Managing Adverse Reactions and Side Effects of Common CLL Treatments

Christina Russomanno

Hi Leigh Ann. I’m glad to be back talking with you about side-effect management for CLL treatments. In our previous conversation, we talked about treating with obinutuzumab and venetoclax. I thought today we could go a bit more in depth on the adverse reactions and side effects of them. First, we have the initial risk of tumor lysis syndrome, which honestly could be its own conversation. A lot of that risk stems from treating with obinutuzumab.

Leigh Ann Childress

Right. If you follow the CLL14 trial, we know that treatment for CLL patients starts with obinutuzumab.¹ In the beginning of treatment, obinutuzumab is given weekly for 3 weeks for the first cycle, which can be a lot. That’s when the highest risk of tumor lysis is, because that's when you're initially debulking these patients. A BCL-2 inhibitor hasn’t been started yet.

Since tumor lysis syndrome is so common, let’s talk about what it is and how we educate our patients on it.

Christina Russomanno

Good idea. With tumor lysis, there is a rapid killing off of the cells, with their contents (such as electrolytes) entering the blood stream. The elevation of these electrolytes in the blood can lead to side effects, such as kidney damage and cardiac events, as well as other effects.

So, we teach the patients about their risk of tumor lysis syndrome. We look at the size of their lymph nodes and how high their white blood cell count is. At that point we can determine whether it's safer for these patients to be treated in a hospital setting, where they can be monitored more closely and receive continuous hydration, or in an outpatient setting due to their disease burden and lysis risk being low enough.

I'll be honest with you, by the time these patients get to treatment, we find that most of them need to be in a hospital setting at least for initiation of obinutuzumab. We always hope they can come out after that and receive the rest of the doses as an outpatient. We mitigate tumor lysis by starting the patient on an antihyperuricemic, such as allopurinol, ahead of time to try to keep uric acid levels in normal limits. We recommend to the patients that they hydrate thoroughly, and we watch their labs very closely, hoping to recognize and address any signs of tumor lysis early on. Of course, tumor lysis in and of itself is not a bad thing; we want to kill off these cells. It just must be monitored and addressed promptly.

Do you have any pearls about tumor lysis and management before we talk about the other possible side effects?

Leigh Ann Childress

The biggest thing is knowing what your patient's baseline laboratory and renal function looks like. Hydrate, hydrate, hydrate is what we really push with our patients. We want to have an idea of how successful they are in keeping themselves hydrated so we know what needs to be done as far as additional IV hydration.

If you're planning to use an antihyperuricemic such as allopurinol, it’s important to educate patients on when to start them and how to take them. Some patients become confused by the fixed duration of allopurinol and think they're supposed to keep taking it, so we need to make sure that they know they’re only going to be on it for a specified period of time.

Electrolyte disturbance is going to be one of the first indicators that the patient is having tumor lysis syndrome. We're looking for hyperuricemia, elevated renal function, hyperkalemia, hyperphosphatemia, and there can be hypocalcemia as well. We’re looking for a 25% or 30% increase from baseline on those electrolytes, and a creatinine greater than 1.6.

Christina Russomanno

Yes, that’s an excellent point. We need to know their baseline and keep an eye on the trend. We know some patients might naturally have electrolytes that are a little high or low, so we need to trend the difference based on their baseline.

As far as other side effects, with obinutuzumab, we need to educate patients on the risk of infusion reactions, which is one of the major risks. They need to know to report any symptoms and that, if warranted, we’ll stop the infusion, give them medications to make the side effects go away, and then restart the treatment. Most patients don’t have an issue after that.

Of course, there are some patients we're more worried about because patients with a higher disease burden are more likely to have a reaction. Sometimes, we'll give them prednisone a few days before they start in an attempt to mitigate any possible reactions. It may not be in the prescribing guidelines recommendations, but these are tricks you learn through clinical practice. We know that a couple days of prednisone before treatment can cut down on the risk of infusion-related reactions.

Leigh Ann Childress

I agree. I educate patients that hypersensitivity reactions and TLS are not all bad. These reactions indicate that the drug regimen is working against their disease, but they need monitoring and sometimes intervention by the oncology team to prevent more serious complications. Helping them understand this is important in preparing the patient for that potential infusion reaction and lessens anxiety. We let the patient know that we’re able to pause the infusion, perhaps give some additional medications, and let things settle down. In most patients, we're able to re-challenge and give the drug successfully.

