Venetoclax-Based Therapy Is Associated With Worse Outcomes in BTK Inhibitor–Resistant, Chemo-Naive CLL

Chronic Lymphocytic Leukemia
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Data from an international retrospective study showed that venetoclax (Venclexta)-based treatment regimens were associated with worse-than-expected outcomes in patients with chronic lymphocytic leukemia (CLL) who were previously exposed to a covalent BTK inhibitor and naive to chemotherapy, particularly those with BTK inhibitor–resistant disease.

Findings presented at the 2024 ASH Annual Meeting showed that from the initiation of treatment with venetoclax, patients with BTK inhibitor–exposed CLL (n = 46)—defined as receipt of prior treatment with a covalent BTK inhibitor without disease progression—experienced a 2-year time to next treatment or death (TTNTD) rate of 73% compared with 65% for patients with BTK inhibitor–resistant CLL, which was defined as disease progression on a prior covalent BTK inhibitor. The median TTNTD was 78 months in the BTK inhibitor–exposed arm vs 30 months in the BTK inhibitor–resistant cohort.

Specifically, within the BTK inhibitor–resistant cohort, the 2-year TTNTD rates were 53% for patients treated with venetoclax monotherapy (n = 5), 62% for those given venetoclax plus rituximab (Rituxan; n = 30), and 100% for patients treated with venetoclax plus obinutuzumab (Gazyva; n = 4).

Furthermore, the median overall survival (OS) was 78 months for the BTK inhibitor–exposed cohort vs 39 months for the BTK inhibitor–resistant group. Notably, 2-year OS rates were 81% for the BTK inhibitor–exposed cohort vs 84% for the BTK inhibitor–resistant cohort.

“Novel therapeutic clinical trial strategies in [the] first- and second-line settings remain a high priority for patients with high-risk CLL,” lead study author Paul J. Hampel, MD, and colleagues wrote in a poster presentation of the data.

Hampel is a hematologist/oncologist in the Department of Hematology at the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota.

Retrospective Study Overview

Investigators designed the retrospective study to evaluate the outcomes of venetoclax-based therapies and identify factors associated with those outcomes. They identified patients with relapsed CLL who were previously treated with a covalent BTK inhibitor and naive to chemotherapy prior to starting treatment with venetoclax. The study included patients who were treated at Mayo Clinic or 1 of 8 centers in France.

OS was analyzed from the start of treatment with a venetoclax-based regimen until death, and TTNTD was defined as the time from the start of venetoclax until the start of next therapy or death.

Investigators utilized a Kaplan-Meier model to evaluate OS and TTNTD, and Cox proportional hazards regression models were utilized to analyze factors associated with these outcomes.

Baseline Patient Characteristics and Additional Data

In the overall study cohort (n = 85), the median age was 69 years (interquartile range [IQR], 62-77), and most patients were male (69%). Patients received a median of 1 prior line of therapy (IQR, 1-2); 38% of patients received a prior anti-CD20 monoclonal antibody, and 9% of patients received prior treatment with 2 covalent BTK inhibitors.

Fifty-three percent of patients received venetoclax in combination with rituximab, 32% were administered the BCL2 inhibitor in combination with obinutuzumab, and 32% received the agent alone.

Among evaluable patients (n = 56), 82% had IGHV-unmutated disease. Forty-one percent of evaluable patients (n = 37) had a complex karyotype, and 45% of evaluable patients (n = 73) harbored TP53 abnormalities.

In the BTK inhibitor–resistant and –exposed populations, the median duration of treatment with a prior covalent BTK inhibitor was 42.3 months and 6.7 months, respectively.

An analysis of risk factors associated with patient outcomes, investigators noted that TP53 disruption was associated with TTNTD in the overall population (HR, 2.23; 95% CI, 1.02-4.87; P = .04). For OS, older age was a prognostic factor (HR, 1.05; P = .02).

Within the BTK inhibitor–resistant group, the duration of prior covalent BTK inhibitor treatment was not associated with survival outcomes. In this group, TP53 disruption was associated with TTNTD (HR, 6.68; 95% CI, 1.51-29.46; P = .01) and OS (HR, 7.95; 95% CI, 1.02-61.97; P = .04).

“The frequency of high-risk disease features, shorter duration of disease control with their initial covalent BTK inhibitor treatment, and small cohort size warrant caution in generalizing these results to all patients with covalent BTK inhibitor–resistant CLL,” study authors concluded.

Reference

Hampel PJ, Rabe KG, Guieze R, et al. Outcomes with venetoclax-based treatment in patients with covalent bruton tyrosine kinase inhibitor (cBTKi)-treated, chemotherapy-naïve chronic lymphocytic leukemia (CLL): an international retrospective study. Blood. 2024;144(suppl 1):1856. doi:10.1182/blood-2024-198200