 In relapse/refractory CLL [chronic lymphocytic leukemia], the landscape has changed quite a bit in the last few years. Previously, patients entering the relapsed/refractory space had had immunochemotherapy. Nowadays, a lot of our patients who are coming in with relapsed/refractory disease have already been exposed to a novel agent. It’s very much a moving target. We’ve learned from a number of trials in the relapsed space that, in general, the targeted agents like the BTK [Bruton tyrosine kinase] inhibitors are better than immunochemotherapy.

In the MURANO trial, venetoclax-rituximab performed much better than bendamustine-rituximab. Acalabrutinib performed better than idelalisib or bendamustine-rituximab in the ASCEND trial. Ibrutinib performed better than immunochemotherapy in the RESONATE trial, so that’s well established. Now the question is how do you manage a patient that’s failing a BTK inhibitor? Alternatively, if the patient received venetoclax, let’s say, a BCL2 inhibitor in the front line, where it’s approved to be given for 12 months. And let’s say they get some period of remission, but now they’re progressing again and they need a second-line treatment. What’s the best way to manage that patient? That’s where we’re lacking a lot of data. We certainly believe you can re-treat these patients with venetoclax-based therapy.

For me, that decision would depend a lot on how long that first remission lasted. If somebody received venetoclax-obinutuzumab for a year and then stopped it, and then 1 year later they’re progressing again, that’s a disappointing result to me. I probably wouldn’t go back to venetoclax-based therapy. I’d be much more likely to go to a BTK inhibitor like acalabrutinib. But what if your patient received venetoclax-obinutuzumab for 12 months and then stopped, and they go 4 more years in remission off-therapy? It might be perfectly reasonable to re-treat that patient with venetoclax-rituximab as was given in the MURANO regimen, and that’s a 2-year fixed-duration strategy. This is an area where we’re just starting to get data, starting to sort this out.

But I’ll admit, there are a lot of unknowns about optimal sequencing. It’s going to get even more complicated in the next few years because we know we’re getting data now for novel-novel combinations in the front line, like time limited. We recently saw results from the CAPTIVATE study and the GLOW study looking at a 12-month fixed duration of ibrutinib and venetoclax. Presumably that 2-drug regimen will get an approval relatively soon, and I’m sure that will get usage. What do you do with those patients who had ibrutinib-venetoclax for 12 months? How are you going to treat them in the second line? It’s going to depend on the quality of that first remission, but we just don’t have much data to guide us. It’s probably going to get more complicated for the next few years in terms of sequencing of treatments because we’re going to have more approvals and more options. The good news is they’re all very good options. There aren’t many bad options here, so these are good problems to have when you have all these effective therapies.

Videos

Before addressing unmet needs in the management of CLL, Brad S. Kahl, MD, outlines optimal sequencing strategies in the current treatment paradigm.  

Moving the Dial on CLL Management: Sequencing Strategies and Unmet Needs

 Toxicity management with BTK [Bruton tyrosine kinase] inhibitors is something we’ve all been getting better at as we’ve gained experience using these agents. Fortunately, the second-generation BTK inhibitors seem to have less risk for toxicity. Nowadays I’m much more likely to prescribe a second-generation BTK inhibitor in CLL [chronic lymphocytic leukemia]. Acalabrutinib isn’t the only choice. Another 1, zanubrutinib, will probably get approval relatively soon, and then we’ll have 2 second-generation BTK inhibitors. Both appear to be better tolerated than ibrutinib.

Zanubrutinib was compared head-to-head against ibrutinib in a trial that was presented at the EHA [European Hematology Association Congress] as a late-breaking abstract. Zanubrutinib had less risk for hypertension and it had less risk for atrial fibrillation and atrial flutter. Interestingly, there was a suggestion it might be more efficacious. The response rate was better for zanubrutinib compared with ibrutinib. That was a surprise to most of us because we always had assumed the efficacy would be essentially the same between these agents, but here are some data suggesting zanubrutinib may be more active.

