Introduction Mediastinal gray zone lymphoma (MGZL) is a rare lymphoma with features intermediate between classical Hodgkin lymphoma (cHL) and diffuse large B cell lymphoma (DLBCL). Due to its rarity and the heterogeneity of its biology, there is a lack of consensus on first line treatment, in the setting of relapse or refractory (R/R) disease, and the role of consolidative autologous hematopoietic cell transplant (auto-HCT). Objective Evaluate effect of consolidative auto-HCT in CR1 and CR2. Methods A retrospective review of adult patients diagnosed with MGZL at University of Kansas Cancer Center from 2012-2025 was completed. Kaplan-Meier model was used to evaluate overall survival (OS). Results Twenty patients were evaluated. Median follow up was 84 months and they had 2 median lines of therapy, and the mean was 2.5 (1-9). First line therapy consisted of 50% DA-EPOCH based therapy, 35% CHOP, 10% AVD, and 5% other. 58% were in CR after first line therapy, 16% PD, and 26% PR. Of the patients in CR, 3/11 were consolidated with BEAM auto-HCT and all have been in CR since transplant. Of the 8 patients that had CR1 that did not undergo consolidative auto-HCT, 5 had relapse of disease (62.5%).65% had R/R disease, with 84.6% (11/13) receiving ICE based therapy, 1/13 Pembro-GVD, and 1/13 R-GemOx. Of those who received ICE based therapy, 63.6% (7/11) had CR and 36.3% (4/11) had PR. The R-Gemox and Pembro-GVD patients achieved CR.All R/R patients that achieved PR or CR underwent auto-HCT, with 7/13 in CR2 and 5/13 in PR prior to auto-HCT. Those in CR2 and underwent auto-HCT, 85.7% (6/7) are still in CR. One patient underwent consolidation with liso-cel and later relapsed of disease. Two patients underwent allogenic hematopoietic cell transplant (allo-HCT), with 1 in PR and 1 was refractory prior to allo-HCT. The patient in PR died due to disease progression, while the one with refractory disease is still in CR. Two patients received CD19 CAR-T, with 1 patient still in CR and the other has relapsed.The total estimated 5-year OS was 69% (95% CI 49-96) and 10-year OS 61% (95% CI 40-92). Those that underwent auto-HCT, the estimated 5-year OS was 82% (95% CI 62-100) and 10-year OS 82% (95% CI 62-100). The estimated 5-year OS for allo-HCT patients was 50% (95% CI 13-100). Conclusion MGZL continues to be a challenging lymphoma subtype to treat in the first line and R/R setting. We observed high R/R disease in this single institution retrospective study that required salvage/further lines of therapy. Results suggest that auto-HCT consolidation in CR1 may be beneficial in avoiding future relapse of disease. Auto-HCT in later line appears to be adventitious with this high R/R population resulting in a high survival rate at 5 and 10 years, as well as durable response. As this is a single institution retrospective with a limited data set, further investigation with additional institutions would be beneficial.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States. One feared complication of CLL is Richter's syndrome (RS), where the leukemia transforms into a more aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). The current standard of care aims to achieve remission with chemoimmunotherapy; however, responses are limited, prompting investigations into novel treatment options. While both pirtobrutinib and epcoritamab have demonstrated efficacy as monotherapies, their combination may represent a promising strategy with potential synergistic effects. Although it remains unclear whether the immunomodulatory effects observed with covalent Bruton's tyrosine kinase inhibitors (BTKis) will also occur with more selective, noncovalent agents such as pirtobrutinib, recent studies suggest that coadministration may potentiate bispecific antibody-mediated cytotoxicity. We discuss two cases that illustrate a management strategy incorporating combination therapy with epcoritamab and pirtobrutinib for DLBCL-RS in the relapsed or refractory setting.

ABSTRACT Background This study compares demographics and geographic factors associated with access to chimeric antigen receptor (CAR)‐T cell therapy for B‐cell malignancies or multiple myeloma: individuals in clinical trials at the University of Kansas Cancer Center (KUCC) and those receiving standard‐of‐care (SOC) CAR‐T at the University of Kansas Health System (TUKHS). Methods Data were collected from electronic medical records and the KUCC Clinical Trial Management System. We evaluated differences in CAR‐T access across race, gender, age, rurality, and HPSA status. SOC patients received FDA‐approved CAR‐T between May 2021 and May 2023; clinical trial patients received investigational CAR‐T between January 2015 and February 2023. Results Most patients (80%) were from urban areas; 54.1% lived within 50 miles of the University of Kansas Medical Center (KUMC). The cohort was 58.4% male, 86.7% white, 60.4% aged 19–64, and 57% lived outside a Health Professional Shortage Area (HPSA). Rural patients made up 20% of both cohorts. No significant demographic differences were observed between clinical trial and SOC recipients. However, rural residence was significantly associated with age 65 or older (OR = 1.80), white race, HPSA status, and living more than 50 miles from KUMC (OR = 27.01). HPSA status was also associated with greater odds of living beyond the 50‐mile radius (OR = 2.29). Conclusions Findings highlight important geographic disparities in CAR‐T access. Targeted outreach to rural and HPSA‐designated communities may improve equity and ensure broader access to advanced therapies.

