Jurczak, Wojciech

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 .

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 >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.

Abstract Aggressive B-cell non-Hodgkin lymphomas represent a clinically heterogeneous group of malignancies characterized by rapid progression and varied molecular features. Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive B-cell non-Hodgkin lymphoma and encompasses a biologically diverse group of diseases, now classified into 18 molecular subtypes (Alaggio et al. Leukemia, 2022). While first-line R-CHOP therapy cures approximately 60% of patients (Coiffier et al. N Engl J Med. 2002), those with relapsed or refractory (R/R) disease face poor outcomes. Although CAR T-cell therapies (e.g. axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel) have improved outcomes, access remains limited due to logistical and disease-related constraints (Locke et al. N Engl J Med. 2022). More recently, bispecific CD20xCD3 antibodies such as epcoritamab and glofitamab have shown clinical activity in the R/R setting after ≥2 prior lines, with complete response (CR) rates of ~40% (Dickinson et al. N Engl J Med. 2022; Thieblemont et al. J Clin Oncol. 2023). However, treatment sequencing and mechanisms of resistance to CD20-targeted therapies remain areas of active investigation. One emerging resistance mechanism to CD20 bispecific antibodies is the downregulation or loss of CD20 expression, which has been associated with treatment failure and disease progression (Bannard et al. Clin. Cancer Research, 2022). This highlights the need for novel strategies to overcome CD20 resistance. Dapolsertib (MEN1703) is a first-in-class dual PIM/FLT3 kinase inhibitor that targets key oncogenic and survival pathways in hematologic malignancies. PIM kinases (PIM1, PIM2, PIM3) regulate translation, metabolism, apoptosis, and immune modulation. Overexpression and mutations in PIM genes are associated with poor prognosis in DLBCL, particularly in the ABC subtype, and are known to cooperate with MYC and BCL6 (Szydłowski et al. Cancer Res. 2021). Simultaneous inhibition of all three PIMs downregulates MYC and induces marked cytotoxicity in preclinical models. In AML, dapolsertib has demonstrated preliminary clinical single-agent activity, with ~10% CR/CRi reported in the DIAMOND study (NCT03008187; Martinelli et al. Blood Neoplasia, in press). Dapolsertib has also shown strong antitumor activity in lymphoma models, both in vitro and in vivo (Bellon et al. Mol Cancer. 2023). Notably, dapolsertib demonstrated synergy with anti-CD20 antibody, rituximab, providing a rationale for combination strategies (Szydłowski et al. Cancer Res. 2021). The rationale for combining dapolsertib with a CD20 bispecific antibody lies in its potential to modulate survival pathways, sensitize malignant B-cells to immunotherapy, and circumvent resistance mechanisms such as CD20 loss by inducing CD20 expression. JASPIS-01 (NCT06534437) is an ongoing, international multicenter, Phase 2 study evaluating dapolsertib as monotherapy or in combination with glofitamab in patients with R/R aggressive B-cell lymphoma after ≥2 prior lines of therapy. The trial consists of three parts: a safety run-in (Part 1), optional enrichment (Part 2), and a potential randomized comparison vs. glofitamab (Part 3). Part 1 will include 2 groups of patients. Group 1 comprises bispecific-naïve patients randomized to a prospective dose-optimization evaluation of the combination with dapolsertib. Patients receive either 125 mg on a 2 weeks on / 1 week off schedule or 150 mg on a 1 week on / 2 weeks off schedule for up to 12 cycles to investigate optimal therapeutic window. Group 2 comprises patients who exhausted therapeutic standard options and who will receive dapolsertib monotherapy at 125 mg on a 2 weeks on / 1 week off schedule until intolerable toxicity or disease progression. The initial safety run-in (Parts 1 of both groups) informs dose selection for Part 2. Dose continuation in Part 2 will be guided by Data and Safety Monitoring Board safety assessments after ≥2 completed treatment cycles. The primary objectives are to assess safety, tolerability, and preliminary anti-lymphoma activity. Key endpoints include incidence of adverse events, overall/complete response rates, and duration of response. As of July 11, 2025, Part 1 is enrolling in France, Poland, Spain and the UK with additional sites activation ongoing.