For me, there are just not a whole lot of reasons to prescribe ibrutinib anymore in CLL. Maybe the 1 exception would be if you had a patient on a proton pump inhibitor, which is considered a contraindication to acalabrutinib—and you don’t have access to zanubrutinib because it’s not approved—then that would be the situation in which I’d go to ibrutinib. Probably in every other situation I would lean toward a second-generation BTK inhibitor.

There was an interesting study at ASCO [American Society of Clinical Oncology Annual Meeting] that looked at risk factors for toxicity. They looked at single nucleotide polymorphism in patients that had been prescribed BTK inhibitors, and they found 4 snips in 3 genes that were predictive for cardiovascular toxicity to ibrutinib. You may be able to identify the patients at the highest risk for getting hypertension or getting atrial fibrillation. But if you have better BTK inhibitors, it may not even be necessary to do that.

The final thing I’ll say about toxicity management is that, at least for me personally, when people get hypertension from a BTK inhibitor, I find it to be very hard to manage it with medications. For most of my patients, the only way I could get the hypertension to get under good control was to get them off the BTK inhibitor. I just couldn’t overcome it with antihypertensives, even adding in a second class of drugs, sometimes the third class. I’ve even gone to 4 classes of antihypertensives and still struggled to get the hypertension under good control. I would caution people to be aware of the hypertension risk. You may have to discontinue your BTK inhibitor if your patient develops significant hypertension.

Brad S. Kahl, MD, shares practical advice on the management of BTK inhibitor–related toxicity in patients with chronic lymphocytic leukemia. 

Optimal Toxicity Management With BTK Inhibitors in CLL 

 One of the more important abstracts presented at ASCO [American Society of Clinical Oncology Annual Meeting] this year was a head-to-head trial, acalabrutinib vs ibrutinib in previously treated CLL [chronic lymphocytic leukemia]. Dr John Byrd presented this in the oral session. This was a big trial, it had over 500 patients, and patients were randomized to ibrutinib vs acalabrutinib. Acalabrutinib is a so-called second-generation BTK [Bruton tyrosine kinase] inhibitor, so this trial is called ELEVATE-RR. This was the first presentation of the results.

The 2 patient populations were perfectly well balanced for baseline characteristics. With regard to efficacy, the 2 drugs performed very similarly. There’s no difference in the progression-free survival. The median for each drug came in at 38 months. Remember, this was a relapsed/refractory population, so the efficacy isn’t as good in relapsed/refractory disease as it is in front line. At 38 months is how both drugs performed for median progression-free survival. Acalabrutinib was deemed noninferior based on that, statistically.

When you start to look at tolerability issues, you start to see some advantages to the acalabrutinib. There was less risk for atrial fibrillation and atrial flutter with acalabrutinib. There was less risk for hypertension with acalabrutinib. These were statistically significant and clinically meaningful differences. There was also a better safety profile for acalabrutinib when it comes to bleeding events, diarrhea, and arthralgia. Acalabrutinib was a little worse than ibrutinib when it comes to headache and cough. When you look at the whole data set in total and look at the whole package, the conclusion of the investigators was that acalabrutinib is preferred over ibrutinib because efficacy is comparable and tolerability is better. I agree with that conclusion.

Considerations for the head-to-head data out of ASCO 2021 comparing acalabrutinib and ibrutinib in previously treated chronic lymphocytic leukemia.  

Head-to-Head Analysis of Acalabrutinib Vs Ibrutinib in Previously Treated CLL

 There was another interesting long-term follow-up presented at ASCO [American Society of Clinical Oncology Annual Meeting] this year from Dr Jeff Sharman which is a 4-year follow up of the ELEVATE Treatment-Naïve study. This was a 3-arm study that led to the approval of acalabrutinib in first-line CLL [chronic lymphocytic leukemia]. There are 3 arms in trial. Some of the patients just received single-agent acalabrutinib, but another group received acalabrutinib plus obinutuzumab the anti-CD20 monoclonal antibody. The control arm was chlorambucil and obinutuzumab with longer follow-up. 

