Optimizing Treatment With Newer Targeted Therapies in Chronic Lymphocytic Leukemia

Amy Goodrich

So, Carmen, as specialists in CLL [chronic lymphocytic leukemia] we’ve seen firsthand how patients with CLL are benefiting from the newer novel agents—especially small-molecule therapies like BTK [Bruton’s tyrosine kinase] inhibitors and BCL-2 [B-cell lymphoma 2] inhibitors. These oral therapies have enabled many patients to forego chemotherapy and those associated toxicities, and they’re achieving comparable or superior therapeutic results, particularly with our 17p or TP53 deletion patients, which we'll talk about. Of course, optimal use requires careful, proactive patient management and best-practice approaches to maximize treatment benefits and minimize adverse effects.

A core issue is the presence of specific cytogenetic abnormalities affecting treatment response and translating into differences in patient management.

Carmen Nobre

Yes, we need to use tools that provide risk stratification and prognostic information, to help us choose appropriate treatment regimens and anticipate the pace of disease progression in CLL. That’s why diagnostic evaluation includes a FISH, or fluorescence in situ hybridization, test on a peripheral blood smear to help detect chromosomal abnormalities. We see that 13q deletion is a favorable finding, 11q deletion is unfavorable, and certainly 17p is the highest risk finding. Another important test to perform at diagnosis is DNA sequencing to detect aberrant TP53. The tumor suppressor gene TP53 is located on the short arm of chromosome 17p. It leads to cell cycle arrest and inhibits apoptosis in DNA-damaged cells. This abnormality may be seen without 17p deletion, but it carries the same high risk.

Amy Goodrich

Of course, as we know from clinical practice, favorable prognostic features can become less favorable over time. But an additional test that we should talk about is of the immunoglobulin variable region heavy chain gene, or IGHV. The IGHV gene encodes antibody that functions in the immune response. The presence or absence of IGHV mutation identifies two subsets of patients with CLL: patients with mutated or hypermutated IGHV have a more favorable prognosis and those with what we typically call unmutated IGHV have a poor prognosis. Fortunately, about 50% to 70% of patients will have IGHV mutations, and so are not high risk from that perspective. So, Carmen, how do we use these cytogenetic findings to make therapy recommendations for these folks?

Carmen Nobre

That's such a good question. Let's start with upfront, initial therapy in high-risk CLL—patients with 17p deletion and/or TP53 mutations. These patients often do not respond well to chemoimmunotherapy and may progress more quickly after treatment if they do respond. Due to the poor success of chemoimmunotherapy, NCCN [the National Comprehensive Cancer Network] now recommends alternative agents for this patient subgroup. Regardless of age, preferred regimens for these patients currently include single-agent treatment with the first-generation BTKi ibrutinib until progression, the second-generation BTKi acalabrutinib with or without the anti-CD20 humanized monoclonal antibody obinutuzumab until progression, or a fixed duration of the BCL-2 inhibitor venetoclax plus obinutuzumab for 1 year.¹

Amy Goodrich

For patients with relapsed/refractory disease, it's venetoclax with rituximab for 2 years. When patients don't have those high-risk features, what we're looking at is overall health, whether they're fit or unfit.

Carmen Nobre

Right, and for patients 65 years of age or older, we determine fitness in multiple ways to help us make the best age-related recommendations. We base our assessment on comorbidities, organ function,  ECOG [Eastern Cooperative Oncology Group] Performance Status, and CIRS [Cumulative Illness Rating Scale]. Amy, can you talk about the conversations you have with our patients, weighing the pros and cons of different treatment options?

Amy Goodrich

Well first, you figure out where a standard-risk patient fits into this algorithm. If a patient is fit, then you're looking at their age and reviewing the treatment options we talked about for 17p deletion or TP53—because those are options for everyone with CLL. But the standard-risk folks also have chemoimmunotherapy options, unlike high-risk folks. So people who don't want to be on an open-ended therapy and who are interested in chemoimmunotherapy may opt for FCR [fludarabine, cyclophosphamide, rituximab] still. Those tend to be the younger fit folks. For the older folks, bendamustine plus rituximab is an option. Again, you can use all of those oral agents as well, but this is really where patient education and shared decision-making becomes so important, because patients have several treatment options.

Having the patient participate in this decision-making improves both satisfaction and adherence. What makes a patient choose a particular therapy? Often, it's a better side-effects profile. It may be the question of how a certain treatment is going to impact their quality of life. Are they going to be able to do their usual activities? How many times would they be traveling to and from the clinic? Most people are really afraid of losing their independence. Sometimes financial considerations come into play, but this is really where the individual patient needs to understand the pros and the cons and the “ins” and “outs” of the different options and really help us decide what the best therapy is for that person, because all of these therapies work well. So let's dive into comparisons between our novel agents.

Carmen Nobre

Starting with the BTK inhibitors, as we’ve said ibrutinib is a first-generation BTKi and acalabrutinib is a second-generation agent. Zanubrutinib, another second-generation BTKi, is currently being studied in the CLL setting. In considering these three agents, while ibrutinib and acalabrutinib may be given in combination with chemotherapy or immunotherapy, it may be helpful for the sake of comparison to focus our discussion on single-agent therapy. Certainly the pivotal trials to consider here are the ones that helped gain their initial FDA approval in the relapsed/refractory setting: the RESONATE trial for ibrutinib and the ASCEND trial for acalabrutinib.