Abstract 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.

Introduction: The primary analysis of the phase 3 ECHO trial (NCT02972840) demonstrated that acalabrutinib plus bendamustine-rituximab (ABR) significantly improved progression-free survival (PFS) vs placebo plus bendamustine-rituximab (PBR) in older patients (pts) with previously untreated mantle cell lymphoma (MCL) (Wang et al. EHA 2024, Abstract #LB3439). Here we present additional efficacy and safety results from the ECHO trial. Methods: Pts aged ≥65 years (y) with previously untreated MCL and ECOG PS ≤2 were randomly assigned 1:1 to receive ABR or PBR. Acalabrutinib (100 mg twice daily) or placebo was administered until progressive disease (PD) or unacceptable toxicity. Induction with BR was administered for 6 cycles followed by rituximab maintenance (A±R maintenance, cycles 7-30) in pts achieving a partial or complete response (PR or CR). Pts progressing on PBR could cross over to receive acalabrutinib monotherapy. PFS (primary endpoint) was assessed by independent review committee. Minimal residual disease (MRD) negativity rate (10-5) was assessed in peripheral blood (every 24 weeks [wks], at CR, and at PD) and bone marrow (at CR) by NGS-based ClonoSEQ assay (Adaptive Biotechnologies). Results: Among the 598 pts randomized to ABR or PBR (299 in each arm), high-risk baseline characteristics included high-risk simplified MIPI score in 24.1% and 24.4%, blastoid histology in 8.7% and 6.7%, pleomorphic histology in 5.0% and 6.0%, centrally tested Ki-67 ≥30% in 46.5% and 49.2%, and known TP53 mutation in 7.4% and 9.7%, respectively. PFS hazard ratios (HRs) for subgroups were 0.78 (95% confidence interval [CI] 0.51-1.19) in pts with high-risk simplified MIPI score, 0.68 (95% CI 0.29-1.58) in pts with blastoid histology, 0.64 (95% CI 0.25-1.66) in pts with pleomorphic histology, 0.69 (95% CI 0.49-0.98) in pts with Ki-67 ≥30%, and 0.88 (95% CI 0.42-1.78) in pts with known TP53 mutation. In the ABR arm, median PFS was 22.2 months (mo) among pts who discontinued acalabrutinib during induction for reasons other than PD or death, 29.4 mo in pts who discontinued acalabrutinib during A±R maintenance (cycles 7-30) for reasons other than PD or death, and not reached in pts who received acalabrutinib for 31 cycles or more. Among evaluable patients who were MRD negative at the end of induction (24 wks), the rate of conversion to MRD positive during maintenance was lower in the ABR arm (5.85%; n=11/188) than in the PBR arm (15%; n=26/171). Conversely, among evaluable pts who were MRD positive at the end of induction (24 wks), 37.5% (n=3/8) in the ABR arm and 20% (n=3/15) in the PBR arm converted to MRD negative during maintenance. Overall rates of AEs were similar in each arm during induction, but were higher in ABR during A±R maintenance (cycles 7-30) and more so in the monotherapy phase (cycle 31+). Grade ≥3 TEAEs (ABR vs PBR) were 70.0% vs 68.7% during induction, 64.9% vs 62.9% during A±R maintenance (cycles 7-30), and 57.0% vs 45.3% during monotherapy (cycle 31+). Similarly, rates of TEAEs leading to discontinuation of acalabrutinib/placebo were 8.1% vs 8.8% during induction, 23.9% vs 19.0% during A±R maintenance (cycles 7-30), and 25.9% vs 13.7% during monotherapy (cycle 31+). Exposure-adjusted incidence rates per 100 person-years reduced the difference between ABR and PBR for clinically relevant TEAE rates (32.6 vs 29.3 for grade ≥3 serious TEAEs; 4.2 vs 4.0 for grade 5 TEAEs; 15.5 vs 12.4 for TEAEs leading to acalabrutinib/placebo discontinuation), possibly due to longer median exposure to acalabrutinib (28.6 vs 24.6 mo). Conclusion: Acalabrutinib in combination with BR provides a significant PFS benefit in pts with previously untreated MCL, including those with high-risk features. Furthermore, the addition of acalabrutinib to BR provided a greater PFS effect among pts in the ABR arm with the longest exposure to acalabrutinib. The PFS improvement may be partially driven by the contribution of acalabrutinib to sustained MRD-negative status and deepened responses after the end of induction. ABR provides this clinical benefit without excess toxicity as shown by attenuated differences between arms in exposure-adjusted incidence rates, suggesting that higher AE rates in the ABR arm are likely due in part to the longer duration of acalabrutinib treatment vs placebo. These data emphasize the benefits of acalabrutinib in frontline MCL treatment in high-risk pts and the additional benefit of continuous therapy.