The phase 3 SYMPATICO study included an open-label cohort to evaluate the efficacy and safety of first-line ibrutinib plus venetoclax in patients with non-blastoid mantle cell lymphoma (MCL) ≥65 years (n=65), or ≥18 years with a TP53 mutation (TP53m) (n=11). Eligible patients received oral ibrutinib 560 mg once daily and venetoclax (5-week ramp-up to 400 mg once daily) for 2 years, then single-agent ibrutinib 560 mg until disease progression or unacceptable toxicity. In total, 78 patients were enrolled. With median time on study of 40.5 months (range, 0.6+ to 46.9), the complete response (CR) rate was 69% (95% CI, 58-79), and the overall response rate was 95% (95% CI, 87-99). The median duration of response was 37.1 months (95% CI, 30.3-not estimable [NE]). Median progression-free survival (mPFS) was 40.2 months (95% CI, 29.4-NE); median overall survival (OS) was not reached (3-year OS rate, 79% [95% CI, 68-86]). In patients ≥65 years, CR rates were 76% (no TP53m) and 44% (with TP53m), mPFS was 40.2 and 22.0 months, and 3-year OS was 85% and 66%, respectively. In adult patients <65 years (with TP53m), the CR rate was 73%, mPFS was 15.4 months, and 3-year OS was 73%. The most common treatment-emergent adverse events were diarrhea (49%), fatigue (37%), neutropenia (35%), and COVID-19 (32%). First-line ibrutinib plus venetoclax showed promising efficacy, with high CR rates and durable remissions, in patients with previously untreated non-blastoid MCL and may be an option for patients ≥65 years or patients of any age with TP53m. NCT03112174

Introduction: The first-generation BCL2 inhibitor,venetoclax, is an effective treatment for CLL/SLL, but its usage may be limited by toxicity. Sonrotoclax, a next-generation BCL2 inhibitor, is a more selective and pharmacologically potent inhibitor of BCL2 than venetoclax, with a shorter half-life and no drug accumulation. BGB-11417-101 (NCT04277637) is an ongoing, phase 1/1b, dose-escalation/expansion study in patients with B-cell malignancies. Presented here are preliminary data for sonrotoclax + obinutuzumab in patients with treatment-naive (TN) CLL/SLL in BGB-11417-101. Methods: Obinutuzumab is administered intravenously at 100 mg on day (D) 1, 900 mg on D2, 1,000 mg on D8 and D15 of cycle (C) 1, and then 1,000 mg on D1 of C2-6 of each 28-day cycle. Beginning on C2D1, sonrotoclax is administered orally once daily with ramp-up to the target doses, 160 or 320 mg. Patients can continue treatment until progressive disease (PD), unacceptable toxicity, or undetectable minimal residual disease (uMRD4; <1 CLL cell per 10,000 leukocytes [<0.01%]) in peripheral blood (PB) by next-generation sequencing (NGS; ClonoSEQ) after 15 treatment cycles. Study endpoints include safety per NCI-CTCAE v5.0, overall response rate (ORR) per iwCLL guidelines, and MRD status in PB per modified ERIC flow cytometry (FC) assay or NGS, depending on the timepoint. Tumor lysis syndrome (TLS) is assessed per Howard (2011) criteria. Results: As of May 16, 2025, 55 patients with TN CLL/SLL were enrolled (160 mg, n=20; 320 mg, n=35), and 21 patients (all 320 mg) have discontinued sonrotoclax + obinutuzumab (due to uMRD4 per NGS as protocol-mandated [n=17], PI decision uMRD4 per FC [n=2], and PD [n=2]). Four patients discontinued obinutuzumab only per PI decision (160 mg, n=1), thrombocytopenia (320 mg, n=2), and prostate cancer prior to starting sonrotoclax (160 mg, n=1). For all patients, the median age was 62 y, 65% were male, and 89% were White. At baseline, 14% of patients (8/55) had high tumor burden and 58% (31/53) had unmutated IGHV. Median study follow-up was 8.9 months (range, 0.4-25.4 months) for all patients; 6.4 months (range, 0.4-9.0 months) for 160 mg; and 16.0 months (range, 2.9-25.4 months) for 320 mg. Maximum tolerated dose was not reached. The most common any-grade treatment-emergent AEs (TEAEs) were thrombocytopenia (56%), infusion-related reaction (56%), and neutropenia (49%). Neutropenia was the most common grade ≥3 TEAE (38%). No deaths due to TEAEs occurred, and no TEAEs led to sonrotoclax discontinuation. Two cases of laboratory TLS occurred after C1D1 of obinutuzumab prior to