Photo Credit: Nemes Laszlo
Treatment resistance and toxicity remain critical challenges in managing chronic lymphocytic leukemia (CLL), according to researchers at the ASH Annual Meeting. A subset of patients develop resistance to both Bruton tyrosine kinase inhibitors (BTKis) and B-cell lymphoma 2 inhibitors (BCL2is), termed double-resistant (DR) CLL, while others discontinue these therapies due to non-progressive disease factors, categorized as double-exposed (DE) CLL. Despite the availability of third-line therapies such as non-covalent BTKis (ncBTKis) and CAR-T therapies, the prognosis for DR patients remains poor, with progression-free survival consistently under two years. For their study, authors examined the molecular characteristics, clinical outcomes, and survival metrics of patients with DR and DE CLL to explore the distinctions between these groups.
The study retrospectively reviewed data from the Dana-Farber Cancer Institute CLL database, focusing on patients who received both BTKi and BCL2i therapies. Patients with progressive disease (PD) on both therapies were classified as DR, while those who discontinued either therapy for other reasons were considered DE. Molecular analyses, including next-generation sequencing (NGS), IGHV sequencing, and cytogenetics, were conducted on blood and bone marrow samples. Time-to-first-treatment (TTFT), time-to-next-treatment (TTNT), and overall survival (OS) were calculated using the Kaplan-Meier method.
Of the 1,024 patients in the database, 95 met the criteria for DR (30 patients) or DE (65 patients) CLL. Median age was comparable between groups (57 years for DR, 58 years for DE), and both cohorts exhibited a male predominance. However, the DR group demonstrated more aggressive disease characteristics, including higher rates of unmutated IGHV (97% vs. 75%), TP53 aberrations (73% vs. 46%), and BTK mutations (59% vs. 27%). The DR group also received a higher median number of lines of therapy (LOT) both overall (6 vs. 3) and before the landmark timepoint (4 vs. 3).
Post-landmark treatments varied significantly. Among DR patients, ncBTKis were the most common therapy (34%, median TTNT 16 months), followed by concurrent covalent BTKi/BCL2i (28%, median TTNT 12 months). CAR-T and allogeneic stem cell transplantation (alloSCT) were utilized in 24% and 10%, respectively. In the DE group, alloSCT was the most frequently used treatment (29%, median TTNT not reached), followed by cBTKi therapies (18%, median TTNT not reached).
Clinical outcomes were markedly poorer for DR patients. Median TTFT and OS from diagnosis were significantly shorter in the DR cohort (1.1 years and 11.6 years, respectively) compared to the DE cohort (2.2 years and 21.4 years, P<0.05). The median OS for DR patients after meeting DR criteria was 2.2 years, with only 29% surviving at three years post-landmark. In contrast, DE patients demonstrated a median OS that was not reached, with an estimated three-year survival of 64%.
DR and DE CLL represent distinct disease states with significant differences in aggressiveness, molecular characteristics, and survival outcomes. DR CLL, defined by resistance to BTKi and BCL2i therapies, is associated with poorer prognosis, higher mutation rates, and limited therapeutic efficacy despite intensive treatment. In contrast, DE CLL reflects a less aggressive disease course with preserved sensitivity to targeted and cellular therapies.
