Recognizing the Side Effects of Newly Approved CLL Therapies

Today we are discussing the management of patients with chronic lymphocytic leukemia (CLL), including incorporating the newest approved therapies for CLL: duvelisib and venetoclax. We are joined by Dr. Ian Flinn, a hematologist/oncologist and the director of the Blood Cancer Research Program at Sarah Cannon Research Institute in Tennessee. Dr. Flinn treats patients with CLL and has taken part in many clinical trials of agents in development for the disease.

-Interviewed by Anna Azvolinsky

Cancer Network: First, what are the most frequently used therapies to treat CLL patients, both those who are treatment-naive and those who are receiving subsequent therapy for relapsed or refractory disease?

Dr. Flinn: The first thing to know here is that not one size fits all, and we really use a more risk-adapted approach when making treatment decisions for patients with CLL, both in the front-line setting as well as for relapse. I have to say that, in general, the trend has been away from cytotoxic chemotherapy-such as fludarabine and cyclophosphamide, rituximab, or bendamustine with rituximab-for some of the more targeted agents, such as ibrutinib or venetoclax and venetoclax combinations. These other therapies, the cytotoxic chemotherapies, are still important and useful in certain patients, but the overall trend has been away from them and towards the more targeted treatment options.

Cancer Network: Venetoclax plus rituximab received a full approval by the US Food and Drug Administration (FDA) this past summer for patients with CLL who have been treated with at least one prior therapy. Most recently, the number of patients who are eligible for this combination was also expanded. Then, in September of this year, duvelisib was approved for previously treated CLL patients. In the context of the prior therapies available for CLL treatment, how are you and your colleagues incorporating these newer drugs into treatment plans for CLL patients?

Dr. Flinn: Both of these regimens are important additions to our armamentarium for patients with CLL. First, let’s take venetoclax plus rituximab. This combination therapy was approved based on the results of the MURANO trial, a large, randomized study of venetoclax plus rituximab vs chemotherapy and ritixumab. This study showed a tremendous improvement in progression-free survival (PFS) and remission rates in patients who received venetoclax. So, this is really going to become a new and important regimen in the second-line setting for patients with CLL. However, the current issue with using venetoclax has been with the logistics of giving this drug: it’s a bit cumbersome. There are also problems with what is known as tumor lysis syndrome, which is when all of the leukemia cells suddenly die off at once. While this may sound attractive to get rid of leukemia so quickly, it can be dangerous. To get around that problem, venetoclax is given at a ramped-up schedule, in which the dose is increased every week for 5 weeks with intensive monitoring of patients’ electrolytes and other measures. When it’s done this way, the treatment is very safe and very effective.

What’s attractive about this regimen is that it is one of these targeted molecules, which offer a fixed duration of therapy. This means patients receive this regimen for about 18 months and then come off. This is in contrast to some of the other regimens, such as front-line use of ibrutinib, which require patients to stay on the drug forever. In addition to this, we are also seeing very high rates of minimal residual disease with the ventoclax plus rituximab combinations. I think this is going to be a very popular and effective regimen, but, again, the issue of whether patients and their doctors can put up with the logistics that surround the dose escalation during the first 5 weeks will come up.

Moving on to duvelisib, this is a new phosphoinositide 3-kinase (PI3K) inhibitor that dually inhibits both the delta and gamma isoforms. It was recently approved for patients with CLL and well as those with low-grade lymphoma based on the results of two trials. In CLL, DUO, a randomized,   phase III trial, assigned patients to receive either duvelisib or ofatumumab. A substantial improvement in both response rates and PFS was seen in patients treated with duvelisib compared with those treated with ofatumumab. In the United States, duvelisib is now FDA-approved for patients who received two prior therapies.

Each of these therapies has some important issues regarding side effects and side effect management. With duvelisib, we need to be cognizant of the potential complications of PI3K inhibitors, including liver function abnormalities, diarrhea or colitis, and infection. With venetoclax, it’s more tumor lysis syndrome, as well as some issues with neutropenia and cytopenias.

