This is a summary of the original research article “Brentuximab Vedotin and Nivolumab in Combination with Chemotherapy for Nonbulky, Early-Stage Classical Hodgkin Lymphoma.” The phase 2 SGN35-027 study (NCT03646123) is a multiple-part clinical trial of brentuximab vedotin (BV), with nivolumab, doxorubicin, and dacarbazine (AN + AD), in classical Hodgkin lymphoma (cHL). Here, we present the efficacy and safety of AN + AD from part C of this study in patients with nonbulky, early-stage cHL. At the time of this analysis, 154 patients had received ≥ 1 dose of AN + AD and 98

ABSTRACT:Pirtobrutinib, a noncovalent, reversible Bruton tyrosine kinase inhibitor (BTKi), demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL), resistant to covalent BTKi (cBTKi). We analyzed genomic correlations with response and resistance to pirtobrutinib in relapsed/refractory (R/R) patients with CLL pretreated with cBTKi enrolled in the phase 1/2 BRUIN trial. DNA sequencing was performed on peripheral blood mononuclear cells at baseline, on treatment, and at progressive disease (PD). Common alterations at baseline included mutations in BTK (43%), TP53 (38%), SF3B1 (25%), NOTCH1 (23%), ATM (19%), XPO1 (11%), PLCG2 (9%), BCL2 (8%), and 17p deletion (28%). Common baseline BTK mutations included C481S (85%), C481R (10%), C481F (6%), and C481Y (4%). At PD, 60 of 88 patients (68%) acquired ≥1 mutation, including 44% with acquired BTK mutations and 24% with other acquired mutations. A total of 55 acquired BTK mutations were detected in 39 patients, including gatekeeper mutations (T474I/F/S/Y/L, 26%), kinase-impaired L528W (16%), C481S/R/Y (5%), V416L (2%), and A428D (1%) and others proximal to the adenosine triphosphate-binding pocket, D539A/G/H (1%) and Y545N (1%). Decrease or complete clearance of BTK C481x was observed at PD in 36 of 43 patients (84%). Using a more sensitive assay, 37% (18/49) of acquired BTK mutations were detected at baseline at low allele frequency. Using a highly sensitive assay at progression, a similar frequency of acquired BTK mutations (39%) was detected, and all patients had detectable acquired mutations. This study highlights the complex clonal dynamics of BTK mutations in patients with R/R CLL undergoing pirtobrutinib treatment, and the extent of resistance without an obvious genomic driver. Trial registration: #NCT03740529 at www.ClinicalTrials.gov.

BACKGROUND:Anthracycline-free regimens are needed for older adults with newly diagnosed diffuse large B-cell lymphoma (DLBCL). We aim to evaluate the efficacy and safety of fixed-duration epcoritamab monotherapy versus epcoritamab with lenalidomide in this patient population. METHODS:This open-label, multicentre, randomised, phase 2 trial was conducted at 44 hospitals across 11 countries in Europe and Asia. Patients had newly diagnosed, histologically confirmed CD20-positive large B-cell lymphoma, were ineligible for anthracycline-based chemoimmunotherapy (age ≥80 or ≥75 years with clinically significant comorbidities), had Ann Arbor stage II-IV disease, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. In stage 1, patients were randomly assigned (1:1) to epcoritamab monotherapy or epcoritamab with lenalidomide using a validated interactive response technology system and stratified by the International Prognostic Index (<3 vs ≥3) and ECOG performance status (0-1 vs 2). Epcoritamab was administered subcutaneously using a two step-up dosing schedule (0·16 mg on cycle 1 day 1 and 0·8 mg on cycle 1 day 8), followed by full 48 mg doses once per week in 28-day cycles during cycles 1-3 and once every 4 weeks during cycles 4-12 for up to 12 cycles. Lenalidomide (10 or 20 mg) was given orally once a day on days 1-21 of 28-day cycles for up to 12 cycles. Based on stage 1, one of the treatment regimens was selected for expansion in stage 2. The primary endpoint was investigator-assessed complete response rate (as of the data cutoff on Dec 5, 2025; Lugano criteria) in the full analysis set (all randomly assigned patients in stage 1 and in all treated patients in stage 2). Safety was analysed in patients who received ≥1 dose of trial treatment. This study is registered with ClinicalTrials.gov, NCT05660967 (active, not recruiting). FINDINGS:Between March 8, 2023, and May 14, 2025, 111 patients were assessed for eligibility (88 in stage 1 and 23 in stage 2) and 108 were treated. Median age was 83·0 years (IQR 80·0-86·0). 51 (47%) of 108 were male, 57 (53%) were female, and 87 (81%) were White. In stage 1, 44 patients each were randomly assigned to epcoritamab monotherapy or epcoritamab with lenalidomide and two did not receive treatment. At data cutoff, the complete response rate in stage 1 was 63·6% (95% CI 47·8-77·6; in 28 of 44 patients) in the epcoritamab monotherapy group and 45·5% (30·4-61·2; in 20 of 44) in the epcoritamab with lenalidomide group. The most common treatment-emergent adverse events (grade ≥3) were infections (eight [18%] of 44 patients) and fatigue (six [14%]) with epcoritamab monotherapy versus neutropenia (17 [40%] of 42) and infections (16 [38%]) with epcoritamab with lenalidomide; with serious adverse events in 28 (64%) versus 34 (81%). Treatment-emergent deaths occurred in six (14%) patients in the monotherapy group (cytomegalovirus infection reactivation, COVID-19 pneumonia, SARS-COV-2 infection, tumour lysis syndrome, neuroendocrine tumour of the lung, tumour haemorrhage) and six (14%) in the combined group (pneumonia, COVID-19 pneumonia, sepsis, general physical health deterioration, multiple organ dysfunction syndrome, acute cardiac failure). Based on differences in complete response rates and safety, epcoritamab monotherapy was selected for stage 2 and one patient did not receive treatment. In the epcoritamab monotherapy group, the complete response rate was 45·5% (24·4-67·8; in ten of 22) in stage 2 and 57·6% (44·8-69·7; in 38 of 66) across stages 1 and 2. The most common treatment-emergent adverse events (grade ≥3) among all patients who received epcoritamab monotherapy were infections (16 [24%]), neutropenia (eight [12%]), and hypertension (seven [11%]); with serious adverse events in 46 (70%). Treatment-emergent deaths occurred in two (3%) patients in stage 2 (multiple organ dysfunction syndrome and acute respiratory failure). INTERPRETATION:Fixed-duration epcoritamab monotherapy showed promising complete response rates and a manageable safety profile in older adults with newly diagnosed DLBCL and comorbidities, with slight differences between stages 1 and 2. Continued investigation of epcoritamab as a first-line chemotherapy-free treatment option is warranted. FUNDING:Genmab and AbbVie.