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), typically administered for 6 cycles, is the standard therapy for DLBCL and is curative in ~60-70% of patients (pts). However, 30-40% of pts have relapsed/refractory (RR) DLBCL following treatment with R-CHOP, with poor clinical outcomes. International Prognostic Index (IPI) scores of 3-5 are used to identify high-risk (HR) pts who are more likely to be RR following treatment. Additionally, pts with IPI scores of 1-2 who also have bulky disease and/or very high lactate dehydrogenase levels (LDH), have been identified as a HR subset with similar outcomes to pts with an IPI score of 3 (Maurer et al. ASH 2023, #4512). First-line therapy represents the greatest opportunity to address the unmet need for these pts. Golcadomide (GOLCA) is a potential first-in-class oral cereblon E3 ligase modulator (CELMoD™) agent purposefully designed for the treatment of lymphoma. GOLCA co-opts cereblon to induce targeted degradation of the transcription factors Ikaros/Aiolos, inducing deep, rapid, and extensive tumor killing, independent of cell of origin, and enhanced immunostimulatory activity. In the phase 1b study CC-220-DLBCL-001, GOLCA combined with R-CHOP was well tolerated, showing promising activity and combinability with high rates of durable responses irrespective of cell of origin in pts with previously untreated aggressive BCL, including those with HR disease (Hoffmann et al. EHA 2024, S235). Additionally, GOLCA has shown encouraging efficacy and safety profiles in pts with RR DLBCL, both as a monotherapy (Michot et al. ICML 2023, P90) and in combination with rituximab (Chavez et al. ASH 2023, P4496). The efficacy and safety data observed in early-phase studies suggest promising activity and a manageable safety profile. This supports further investigation of the GOLCA + R-CHOP combination in the phase 3 setting. Here, we present the study design of GOLSEEK-1, a multicenter, randomized, double-blind, placebo-controlled phase 3 study (NCT06356129) comparing the efficacy and safety of GOLCA + R-CHOP vs placebo + R-CHOP in pts with previously untreated HR LBCL. Study Design and Methods Approximately 850 pts with previously untreated LBCL will be randomized 1:1 to either GOLCA + R-CHOP or placebo + R-CHOP. Pts must have a histologically confirmed diagnosis of LBCL according to WHO 2022 classification, including: DLBCL, not otherwise specified (NOS) including ABC and GCB subtypes; high-grade B-cell lymphoma with MYC and BCL2 rearrangements, or NOS; T-cell/histiocyte-rich LBCL; Epstein-Barr Virus-Positive DLBCL. Other key inclusion criteria include an IPI score of 1 or 2 considered HR (LDH > 1.3 × upper limit of normal and/or bulky disease, defined as a single lesion of ≥ 7 cm [Maurer et al. ASH 2023, #4512]), or IPI score ≥ 3; and measurable disease as defined by the Lugano classification. Key exclusion criteria include 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, as well as documented or suspected central nervous system involvement. Randomization will be stratified by IPI score (1-2 with risk factors and 3 vs 4-5) and bulky disease (> 7 cm vs ≤ 7 cm). After a screening period of ≤ 4 weeks, pts will receive GOLCA (0.4 mg) or placebo orally once daily for 7 consecutive days in each of 6 cycles in combination with R-CHOP in 21-day cycles. The primary endpoint of this study is progression-free survival (PFS) in untreated HR LBCL, assessed by investigator based on the Lugano Response Criteria. Key secondary endpoints include PFS in untreated non-high-grade BCL, event-free survival in pts with untreated HR LBCL, independently assessed complete metabolic response rate, undetectable minimal residual disease by PhasED-Seq (defined as undetectable circulating tumor DNA levels at treatment end), and overall survival. Patient follow-up will occur for up to approximately 67 months after beginning treatment. This study is recruiting at 293 sites in 37 countries, across the United States, Europe, Latin America, and East Asia.