However, I think that both of these drugs are going to be important. Duvelisib will probably be used third-line for patients with CLL, and venetoclax and rituximab will likely be used as a second-line regimen. That said, we will soon see data on combination venetoclax and obinotuzumab, another anti-CD28 antibody, in the frontline setting, so it is possible that venetoclax combinations will become a front-line therapy soon.

Cancer Network: You mentioned some of the side effect issues with these more recent therapies. Are there any other important side effects that hematology/oncology nurses and clinicians may not be used to, or that need to be monitored carefully by both the clinical team and the patient?

Dr. Flinn: I think that most clinicians are used to the side effects we see with cytotoxic chemotherapies, such as fludarabine and bendamustine, including their suppression of the immune system and cytopenia. Hematologists and oncologists are already practiced in monitoring patients for these complications. The newer molecules bring on different side effects. Let’s first start with ibrutinib, which is a Bruton’s tyrosine kinase inhibitor. This drug is now FDA-approved in the front-line setting and is commonly used in the relapsed setting as well. Once this therapy is started, patients have to stay on it for, basically, as long as it is helping them. Side effects can occur, but, luckily, most of them are relatively moderate in intensity. For ibrutinib, the most common side effect is diarrhea, and about 3% to 5% of patients can develop atrial fibrillation. Rashes can also occur. There are some additional side effects that are common but not necessarily very important to patients, such as brittle nails. However, when the drug is used in the front-line setting, we are seeing more side effects that are harder to tolerate, such as arthralgia and myalgia. From real-world experience, about 20% to 25% of patients have to discontinue ibrutinib because of these side effects. One other thing to mention is that many patients will also experience easy bruising. While this is not caused by an on-target effect of ibrutinib or from targeting Bruton’s tyrosine kinase, it likely results from inhibiting some of the other tyrosine kinases that ibrutinib also targets.

So, these are side effects that clinicians need to be aware of, to watch out for, and to ask their patients about. Sometimes they can be handled well. Probably the most serious one is atrial fibrillation. This is an issue because anticoagulation is often needed afterward, and some of the antiarrhythmic dosing is dependent on the antiarrhythmic drug used, so there is potential for drug-drug interactions. With venetoclax, I went through some of the side effects. The biggest and most challenging issue is tumor lysis syndrome, which can be easily managed by ramping up fluids and by monitoring for electrolyte abnormalities.

New regimens are coming out that are trying to reduce patients’ tumor load, white [blood cell] count, and lymph node size in order to help minimize some of these issues with tumor lysis syndrome. We will have to wait for some of these data to come out in the future. These regimens might make venetoclax easier to give and, hopefully, more commonly used, because this is a fantastic drug.

Finally, the side effects of the PI3K inhibitors are also important for patients and caregivers to know. Almost all of the PI3K inhibitors can cause diarrhea and liver function abnormalities. Both idelalisib and duvelisib inhibit the delta isoform of the PI3K family, which has been associated with autoimmune problems, the biggest ones being colitis and pneumonitis. Should either of these conditions occur, treatment needs to be withheld quickly. For example, if severe diarrhea leads to colitis, discontinuing the drug early and starting medication such as budesonide, an oral non-absorbable steroid that coats the bowel, might help avoid hospitalization and severe complications. Liver function abnormalities are also seen with these two drugs and generally occur early in the course of therapy. For both drugs, if therapy is stopped until liver function abnormalities improve, then restarted at a lower dose or sometimes the full dose, most patients can successfully resume these treatments. I think many doctors are now familiar with these sets of side effects. Once you are familiar with them, it makes it much easier to recognize the symptoms early and intervene in a quick manner to avoid some of the more severe toxicities.

Cancer Network: Thank you so much for joining us today Dr. Flinn.

Dr. Flinn: Thank you.