starting sonrotoclax; no clinical or laboratory TLS occurred during sonrotoclax ramp up. No meaningful safety differences were observed among sonrotoclax dose cohorts. In 37 efficacy-evaluable patients (160 mg, n=7; 320 mg, n=30), the ORR was 89%; for the 320-mg cohort, ORR was 93% (28/30). Complete response (CR) rates (CR + CR with incomplete marrow recovery [CRi]) were 46% (all patients) and 43% (320 mg). For 23 patients in the 320 mg cohort who reached the C15 MRD assessment, the best C15 uMRD4 rate per FC was 87% (20/23; 2 not evaluable; 1 missing); per NGS, the uMRD4 rate at C15 was 78% (18/23; 5 missing). All patients with an available C15 MRD assessment achieved uMRD4 and remain in remission as of the data cutoff date. The median time from reaching sonrotoclax target dose to uMRD4 was 2.3 months (range, 1.4-5.6 months) in the 320-mg cohort. Three patients experienced PFS events: 1 died from an indeterminate cause (160 mg, discontinued treatment after C1D9 of obinutuzumab) and 2 had PD (320 mg; both Richter's transformation at C6 and C2). Conclusions: Sonrotoclax + obinutuzumab was generally well tolerated in patients with TN CLL/SLL, with no sonrotoclax discontinuations or deaths due to TEAEs. No laboratory or clinical TLS events occurred during sonrotoclax ramp-up. Encouraging antitumor activity was observed with sonrotoclax 320 mg. High rates of blood uMRD4 occurred early and deepened over time. All patients with an available C15 MRD assessment by NGS or FC achieved uMRD4 and remain in remission. A registrational phase 3 study (CELESTIAL-RRCLL, BGB-11417-303) assessing this combination with sonrotoclax 320 mg is currently recruiting.

Introduction: Mediastinal gray zone lymphoma (MGZL) is a rare lymphoma with features intermediate between classical Hodgkin lymphoma (cHL) and diffuse large B cell lymphoma (DLBCL). Due to its rarity and the heterogeneity of its biology, there is a lack of consensus on first line treatment as well as treatment in the setting of relapse or refractory (R/R) disease. Methods: A retrospective review of adult patients diagnosed with MGZL at University of Kansas Cancer Center between 2012 and 2025 was included. The Kaplan-Meier model was used to evaluate overall survival (OS). OS was determined from date of initial diagnosis to last follow up appointment or date of death. Categorical variables were summarized using frequencies and percentages to provide a comprehensive overview of the dataset. Results: Ultimately, 20 patients were evaluated. The median age at diagnosis was 35.5 years (20-75), 55% (11/20) were male, 65% (13/20) were white/Caucasian, and 100% had an ECOG PS scale of 0-1. 60% (12/20) had mediastinal involvement, 10% (2/10) had bone marrow involvement, 55% (11/20) had B symptoms, 55% (11/20) had extra-nodal involvement, 35% (7/20) had a ki67 >40%, 40% (8/20) had an elevated LDH, and 75% (15/20) were stage 3-4 at diagnosis. The median follow up was 84 months (95% CI 62.1- 105.9). The median lines of therapy were 2, and the mean was 2.5 (1-9). First line therapy consisted of 50% (10/20) with dose adjusted EPOCH based therapy, 35% (7/20) with CHOP based therapy, 10% (2/20) with AVD based therapy, and 5% (1/20) were other. 35% of patients underwent consolidative radiation. 58% were in complete remission (CR) after first line therapy, 16% had progressive disease (PD), and 26% had a partial response (PR). Of the patients that had CR after first line therapy (CR1), 27.2% (3/11) underwent consolidation with BEAM autologous transplant (auto-HCT). All of those who underwent consolidation after CR1 have been in CR since transplant. Of the 8 patients that had CR1 that did not undergo consolidative auto-HCT, 5 had relapse of disease (62.5%). 65% (13/20) had R/R disease (61.5% (8/13) refractory disease; 38.5% (5/13) relapsed disease). 84.6% (11/13) of salvage regimens were ICE based therapy, 1/13 was Pembro- GVD, and 1/13 was R-GemOx. Of the patients who received ICE based therapy 63.6% (7/11) had CR and 36.3% (4/11) had CR. Both the R-Gemox and Pembro-GVD patients were in CR after receiving these therapies. 