Dr. Bhat: Hi, I'm Dr. Bhat. I am one of the CLL physicians at the Ohio State University. My expertise is treating patients with CLL throughout the spectrum. You will be diagnosed to relapsed/refractory patients with CLL.
Can BTK Inhibitors Be Used Interchangeably?
This is a very interesting question and a frequent scenario that we encounter in our clinical practice. The first BTK inhibitor that was approved was ibrutinib (Imbruvica) and it works very well. But some patients experience adverse effects, which do impact their day-to-day functioning. There is another option called acalabrutinib (Calquence), which is more selective compared to ibrutinib and has a slightly better toxicity or adverse effect profile. So, for adverse effects, for example, if a patient is having joint pains, muscle pains, or irregular heart rate with ibrutinib, those patients can be switched over from ibrutinib to the second-generation BTK inhibitor called acalabrutinib without a problem. In most of the cases, the side effects do not happen again with the switch. They tolerate acalabrutinib much better. But in case of patients who have progression… disease progression on ibrutinib, that's more tricky.
These are similar drugs. They work on the similar pathway within the CLL cell. So, if a patient progresses on ibrutinib, the most common mechanism of progression on ibrutinib is development of resistance to ibrutinib. By change in the molecule BTK inhibitor, it undergoes a change, acquires a mutation by which it does not let ibrutinib bind to the site where it acts. Therefore, it becomes ineffective. Now, acalabrutinib also binds at the same site. So, if a patient develops a mutation or resistance to ibrutinib, they're automatically resistant to acalabrutinib. In those cases, we do not switch over from ibrutinib to acalabrutinib.
The good news is that we have newer BTK inhibitors in clinical development and clinical trials, which do not require that particular binding site. They work on a different site. Those are called reversible BTK inhibitors. You must have all heard about the new drug, LOXO-305. Those are the ones which are in development and hopefully will be approved soon so that patients can be switched over from these irreversibly binding BTK inhibitors, ibrutinib and acalabrutinib to the newer reversibly binding BTK inhibitors, which are not impacted by the mutations that patients can develop while on ibrutinib or acalabrutinib.
What Is the Protocol for Sequencing BTK Inhibitors and Bcl-2 Inhibitors?
The question arises that, can we sequence them? If a patient has been on a BTK inhibitor, can they go on a Bcl-2 inhibitor, and how do they do on a Bcl-2 inhibitor? Is the reverse also — does that hold good too? Yes. There is enough data to suggest that a patient who has either toxicity, adverse effect to a BTK inhibitor or even progresses on a BTK inhibitor like ibrutinib and acalabrutinib, they can go on to Bcl-2 inhibitor. Which currently we have one approved, which is venetoclax (Venclexta), and they have had great responses to the Bcl-2 inhibitor.
Now we have greater experience with ibrutinib, acalabrutinib, which are BTK inhibitors. In our experience, is the reverse also true? Yes. We have had patients who have been treated on Bcl-2 inhibitors upfront before they were treated with a BTK inhibitor. Those patients, if and when they progress, or they encounter a side effect to venetoclax, when they are transitioned or switched over to ibrutinib or acalabrutinib, they have good responses. So, both ways it is feasible, and it does not impact the response.
Under What Conditions Is a PI3 Kinase Inhibitor a Treatment Option?
PI3 kinase inhibitors are another class of medications that are approved for targeted agents, that are approved for treatment of CLL. These are different from BTK inhibitors or Bcl-2 inhibitors, but they also act on the same pathway that is deranged in these cells, the B cell receptor pathway. There are multiple steps in this pathway, and each of these different agents act on a particular step. Now, these PI3 kinase inhibitors act at the PI3 kinase step.
We currently have two approved PI3 kinase inhibitors for treatment of CLL in the relapsed/refractory setting. Idelalisib (Zydelig) is one of them and duvelisib (Copiktra) is the other one. Most of the data is in the relapsed/refractory setting. We may soon have an upfront PI3 kinase inhibitor approved called umbralisib (Ukoniq). But for now, these are reserved in the relapsed/refractory setting. These are slightly more difficult to tolerate compared to a Bcl-2 inhibitor, or venetoclax, or BTK inhibitors ibrutinib or acalabrutinib. The major toxicities are inflammatory toxicities. They can cause inflammation of the gut or the intestines leading to diarrhea. They can cause inflammation of the lungs leading to pneumonitis or inflammation of the liver, leading to increase in the liver function tests. So slightly difficult to tolerate, but definitely an option for patients who are either intolerant to Bcl-2 inhibitor or BTK inhibitor, or who progress on those agents.