We still see that the 2 acalabrutinib arms are performing much better than chlorambucil obinutuzumab. The interesting thing from this update has to do with the contribution of the anti-CD20 monoclonal antibody to the package. When the data was first presented and published there was a very small progression-free survival benefit for the addition of the obinutuzumab. The addition of the obinutuzumab also resulted in a few more adverse events, particularly infections. It was a trade-off: little better disease control, but little more risk for infections. With longer follow-up, the benefit of the obinutuzumab has increased slightly. For example, at 4 years, 78% of the acalabrutinib patients are still in remission vs 87% of the acalabrutinib-obinutuzumab patients, so we’re up to a 9% absolute difference in progression-free survival at 4 years. It’s starting to tip the risk-benefit ratio a little more toward the inclusion of the anti-CD20 monoclonal antibody. This can be individualized because there’s no overall survival advantage, it’s just a progression-free survival advantage.

When do I consider including the obinutuzumab? I consider it if I have younger, healthier patients, in whom I’m less worried about the infectious risks and the so-called hassle factor of getting the intravenous treatment is less of an issue. For some of our older patients, they’re frailer, so coming to clinic is a bigger inconvenience. Maybe they need transportation, or maybe they need rides. Because I’m more worried about infections in the older people, and because the back and forth of the clinic may be more problematic for them, I’m less likely to give the older patients the anti-CD20. But for the younger patients, I’d be a little more likely to include it because of this slight but significant progression-free survival advantage.

Insight on the 4-year follow-up data from ELEVATE-TN and the frontline use of acalabrutinib, with or without anti-CD20 therapy, in patients with CLL.

4-Year Follow-up Data From ELEVATE-TN: Frontline Acalabrutinib in CLL 

 We’re learning a lot about long-term BTK [Bruton tyrosine kinase] inhibitor exposure from the long-term follow-up from some of the earliest studies. The study that really led to ibrutinib getting a frontline approval in CLL [chronic lymphocytic leukemia] was RESONATE-2. Dr [Paul] Barr reported 7-year follow up at ASCO [American Society of Clinical Oncology Annual Meeting] this year, and there were some interesting things to learn. With 7 years of follow-up, 41% of patients are still taking their ibrutinib. That’s a significant proportion of patients still on treatment. We haven’t had to stop it because of disease progression or adverse effects, so that’s great. Sixty-one percent of patients are still in their first remission, so I guess that means 20% of people stopped the ibrutinib for some reason but are holding their remission, because 41% of patients are still on drugs; 61% of patients are still in remission. It’s great to see those long-term follow-up data to know that for a significant proportion of patients, ibrutinib is well tolerated. There’s ongoing risk for hypertension and atrial fibrillation, but that risk doesn’t seem to be increasing over time; it’s a slow, steady risk. They’re not seeing a whole lot of new toxicity signals, just the old toxicity signals that we already knew about with ibrutinib.

The discontinuation rate for ibrutinib with this long follow-up is about 5% per year. Most of the discontinuations at this point are from disease progression rather than adverse events. In other words, if someone was going to have an adverse event with ibrutinib, they probably would have already had it. It would have declared itself as being intolerable for that patient. If they make it 5 years on the drug, then the odds are they’re going to continue to tolerate it well.

Brad S. Kahl, MD, reflects on the 7-year follow-up data from the RESONATE-2 trial, which tested ibrutinib as frontline therapy in patients with CLL.

Frontline BTK Inhibition in CLL: 7-Year Follow-up Data From RESONATE-2 

 The development of novel targeted agents in CLL [chronic lymphocytic leukemia] has revolutionized this field. Not surprisingly, these new agents have consistently performed better than traditional cytotoxic chemotherapy in phase 3 trials. Not surprisingly, when groups are starting to analyze population-based data for long term outcomes, they’re seeing improvement in those outcomes. We assume this is because of the availability of these new agents. Ibrutinib has been around for a few years in CLL now and had ample opportunity to make an impact. Then we had venetoclax added to the options and then acalabrutinib, and we’ve had the PI3 kinase inhibitors for a number of years—a whole host of new targeted therapy options in CLL.

