Imbruvica (ibrutinib)

Aberrant B cell receptor signaling occurs in several B cell neoplasms including follicular lymphoma (treated with zanubrutinib, a BTK inhibitor), mantle cell lymphoma (acalabrutinib, pirtobrutinib, zanubrutinib), marginal zone lymphoma (zanubrutinib), chronic lymphocytic leukemia and small lymphocytic lymphoma (ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib), and Waldenström macroglobulinemia (ibrutinib, zanubrutinib)...Pirtobrutinib fails to form a covalent bond and is a reversible BTK inhibitor. The FDA-approvals of rilzabrutinib and remibrutinib (2025) represent the first nononcologic authorizations for BTK antagonists.

P1/2, N=217, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: May 2028 --> Jun 2027

P1, N=50, Active, not recruiting, Karolinska University Hospital | Recruiting --> Active, not recruiting

By drug screening, Ibrutinib is identified as an effective inhibitor of HGSOC cells and patient-derived organoids with CBX2 condensates. Overall, CBX2 phase separation enhances DSB repair-mediated drug resistance in HGSOC cells, and Ibrutinib may offer a viable therapeutic option for CBX2-positive HGSOC patients.

The phase 3 CLL13/GAIA trial assesses three time-limited combinations: venetoclax-rituximab (RV), venetoclax-obinutuzumab (GV), and venetoclax-obinutuzumab-ibrutinib (GIV) compared to chemoimmunotherapy (CIT). Fit patients with CLL without TP53 aberrations were randomized between six cycles of CIT (fludarabine-cyclophosphamide-rituximab [FCR], bendamustine-rituximab [BR]) or 12 cycles of RV, GV or GIV (GIV: ibrutinib continuation until cycle 36 if measurable residual disease [MRD] at months 12/15)...In the GIV arm, clinically relevant QoL improvements occurred later (month 15, after the end of treatment in most patients) than with GV/RV, likely due to a higher treatment-related symptom burden. The trial is registered at clinicltrial.gov with the identifier, NCT02950051.

Ibrutinib plus rituximab therapy was administered, resulting in a partial response sustained to date. Bone involvement and amyloidosis are rare but critical extranodal manifestations of LPL, necessitating careful screening and follow-up even in asymptomatic patients. When these manifestations are suspected, prompt pathological and genetic evaluation is warranted, especially in non-IgM LPL cases.

P1, N=68, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | Trial completion date: Jun 2027 --> Dec 2027

To date, ten abstracts or published manuscripts have reported on venetoclax retreatment, as continuous monotherapy or with FD/MRD guided combinations with anti-CD20 monoclonal antibodies (rituximab, obinutuzumab) or covalent Bruton tyrosine kinase inhibitors (ibrutinib, acalabrutinib). Median progression-free survival, when available, ranged from 23 to 58 months. Optimal patient selection remains to be defined, but the depth of the initial venetoclax response and time to progression from last venetoclax exposure may predict rechallenge efficacy and are incorporated in new clinical trial criteria allowing previous FD venetoclax treatment.

Given the deep and durable responses seen in this study, concurrent BTK and BCL-2 inhibition warrants further development in WM. TP53 mutations emerged as an adverse factor in WM in this combination study.

The patient was treated with six cycles of Dara-CHOP, followed by autologous stem cell transplantation and maintenance therapy with daratumumab and ibrutinib. This case highlights a rare example of synchronous CLL/SLL-to-PBL transformation in an immunocompetent patient. Integration of detailed molecular diagnostics enabled early recognition and guided a personalized treatment approach incorporating CD38-targeted therapy and BTK inhibition, resulting in an excellent long-term clinical outcome.

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.

P4, N=289, Recruiting, Medizinische Hochschule Hannover | N=128 --> 289