included SPM case reports as well as cohort studies. Across published cohorts, secondary cutaneous or peripheral T-cell lymphoma (PTCL) after diffuse large B-cell lymphomas (DLBCLs) have been reported at low incidence (generally in the low single-digit percentage range). While CAR T-cell therapy is associated with these rare secondary malignancies and lineage-switch events primarily described in acute leukemia, they are clinically significant and have resulted in increased surveillance. The currently available evidence suggests that most secondary malignancies after CAR T-cell therapy are due to background risk and prior treatment exposures rather than direct CAR T-cell therapy induced oncogenesis. However, rare CAR T-cell therapy-associated second primary T-cell malignancies have been reported. To properly define incidence, mechanisms, and risk factors for CAR T-cell therapy-associated malignancies, continued prospective registry follow-up and additional research will be needed.

Abstract Secondary central nervous system (CNS) large B-cell lymphoma (SCNSL) occurs in the de novo setting, as a CNS-isolated relapse, or synchronous (concomitant CNS and systemic) relapse. SCNSL is a devastating event without therapeutic consensus. Thus, we aimed to evaluate treatment outcomes in an international cohort. Progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR, estimated using competing-risk models) were reported. Prognostic factors were identified in a 6-month landmark multivariate analysis. Outcomes after thiotepa autologous stem cell transplant (ASCT) and chimeric antigen receptor (CAR) T-cell therapy (CAR-T) delivered at relapse were compared after propensity score matching (PSM). A total of 1139 patients were included in the analysis (de novo: 537; relapsed SCNSL: 602). Two-year PFS estimates were 40.4%, 43.9%, and 16.2% for de novo SCNSL, CNS-isolated relapse, and synchronous relapse, respectively. Patients with CNS-isolated relapse demonstrated low rates of systemic recurrence (24-month CIR, 6%). Thiotepa-ASCT correlated with longer survival in de novo SCNSL (PFS: hazard ratio [HR], 0.57; P = .005; and OS: HR, 0.62; P = .023) and CNS-isolated relapses (PFS: HR, 0.55; P = .002; and OS: HR, 0.39; P&lt; .0001). ASCT (thiotepa or no thiotepa) also associated with improved survival in synchronous relapses (PFS: HR, 0.57; P = .023; and OS: HR, 0.48; P = .019). Higher survival with thiotepa-ASCT than CAR-T was observed after PSM (PFS: HR, 0.45; P = .005 and OS: HR, 0.41; P = .014). These data support thiotepa-ASCT in eligible patients, particularly de novo disease and CNS-isolated relapses. CNS-isolated relapse was infrequently associated with systemic recurrence, supporting treatment regimens adopted from primary CNS lymphoma.

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&lt; .001) as well as overall survival (OS; median, 109.5 vs 74.2 months; P&lt; .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&lt; .001]; median OS, 136.1 vs 75.3 months [P&lt; .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: Epcoritamab (epcor) was the first CD3xCD20 bispecific antibody approved for treatment of R/R DLBCL in May 2023 based on its efficacy and safety in EPCORE NHL-1. Patients (pts) enrolled in clinical trials are highly selected, and those with high-risk features, such as primary refractory disease, early post-CAR T relapse, poor Eastern Cooperative Oncology Group (ECOG) performance status (PS), and CD20+ status are often underrepresented or excluded. As epcor use expands in more heterogeneous, real-world populations, there is increasing interest in understanding pt characteristics and response outcomes associated with its use outside of clinical trials. In particular, pts with DLBCL that is resistant to, or relapse soon after, CAR T are left with limited treatment options and often present with rapidly progressive, resistant disease, making them especially challenging to manage. Generating real-world evidence is critical for informing optimal use of epcor in routine practice. Methods: Real-EPCOR is a multicenter US retrospective chart review study at &gt;8 academic and community oncology centers designed to evaluate the real-world use of epcor. Eligible pts are adults (≥18 years) with R/R DLBCL and ≥2 prior lines of therapy (LOT) who initiated epcor outside of a clinical trial after 5/19/23. Pt demographic, clinical, and treatment data were collected, including ECOG PS, refractory status, prior CAR T, and CD20+ status. Overall response rate (ORR) was evaluated during epcor treatment and defined as the proportion of pts achieving complete response (CR) or partial response among pts with ≥1 evaluable response assessment or who died due to disease progression before response assessment. ORR and CR rate were calculated for the entire cohort, for pts receiving ≥2 cycles of epcor (full cycle is 28 days), and for pts who received prior CAR T. Results: This interim analysis included 34 pts from 2 centers. Data collection and analysis is ongoing and updated results with additional pts and longer follow-up may be included at time of presentation. Median age was 67 years; 68% pts were male and 85% were White. Median time from DLBCL diagnosis to initiation of epcor was 15.5 months. The most common comorbidities were cardiovascular disease (59%) and diabetes mellitus (29%). ECOG PS was ≥2 in 29% of pts, and 85% of pts had Ann Arbor stage 3-4 disease. Nearly all (97%) had CD20+ DLBCL. High-risk features were common at time of epcor initiation, including 53% with International Prognostic Index (IPI) ≥3, 26% with double-hit, and 24% with non-GCB subtype. Among pts who received ≥2 cycles of epcor (n=15), 20% had ECOG PS ≥2 and 33% had IPI ≥3; in post-CAR T pts, 22% had ECOG PS ≥2 and 57% had IPI ≥3. Median number of prior LOT was 3 (range: 2–9); 44% of pts initiated epcor as 3L therapy. Prior to epcor, 41% had primary refractory disease. Following their most recent therapy, 72% had refractory disease, and 43% had DLBCL that was refractory to all prior LOT in those with known refractory status. Most pts (68%) received prior CAR T, with a median interval of 4.6 months from infusion to epcor initiation, and 23% initiated epcor ≤2 months from CAR T. 15 pts (44%) received CAR T in the LOT immediately prior to epcor, 9 (60%) of whom were refractory to CAR T. The ORR was 50% and CR rate was 29% in the overall evaluable population (n=24). 10 pts were not evaluable, as they did not undergo a response assessment either because they remained alive without assessment or experienced a non-progression-related event. Among pts who received ≥2 cycles of epcor, ORR was 85% and CR rate was 54% in the evaluable population (n=13). Among 23 post-CAR T pts, ORR was 53% and CR rate was 33% in the evaluable population (n=15). Conclusion: In this real-world interim analysis, pts with R/R DLBCL treated with epcor had a high proportion of CD20+ disease, higher-risk clinical features, greater comorbidity burden, and more complex treatment histories, including a substantial proportion with prior CAR T, compared to pts in EPCORE NHL-1. Therefore, the ORR remains highly meaningful in the overall cohort despite being lower than the trial. Encouraging ORRs among those who received ≥2 cycles of epcor or had prior CAR T suggest that epcor monotherapy may provide clinical benefit even in difficult-to-treat pts in the real-world setting. Ongoing real-world survival analyses will inform the optimal use of epcor within the evolving treatment landscape of R/R DLBCL.