7053 Background: In ECHELON-1 (NCT01712490), 6-year follow-up (FU) analyses demonstrated significant improvements in overall survival (OS) and progression-free survival (PFS) with A+AVD (brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), with a comparable safety profile. Here, we report data at 7-year median FU. Methods: Analyses of OS and PFS per investigator were conducted in the intent-to-treat (ITT) population (data cut-off March 11, 2023). Patients (pts) were randomized 1:1 to receive ≤6 cycles of A+AVD (n=664) or ABVD (n=670) on days 1 and 15, every 28 days. PET scan after cycle 2 (PET2) evaluation was mandatory. Long-term safety outcomes in the safety population included resolution or improvement of peripheral neuropathy (PN), second malignancies, and pregnancies. Results: At median FU of 89.3 months (95% CI 87.0–90.2), 7-year OS rates were 93.5% (95% CI 91.1–95.2) with A+AVD and 88.8% (95% CI 85.8–91.1) with ABVD; OS favored A+AVD over ABVD (HR 0.62; 95% CI 0.42–0.90; p=0.011). Subgroup analyses showed consistent OS benefit for A+AVD, including in the age <40 years and Stage IV disease subgroups (Table). 7-year PFS rates with A+AVD vs ABVD were 82.3% (95% CI 79.1–85.0) vs 74.5% (95% CI 70.8–77.7; HR 0.68 [95% CI 0.53–0.86]; p=0.001). PN improved/resolved in most pts at last FU (A+AVD: 86%; ABVD: 87%). Median (range) time to complete resolution of PN (A+AVD vs ABVD) was 16 (0–373) vs 10 (0–343) weeks; median (range) time to improvement was 42 (2–182) vs 19 (15–142) weeks. PN was ongoing in 28% (4% grade ≥3) of A+AVD and 20% (1% grade ≥3) of ABVD pts. Second malignancies were reported in 5% of A+AVD and 6% of ABVD pts. Pts and their partners reported 84/92 livebirths/pregnancies with A+AVD and 59/73 with ABVD; no stillbirths were recorded. Conclusions: At 7-year median FU, pts with stage III/IV cHL who received A+AVD showed a sustained PFS and OS benefit vs ABVD, with PFS rates indicating potential curability. The safety profile in pts treated with A+AVD showed no new safety signals at 7 years. Clinical trial information: NCT01712490 . [Table: see text]

Background:Richter transformation (RT) occurs in up to 10% of patients with chronic lymphocytic leukemia (CLL), typically presents as an aggressive diffuse large B-cell lymphoma (DLBCL) and is associated with poor survival. RT has no approved standard therapy; and clinical trial enrollment is the preferred first line of therapy. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, that inhibits both wildtype and C481-mutant BTK with equal low nM potency, has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval. Pirtobrutinib demonstrated durable overall response rates (ORR) and was well tolerated in patients (pts) with poor-prognosis B-cell malignancies regardless of prior therapy. Here we provide updated safety and efficacy of pirtobrutinib in RT pts from the phase 1/2 BRUIN trial (NCT03740529). Methods: Pts with previously treated, histologically confirmed RT were eligible in the global, multicenter, phase 1/2 BRUIN study. Pts with untreated RT became eligible after Amendment 10. All but one patient received the recommended phase 2 dose of 200 mg