Chronic Lymphocytic Leukemia
Evolving Role of Bruton Tyrosine Kinase Inhibitors and Novel Agents in Chronic Lymphocytic Leukemia
Bruton tyrosine kinase (BTK) inhibitors have helped to revolutionize the treatment of chronic lymphocytic leukemia (CLL). Investigations into new agents in this class with improved safety and/or efficacy in patients who have developed BTK inhibitor resistance are producing promising results.
How are newer BTK agents changing the landscape?
Professor and D.B. Lane Cancer Research Distinguished Professor
“In my clinical experience, the second-generation BTK inhibitors acalabrutinib and zanubrutinib tend to have fewer of these adverse events.”
Ibrutinib is the BTK inhibitor that has been available the longest and is referred to as a first-generation compound. It produces extremely good long-term disease control, but it is associated with some side effects and toxicities that can limit a person’s dose or their ability to stay on treatment. Effects such as arthralgia, myalgia, fatigue, and cardiovascular effects (eg, atrial fibrillation and bleeding) can be treatment limiting in a minority of patients.
In my clinical experience, the second-generation BTK inhibitors acalabrutinib and zanubrutinib tend to have fewer of these adverse events. This appears to be confirmed based on a January 2021 press release announcing the results of the ELEVATE-RR trial, which compared acalabrutinib with ibrutinib in patients with previously treated CLL. Results showed that there was no difference in effectiveness between these agents, but acalabrutinib was associated with a significantly lower risk of atrial fibrillation compared with ibrutinib. The ongoing ALPINE trial (NCT03734016) is comparing zanubrutinib with ibrutinib in patients with relapsed or refractory CLL, so comparative data on the efficacy and safety of these agents will soon be available. We have also recently seen data presented at the 62nd American Society of Hematology Annual Meeting and Exposition regarding the reversible BTK inhibitor LOXO-305 that looks very promising, including for patients who have developed resistance to ibrutinib or other irreversible inhibitors.
Fortunately, the scientific and clinical development of BTK inhibitors continues, and it will remain a very important target in CLL therapeutics. BTK inhibitors are typically used as monotherapy, but the one situation where I do consider including a CD20 antibody is for a patient who has anemia, is symptomatic, and has a high white blood cell count. This is because I think that you get a bit better and quicker disease control with the combination vs BTK inhibitor monotherapy in such patients. In this situation, my preference is to use obinutuzumab with either acalabrutinib or ibrutinib. But the paradigm is definitely BTK inhibitor monotherapy right now, for the most part.
“If we had an alternative BTK inhibitor that produces durable responses in patients with resistance to ibrutinib, we would still have venetoclax in our back pocket for future use.”
There is a lot of excitement about the investigational reversible BTK inhibitor LOXO-305 for a couple of reasons. Right now, if we have a patient who is clinically resistant to ibrutinib, we know that venetoclax works well in that setting—but that is just about the only option we have. We do not have any data on whether a PI3K inhibitor will have efficacy in that setting. I think that the default in such patients is to use venetoclax, whether or not they have had prior chemotherapy. But what comes after that? There are no other US Food and Drug Administration–approved options right now. So, what if we could switch to another BTK inhibitor that would work in the setting of resistance to ibrutinib or acalabrutinib? If we had an alternative BTK inhibitor that produces durable responses in patients with resistance to ibrutinib, we would still have venetoclax in our back pocket for future use. In addition, LOXO-305 seems to be incredibly well tolerated with very few side effects, which is impressive and important. Thus, there is a lot of enthusiasm for this class of drugs in general and for LOXO-305 in particular. ARQ 531 is another BTK inhibitor in development, but we have not seen as much data as we have with LOXO-305.
In terms of adding an antibody to BTK inhibitors, the initial data with combination therapy suggested that adding rituximab did not improve efficacy over ibrutinib monotherapy. However, the ELEVATE TN trial showed a trend toward better progression-free survival with acalabrutinib plus obinutuzumab compared with acalabrutinib monotherapy. Obinutuzumab is arguably a more potent antibody, so perhaps with longer-term follow-up, the combination will show a benefit over BTK monotherapy and this combination could become more common in the future.
Associate Professor of Medicine
“I think that as the field continues to evolve, there will be subgroups of patients with CLL who will benefit from a combined strategy of a BTK inhibitor plus a BCL-2 inhibitor.”
The COVID-19 pandemic has altered treatment patterns with BTK inhibitors, but the pattern has gone back and forth. When we had a peak of infections in the spring of 2020, we had many patients who required CLL therapy and preferred to start on a BTK inhibitor and not have to come in for venetoclax monitoring and for infusions with obinutuzumab. But when the COVID-19 numbers went down last summer, we used a fair amount of venetoclax-obinutuzumab. More recently, the pendulum has swung back, and I have had some patients preferring BTK inhibitors again due to the convenience of starting these drugs. So, I think that this trend of going back and forth will continue, but, eventually, COVID-19 will hopefully not be a major factor in the treatment decisions as we get beyond the pandemic.
When BTK inhibitors are selected for use, it is primarily as monotherapy. This is because the data have shown no benefit of adding rituximab, although there are some hints that obinutuzumab may provide some progression-free survival benefit in combination with acalabrutinib. Nevertheless, most patients use BTK inhibitors as monotherapy. I think that as the field continues to evolve, there will be subgroups of patients with CLL who will benefit from a combined strategy of a BTK inhibitor plus a BCL-2 inhibitor. This approach will likely be particularly beneficial for younger, fit patients and for those with higher-risk disease.
The evolution of the BTK inhibitor class will also be interesting to follow in terms of which agent will be used most commonly. At first, every patient was on the first-generation agent ibrutinib, but we now have acalabrutinib and will soon have zanubrutinib; in addition, we will also likely soon have the reversible inhibitors LOXO-305 and ARQ 531. While this class of drugs is exciting, I can see how it might be confusing for those who are not in this field to understand the nuances and differences among these drugs.
Calquence met primary efficacy endpoint in head-to-head trial against ibrutinib in chronic lymphocytic leukaemia. Press release. AstraZeneca; January 25, 2021. Accessed March 23, 2021. https://www.astrazeneca.com/media-centre/press-releases/2021/calquence-met-primary-endpoint-against-ibrutinib.html
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Mato AR, Pagel JM, Coombs CC, et al. LOXO-305, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: results from the phase 1/2 BRUIN study [abstract 542]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.
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Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (CLb) in patients (pts) with treatment-naive chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl 1):31. doi:10.1182/blood-2019-128404