Bruton’s tyrosine kinase (BTK) inhibitor is a promising novel agent that has potential efficiency in B-cell malignancies. It took approximately 20 years from target discovery to new drug approval. The first-in-class drug ibrutinib creates possibilities for an era of chemotherapy-free management of B-cell malignancies, and it is so popular that gross sales have rapidly grown to more than 230 billion dollars in just 6 years, with annual sales exceeding 80 billion dollars; it also became one of the five top-selling medicines in the world. Numerous clinical trials of BTK inhibitors in cancers were initiated in the last decade, and ~73 trials were intensively announced or updated with extended follow-up data in the most recent 3 years. In this review, we summarized the significant milestones in the preclinical discovery and clinical development of BTK inhibitors to better understand the clinical and commercial potential as well as the directions being taken. Furthermore, it also contributes impactful lessons regarding the discovery and development of other novel therapies.

Whether immunotherapy combined with different histone deacetylases (HDAC) inhibitors in refractory or relapsed natural killer/T-cell lymphoma (NKTCL) is superior to each agent is still lacking in head-to-head clinical trials or preclinical evidence. NKTCL cell line xenograft models (CDX) in immunocompetent, human programmed cell death protein 1 (PD1) knock-in genetically engineered mice were used to investigate the combination effects. Different types and dosages of HDAC inhibitors were investigated. We explored the underlying mechanisms by RNA-sequencing and ChIP-sequencing. Two clinical cases treated with anti-PD1/chidamide were presented. Anti-PD1/chidamide shows significant tumour rejection in two CDX models. RNA-seq and CHIP-seq revealed that chidamide is synergistic to enhance T-cell chemokine expression, augment the Ifn-γ response, and increase CD8 T-cell infiltration via histone modification. Ifn-γ neutralizing antibody can attenuate the efficacy of combination drugs. However, the anti-PD1/romidepsin failed to augment the Ifn-γ response. The expressions of Ifn-γ related gene set signatures are significantly correlated with tumour rejection in anti-PD1/chidamide. In the clinic, two NKTCL patients treated with the PD1/chidamide show promising efficacy and limited toxicity. Anti-PD1/chidamide enhances T-cell chemokine expression and augments the IFN-γ response in preclinical NKTCL immunocompetent models. IFN-γ signatures may be good response biomarkers for the selection of potentially benefit patients. This study was supported by the Chinese National Major Project for New Drug Innovation (2017ZX09304015) and the Chinese Society of Clinical Oncology Research Fund (Y-BMS2019-026).

Understanding the process of myeloid differentiation offers important insights into both normal and abnormal developmental processes but is limited by the dearth of experimental models. Here we show that myeloid progenitors can be derived from embryonic stem cells, immortalized, and applied to the study of the mechanisms underlying myeloid differentiation. The embryonic stem cell–derived myeloid progenitors, when immortalized with estrogen-regulated Hoxb8 protein, demonstrate normal karyotyping, are genetically tractable, and can be differentiated into functional neutrophils. Using this model, we identified mammalian target of rapamycin complex 1 as a critical regulator of myeloid differentiation. Together, our studies led to a convenient, karyotypically normal, and genetically manipulatable cellular system, which can be used to shed new light on the mechanisms for myeloid differentiation.

Background: Patients with relapsed/refractory diffuse large B‐cell lymphoma (r/r DLBCL) have poor outcomes and few treatment options. We report the preliminary results of the efficacy and safety of PD‐1 monoclonal antibody (mab) plus Rituximab for r/r DLBCL.Methods: In this single‐center, single‐arm phase 2 and retrospective study, r/r DLBCL patients received PD‐1 mab and Rituximab every 3 weeks. Immunohistochemistry, fluorescence in situ hybridization, and probe capture‐based high‐resolution sequencing were performed. Efficacy, safety and prognostic factors were analyzed.Results: Between October 16th, 2018, and July 10th, 2022, 36 patients (10 patients in retrospective study and 26 patients in phase 2 study) were enrolled and received at least one dose of PD‐1 mab combined with Rituximab. The objective response rate was 52.8%. The median progression free survival (PFS) and overall survival was 2.8 and 19.6 months, respectively. The median duration of response was 18.7 months. Rare grade 3 or 4 treatment related adverse events were observed. B2M mutations correlated with a significantly poor PFS (p = .013) and OS (p = .009) in DLBCL patients treated with this regimen.Conclusion: PD‐1 mab combined with Rituximab could be a potential treatment option for r/r DLBCL with manageable safety profile.

