Novel Combination Advances in CLL - Episode 5
Sameer Parikh, MBBS:The median age at which CLL [chronic lymphocytic leukemia] is diagnosed is approximately 70 years of age. About 70% of all patients who have a diagnosis of CLL do not need treatment at the time of diagnosis. A number of these patients are observed. The median age at which treatment is initiated is approximately 75 years of age. Therefore, I think it is important for us to understand that the treatments that we offer to our patients have to be consistent with what an average 75-year-old patient may have, in terms of comorbidities, what their performance status would be, and what their life expectancy is going to be.
And so, I think with the current treatment options that we have available, the importance of comorbidities becomes extremely important to understand. Some of these treatments can cause tumor lysis syndrome. If a patient has a significant kidney dysfunction at baseline, then those treatments need to be reconsidered.
On the other hand, some treatments have toxicities of worsening hypertension and atrial fibrillation. In those patients, perhaps, these treatments should be avoided.
In my practice, a lot of our elderly patients need therapy. The way I think about them is, are these patients elderly? What kind of comorbidities do they have? I also look at what their life expectancy is. In someone who is over 80 years of age, who has many other comorbidities, and their life expectancy is less than 2 to 3 years, I would sometimes consider simply treating them with single-agent obinutuzumab or obinutuzumab in combination with chlorambucil. This treatment is fairly effective and can get patients into a decent remission, although this is not my preference. But in some patients, that may be the only thing that we can do to offer them palliation.
In contrast, in many other elderly patients who need treatment, I have considered the use of ibrutinib or venetoclax-based treatments. The choice of ibrutinib versus venetoclax simply depends on what kind of comorbidities these patients have. So, for example, a patient may have hypertension and a history of atrial fibrillation, or other cardiovascular comorbidities. In these types of patients, I would typically consider the use of a venetoclax-based regimen upfront, because I believe that the chances of these cardiovascular toxicities getting worse is low with the use of venetoclax-based treatments.
On the other hand, in patients who have bulky disease, or who have baseline chronic kidney disease, I believe that treatment with venetoclax can cause problems with significant tumor lysis syndrome, in which case treatment with ibrutinib or other BTK [Bruton tyrosine kinase] inhibitors may be the way to go.
With an increasing use of ibrutinib, both in the frontline and the relapsed/refractory setting, we have now come to realize that there are a number of cardiovascular toxicities in our patients who receive ibrutinib-based therapy. The most important cardiovascular toxicities include worsening hypertension. That can happen in as many as 70% of patients; or atrial fibrillation, which can happen in about 10% to 15% of patients. Rarely, we have also seen patients develop ventricular arrhythmiasin less than 1% of patients.
These are important toxicities that need to be monitored over time. For most of the patients who develop any of these complications, we typically will work with our colleagues in cardiology and cardio oncology to be able to integrate their assessments into the management of our patients. Patients who develop hypertension generally are able to continue with ibrutinib, where we treat their hypertension effectively. In patients who develop atrial fibrillation, depending on what their risk of stroke is, we may or may not need to anticoagulate them. And then, again, we would work with our colleagues in cardiology to determine what the safest anticoagulant to be used is, in conjunction with ibrutinib. And then we also consider lowering the dose of ibrutinib in a subset of patients, if continuing ibrutinib causes further worsening of atrial fibrillation.
And finally, if atrial fibrillation becomes a significant problem, we have considered stopping ibrutinib and switching our treatment to venetoclax or other treatments that are not associated with a higher risk of cardiovascular toxicities.
Toxicity management for ibrutinib should be considered according to the label that is available. There are a number of patients who develop toxicities. But with appropriate dose reductions and dose modifications, we are able to allow patients to continue with these treatments. And although there is a lot of data out there, and up to a third of patients who are on ibrutinib stop treatment because of toxicities, I believe that it is imperative that we try to modify doses of ibrutinib before we switch treatments out. We have successfully been able to continue ibrutinib at a lower dose in a number of our patients who develop toxicities.
On the other hand, once patients develop toxicities that persist despite treatment interruption or dose modification, then I believe there are excellent choices available in the post-ibrutinib setting, either with a second-generation BTK inhibitor such as acalabrutinib, which is now approved for the treatment of relapsed CLL, or switching to a venetoclax-based regimen.
Transcript edited for clarity.