Imbruvica (ibrutinib)

P2, N=66, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2026 --> Jun 2028 | Trial primary completion date: Jun 2026 --> Jun 2028

P1, N=33, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Jun 2027

The results confirm watch-and-wait as standard of care for early-stage CLL patients, especially in high-risk CLL characterized by del(17p) and/or mutated TP53. EudraCT Number: 2013-003211-22.

Ca2+-flux and cell viability assays using patient-derived BCRs expressed in murine B-cells confirmed reduced ibrutinib efficacy in IGLV3-21R110 cases, especially regarding inhibition of antigen-stimulated signaling. In summary, IGLV3-21R110 is an independent prognostic factor for shorter EFS in early-stage CLL and reduces ibrutinib effectiveness clinically and in vitro.

P1/2, N=87, Active, not recruiting, Kerry Rogers | Trial completion date: Apr 2026 --> Apr 2027

Combination treatment with BTK inhibitor ibrutinib improves anti-tumor efficacy of oHSV in both human GBM12 xenograft and syngeneic murine GSC005 models...Further analysis shows that BTK inhibition, with or without IDO inhibition, promotes the formation of tumor-infiltrating tertiary lymphoid structures (TLS) during intratumoral oHSV treatment, subsequently remodeling T cell, NKT cell, and monocyte-macrophage populations. These results indicate that BTK inhibition exerts multifaceted effects in enhancing the anti-tumor efficacy of oHSV therapy.

These findings inform the long-term comparative efficacy of Bruton tyrosine kinase inhibitors and suggest that zanubrutinib may confer sustained PFS and OS benefits compared with ibrutinib and acalabrutinib in similar treatment-naive CLL populations. Graphical abstract and video available for this article. Overview of the Comparative Efficacy of Covalent BTK Inhibitors in Treatment-Naïve CLL/SLL With Six-Year Follow-Up (MP4 345006 kb).

Importantly, primary ZMYM3-mutated CLL cells exhibited increased sensitivity to BCL-XL inhibition and ibrutinib. Overall, this work establishes the clinical relevance of ZMYM3 mutations and provides novel insights into their contribution to CLL pathophysiology.

Chronic lymphocytic leukaemia (CLL) most commonly transforms into aggressive lymphoma; development of chronic myeloid leukaemia (CML) in a patient with CLL should prompt evaluation for an independent myeloid clone rather than presumed transformation.Myeloid neoplasms in patients with CLL may arise from therapy-related leukemogenesis or divergent evolution from a shared hematopoietic progenitor, highlighting the importance of molecular characterization.Management of coexisting CLL and CML requires individualized risk-benefit assessment, particularly in elderly patients with prior solid tumours and immune dysfunction.

After six cycles of azacitidine, she achieved remission of MDS but rapidly progressed to AML and ultimately died. This case provides a key clinical lesson: persistent cytopenias during ibrutinib therapy were attributable to MDS progression rather than SWM, underscoring the importance of re-evaluation. Furthermore, it completely documents clonal evolution from 2.5% blasts (MDS with low blasts) to 6% blasts (MDS with increased blasts-1) and ultimately to AML (66% blasts), and it introduces the emergence of an FLT3-ITD mutation that rapidly drove the disease into AML even after the patient had achieved MDS remission. We also review the rare coexistence of WM and MDS/AML, and MGUS with MDS.

P2, N=37, Completed, Northwestern University | Active, not recruiting --> Completed

In our study, REC-1 cells that acquired resistance to BTKi tirabrutinib by long-term treatment gained a splice-site mutation (SSM) c.2236-1G>T in PLCG2. Expression analysis in CLL cells isolated from patients before and after targeted treatments revealed a decrease in expression of ∆20-22 post-venetoclax (p = 0.02)while no change in expression was observed after ibrutinib treatment, indicating that these variants may persist in the presence of ibrutinib but might be lost in the absence of drug selection pressure. Our study reveals novel PLCG2 splice-site alterations and exon-skipped variants beyond the classical BTK or PLCG2 mutations, to have a potential role in BTKi resistance and inform treatment selection.