Hematol Oncol. 2026 Mar;44(2):e70184. doi: 10.1002/hon.70184.
ABSTRACT
B-cell receptor inhibitors (BCRi) and B-cell lymphoma-2 inhibitor (BCL2i) improved outcomes of patients with chronic lymphocytic leukemia (CLL), but relapsing after two inhibitors still represent an unmet clinical need. This multicenter real-world study analyzes outcomes of a cohort treated in Italy between May 2017 and September 2023 following prior exposure to both BCRi and BCL2i. The median follow-up after venetoclax initiation was 47 months (IQR 28-56). Of 153 double-exposed patients, 104 (68%) discontinued venetoclax and 53 of them (51%) received a subsequent treatment. Venetoclax was discontinued due to progressive disease (PD) in 51/104 cases (49.0%), with nine deaths occurring rapidly after PD without the administration of any further treatment. 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). Overall response rate was 50%; median event free survival (EFS) in the groups of inhibitors, CT and HSCT was 11, 2, and 10 months, respectively (p < 0.0001); median overall survival (OS) was 12, 5, and 10 months, respectively (p = 0.020). Disease progression during venetoclax treatment was associated with shorter subsequent EFS compared to discontinuation for other reasons, even if the finding did not reach statistical significance (median EFS 4 vs. 10 months; p = 0.11). No decrease in EFS was associated with del17p and/or TP53 mutations, the use of venetoclax monotherapy or a previous treatment with one versus multiple BCRi. 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.
PMID:41778381 | DOI:10.1002/hon.70184
