BACKGROUNDInhibition of Bruton's tyrosine kinase with ibrutinib blocks the function of myeloid-derived suppressor cells (MDSC). The addition of nivolumab significantly increased circulating NK and CD8+ T cells and increased CD8+ T cell proliferation. Exploratory analyses suggest that MDSC and T cell gene expression and TCR repertoire diversity were differentially affected by BTK inhibition according to patient response.CONCLUSIONIbrutinib and nivolumab were well tolerated and affected MDSC and T cell function in patients with solid metastatic tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT03525925.FUNDINGNIH; National Cancer Institute Cancer; National Center for Advancing Translational Sciences; Pelotonia.

Research has shown that Bruton's tyrosine kinase (BTK) is a critical regulator of the NLRP3 inflammasome and that the pharmacological inhibition of BTK using the FDA-approved inhibitor ibrutinib diminishes NLRP3-dependent inflammatory response...In our drug discovery efforts, we identified 5,6,7,8-tetrahydropteridines as underutilized scaffolds in medicinal chemistry. We report the synthesis of 5,6,7,8-tetrahydropteridines with potential as anti-inflammatory compounds.

P2, N=27, Completed, Principia Biopharma, a Sanofi Company | Active, not recruiting --> Completed

P1, N=15, Completed, Merck Sharp & Dohme LLC

P2, N=15, Active, not recruiting, Bnai Zion Medical Center | Recruiting --> Active, not recruiting | Trial primary completion date: Mar 2024 --> Dec 2024

P2, N=66, Recruiting, Telios Pharma, Inc.

P=N/A, N=25, Not yet recruiting, The second hospital of Dalian Medical University; The second hospital of Dalian Medical University

P4, N=33, Recruiting, Shanghai Ninth Peopole's Hospital, Shanghai Jiaotong University School of Medicine; Shanghai Ninth Peopole's Hospital, Shanghai Jiaotong University Sc

P2, N=170, Not yet recruiting, Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

P1/2, N=80, Recruiting, Beijing Tiantan Hospital, Capital Medical University; Hyperway Pharmaceutical Co.,Ltd.

Two pts were switched to zanubrutinib due to PD on U2, both achieved response. AU2 is a highly effective regimen in pts with previously untreated MCL, including those with high-risk genetics (100% CR rate), and achieves a high molecular uMRD rate. Pts who develop progressive disease can be effectively salvaged with subsequent therapies.

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.

Introduction – We previously reported the efficacy and safety results of a combination of ibrutinib with rituximab in patients (pts) with mantle cell lymphoma (MCL) ≥ 65 years. Conclusions – Chemotherapy-free frontline therapy with AR is highly effective, safe, induces deep MRD negative responses and alters immune landscape in older pts with MCL. Randomized studies are needed to confirm whether this regimen can be the new first line standard treatment for older MCL patients.

The combination of the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib, the BCL-2 inhibitor venetoclax (V), and the anti-CD20 monoclonal antibody (mAb) obinutuzumab (O) has demonstrated safety and efficacy in R/R and TN MCL (Le Gouill, Blood 2021). AVO is safe and active in pts with R/R and TP53-aberrant/transplant ineligible TN MCL. Preliminary efficacy and feasibility of an MRD-guided treatment approach is encouraging in this high-risk TN cohort B. Our data supports further investigation of a targeted triplet approach, and the phase II TN transplant eligible and TP53 wild type cohort is enrolling based on demonstrated safety and efficacy in cohort B. Updated results will be presented at the meeting.

Responses are durable, with 89%, 87%, and 77% 4-yr PFS in all-comer, uIGHV, and TP53 aberrant pts. Our data support further study of AVO for pts with TN high risk CLL in GCLLSG CLL16 and future trials.

Zanubrutinib is a second-generation BTKi with superior PFS and safety compared with ibrutinib (Brown NEJM 2023). Five-year follow up of the BOVen regimen demonstrates frequent uMRD4 in PB (96%) and BM (92%), and uMRD4 was durable with a median MRD4-free survival of 34 mo. Retreatment with zanubrutinib-venetoclax was also well-tolerated and effective. A phase 2 trial of BOVen with ΔMRD400-directed treatment duration is ongoing.

The combination of durvalumab and acalabrutinib showed encouraging preliminary clinical activity in a heavily pre-treated cohort with relapsed/refractory aggressive B-cell lymphoma. The combination was well tolerated and deliverable to a predominantly elderly and frail population and warrants further study in this context.

Induction with 3 cycles of bendamustine and rituximab followed by 3 cycles of cytarabine and rituximab (BR/CR) is associated with high complete metabolic response (CMR) and uMRD rates (Armand et al., BJH 2016; Merryman et al., Blood Adv 2020). Bruton’s tyrosine kinase inhibitors (BTKi) including ibrutinib and acalabrutinib (A) in combination with CIT are highly effective in MCL (Wang et al., EHA 2024, LBA 3439)... High PET/CT CMR uMRD rates were seen in all 3 arms. BR/CR can be considered as a standard induction in pts ≤ 70. Addition of acalabrutinib to the standard arm added toxicity without improvement in efficacy, suggesting acalabrutinib should be avoided during Ara-C cycles.