30.8% of salvage regimens were an immune checkpoint inhibitor (ICI)-chemotherapy combination regimen. Of the patients who received ICI therapy, 1 patient had a grade 2 ICI-related toxicity of auto-immune hepatitis. All R/R patients that had PR or CR after salvage or second line therapy underwent autoHCT, with 53.8% (7/13) in CR2 prior to auto-HCT and 38.4% (5/13) in PR prior to auto- HCT. Of those who were in CR2 and underwent auto-HCT, 85.7% (6/7) were in CR at last follow up appointment. One patient underwent consolidation with chimeric antigen receptor therapy (CAR-T) with liso-cel and later had relapse of disease. Two patients underwent allogenic stem cell transplant (allo-HCT), with 1 in PR and 1 with refractory disease prior to allo-HCT. The patient with refractory disease that underwent allo-HCT was in CR at last follow up appointment, while the patient in PR that underwent allo-HCT died due to disease progression. Two patients underwent CD19 directed CAR-T therapy with 1 patient who is in CR at last follow up appointment and the other has relapsed. The total study population estimated 5-year OS was 69% (95% CI 49-96) and 10-year OS was 61% (95% CI 40-92). Of the patients that underwent auto-HCT, the estimated 5-year OS was 82% (95% CI 62-100) and 10-year OS was 82% (95% CI 62-100). The estimated 5- year OS for the patients that underwent allo-HCT was 50% (95% CI 13-100). Conclusion: MGZL continues to be a challenging lymphoma subtype to treat in the first line and R/R setting. We observed high R/R disease in this single institution retrospective study that required salvage/further lines of therapy. Results suggest that auto-HCT consolidation in CR1 may be beneficial in avoiding future relapse of disease. Auto-HCT in later line appears to be adventitious with this high R/R population resulting in a high survival rate at 5 and 10 years, as well as durable response. As this is a single institution retrospective with a limited data set, further investigation with more institutions would be beneficial.

Avoiding apoptosis facilitates abnormal tumor cell survival; therapeutic targeting of antiapoptotic Bcl-2 family proteins can induce tumor cell death. This Phase 1 study evaluated the safety, pharmacokinetics, and efficacy of LOXO-338, a Bcl-2 inhibitor, in patients with advanced hematologic malignancies. LOXO-338 was well tolerated and exhibited preliminary efficacy. Background: LOXO-338 is a novel, orally bioavailable small-molecule inhibitor of Bcl-2, designed to achieve selectivity for Bcl-2 over Bcl-xL, thus avoiding dose-limiting thrombocytopenia associated with Bcl-xL inhibition. This first-in-human, open-label, Phase 1 study investigated LOXO-338 in patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or B-cell non-Hodgkin lymphoma (NHL) (NCT05024045). Patients and Methods: Patients with histologically confirmed advanced B-cell malignancies who had received >= 2 prior therapies were enrolled in Phase 1 dose escalation (interval 3 + 3 design). LOXO-338 was administered orally as 50 to 300 mg once-daily dose until discontinuation due to progressive disease or unacceptable toxicity. The primary objective was to determine the maximum tolerated dose (MTD)/recommended Phase 2 dose of LOXO-338. Secondary objectives included safety, tolerability, pharmacokinetics, and preliminary antitumor activity. Results: In total, 27 patients with CLL/SLL ( n = 10) or NHL ( n = 17) were treated. No dose-limiting toxicities occurred and the MTD was not reached. Treatment-emergent adverse events occurred in 23 patients (85%); anemia (22%) and fatigue (22%) were the most prevalent. Treatment-related adverse events (TRAEs) occurred in 15% and were mostly grade 1 (11%) or 2 (4%); grade >= 3 or serious TRAEs were not reported. Tumor lysis syndrome was not observed. The overall response rate was 19% (95% CI: 6.3, 38.1) and disease control rate was 67% (95% CI: 46, 83.5). LOXO-338 was orally bioavailable with dose-dependent increases in exposure. Conclusion: LOXO-338 was well tolerated with a favorable safety profile in previously treated patients with advanced hematologic malignancies. Preliminary efficacy was observed in this heavily pretreated population supporting further investigation.

