What Next for Patients with CLL After Stopping Venetoclax?
Standard care for untreated patients with chronic lymphocytic leukemia (CLL) is therapy based on venetoclax. However, managing further treatment when venetoclax needs to be discontinued remains a relatively unexplored area without standardized protocols.
Sequence of CLL Therapy
In recent years, treatment standards for CLL have rapidly evolved along with the results of clinical trials of new drugs. Venetoclax, a potent selective oral low-molecular-weight BCL2 protein inhibitor, is approved for use in patients with relapsed/refractory CLL both as monotherapy and in combination with anti-CD20 monoclonal antibodies, and now represents a key component of treatment protocols. We have sufficient information from clinical trials and retrospective cohort studies about the use of venetoclax following prior treatment with ibrutinib or the idelalisib/rituximab combination.
Given the excellent results of recent clinical trials and the favorable safety profile, venetoclax is increasingly prescribed in the first line of treatment. This brings with it numerous questions about the next steps in therapy after its discontinuation. The presented international study assessed the effectiveness of subsequent therapies in patients with relapsed/refractory CLL who discontinued venetoclax for any reason.
Study Methodology
The international multicenter retrospective cohort study included 326 patients treated between 2014 and 2019 at one of 31 centers in Europe or America.
The primary aims of the study were the overall response rate (ORR) and progression-free survival (PFS) of subsequent treatment regimens, depending on the type of treatment (cell therapy, use of Bruton tyrosine kinase [BTK] inhibitors, or PI3K kinase inhibitors).
Results
Patients who discontinued venetoclax treatment (4% in the first line, 96% in further lines after disease relapse) were identified based on medical records. Before starting venetoclax treatment, patients underwent an average of three therapeutic regimens, 40% of patients had not yet been treated with BTK inhibitors, and 81% had not yet been treated with the PI3K inhibitor idelalisib.
BTK inhibitors (ibrutinib and others) were the most commonly administered treatments after discontinuation of venetoclax. The ORR for patients not previously treated with BTK inhibitors was 84% (with 9% achieving complete remission), and the estimated median PFS was 32 months. For patients who had already been treated with BTK inhibitors, the ORR was 54%. The median PFS was not achieved in patients who did not tolerate previous BTK treatment. For patients whose disease was resistant to prior BTK treatment, resistance remained, with a PFS of only four months. Patients treated with PI3K inhibitors (n=17) had an ORR of 46.9%, but the treatment response was unstable, with a median PFS of about five months.
Conclusion
It appears that the effectiveness of BTK inhibitors is not significantly compromised by prior venetoclax treatment, which is certainly reassuring for clinical practice. The most effective strategy to achieve long-term treatment response after venetoclax discontinuation seems to be either allogeneic bone marrow transplantation or the administration of BTK inhibitors to patients who had not used them before or were still responding to treatment at the time of discontinuation.
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Source: 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 Mar 20, doi: 10.1158/1078-0432.CCR-19-3815 [Epub ahead of print].
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