TP53 mutation + Chr del(17p)

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.

The phase 3 CRISTALLO trial (NCT04285567) compared first-line fixed-duration venetoclax-obinutuzumab (VenO) vs fludarabine, cyclophosphamide, and rituximab (FCR)/bendamustine-rituximab (BR) in patients with chronic lymphocytic leukemia, using undetectable minimal residual disease (uMRD) as the sole primary endpoint. No patient in the VenO arm was deemed high-risk for tumor lysis syndrome following obinutuzumab debulking; no clinical TLS occurred. These results confirm and extend the findings from the GAIA-CLL13 trial, validating increased depth of response with VenO vs chemoimmunotherapies.

pseudo-RT is a reversible event, and awareness of its characteristic features is essential to prevent overtreatment.

P1/2, N=82, Not yet recruiting, French Innovative Leukemia Organization

Time-limited and continuous targeted therapies are used with similar frequency for CLL/SLL, with selection shaped by age, TP53 aberrations, geography, and patient preferences. These findings highlight the importance of personalized care and the need to reduce access barriers to time-limited strategies.

Grade ≥3 neutropenia and thrombocytopenia occurred in 38% and 13% of patients, respectively. The 24-cycle ibrutinib + venetoclax combination led to high rates of CR/CRi and bone marrow U-MRD4 in patients with R/R CLL.

In the phase 3 randomized SEQUOIA study (NCT03336333), zanubrutinib (arm A) demonstrated superior progression-free survival (PFS) compared with bendamustine-rituximab (BR; arm B) in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) without del(17p). In the phase 3 AMPLIFY study (NCT03836261), acalabrutinib-venetoclax with or without obinutuzumab demonstrated prolonged PFS vs chemoimmunotherapy (investigator's choice of fludarabine, cyclophosphamide, and rituximab [FCR] or BR) in patients with treatment-naive CLL without del(17p) or TP53 mutations...Zanubrutinib also demonstrated longer PFS whether adjusted for age (PFS-INV hazard ratio &lsqb;HR], 0.26; 95% CI, 0.13-0.54; P<.0003) or unadjusted (PFS-INV HR, 0.45; 95% CI, 0.23-0.88; P=.0197). These results highlight zanubrutinib monotherapy as an effective treatment option for all patients with treatment-naive CLL/SLL, including patients who might otherwise be considered for more intensive fixed-duration combination regimens.

P1, N=7, Completed, Iovance Biotherapeutics, Inc. | Phase classification: P1/2 --> P1

P=N/A, N=500, Recruiting, AbbVie | Active, not recruiting --> Recruiting | N=350 --> 500 | Trial completion date: Dec 2025 --> Dec 2030 | Trial primary completion date: Dec 2025 --> Dec 2030

Considering that TP53 alterations accumulate during MM progression and are associated with drug resistance even in the context of novel therapies, our study further emphasizes the need for routine evaluation of both del(17p) and TP53 mutations. Patients with multi-hit TP53 should be prioritized for inclusion in trials of novel therapeutic strategies.

This new strategy, along with the improved tolerability of these agents, offers particular benefit to older and frail patients, with dosing tailored to comorbidities and concomitant therapies.Given the heterogeneity in older patients' health status, geriatric assessments (e.g., CIRS, FRAIL score) are additional key for individualized therapy decisions and adverse events influence therapy choice (e.g. cardiovascular risk with BTK inhibitors. Beyond clinical factors, patient preferences-such as opting for continuous (e.g., BTK inhibitor monotherapy) versus time-limited therapy (e.g., venetoclax plus obinutuzumab or ibrutinib plus venetoclax)-and treatment tolerability are decisive.

P1/2, N=144, Recruiting, AVM Biotechnology Inc | Trial completion date: Jun 2025 --> Dec 2026 | Trial primary completion date: Apr 2025 --> Apr 2026