Efficacy of Bruton Tyrosine Kinase Inhibitors After Venetoclax Therapy in Patients with CLL
Targeted therapy has changed the treatment approach for chronic lymphocytic leukemia (CLL), showing higher efficacy and safety compared to standard chemoimmunotherapy. Until recently, an important question remained unanswered: whether the administration of Bruton tyrosine kinase inhibitors (BTKi) after previous therapy with the BCL-2 inhibitor venetoclax provides sufficient clinical effect.
Introduction
Among the most commonly used targeted drugs in patients with CLL are Bruton tyrosine kinase inhibitors ibrutinib and acalabrutinib, and the BCL-2 protein inhibitor venetoclax. Both groups are approved for use in patients without previous treatment or in those with relapsed/refractory CLL, showing similar efficacy and high therapeutic response rates even in individuals with high cytogenetic risk.
They differ in their toxicity profiles. BTKi are associated with an increased risk of bleeding and atrial arrhythmias, while venetoclax can cause tumor lysis syndrome (TLS). Patients with reduced renal function (CrCl < 80 ml/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS at the start of therapy and during the dose-titration phase. Another difference lies in the duration of therapy. Venetoclax can currently be administered in combination with an anti-CD20 monoclonal antibody for a fixed period of 12 or 24 months or as monotherapy until disease progression. BTKi must be administered until disease progression.
Study Results
While clinical results of venetoclax administration following previous BTKi treatment have already been published, the opposite sequence is less studied. An important analysis, therefore, comes from a retrospective study conducted by Mato et al. Data from a total of 326 patients with CLL who were given venetoclax, predominantly in monotherapy (73%), were evaluated. This was a relatively high-risk cohort of patients with a median of 3 therapies before venetoclax initiation, and 53% of whom were diagnosed with a TP53 gene mutation. Before starting venetoclax, 60% of the patients were using BTKi.
Patients used venetoclax for 9 months (median; minimum 0.1 months, maximum 60 months). Subsequent therapy was undertaken by 188 (58%) patients, most frequently with ibrutinib and acalabrutinib (74 patients; 39%). The overall response rate (ORR) to therapy was significantly higher in patients who had not previously used BTKi compared to those who had (84 vs. 54%; p < 0.001).
The treatment response to BTKi after venetoclax differed in patients who had previously used BTKi depending on whether they discontinued the previous BTKi treatment due to intolerance or disease progression (ORR 70 vs. 50%). This was also reflected in the progression-free survival (PFS) of these two patient groups (median PFS: not reached vs. 4 months).
Conclusion
The result should be taken with some caution due to the small sample size and short follow-up period, but it suggests that BTKi therapy has good outcomes in patients without signs of resistance to BTKi before venetoclax administration. The administration of Bruton tyrosine kinase inhibitors after previous venetoclax therapy in patients with chronic lymphocytic leukemia is thus feasible and should be further studied.
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Resources:
1. Rogers K. A. Collectively answering the venetoclax BTK inhibitor sequencing question in CLL. Clin Cancer Res 2020 Jul 15; 26 (14): 3501–3502, doi: 10.1158/1078-0432.CCR-20-1035.
2. Mato A. R., Roeker L. E., Jacobs R. et al. Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res 2020 Jul 15; 26 (14): 3589–3596, doi: 10.1158/1078-0432.CCR-19-3815.
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