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase I/II BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with relapsed / refractory B-cell malignancies (clinicaltrials.gov 03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (N=40, 31.5%), specifically atrial fibrillation (N=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%) or death (5.5%). The most frequent treatment-emergent AE were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 chronic lymphocytic / small lymphocytic lymphoma (CLL/SLL) and 21 mantle cell lymphoma (MCL) patients intolerant to prior BTKi, overall response rate to pirtobrutinib was 76.9% and 81.0%, respectively. Median progression-free survival for CLL/SLL was 28.4 months but was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

BACKGROUND:Bruton's tyrosine kinase inhibitors (BTKi) have prolonged survival in chronic lymphocytic leukemia (CLL), however continuous administration increases toxicity. Little is known about clinical outcomes of patients who discontinue BTKi for reasons other than CLL progression. We aimed to report these outcomes. PATIENTS/METHODS:With the CLL Society, we solicited volunteers with CLL who self-reported BTKi discontinuation for reasons other than CLL progression to participate in a web-based survey. RESULTS:In 170 patients, BTKi was discontinued for toxicity, because CLL was in remission, or personal choice in 62%, 14% and 8%, respectively. When asked how they felt about stopping the BTKi, most were relieved that they may eliminate toxicity (45%), could focus less on CLL (11%), and would not have to pay for the medicine (7%), while 29% experienced anxiety. A statistically significant increase in perceived quality of life (QOL) was observed from prior- versus post-BTKi discontinuation. Of patients who reported that they experienced clinical CLL progression (n = 80), 46% reported that these events did not happen for ≥ 1 year after BTKi discontinuation. Those that were on a BTKi for ≥ 2 years before discontinuation had more time without CLL relapse. CONCLUSIONS:These data provide a unique report of patient experiences. The data suggest that BTKi may be feasible and result in a period of treatment-free remission. The data also indicate that patients are generally relieved when they anticipate BTKi discontinuation and observe significant QOL improvements after BTKi discontinuation. As such, these data should prompt prospective study of time-limited BTKi therapy for CLL.

PURPOSE In metastatic breast cancer (MBC), oral capecitabine prescribed at the US Food and Drug Administration (FDA)–approved dose of 1,250 mg/m 2 twice daily, 14 days on, 7 days off, is associated with poor tolerance. Mathematical models suggest that a fixed-dose (FD), dose-dense schedule may optimize efficacy. We conducted a randomized, open-label trial to compare the efficacy and tolerability of FD capecitabine, 1,500 mg twice daily, 7 days on, 7 days off (FD-7/7), with the FDA-approved dose and schedule (standard-dose [SD]-14/7). METHODS Females with MBC and any previous lines of therapy were included. Patients were randomly assigned 1:1 to either FD-7/7 or SD-14/7. The primary end point was 3-month progression-free survival (PFS). Capecitabine-related toxicities were graded at each visit. RESULTS Between October 2015 and April 2021, 153 patients were enrolled (n = 80 FD-7/7, n = 73 SD-14/7). The 3-month PFS was 63.1% (95% CI, 52.0 to 74.2) in the FD-7/7 arm and 67.2% (95% CI, 54.5 to 79.9) in the SD-14/7 arm. Restricted mean survival time was used to report estimates of effect. The PFS (restricted mean) at 33 months was 10.1 months (95% CI, 7.6 to 12.6) in the FD-7/7 arm compared with 9.1 months (95% CI, 6.6 to 11.7) in the SD-14/7 arm. The overall survival (restricted mean) at 80 months was 30.6 months (95% CI, 23.6 to 37.6) in the FD-7/7 arm versus 24.5 months (95% CI, 18 to 31.1) in the SD-14/7 arm. Toxicity-related treatment discontinuation occurred in 24 patients (32.9%) in the SD-14/7 arm compared with seven patients (8.8%) in the FD-7/7 arm ( P = .0002). Grade 2 to 4 toxicities occurred in 79.5% in the SD-14/7 arm compared with 37.5% in the FD-7/7 arm ( P < .0001). CONCLUSION In MBC, FD capecitabine 1,500 mg twice daily on a 7/7 schedule has less toxicity and similar efficacy when compared with body surface area-based dosing on a 14/7 schedule.

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 >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 <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.

