Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition

Abstract

Covalent Bruton tyrosine kinase inhibitors (BTKis) and the BCL2 inhibitor venetoclax have significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL), especially those with biologically adverse disease. Patients with CLL resistant to their first targeted agent (TA) can be effectively treated with the alternative class. However, relapses are expected with second-line TA therapy, and the clinical challenge of double class-resistant disease is now emerging with increasing frequency. To define the characteristics and outcomes of patients with double class-resistant disease, we retrospectively analyzed 17 patients who developed progressive disease (PD) on both TA classes for CLL (venetoclax, then BTKi, n=12; BTKi, then venetoclax, n=5). The cohort was heavily pre-treated (median lines of prior therapy: 4) and enriched for adverse disease genetics (complex karyotype: 12/12 tested, 100%; del(17p)/TP53 mutations: 15/17, 88%). The median time to progression on prior venetoclax was 24 (range 6-94) months, and on prior BTKi was 25 (range 1-55) months. Progression on second-line TA was manifest as progressive CLL in 11 patients and as Richter transformation in six. The median overall survival after progression on second-line TA was 3.6 (95%CI 2-11) months. Patients with double class-resistant CLL have a dismal prognosis, representing a group of high unmet need.

Biology and Treatment of Richter Transformation

“…RT after ibrutinib or venetoclax shows an aggressive behavior. The median OS after progression for double class-resistant CLL patients (i.e., CLL resistant to both BTK and BCL2 inhibitors) is 3.6 months, and this class of patients represents a clinical unmet challenge in the era of novel agents ( 66 ).…”

Cellular Therapy in High-Risk Relapsed/Refractory Chronic Lymphocytic Leukemia and Richter Syndrome

“…Accumulating evidence suggests that the order of such therapy is of relatively little importance with evidence of cross-resistance of drug classes lacking ( 45 – 47 ). Although high-risk patients are still often defined as those with IGVH-unmutated disease, TP53 mutations and/or 17p deletion, and CK, outcomes are demonstrably poor in the relatively small published patient series who develop resistance or intolerance to both major classes of targeted inhibitors, namely, cBTKi and BCL2i ( 11 , 45 , 48 , 49 ).…”

“…A series of 17 patients who developed progressive disease (PD) after both cBTKi and BCL2i classes were recently reported ( 49 ). The cohort was heavily pre-treated with a median of four prior lines of therapy and displayed high-risk genomic features (CK in 12/12 tested, del17p/TP53 mutations in 15/17).…”

Single-cell sequencing demonstrates complex resistance landscape in CLL and MCL treated with BTK and BCL2 inhibitors

“…In particular, outcomes for patients with progressive disease after sequential treatment with both TA classes are poor. 1 Resistance mechanisms of the BTKi ibrutinib include BTK mutations at the Cys481 residue, which alter drug binding, 2,3 and PLCG2 -activating mutations, which effectively bypass BTK. 4 Venetoclax resistance mechanisms include BCL2 mutations that affect drug binding 5-7 as well as overexpression of alternative prosurvival BCL2 family members mantle cell lymphoma 1 (MCL1) 8 and BCLxL.…”