Amy Goodrich

In considering BTK inhibitors as a treatment option in CLL, one of the first discussions I like to have with patients is to reassure them about lymphocytosis. This is a class effect with B-cell pathway inhibitors, including BTK inhibitors. B-cell receptor signaling is interrupted by these agents, and not only is critical functioning altered but also signaling migration and adhesion. What happens is, lymphocytes are released from the lymph nodes out into the peripheral blood. This transient condition usually occurs early in therapy. Lymphocytosis can be alarming and patients need to be ready for it—but this is an on-target effect and does not indicate disease progression.

About 66% of patients on ibrutinib and about one quarter receiving acalabrutinib will experience lymphocytosis. It's also seen with zanubrutinib, but zanubrutinib is not approved yet for CLL so the exact incidence is not well reported at this time.

Carmen Nobre

Amy, that's such an excellent clinical pearl about possible lymphocytosis and counseling our patients, since they may be following their own lab results in the online patient portal and it can sometimes be a little alarming to see upfront. Some of the common adverse events we see with the BTK inhibitors are due to off-target effects of these agents. At this time all the BTK inhibitors carry warnings and precautions, specifically with regard to risk of bleeding, infections, cytopenias, and atrial fibrillation. We also see that ibrutinib and acalabrutinib PIs additionally point out the potential for secondary primary malignancies. Right now, ibrutinib is the only BTKi that has specific warnings/precautions for hypertension and tumor lysis syndrome.

I think it is helpful to consider the most common side effects within the BTKi class—things like bleeding and bruising. This is an overall effect seen with this class; the overall incidence of any bleeding-related adverse effects is 44% for ibrutinib² and 26% for acalabrutinib.³ Typically patients can experience easy bruising and sometimes minor bleeding that can include bleeding of the gums when brushing or flossing, or even blood flecks with blowing the nose. For all our BTK inhibitors, we want to counsel patients that we may need to hold therapy anywhere from 3 to 7 days¹ before and after any procedures that could carry a risk of bleeding.

We try to avoid anticoagulation and use caution when it comes to antiplatelet therapy because of this risk of bleeding. We also prefer the use of acetaminophen to agents like NSAIDs when we need to use an over-the-counter analgesic. Another consideration is if we are seeing that bleeding is of concern for a patient, we may opt to start the patient on acalabrutinib instead of ibrutinib, due to acalabrutinib’s lower associated incidence of bleeding.

Amy Goodrich

We would also consider switching one BTKi for another, depending on the side effects we see. If someone has bleeding on ibrutinib, we might switch to a second-generation drug. Another side effect that we see pretty commonly is diarrhea, which can be an early effect. It’s typically mild, but it is bothersome to patients to have diarrhea or urgency. It typically reduces over time, and many will benefit from loperamide, changing their diet, and avoiding greasy or spicy foods. But we always have to keep infections such as C. diff [Clostridium difficile] in the back of our minds with these folks as well. And like we've talked about, there’s a diarrhea incidence of about 48% with ibrutinib, but it's only about 18% with acalabrutinib. So that's where many of these off-target effects are lower with use of the second-generation agents.

Carmen Nobre

Nausea is another early side effect that we consider here. It does respond well to antiemetics. Things to consider for our patients are to make sure we counsel them on what to expect and what to do if nausea or vomiting occurs. Having a PRN antiemetic available to them is a reasonable thing to do. We see the incidence of any-grade nausea for ibrutinib to be 26%, with 2% being grade 3 or higher²—whereas with acalabrutinib, it's less at 7%, with really no cases, at least reported in the trials, of grade 3 or higher.³ Another consideration is timing of the medications. For example, if a patient is taking ibrutinib in the morning and we’re noticing that nausea is most often happening during the day, we could consider having a patient switch to bedtime dosing so they're sleeping through that peak nausea period.

Amy Goodrich

We also see arthralgias and musculoskeletal pains, typically early side effects that tend to improve with time—and again, reminders for using acetaminophen only if patients need something for pain due to that increased risk of bleeding with NSAIDs or other over-the-counter analgesics. Pulse steroids tend to work well, too. About 17% of patients will have arthralgias with ibrutinib,² and 16% do with acalabrutinib.³ This is another issue that can be really bothersome to patients.

Carmen Nobre

Rash is another early side effect that’s sometimes encountered. In this case, we could use topical steroids or even oral antihistamines, especially for pruritus, which can be very bothersome. In terms of all-grade incidence, we're seeing 24% with ibrutinib monotherapy² and around 25% with acalabrutinib monotherapy.³ Another common bothersome side effect is fatigue.

Fatigue is mentioned as a potential side effect with many anticancer therapies. In the context of our BTK inhibitors, we're seeing a 20% incidence of any-grade fatigue with ibrutinib² compared to 9% with acalabrutinib.³ One way of managing this is to encourage our patients to stay active and exercise, as they are able, to help promote extra energy.

