Zydelig (idelalisib)

This premilinary in vitro data suggest a trend toward ibrutinib resistance in Oxphos-type cell lines. More research is warranted both in preclinical models as well as in clinical datasets.

The patient developed persistent severe thrombocytopenia despite multiple lines of therapy, including corticosteroids, intravenous immunoglobulin, rituximab, splenectomy, and thrombopoietin receptor agonists. Subsequent treatments with ibrutinib and a venetoclax-based regimen failed to improve platelet counts and were discontinued due to worsening cytopenia...Refractory thrombocytopenia in CLL should be approached as a manifestation of complex disease biology rather than an isolated complication. This single observation indicates that in TP53 aberrant cases with multi-mechanism thrombocytopenia, disease-directed targeted therapy may contribute significantly to platelet recovery.

P1, N=106, Completed, Alliance for Clinical Trials in Oncology | Phase classification: P2 --> P1

Mechanistically, CAL-101-treated T cells maintain high expression of stemness-associated genes (Tcf7, Slamf6) while resisting expression of genes associated with terminal exhaustion (Tim3, Mt1/2). These findings reveal the mechanisms behind how PI3Kδ inhibition generates T cells capable of establishing and maintaining an antitumor immune response, suggesting a promising strategy for improving adoptive cell therapy outcomes in solid tumors.

P2, N=150, Active, not recruiting, Calluna Pharma AS | Trial completion date: Nov 2027 --> Feb 2027 | Trial primary completion date: Aug 2027 --> Nov 2026

P4, N=150, Recruiting, Eli Lilly and Company | Not yet recruiting --> Recruiting

P2, N=150, Active, not recruiting, Calluna Pharma AS | Recruiting --> Active, not recruiting

In patients with cBTKi-pretreated relapsed/refractory (R/R) CLL, the BRUIN-CLL-321 trial demonstrated improved progression-free survival (PFS) and time to next treatment (TTNT) compared with idelalisib/rituximab or bendamustine/rituximab, accompanied by a favorable tolerability profile. Data from randomized phase III BRUIN-CLL-313 and BRUIN-CLL-314 trials demonstrate the superiority of pirtobrutinib over chemoimmunotherapy in untreated patients and non-inferiority to ibrutinib in untreated patients or in patients with R/R disease who had no prior exposure to cBTKis. These data are not sufficient to justify a change in clinical practice; however, they lay the groundwork for a potential future repositioning of pirtobrutinib from the treatment of R/R CLL to earlier lines of therapy. In this review, we address a range of current and prospective aspects of pirtobrutinib-based therapies: (1) the strengths and limitations of the trial datasets; (2) the biological rationale for frontline noncovalent BTK inhibition; (3) sequencing trade-offs; and (4) prospective scenarios, including combination strategies and time-limited regimens.

Fifty-three patients received treatment after venetoclax: 29/53 (54.7%) received inhibitors (13 cBTKi, 11 idelalisib, 2 BCL2i, 3 non-covalent BTKi), 19/53 (35.8%) received chemoimmunotherapy (CT: 16 intensive, 3 palliative), 5/53 (9.4%) received hematopoietic stem cell transplantation (HSCT). Despite its limitations, this real-world study provides additional insights into double-exposed patients, who still pose a clinical challenge, demonstrating the superior efficacy of inhibitors over alternative treatment options. Enrollment in clinical trial and treatments with novel molecules, if available, may help address this unmet clinical need.

Tamoxifen promotes IPF via miR-432-3p-mediated EGFR suppression, establishing it as a pulmonary toxicant. Integrated network toxicology identifies EGFR as a diagnostic biomarker, highlighting environmental and clinical risks of tamoxifen exposure.

P2/3, N=55, Recruiting, Dizal (Jiangsu) Pharmaceutical Co. Ltd.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, and B-cell receptor (BCR) pathway inhibitors such as idelalisib and ibrutinib are currently established therapies for CLL. We conclude that BCR pathway inhibitors enhance AID mutational activity in CLL, but this does not appear to be directly involved in driving drug resistance. AID-targeted loci may nonetheless serve as biomarkers for monitoring genomic instability during treatment and inform further study.