PURPOSE:Mantle cell lymphoma (MCL) is a rare and typically aggressive B-cell non-Hodgkin lymphoma characterized by recurrent relapse after short remissions. Sonrotoclax (BGB-11417) is a next-generation B-cell lymphoma 2 inhibitor with greater selectivity and potency than venetoclax, a shorter half-life, and no drug accumulation. Sonrotoclax monotherapy was evaluated in Bruton tyrosine kinase inhibitor-pretreated patients with relapsed/refractory (R/R) MCL. METHODS:BGB-11417-201 (ClinicalTrials.gov identifier: NCT05471843) is an ongoing global, open-label, phase I/II trial. Sonrotoclax was orally administered once daily with gradual, 4-week ramp-up to 160 mg or 320 mg to mitigate tumor lysis syndrome (TLS). The primary end point was overall response rate by the independent review committee (ORR-IRC) per Lugano classification; secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS:Overall, 125 patients were enrolled and assigned to receive sonrotoclax 160 mg (n = 10) or 320 mg (n = 115) target doses once daily. Most patients had advanced disease (stage IV, 78.3%) and were heavily pretreated (median prior therapies, 3). In efficacy-evaluable patients (n = 103), the ORR-IRC was 52.4% (95% CI, 42.4 to 62.4), a statistically significant increase versus the historic control ORR (30%; P < .0001); the complete response rate was 15.5%. Responses were seen across high-risk subgroups, including patients with TP53 mutation (59.1%). With a median study follow-up of 14.2 months, the median DOR-IRC was 15.8 months, and the median PFS-IRC was 6.5 months. Median OS was not reached. The most common all-grade/grade ≥3 treatment-emergent adverse events were neutropenia (35.7%/19.1%), thrombocytopenia (24.3%/9.6%), and anemia (24.3%/7.8%). TLS occurred in 7.0% of patients; all cases resolved without sequelae. CONCLUSION:Sonrotoclax demonstrated rapid, durable responses and manageable safety in heavily pretreated patients with R/R MCL, including high-risk subgroups, supporting its further clinical evaluation as an oral therapy for R/R MCL.