daily. Key endpoints included investigator-assessed ORR, DoR per Lugano 2014 criteria, OS, and safety. A data cut of 05 May 2023 was utilized. To assess clonal relationship, IGH rearrangement studies were done on tissue biopsies with RT involvement, and baseline blood or bone marrow (BM) samples with CLL involvement. Results: Among all pts with RT (N=82) the median age was 67 (range, 26-95) and the median total number of lines of prior systemic therapy was 4 (range, 0-13). Pts with prior treatment had a median of 2 CLL-directed therapies and 2 RT-directed therapies. Eight pts did not have a previous line of RT-directed therapy, and 1 patient received neither RT- nor CLL-directed therapy. Common prior RT- and CLL-directed therapies (RT, CLL) included: chemotherapy (76%, 52%), cBTKi (34%, 62%), anti-CD20 antibody (78%, 66%), BCL2i (38%, 49%), stem cell transplant (SCT; 6%, 7%), and CAR-T (11%, 4%). Of 29 pts with bone marrow screening, 41.4% had CLL alone present in BM, 13.8% had DLBCL present and 24.1% had both CLL and DLBCL present. For 39 pts with available PET data, the median SUVmax was 19.1 (range, 2.6-41.2). For all 82 pts, the ORR was 50.0% (95% CI, 38.7-61.3) including complete (13.4%, n=11) and partial (36.6%, n=30) responses. For 61 pts who received prior cBTKi therapy, the ORR was 45.9% (95% CI 33.1-59.2). Among 28 pts with an RT-directed cBTKi and 51 pts with prior CLL-directed cBTKi, the ORR was 42.9% (95% CI, 24.5-62.8) and 43.1% (95% CI, 29.3-57.8), respectively. In 50 pts who discontinued prior cBTKi due to disease progression, the ORR was 42.0% (95% CI, 28.2-56.8). At median follow-up time of 9.7 months, the median DoR for all 82 RT pts was 7.4 months (95% CI, 3.1-19.1) and the estimated rate at 12 months was 45.9% (95% CI, 28.3-61.8). The median time on treatment for the 41pts who responded to treatment was 8.3 months. Eight pts stopped pirtobrutinib to pursue curative-intent allogeneic SCT and DoR was censored at the last preceding disease assessment. At a median survival follow-up of 18.3 months, the median OS for the entire RT cohort was 12.5 months (95% CI, 6.9-20.5). At 18 months, the OS rate was 44.3% (95% CI, 32.5-55.4). Frequent treatment-emergent adverse events (TEAE) in the RT cohort (n=82) were neutropenia/decreased neutrophil count (29.3%, n=24), fatigue (24.4%, n=20) and diarrhea, dyspnea, thrombocytopenia, and pyrexia (18.3% each, n=15). Common grade ≥3 TEAEs were neutropenia/decreased neutrophil count (23.2%, n=19), thrombocytopenia (11.0%, n=9), plus anemia and sepsis (9.8% each, n=8). Any grade hypertension (3.7%, n=3) or atrial fibrillation (1.2%, n=1) were infrequent. Three pts (3.7%) had treatment-related AEs leading to dose reductions, but no pt had a treatment-related AE leading to pirtobrutinib discontinuation. Analyses of clonality will be presented. Conclusions: Continued follow-up from BRUIN demonstrates encouraging response and OS in pts with RT. Pirtobrutinib remains well-tolerated with low rates of discontinuation and manageable safety profile. While RT remains a challenging diagnosis, pirtobrutinib represents a potential treatment option that warrants further investigation.