Ibrutinib treatment extended time to active disease in early stage chronic lymphocytic leukemia.

  • Major Finding: Ibrutinib treatment extended time to active disease in early stage chronic lymphocytic leukemia.

  • Concept: The occurrence of serious adverse events was similar between both ibrutinib- and placebo-treated groups.

  • Impact: Change to the current standard of observation is not yet justified due to lack of demonstrated survival benefit.

While observation has been the standard of care for patients with early stage asymptomatic chronic lymphocytic leukemia (CLL), whether early intervention could benefit patient outcome is unknown. Early stage disease clinical course has been improved by the proposal of the German CLL Study Group (GCLLSG) score which demonstrated four risk groups of CLL based on clinical and laboratory markers and allows for the identification of patients at early stages who are at a high risk of rapid progression. To determine whether intervention in early-stage high-risk patients based on this GCLLSC score could benefit patient outcome, Langerbeins and colleagues designed a placebo-controlled, double-blind, randomized phase III clinical trial (CLL12) to test ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK), in early-stage treatment-naïve Binet stage A patients with CLL who were at high risk of progression. A total of 515 patients were enrolled and further stratified into intermediate, high, and very high risk based on GCLLSG scores and were randomized to receive either placebo or ibrutinib. The primary endpoint was defined as event-free survival, or the time from randomization to active disease progression with treatment. There were significantly fewer patients who had the primary endpoint in the ibrutinib group as compared to the placebo group. Three-year event-free survival as well as the time to next CLL treatment were also longer in the ibrutinib-treated group. While ibrutinib treatment was not associated with a higher rate of serious adverse events, it was associated with cardiovascular and bleeding events, which could be mitigated by preventing use of oral anticoagulants and avoidance of CYP3A4 drug–drug interactions. At the time of this study, there was an insufficient demonstration of overall survival benefit due to pending survival analysis. In summary, this study reveals ibrutinib as an effective treatment in patients with early-stage CLL who demonstrate a high risk of progression, but does not yet justify changing the current recommendation of a watch-and-wait strategy.

Langerbeins P, Zhang C, Robrecht S, Cramer P, Fürstenau M, Al-Sawaf O, et al. The CLL12 trial: Ibutrinib versus placebo in treatment–naïve, early stage chronic lymphocytic leukemia. Blood 2021 Nov 10 [Epub ahead of print].

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