Fixed-duration ViPOR x 6C without maintenance achieved CR in 100% and uMRD in 97% of MCL pts, with ongoing CR in 95% and 73% of TN and R/R pts, respectively, and only 1 R/R pt receiving consolidative allo-HSCT. This includes blastoid, TP53 mutated, and post-BTKi high-risk subsets. ViPOR with a 12d VEN ramp-up on C2 is safe in MCL pts of all ages without significant TLS or febrile neutropenia.

This study demonstrates that the ALR regimen has high rates of durable complete and molecular responses, and is feasible as a time-limited initial therapy for patients with both TP53 wild type and mutant MCL. The ALO regimen is feasible with encouraging initial safety and efficacy. MRD and cfDNA analyses provide real-time and non-invasive monitoring of molecular response and mutational evolution, which warrants further evaluation in response-adapted strategy.

Introduction: Combined treatment with covalent BTK-inhibitor (cBTKi), such as ibrutinib, acalabrutinib, or zanubrutinib with BCL2-inhibitor, venetoclax, +/- CD20 monoclonal antibody obinutuzumab showed high rates of undetectable MRD (U-MRD4, 10-4 sensitivity) remission in patients (pts) with CLL (Jain, NEJM 2019; Munir NEJM 2023; Wierda, JCO 2021; Kater, NEJM Evidence 2022). We report results of combined pirtobrutinib, venetoclax, and obinutuzumab in pts with previously untreated CLL. We observed a very high rate of BM U-MRD6 at 6-months and 12-months of combined treatment. Adverse event profile was similar to what was noted in previous studies with these agents.

In preclinical studies, lenalidomide has been shown to induce cytotoxicity in ABC DLBCL cells by inhibiting NF-κB signaling and a synergistic effect is seen when B-cell receptor signaling is inhibited by the BTK inhibitor ibrutinib. The results of the BGB-3111-110 study demonstrated that the RP2D of zanubrutinib 160 mg twice daily plus lenalidomide 25 mg once daily had a manageable safety profile and promising efficacy in patients with R/R DLBCL. Similar efficacy was observed across DLBCL subtypes; ORR was numerically higher in the ABC subtype. Further molecular analysis is ongoing.

Our findings contribute to the evolving standard of care for this specific population and highlight the clinical benefits of targeted cancer therapies.

P=N/A, N=104, Completed, AstraZeneca | Active, not recruiting --> Completed

P1/2, N=24, Recruiting, Jonsson Comprehensive Cancer Center | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

P1, N=10, Not yet recruiting, City of Hope Medical Center

P1, N=0, Withdrawn, Daewoong Pharmaceutical Co. LTD. | N=72 --> 0 | Not yet recruiting --> Withdrawn

P2, N=100, Not yet recruiting, VA Office of Research and Development | Trial completion date: Dec 2029 --> Dec 2030 | Trial primary completion date: Jun 2029 --> Jun 2030

P2, N=60, Active, not recruiting, Jennifer R. Brown, MD, PhD | Trial primary completion date: Dec 2023 --> Dec 2026

P1, N=24, Recruiting, Biogen | Not yet recruiting --> Recruiting

P2, N=19, Not yet recruiting, Ruijin Hospital

P2, N=80, Not yet recruiting, Navy General Hospital, Beijing

P=N/A, N=67, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting | N=50 --> 67

P2, N=29, Active, not recruiting, French Innovative Leukemia Organisation | Trial completion date: Jun 2026 --> Dec 2025

P2, N=80, Not yet recruiting, Navy General Hospital, Beijing

P1/2, N=50, Recruiting, University of Washington | Trial completion date: Mar 2030 --> Mar 2031 | Trial primary completion date: Mar 2025 --> Mar 2026

P2, N=120, Active, not recruiting, French Innovative Leukemia Organisation | Trial completion date: Jun 2026 --> Jan 2025

P=N/A, N=200, Recruiting, AstraZeneca | Trial completion date: Apr 2026 --> Oct 2026 | Trial primary completion date: Apr 2026 --> Oct 2026

P1, N=119, Completed, BeiGene | Phase classification: P1b --> P1

The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling...To bypass the C481S mutation, non-covalent BTKi, such as Pirtobrutinib, were developed and are active against both wild-type and the C481S mutation...In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTKi and the development of new therapeutic strategies highlight the ongoing advances being made towards the pursuit of a cure for B-cell lymphoid malignancies.

A 75-year-old man presented with uveitis masquerade syndrome while undergoing treatment for MCL with rituximab-bendamustine. During the study course, CD5 and CD20 positive cells were identified in the anterior chamber of the eyes via flow cytometry, which was consistent with the pathological findings of biopsies. Ibrutinib may improve recurrent MCL intraocular lesions.

P2, N=29, Not yet recruiting, Ruijin Hospital