CLL12: a positive answer to a poorly phrased question

In this issue of Blood, Langerbeins et al on behalf of the German CLL Study Group (GCLLSG) report “positive” results of the CLL12 trial investigating the ability of ibrutinib to prolong event-free survival (EFS) compared with placebo in patients with treatment-naive asymptomatic early-stage chronic lymphocytic leukemia (CLL) without an indication for treatment.¹ Based on the current International Workshop on Chronic Lymphocytic Leukemia (iwCLL) and other guidelines, disease-directed treatment of CLL is only indicated for symptomatic or active disease.² Up to 30% of patients diagnosed with CLL may never require therapy during their lifetime, and previous trials of chemo(immuno)therapy did not demonstrate any long-term benefit from early treatment and were associated with increased toxicity.^3-5 

Ibrutinib, the first-in-class inhibitor of Bruton tyrosine kinase (BTKi), is a proven highly efficacious agent against CLL that was US Food and Drug Administration approved in 2014 for relapsed disease and in 2016 for first-line treatment. The CLL12 study, activated in 2014, aimed to illuminate the issue of whether early application of ibrutinib would be beneficial. To try and spare patients at low-risk of disease progression and enrich the event rate to provide an earlier readout for the study, they used GCLLSG score to identity patients at increased predicted risk of disease progression for study entry into this double-blind placebo-controlled trial. These elements are all excellent study design features. Other features of the study were more questionable; the measure of “benefit” used for the protocol-specified primary endpoint was EFS, where events were any of the following: (1) development of active disease by iwCLL criteria, (2) delivery of nonprotocol anti-CLL therapy, or (3) death. The study was strongly “positive” for this primary endpoint: hazard ratio, 0.25 (0.14-0.43; P < .001). Three-year EFS rates were 87.3% for ibrutinib and 60.4% for placebo. Inexplicably the disease progression rate in the placebo group was much lower than predicted by the index (predicted median EFS of 24 months), clearly indicating that we need better and more robustly externally validated predictive indices to identify appropriate patients for any future early intervention trials.⁶ 

Time to “next” treatment was also better, but patients in 1 arm had already received a proven active treatment: ibrutinib. How meaningful are these end points? It is methodologically appropriate and statistically rigorous to analyze and report prospectively protocol-specified objectives, but my personal view here is that this trial asked the wrong question. It would have been far more clinically relevant to design an early vs conventional initiation of ibrutinib treatment study, which would have been more complex to conduct and a much longer-term undertaking, needing to follow patients initially randomized to the placebo arm through the initiation of therapy according to conventional criteria and ideally to measure and compare the time to ibrutinib failure between treatment arms. Such a design would also have provided a robust assessment of impact on overall survival (OS), whereas in CLL12 most patients needing treatment in the placebo arm have received immunochemotherapy (predominantly bendamustine and rituximab). Thus, any OS data will be confounded by the uniform use of a targeted agent as first-line treatment in the investigational arm.

With a median follow-up of 31 months, no meaningful data are currently available on OS, the ultimate measure of patient benefit.

Another unanswered question is the potential for early use of ibrutinib to hasten the development of clones carrying resistant BTK mutations, such as the C481S. The factors influencing such clonal selection are incompletely defined, but of some concern is that 2 of the factors used to identify patients for study entry in CLL12, elevated serum β₂-microglobulin and TP53 mutation status, were also associated with an increased probability of development of BTK resistance mutations.⁷ 

The authors comment on a similar safety profile for ibrutinib- and placebo-treated patients based on crude incidence of total adverse events (AEs) (94.9% vs 94.8%, respectively), and any grade 3+ AEs (43.2% vs 50.6%, respectively), some of which will be manifestations of the impact of the disease burden of the CLL itself. However, closer evaluation of specific events suggests an increased toxicity burden in the ibrutinib arm (see table), which included 1 subdural hematoma (prior to protocol safety amendment) and 1 case of ventricular arrhythmia with an ultimately fatal outcome. This crude AE incidence rate is a simplistic measure that is not sensitive to persistence or prevalence of AEs, and newer toxicity assessment methods are available that better assess the total toxicity burden of chronic oral anticancer therapies.⁸ The long-term safety of any continuously administered agent chosen for early intervention studies is critical, and the increasing recognition of the breadth of the cardiovascular risk profile of ibrutinib suggests it may not be the optimal agent to be used in this setting. Albeit with less than 4-year follow-up in the relapse setting, the second-generation BTKi acalabrutinib has a lower rate of arrhythmias and hypertension,⁹ and such agents may be preferable.

CLL remains an incurable and burdensome disease for most afflicted patients, and we must therefore continue to strive to improve our current management. Given the observation that clonal evolution, including acquisition of the biologically adverse features, such as TP53mut and complex karyotype, can emerge between diagnosis and initiation of first treatment,¹⁰ well-designed early intervention trials should continue to be pursued. However, careful selection of outcome measures that consider the longitudinal nature of the disease is critical.

The authors’ concluding statement is important and bears emphasizing: the results (of CLL12) do not justify any change to the current standard of “watch and wait.”