Background: The chronic lymphocytic leukemia treatment strategies have transitioned from chemotherapy and chemoimmunotherapy to chemotherapy-free regimens. Frequentist network meta-analysis allows for direct and indirect comparisons between different treatments. Methods: Randomized controlled trials assessing first-line treatments were included. Outcomes were progression-free survival (PFS), overall survival, undetectable minimal residual disease, objective response rate, and adverse events. Studies with comparable characteristics also underwent subgroup analysis, stratifying by age, comorbidities, IGHV status, and cytogenetic abnormalities. Results: A total of 30 eligible trials involved 12 818 patients, and 30 treatments were included. Acalabrutinib demonstrated a PFS advantage over ibrutinib and obinutuzumab-venetoclax in patients aged older than 65 years or with unmutated IGHV. In younger patients with comorbidities, acalabrutinib-obinutuzumab had superior PFS compared with ibrutinib-obinutuzumab, ibrutinib-venetoclax, and obinutuzumab-venetoclax. For older patients with comorbidities, acalabrutinib and acalabrutinib-obinutuzumab outperformed obinutuzumab-venetoclax without statistically difference between them. Minimal residual disease–guided ibrutinib-venetoclax surpassed obinutuzumab-venetoclax in patients without comorbidities. Ibrutinib-obinutuzumab exhibited extended PFS benefits compared with obinutuzumab-venetoclax in patients with mutated IGHV or with del(17p) and/or TP53 mutations. Ibrutinib-venetoclax and ibrutinib-obinutuzumab had lower neutropenia rates than obinutuzumab-venetoclax. Ibrutinib-venetoclax had fewer infections than acalabrutinib and acalabrutinib-obinutuzumab. Acalabrutinib-obinutuzumab caused less diarrhea than ibrutinib-venetoclax but more headaches than ibrutinib-obinutuzumab and obinutuzumab-venetoclax. Obinutuzumab-venetoclax had lower hypertension rates than ibrutinib-obinutuzumab. Ibrutinib-venetoclax had fewer arthralgia than acalabrutinib-obinutuzumab. For any grade secondary primary neoplasms, ibrutinib-venetoclax and obinutuzumab-venetoclax was less than acalabrutinib-obinutuzumab. Conclusion: Tailored chemotherapy-free regimens can be selected based on age, comorbidities, IGHV status, and cytogenetic abnormalities to optimize treatment outcomes while considering different adverse events spectra.

Aim: To evaluate the therapeutic value and find out potential combination agents of programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) monoclonal antibody (mAb) in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). Methods: We conducted a meta-analysis to assess the efficacy and safety of PD-1/PD-L1 mAb in r/r DLBCL, potential qualified studies were searched in PubMed, Embase, Web of Science, and ClinicalTrials.gov. This meta-analysis had been registered on the PROSPERO platform (CRD42023340031). Results: After systematic screening, a total of 32 records involving 29 studies were included, pooled survival curves indicated better progression-free survival (PFS) ( p < 0.0001; HR = 0.51, 95% CI [0.42–0.62]) and overall survival (OS) ( p = 0.013; HR = 0.71, 95% CI [0.57–0.88]) for combination therapy compared with monotherapy. Combination therapy group also achieved a better pooled complete response rate (CRR) (14.6% vs. 3.0%; p < 0.001) and overall response rate (ORR) (30.5% vs. 10.3%; p < 0.001). Analysis of the incidence of adverse events (AEs) did not demonstrate additional toxicities of combination therapy. The limitation was the predominance of single-arm trials, precluding the direct comparison of combination versus partner agents alone. Conclusions: These findings support further exploration of PD-1/PD-L1-mAb-based combination therapy to identify long-term survival benefits, while application of monotherapy in unselected DLBCL patients is not recommended.