Imbruvica (ibrutinib)

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

P1/2, N=68, Active, not recruiting, LYSARC | Recruiting --> Active, not recruiting

P4, N=128, Recruiting, Medizinische Hochschule Hannover | N=52 --> 128

P2, N=81, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Mar 2026 --> Mar 2028 | Trial primary completion date: Mar 2026 --> Mar 2028

P3, N=94, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2026

P2, N=194, Active, not recruiting, The Lymphoma Academic Research Organisation | Recruiting --> Active, not recruiting

P3, N=465, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Dec 2026

P=N/A, N=8, Terminated, Centre Hospitalier Universitaire Dijon | N=100 --> 8 | Trial completion date: Mar 2027 --> Aug 2025 | Recruiting --> Terminated | Trial primary completion date: Mar 2027 --> Aug 2025; premature shutdown due to change in processing line