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 &gt; 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 Background and Significance Diffuse large B-cell lymphoma (DLBCL) and other LBCLs account for 35–40% of non-Hodgkin lymphoma cases in North America, Europe, and East Asia. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard first-line treatment for DLBCL, achieving cure rates in approximately 60–70% of patients. However, 30–40% of patients will relapse or become refractory (R/R) to treatment, facing poor prognosis. Patients with high International Prognostic Index (IPI) scores (3–5) and those with IPI 1–2 who have bulky disease and/or very high lactate dehydrogenase (LDH) are recognized as high-risk (HR) subsets with suboptimal outcomes (Maurer et al, ASH 2023, #4512). Novel combination strategies are an area of focus for improving efficacy in this population. 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 [COO]) and immunomodulatory activity. In the Phase 1b study CC-220-DLBCL-001, GOLCA in combination with R-CHOP demonstrated a predictable and manageable safety profile with high rates of durable responses, irrespective of COO, in previously untreated aggressive B-cell lymphomas (BCL), including promising activity in HR patients (Amzallag et al, ASH 2024, #579). The median relative dose intensity for GOLCA and CHO components was high (97–99%), indicating uncompromised delivery of curative standard-of-care treatment and combinability. GOLCA ± rituximab has also shown encouraging efficacy and safety in patients with R/R DLBCL (Bachy et al, ICML, #148). These findings support the further study of GOLCA + R-CHOP combination in the Phase 3 setting. Study Design and Methods GOLSEEK-1 (NCT06356129) is a randomized, double-blind, placebo-controlled, Phase 3 study evaluating GOLCA + R-CHOP versus placebo + R-CHOP in patients with previously untreated HR LBCL. Approximately 850 patients with previously untreated LBCL will be randomized 1:1 to either GOLCA + R-CHOP or placebo + R-CHOP. Eligible patients include those with histologically confirmed LBCL per WHO 2022 criteria—including DLBCL (not otherwise specified [NOS], ABC/GCB), high-grade BCL with MYC and BCL2 rearrangements or NOS, T-cell/histiocyte–rich LBCL, or Epstein Barr Virus-positive DLBCL. HR status is defined by IPI ≥3, or IPI 1–2 with HR features: LDH &gt;1.3× upper limit of normal and/or bulky disease (≥7 cm lesion). All patients must have measurable disease as defined by Lugano criteria. Key exclusion criteria are other lymphoma subtypes such as primary mediastinal LBCL; primary cutaneous DLBCL-leg type, grade 3b follicular lymphoma (FL); transformed indolent lymphoma; anaplastic lymphoma kinase (ALK) positive LBCL; primary effusion lymphoma; and Burkitt lymphoma and known or suspected central nervous system involvement. Randomization will be stratified by IPI score (HR 1–2 and 3 vs 4–5) and bulky disease status (≥7 cm vs &lt;7 cm). After a screening period of ≤4 weeks, patients will receive either GOLCA (0.4 mg) or placebo orally once daily for 7 consecutive days in each of 6 cycles, combined with R-CHOP every 21 days. The primary endpoint is progression-free survival (PFS) by investigator assessment per Lugano Response Criteria. Key secondary endpoints include PFS in non–high-grade BCL, event-free survival, independently assessed complete metabolic response, undetectable minimal residual disease by PhasED-Seq (defined as undetectable circulating tumor DNA levels at end of treatment), and overall survival. Patients will be followed up for up to approximately 67 months after beginning treatment. This study is currently recruiting at 309 sites in 36 countries , across the United States, Europe, Latin America, and East Asia. Acknowledgement BMS Artificial Intelligence was used to revise existing text with human author oversight.