7046 Background: Cohort 1 of the phase 3 SEQUOIA trial assessed zanu, a next-generation BTKi, compared to BR in TN CLL/SLL without del(17p). Zanu previously demonstrated sustained superiority in progression free survival (PFS) and time to next treatment (TTNT) vs BR. However, evidence regarding outcomes on subsequent therapies (tx) after progressive disease (PD) on zanu remain limited. Here, we present results on follow-up (FU) tx after zanu, including PFS2. Methods: Pts without del(17p) were randomized to receive continuous zanu or six cycles of BR. Pts who received BR could crossover to receive zanu after PD. All pts were followed post-PD for details on any subsequent anti-CLL treatments. This analysis evaluated PFS, TTNT, TTNT or death (TTNT-D) and PFS2. P -values are descriptive. Results: In total 479 pts were randomized; 241 to zanu and 238 to BR. Baseline demographics and disease characteristics were well balanced between the arms. As of 31 October 2025, median FU was 78.7mo (range, 0.0-96.0). Sustained PFS superiority with zanu vs BR was observed (HR, 0.28; 95% CI, 0.21-0.38; P <.0001) with 78mo PFS estimates of 70.9% (95% CI, 64.2-76.6) for zanu and 28.6% (21.7-35.8) for BR. Overall, 211/241 (87.6%) of pts treated with zanu had not received subsequent tx and 34 pts had died without subsequent tx. TTNT and TTNT-D favored zanu over BR (HR, 0.23 [95% CI, 0.15- 0.35; P <.0001] and 0.37 [0.27-0.50; P <.0001], respectively). Overall, 24/241 (10.0%) zanu pts and 82/238 (34.0%) BR pts had PD after study treatment and received subsequent tx. Of the 24 zanu pts receiving subsequent tx after PD, 13 (54.2%) received BCL2i-based regimens, 8 (33.3%) received chemoimmunotherapy (CIT) (incl. anti-CD20 antibody monotherapy), and 3 (12.5%) received BTKi. Of the 82 BR pts receiving subsequent tx after PD, 77 (93.9%) received BTKi (incl. 71 crossover pts), 3 (3.7%) received BCL2i-based regimens and 2 (2.4%) received CIT. Median time from PD following first tx to initiation of next tx was 2.1mo for zanu (range 0-25.7) and 7.4mo (0.3-48.0) for BR. Zanu pts who had PD and received subsequent BCL2i-based tx had a median FU of 33.5mo from initiation of next-line tx. Among these pts, 10 remain alive and without PD, two had died, and one had PD. Overall, PFS2 significantly favored zanu over BR (HR, 0.66; 95% CI, 0.45-0.98; P <.05) with 78mo PFS2 estimates of 81.3% (95% CI, 75.6-85.8) vs 73.8% (67.2-79.3), respectively. Conclusions: PFS2 remained superior with zanu despite broad use of novel subsequent tx (including crossover) in BR pts. Importantly, BCL2i-based salvage after initial zanu achieved high PFS rates at almost 3 years of FU. Together, these findings support that initial zanu provides durable benefit while preserving sensitivity to effective subsequent tx. Clinical trial information: NCT03336333 .

This phase 2 trial evaluated the safety and efficacy of acalabrutinib used to reduce tumor burden before allogeneic hematopoietic cell transplantation (allo-HCT) and as a maintenance therapy after transplantation in patients with relapsed/refractory mantle cell lymphoma (R/R MCL). Patients were treated with acalabrutinib 100 mg BID for 3–6 months. Those achieving complete or partial response (CR, PR) were referred for allo-HCT. Acalabrutinib was restarted 30–90 days after allo-HCT and administered for the subsequent 9 months. The remaining patients continued acalabrutinib until progression or unacceptable toxicity. Out of the 28 included patients, 16 subjects (57

TPS7101 Background: Patients with high-risk CLL/SLL not achieving a complete response (CR) after ≥ 12 months of BTK inhibitor (BTKi) monotherapy remain at risk for early progression due to residual disease and BTKi resistance. A BCL-2 inhibitor (BCL-2i) introduces a complementary, BCR-independent apoptotic mechanism that may deepen responses and prolong progression-free survival (PFS). Lisaftoclax, a selective oral BCL-2i with a short half-life (4-6 h), enables once-daily dosing and is approved in China as second-line CLL therapy. Lisaftoclax monotherapy has demonstrated overall response rates (ORRs) of 67% in relapsed/refractory CLL and 62.5% in BTKi-refractory disease, including del(17p)/ TP53 -mutated cases. Lisaftoclax combined with acalabrutinib achieved ORRs >97% with favorable tolerability. This study evaluates whether lisaftoclax plus BTKi (acalabrutinib, zanubrutinib, or ibrutinib) improves PFS and/or overall survival (OS) (vs continued BTKi monotherapy) in patients with CLL/SLL and residual disease after prolonged BTKi treatment. Methods: This study will enroll approximately 440 patients randomly allocated to receive lisaftoclax plus BTKi or BTKi alone. Eligible patients have CLL/SLL and, after ≥12 months of BTKi monotherapy (lines 1-3), have achieved neither CR nor progressive disease (PD). Randomization is stratified by del(17p)/ TP53 status. Key inclusion criteria include age ≥18 years, ECOG PS 0-2, and residual disease with either high-risk features (del(17p)/ TP53 mutation, unmutated IGHV , or complex karyotype [≥5 abnormalities]), or measurable residual disease with lymph nodes ≥2.5 cm in the absence of high-risk features. Exclusion criteria include prior BCL-2i therapy or Richter transformation. Patients in the investigational arm will undergo a 5-day oral lisaftoclax ramp-up to 400 mg once daily plus physician's choice of BTKi in 28-day cycles until progression or toxicity. Control patients continue their current BTKi monotherapy. Safety and disease assessments (CT/MRI) will occur regularly. The primary endpoint is PFS by independent review committee (iwCLL 2018); key secondary endpoint OS; and other secondary endpoints, PFS by investigator, ORR, duration of response, MRD negativity, and safety. Enrollment is ongoing across 126 sites in 18 countries (ClinicalTrials.gov ID: NCT06104566). Clinical trial information: NCT06104566 .