7017 Background: The phase 3 SYMPATICO study evaluated ibrutinib (Ibr) combined with venetoclax (Ven) in 3 cohorts of patients (pts) with MCL: an open-label safety run-in phase to evaluate concurrent initiation of Ibr+Ven in relapsed/refractory (R/R) MCL; a randomized phase to evaluate Ibr+Ven vs Ibr+placebo (Pbo) in R/R MCL; and an open-label cohort to evaluate first-line Ibr+Ven in treatment-naive (TN) MCL. Primary analysis of the randomized phase showed superior PFS with Ibr+Ven vs Ibr+Pbo in pts with R/R MCL (Wang M et al, Lancet Oncol , in press). Here, we report efficacy and safety of Ibr+Ven in pts with TN MCL in older pts (≥65 y) or younger pts with a TP53 mutation ( TP53 mut) (≥18 y) who are in need of novel and better tolerated treatment options. Methods: Older pts (≥65 y) or pts with a TP53 mut with TN MCL received oral Ibr 560 mg once daily and Ven (5-wk ramp-up to 400 mg once daily) for 2 y, then single-agent Ibr 560 mg until PD or unacceptable toxicity. Primary endpoint was complete response (CR) rate assessed by investigator per Lugano. Key secondary endpoints included overall response rate (ORR), duration of response (DOR), PFS, OS, and time to next treatment. Subgroup analyses were performed according to TP53 mut status and age. Results: In total, 78 TN MCL pts were enrolled. At baseline, 83% of pts were ≥65 y, 97% had ECOG PS of 0–1, 45% had high-risk simplified MIPI score, 31% had bulky disease (≥5 cm), 78% had bone marrow involvement, 46% had splenomegaly, and 37% had TP53 mut. Median time on study was 40.5 mo (range, 0.6+–46.9). CR rate was 69% (95% CI, 58–79), and ORR was 95% (95% CI, 87–99). Median DOR was 37.1 mo (95% CI, 30.3–NE). Median PFS was 40.2 mo, and 3-y OS was 79%. CR rate was 76% in pts ≥65 y without TP53 mut, 44% in pts ≥65 y with TP53 mut, and 73% in pts <65 y with TP53 mut; median PFS was 40.2, 22.0, and 15.4 mo, and 3-y OS was 85%, 66%, and 73%, respectively (Table). Median duration of treatment was 24.0 mo (range, 0.3–46.9). Most common AEs were diarrhea (49%), fatigue (37%), neutropenia (35%), and COVID-19 (32%). Most common grade ≥3 AE was neutropenia (29%). Conclusions: First-line Ibr+Ven showed promising efficacy with high CR rates and durable remissions in pts with TN MCL with and without TP53 mut. Safety was acceptable and trended better in younger pts. Ibr+Ven may be an option for older pts with TN MCL or pts of any age with TP53 mut. Clinical trial information: NCT03112174 . Outcomes (95% CI) Without TP53 mutn=44 With TP53 mut n=29 ≥65 y without TP53 mutn=42 ≥65 y with TP53 mutn=18 <65 y without TP53 mutn=2 <65 y with TP53 mutn=11 TotalN=78 CR rate, % 77(62–89) 55(36–74) 76(61–88) 44(22–69) 100(16–100) 73(39–94) 69(58–79) ORR, % 98(88–100) 90(73–98) 98(87–100) 89(65–99) 100(16–100) 91(59–100) 95(87–99) Median PFS, mo 40.2 (37.2–NE) 22.0(9.2–NE) 40.2(37.2–NE) 22.0(11.3–NE) NR(11.1–NE) 15.4(8.2–NE) 40.2(29.4–NE) 3-y OS, % 86(71–93) 68(47–82) 85(70–93) 66(39–83) 100(100–100) 73(37–90) 79(68–86)

BACKGROUND:The combination of ibrutinib and venetoclax leverages complementary mechanisms of action and has shown promising clinical activity in mantle cell lymphoma (MCL). This study evaluated the efficacy and safety of ibrutinib-venetoclax compared with ibrutinib-placebo in patients with relapsed or refractory MCL. METHODS:SYMPATICO is a multicentre, randomised, double-blind, placebo-controlled, phase 3 study performed at 84 hospitals in Europe, North America, and Asia-Pacific. Eligible patients were adults (aged ≥18 years) with pathologically confirmed relapsed or refractory MCL after one to five previous lines of therapy and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients were randomly assigned (1:1) to receive oral ibrutinib 560 mg once daily concurrently with oral venetoclax (5-week ramp-up to 400 mg once daily) or placebo for 2 years, then single-agent ibrutinib 560 mg once daily until disease progression or unacceptable toxicity. Randomisation and treatment assignment occurred via interactive response technology using a stratified permuted block scheme (block sizes of 2 and 4) with stratification by ECOG performance status, previous lines of therapy, and tumour lysis syndrome risk category. Patients and investigators were masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03112174, and is closed to enrolment. FINDINGS:Between April 26, 2018, and Aug 28, 2019, 267 patients were enrolled and randomly assigned; 134 to the ibrutinib-venetoclax group and 133 to the ibrutinib-placebo group. 211 (79%) of 267 patients were male and 56 (21%) were female. With a median follow-up of 51·2 months (IQR 48·2-55·3), median progression-free survival was 31·9 months (95% CI 22·8-47·0) in the ibrutinib-venetoclax group and 22·1 months (16·5-29·5) in the ibrutinib-placebo group (hazard ratio 0·65 [95% CI 0·47-0·88]; p=0·0052). The most common grade 3-4 adverse events were neutropenia (42 [31%] of 134 patients in the ibrutinib-venetoclax group vs 14 [11%] of 132 patients in the ibrutinib-placebo group), thrombocytopenia (17 [13%] vs ten [8%]), and pneumonia (16 [12%] vs 14 [11%]). Serious adverse events occurred in 81 (60%) of 134 patients in the ibrutinib-venetoclax group and in 79 (60%) of 132 patients in the ibrutinib-placebo group. Treatment-related deaths occurred in three (2%) of 134 patients in the ibrutinib-venetoclax group (n=1 COVID-19 infection, n=1 cardiac arrest, and n=1 respiratory failure) and in two (2%) of 132 patients in the ibrutinib-placebo group (n=1 cardiac failure and n=1 COVID-19-related pneumonia). INTERPRETATION:The combination of ibrutinib-venetoclax significantly improved progression-free survival compared with ibrutinib-placebo in patients with relapsed or refractory MCL. The safety profile was consistent with known safety profiles of the individual drugs. These findings suggest a positive benefit-risk profile for ibrutinib-venetoclax treatment. FUNDING:Pharmacyclics (an AbbVie Company) and Janssen Research and Development.