Christina Russomanno

That's a very good point. We know that obinutuzumab is a very strong drug. It's great, and we know how well it works in our CLL patients, but it has an aggressive side and can cause severe cytopenias. A patient who initiates obinutuzumab could have a white blood count of 400,000, and three days later when they leave the hospital it could be down to 3,000. Or they might be anemic and thrombocytopenic, and they're confused as to why their counts are so low, possibly even so low that the next obinutuzumab dose has to be held or delayed. So, we tell them it's all a means to an end. We talk about resetting the bone marrow by bringing the counts down so that they come back and the patient can start producing normal cells.

We also talk to the patient about tumor lysis. Obinutuzumab is given first, but it doesn't mean that venetoclax, the oral portion that is time-limited and added in later, doesn't also have a risk of tumor lysis syndrome. We just hope that we've debulked the patient enough or brought their disease burden down enough so that once they start the venetoclax, any tumor lysis is minimal. 

Leigh Ann Childress

I find that in clinical practice I’m not seeing a super high rate of TLS when we add venetoclax. Is it the same for you?

Christina Russomanno

Yes it is. Of course, venetoclax has its own side effects, so I stress with the patients that they will likely experience some GI issues. They may have some diarrhea at initiation. In my experience, one of the more common complaints patients have is bloating and gassiness, so we talk a lot about that in the beginning. We talk about cytopenias, because we know venetoclax can knock their blood counts down, particularly the neutrophil and platelet counts. We let patients know that we'll monitor that and they might need some growth factor at some point to bring their blood counts up. They may warrant drug holds or dose reductions, and that’s ok. 

One of the things we really stress to patients is that not everyone is able to handle 400 mg of venetoclax. We might give the patient a large dose and then find we need to reduce it. They might never be able to get to the target dose of 400 mg. It’s important that they know that everyone responds differently to treatment and there's no way for us to look at a patient and know exactly what their ideal dose is. We don’t want them to think something is wrong because their dose is lower than what the dosing guidelines state.

Leigh Ann Childress

Right. Those are all great points.

Christina Russomanno

Obinutuzumab and venetoclax are great options for upfront therapy, especially in those where time-limited therapy is desired. In the second line, when further therapy is warranted, other options are available, as well as new drugs or combinations of drugs in clinical trials. 

Leigh Ann Childress

Speaking of venetoclax, the AMPLIFY data that was just recently published was intriguing in that it offers AV, so acalabrutinib plus venetoclax, or AVO, which is acalabrutinib, venetoclax, and obinutuzumab, in a fixed duration regimen in treatment-naive CLL patients. Deep and durable responses were seen as well as a manageable safety profile when compared to FCR, which is fludarabine, cyclophosphamide, and rituximab, or BR, which is bendamustine plus rituximab.² How do you see this fitting into your practice?

Christina Russomanno

We are awaiting FDA approval and feel upfront time-limited therapy with two oral drugs will be game-changing. This eliminates the IV portion of treatment seen in CLL14, as well as the chance of needing hospitalization at initiation. Plus, starting treatment with a BTKi will debulk the patient before the BCL-2 inhibitor is introduced. I think patients will prefer this regimen over venetoclax or obinutuzumab. The only time we might argue strongly for venetoclax or obinutuzumab is if autoimmune phenomena (e.g., immune thrombocytopenic purpura, autoimmune hemolytic anemia) are involved, especially if there is no robust improvement when treated with steroids, since we know obinutuzumab will work on those issues more quickly.  

Leigh Ann Childress

Let’s talk about pirtobrutinib and how you’re sequencing this therapy in CLL. It’s been suggested that it may preserve the quality of T-cells, so are you primarily using this as a bridge to CAR-T, or are you using this more often as a third-line option after covalent BTKi and a BCL-2 inhibitor?

Christina Russomanno

This one is interesting, as there are some good trials in the works looking at pirtobrutinib upfront and in combination with other drugs.^3,4 Currently, we are using it in third line, after a covalent BTKi and a BCL-2 inhibitor-based regimen. That said, we’ve been leaning more toward pirtobrutinib in those deemed to have accelerated CLL. We also use it as a bridge to CAR-T, which goes along with using it in third line and beyond. 

Leigh Ann Childress

That’s good to know. Thanks, Christina.

Christina Russomanno

You’re welcome. Knowing what to look for and how to manage adverse reactions and side effects is a big part of our job.