There was an interesting analysis at ASCO [American Society of Clinical Oncology Annual Meeting] this year, where this group of investigators looked at a SEER [Surveillance, Epidemiology, and End Results] database analysis, and the time frame they used was 1985 to 2017. They were able to show that the 5-year overall survival from the earliest time interval—they chunked it into 5-year time intervals—improved in men from 72% to 88%, comparing the earliest time interval to the latest time interval, and for women from 76% to 90%, from the earliest time interval to the latest time interval. There it is in black and white, strong evidence that these new therapies are having a positive, beneficial effect on overall survival in CLL.

When we’re assessing risk in CLL, there are 2 main parameters to look at. There are some more esoteric ones, but those aren’t as key as these 2 main ones. It’s pretty simple. It’s the immunoglobulin heavy-chain gene mutational status, 

. This refers to that CLL cell in its maturation, when it turned into a malignant cell, or where that B cell can be thought of as like the cell origin: where the cell of origin was when it turned into a CLL cell. Cells that have had trafficking through the germinal center of a lymph node undergo what’s called somatic hypermutation. That can be measured, so for patients with CLL whose CLL cells are somatically hypermutated, or so-called 

 mutated, that turns out to be favorable or good in CLL. If patients have the mutated version of 

, everything works better. Immunochemotherapy works better. Venetoclax works better. With BTK [Bruton tyrosine kinase] inhibitors, it’s not so clear that those work better. They work equally great in both mutated and nonmutated, but to have the mutated version of 

The other thing to look at is the CLL FISH [fluorescence in situ hybridization] panel. If people have a 17p deletion, then that’s a strong adverse prognostic marker. Nowadays it’s probably worth sending the material for a 

 mutation go hand in hand—travel together—but not always. That’s such an important adverse risk factor, that it’s worth knowing both 17p deletion status and 

 mutational status. Those are the 3 things I recommend. A CLL FISH panel, 

 mutational testing. Then you can have your patient risk stratified adequately. The 

-mutational status shouldn’t change over time—you should have to do that test only once—but patients can acquire a 17p deletion or a 

 mutation over time. Before each time you start a new line of treatment, it’s worth repeating the FISH panel and the 

The criteria for initiating treatment doesn’t depend on those risk factors we just mentioned. In other words, if you have a patient who has biologically high-risk disease, because they’re 

 mutated, that by itself isn’t a reason to start treatment. The criteria for starting treatment are the traditional criteria that have been published many times. Does the patient have symptoms? If they have symptoms, then starting treatment is appropriate. Are they becoming significantly anemic? A hemoglobin level less than 11 g/dL is a good line in the sand. Are they becoming significantly thrombocytopenic? A platelet count of 100,000 per mm3 is a pretty good line in the sand. Those are the strongest criteria. A little softer are things like the lymphocyte doubling time. If the lymphocytes double in 2 months, some people say it’s time to consider starting treatment. I don’t start treatment based on the absolute lymphocyte count; that’s not an indication for treatment. Sometimes your patients are getting significantly bulky lymphadenopathy, and that would be a reason to start, or symptomatic splenomegaly. They’re uncomfortable from a big spleen. That’s a reason to start. Cytopenias, significantly lymphadenopathy, significant splenomegaly, or the development of symptoms. Those are the main reasons to initiate treatment in CLL.

A comprehensive analysis of the CLL treatment landscape, including available agents, risk stratification, and triggers to initiate therapy.

Brad S. Kahl, MD, Washington University School of Medicine

Articles

Moving the Dial on CLL Management: Sequencing Strategies and Unmet Needs

Optimal Toxicity Management With BTK Inhibitors in CLL

Head-to-Head Analysis of Acalabrutinib Vs Ibrutinib in Previously Treated CLL

4-Year Follow-up Data From ELEVATE-TN: Frontline Acalabrutinib in CLL

Frontline BTK Inhibition in CLL: 7-Year Follow-up Data From RESONATE-2

Revolutionizing the Management of Chronic Lymphocytic Leukemia