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.

Background: Host immunity at time of apheresis and infusion represent distinct periods which may influence response to CAR-T therapy and the incidence of side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Therefore, absolute lymphocyte count (ALC) at these timepoints may have value as a predictor of response to therapy and adverse events. This study performed a retrospective analysis of patients receiving B-cell maturation antigen (BCMA) and cluster of differentiation (CD)19 directed CAR-T products to identify whether ALC at apheresis and infusion was associated with incidence of CRS/ICANS and efficacy in patients with non-Hodgkins lymphoma (NHL), multiple myeloma (MM), and acute lymphoblastic leukemia (ALL). Methods: 315 patients receiving CAR-T Therapy for NHL, MM, and ALL at the University of Kansas Medical Center from Dec 2017-Dec 2023 were included in the study. ALC was measured and recorded on day of apheresis and day 0 of CAR-T infusion (only when ≥ 0.1 cells/µL). ALC was analyzed as a continuous variable and Wilcoxon rank-sum tests were performed to evaluate whether ALC at apheresis and infusion differed significantly by CRS status, ICANS/CRES status, and combined status (where both CRS and ICANS/CRES = 0 vs. either > 0). Overall survival (OS) and progression-free survival (PFS) at 1-year was used to compare status between groups. All statistical tests were conducted at a 0.05 significance level and analyses were performed using R software. Results: Patients with NHL comprised 69.8% of the study population (n=220) and had a median age of 66 years (range: 29-92). 72% of the population had diffuse large B-cell lymphoma (DLBCL) and 65% of the cohort received axicabtagene ciloleucel. Patients with MM comprised 24.4% of the study (n=77) and had a median age of 69 years (range:45-83). 68% of this group had IgG MM and 52% of the cohort received idecabtagene vicleucel. Patients with ALL comprised 5% of the study (n=18) and had a median age of 39 years (range:21-70). 56% of the ALL cohort received brexucabtagene autoleucel. The most common causes of non-relapse mortality in the study were CRS/ICANS (n=16) and infection (n=6). For the whole study population including patients with NHL, MM, and ALL, ALC at infusion showed statistically significant differences across all three status variables: CRS (p= 0.029), ICANS (p=0.002), and combined CRS and ICANS (p=0.0004). ALC at apheresis did not show an association with CRS (p=.460), ICANS (p=.749), or combined CRS and ICANS (p=.449). In the NHL cohort, patients who had progression had a lower mean ALC at apheresis compared to patients who did not progress (Mean ALC= 0.85 ± 0.72 versus 0.97 ± 0.57 cells/µL). There was a statistically significant difference in ALC at apheresis (p=0.012) and ALC at infusion (p=0.038) in NHL patients with versus without progression. There was no statistically significant difference in survival status based on ALC at apheresis (p=0.213) or at infusion (p=0.093). In the MM cohort, patients who had progression had a lower mean ALC at apheresis compared to patients who did not progress (Mean ALC=1.08 ± 0.86 versus 1.16 ± 0.86 cells/µL). There was a significant difference between ALC at infusion and overall survival status (p=0.024). There were no significant associations between ALC at apheresis for progression (p=.772) or survival status (p=0.609), or for progression status and ALC at infusion (p=0.095) in the MM cohort. For the whole study population including NHL, MM, and ALL, there was a statistically significant difference between ALC at apheresis (p=0.021) and infusion (p=0.013) with progression status, and with ALC at infusion and overall survival (p=0.008). There was no significance between ALC at apheresis and survival (p=0.094). Conclusion: ALC at time of apheresis and infusion may influence progression/survival status and incidence of CRS/ICANS. ALC at apheresis may be predictive of the quantity of lymphocytes being collected and ALC at infusion may effect CAR-T expansion by impacting the cellular immune environment. These findings were more pronounced in the NHL cohort than in the MM or ALL cohorts, which may reflect the effect of disease specific characteristics as well as the confounder of circulating leukemic cells registering as lymphocytes. Further analysis should investigate the relationship between low versus high ALC and its impact on CAR-T therapy outcomes.

