Zydelig (idelalisib)

P3, N=250, Recruiting, Dizal (Jiangsu) Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting

We present a case of invasive cutaneous mucormycosis in an elderly man with chronic lymphocytic leukemia (CLL), who was receiving a Bruton tyrosine kinase (BTK)-targeted protein degrader trial drug (BGB-16673), obinutuzumab, a newer anti-CD20 monoclonal therapy, and idelalisib, a phosphoinositide 3-kinase inhibitor. Clinical cure was achieved with limb amputation, given the extent of disease. This case underscores the necessity of a low index of suspicion for mucormycosis on presentation, critical appraisal of the patient's risk factors, and a multimodal approach to diagnosis.

P4, N=150, Not yet recruiting, Eli Lilly and Company

This study examined the effects of signaling pathway inhibitors ibrutinib, idelalisib, duvelisib, and venetoclax on the expression of immune checkpoint ligands: Programmed death ligand 1 (PD-L1), galectin-9 (Gal-9), cluster of differentiation (CD)200, CD155, and herpes virus entry mediator (HVEM) in CLL leukemic cells. Altogether, the treatment of leukemic cells with different SMIs in this study indicated increased or decreased variations in the expression level of immune checkpoint inhibitory ligands in CLL. Therefore, these mechanisms should be considered for further treatment approaches, especially for combinational strategies.

We comprehensively evaluate FDA-approved targeted agents, including monoclonal antibodies (rituximab, brentuximab vedotin, obinutuzumab, mogamulizumab), immune checkpoint inhibitors (nivolumab, pembrolizumab), CAR T-cell therapies (axi-cel, tisa-cel, liso-cel, brexu-cel), bispecific T-cell engagers (mosunetuzumab, epcoritamab), and small-molecule inhibitors (ibrutinib, idelalisib, venetoclax). In conclusion, understanding the molecular basis of lymphoma and resistance mechanisms is critical to optimizing targeted therapy. This review synthesizes current evidence to inform clinical decision-making and outlines future directions for durable, personalized lymphoma care.

In cases of phosphoinositide-3-kinase δ (PI3Kδ) inactivation, such as in patients receiving PI3Kδ inhibitor idelalisib as a cancer treatment, breakdown of intestinal immune tolerance occurs frequently in the form of diarrhea and colon inflammation...We demonstrate reduced extrathymic Treg induction, in vitro and in vivo, from naïve CD4+ T cells with inactive PI3Kδ, along with dysregulation of a tissue-resident phenotype. These results suggest a nonredundant role for PI3Kδ-dependent pTreg differentiation in maintaining tolerance to commensal microbial antigens in the gut.

HL-60 cells were treated with Idelalisib, MK-2206, and Everolimus, selective PI3K, AKT, and mTOR inhibitors, either individually or in combination. PI3K/AKT/mTOR inhibitors significantly induce autophagy-related gene expression in AML cells. These findings support combining such inhibitors with autophagy modulators as a potential strategy to improve AML treatment outcomes.

P3, N=250, Not yet recruiting, Dizal (Jiangsu) Pharmaceutical Co., Ltd.

Treatment of B-cell malignancies with the PI3K inhibitor (PI3Ki) idelalisib often results in high toxicity and resistance, with limited treatment alternatives for relapsed/refractory patients since idelalisib is recommended as a later or last line therapy...Treatment induced Bim and Mcl-1 upregulation and reduced cytotoxic CD8+ T-cell and CD56dim NK-cell populations. Our findings suggest that PIs may overcome resistance to targeted therapies, and warrant further studies to optimize clinical responses.

P2, N=17, Completed, University of Maryland, Baltimore | Active, not recruiting --> Completed | Trial completion date: Mar 2025 --> Sep 2024

P2, N=150, Recruiting, Calluna Pharma AS | Not yet recruiting --> Recruiting

Notably, TYM-3-98 demonstrated superior anti-tumor efficacy compared to Idelalisib at equivalent doses, without causing significant weight loss in mice. These findings suggest that PI3Kδ may play a critical role in BL pathogenesis and represents a promising therapeutic target. Further investigation is warranted to advance its clinical application.