Background: Despite the efficacy of covalent Bruton tyrosine kinase inhibitors (cBTKi) in R/R MCL, patients (pts) ultimately discontinue treatment due to intolerance or development of resistance and disease relapse. Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits BTK with low nM potency throughout the daily dosing interval. Pirtobrutinib was safe and effective in the phase 1/2 BRUIN study in pts with R/R B-cell malignancies, including those previously treated with a BTKi. Pirtobrutinib is approved in the EU for adults with R/R MCL after prior treatment with a BTKi (EMA Conditional Approval, Oct 2023), and in the USA for adults with R/R MCL after ≥ 2 lines of systemic therapy, including a BTKi (FDA Accelerated Approval, Jan 2023).Here, we report the final results from the phase 1/2 BRUIN study (NCT03740529), with a follow-up period of up to 5 yrs, focusing on the efficacy and safety of pirtobrutinib in all R/R MCL pts. Methods: Pts with R/R MCL who received ≥1 prior lines of therapy (including BTKi) were eligible for treatment with pirtobrutinib monotherapy. Key endpoints included overall response rate (ORR), duration of response (DOR) and progression-free survival (PFS), all assessed by independent review committee (IRC) per Lugano 2014 criteria (presented here) and investigator, overall survival (OS), and safety. Pts were included across the range of doses evaluated in dose escalation and expansion (25-300 mg/day). A data cutoff on 27 January 2025 was utilized, with a median study follow-up of 17.5 months (range, 0.5-69.6). Results: Among the 166 pts with R/R MCL, 153 (92%) received the pirtobrutinib approved dose of 200 mg/day, 152 (92%) had received prior cBTKi, of which 128 (84.2%) discontinued any prior cBTKi due to progressive disease (PD), and 15 (9.9%) due to toxicity. The cBTKi-pre-treated pts had a median age of 70 yrs (range, 46-88), 52% had intermediate-risk and 28.3% had high-risk sMIPI scores. The median number of prior lines of therapy was 3 (range 1-9), with most pts having received a prior anti-CD20 antibody (96.7%) and chemotherapy (90.1%). Additional prior therapies included hematopoietic stem cell transplantation (21.7%; 19.7% auto and 4.6% allo), BCL-2 inhibitor (15.8%), CAR-T cell therapy (8.6%). As of the data cutoff, 11 (7.2%) pts who received a prior cBTKi and 6 (42.9%) cBTKi naïve pts remained on treatment. The cBTKi pre-treated pts had an ORR of 49.3% (95% CI, 41.1-57.6), including 15.8% complete responses (CR) (n=24) and 33.6% partial responses (PR) (n=51). The 75 responding pretreated pts had a median DOR of 21.6 months (95% CI, 9.2-27.2) at a median follow-up of 24 months. The ORR among 128 pts who had discontinued any prior cBTKi due to PD and 15 pts who discontinued due to toxicity was 43.0% and 93.3%, respectively. The median PFS and OS for cBTKi pre-treated pts were 5.6 months (95% CI, 5.3-9.2) and 23.9 months (95% CI, 17.3-51.5), respectively. Fourteen pts (9.2%) were censored for PFS due to subsequent anticancer therapy without documented PD, including 8 pts who received CAR-T. The cBTKi naïve pts (n=14) had an ORR of 85.7% (95% CI, 57.2-98.2), including 50.0% CR (n=7) and 35.7% PR (n=5). The 12 responding naïve pts had a median DOR of 42.7 months (95% CI, 25.8-NE) at a median follow-up of 43 months. The median PFS and OS in the cBTKi naïve pts were 44.6 months (95% CI, 16.7-NE) and not reached (95% CI, 33.5-NE), respectively. Among all R/R MCL pts (n=166), the most frequent treatment-emergent adverse events (TEAE), regardless of attribution, were fatigue (31.9%), diarrhea (22.9%), anemia (18.1%), and dyspnea (18.1%). The most common Grade ≥3 TEAE was neutropenia/neutrophil count decreased (13.3%), and the rate of Grade ≥3 infections was 21.1%. Grade ≥3 hemorrhage/hematoma (2.4%) and all-grade atrial fibrillation/flutter (3.6%) were infrequent. In total, 13 (7.8%) pts had a fatal TEAE, with 4 (2.4%) classified as infections. Overall, 8 pts (4.8%) had treatment-related AE leading to dose reductions, and 6 (3.6%) had treatment-related AE leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate efficacy in pts with heavily pre-treated R/R MCL including both those who previously received a cBTKi and those who were BTKi-naïve. The safety profile of pirtobrutinib remained favorable with a low-rate of dose reductions/discontinuations due to drug-related toxicity. No new safety signals were identified after up to 5 yrs of follow-up.