Amy Goodrich

That's so important. These are things that make or break the side-effect profile for patients, even though we tend to be more alarmed about the more severe issues in terms of holding drug or reducing drug. One of those issues is infections. With ibrutinib, about 70% of patients will have some sort of infection, and about a quarter will have severe infections.² With acalabrutinib, about 15% will have infections.³ This is something you always have to think about. They tend to be pulmonary, upper or lower respiratory tract. They can be fungal, and although uncommon you have to keep that in the back of your mind. The NCCN Guidelines recommend considering PJP/PCP [Pneumocystis jirovecii pneumonia, also known as Pneumocystis carinii pneumonia] and VZV [varicella zoster virus] pneumonia prophylaxis, and monitoring for fungal infections.¹ The other thing that you always need to think about is hypogammaglobulinemia. There are some other AEs to keep on your radar as well, but infections are one of the more severe side effects that this entire class of drugs can cause. And there are certainly others.

Carmen Nobre

Yes, there are. Another side effect that we've talked about is atrial fibrillation, as well as atrial flutter and other cardiac arrhythmias. A-fib is a serious side effect that tends to occur more rarely as a result of off-target effects. RESONATE and ASCEND reported about a 5% incidence of all-grade atrial fibrillation.^2,3 If it does occur, our management is per standard clinical care for a-fib. If it continues to be poorly controlled on an agent such as ibrutinib, we may want to consider switching to a second-generation BTK inhibitor. Cytopenias are another treatment effect that clinicians are oftentimes managing.

Amy Goodrich

Right, and that's something that can occur early or late. And so you get somebody started [on treatment] and you think you're good to go and then months into it, folks can develop cytopenias. With ibrutinib, about 23% of patients will develop anemia,² compared with 14% with acalabrutinib.³ Neutropenia occurs in 22% for ibrutinib,² 19% for acalabrutinib.³ Thrombocytopenia has a 17% incidence with ibrutinib² and 11% incidence with acalabrutinib³—definitely common with this whole family of medications, but less so with acalabrutinib, being second generation. Both of these agents’ PIs recommend CBC monitoring.^4,5 So you really have to make sure you're keeping an eye on these patients. But there are some agent-specific side effects too, Carmen, aren't there?

Carmen Nobre

Hypertension is most commonly seen with ibrutinib, and it is one of the only toxicities that actually can increase over time. Here again, we would manage per standard of care for hypertension management. Rarely do we see uncontrolled peaks at 19% to 20% incidence at 3 to 4 years on therapy,² and then low rates with acalabrutinib, which are about 3% overall incidence of hypertension.³ So that's one consideration for ibrutinib.

With acalabrutinib, headaches are more likely. We're seeing about 22% incidence of headaches with acalabrutinib, with 1% being severe headaches.² These headaches do tend to occur early on in therapy and tend to improve over the first couple of months. It is helpful to counsel our patients that this may occur and that these headaches may respond well to hydration, sometimes caffeine, or even acetaminophen. But it is certainly a side effect that we want to consider, especially in patients who may be predisposed to having headaches or migraines. Amy, could you talk about some other agents that may be options for our CLL patients but that are not BTK inhibitors?

Amy Goodrich

We can't forget about our BCL-2 inhibitor, venetoclax.⁶ We've talked a little about it, whether it's monotherapy or given with obinutuzumab or rituximab, so it's used first-line and in relapsed/refractory patients. It can be open-ended, it can be time-limited, but it's really hard to think about starting a patient on venetoclax without thinking about tumor lysis syndrome. There's the 5-week ramp-up that is designed to minimize tumor lysis syndrome. If you look at the package insert­ (and I truly look at this all the time), depending on the patient's lymphocyte count, the size of their lymph nodes, and their renal function, patients are stratified as high, moderate, or low risk for tumor lysis syndrome.⁶

There are recommendations of starting them inpatient versus outpatient. They all require vigorous hydration, and that varies based on whether you're going to treat them inpatient or outpatient. They all get antihyperuricemics and TLS monitoring. And there are absolutely other side effects after you get through with the ramp up. Carmen, do you want to talk about other side effects we see once we get them through that tumor lysis risk time?

Carmen Nobre

Absolutely. And I certainly break it up that way for patient counseling between the side effects within that first month that we're focused on TLS and then general tolerability thereafter. Some common side effects are diarrhea, nausea, and fatigue, somewhat similar to the BTK inhibitors. With venetoclax monotherapy in previously treated CLL, we're seeing diarrhea happen in about 43% of patients overall. Overall, all-grades nausea is reported in 42% of patients, fatigue is reported in 32%, and then cytopenias, including neutropenia, in 50%. A 6% incidence of febrile neutropenia is reported. We're seeing anemia in 33% of these folks, and then 29% are reported with thrombocytopenia.⁶

As with the BTK inhibitors, we’re concerned about some infection risks here; pneumonia and upper and lower respiratory tract infections have been seen in upwards of 61% of patients, with 11% being grade 3 or higher.⁶ There is a slightly different side-effect profile when venetoclax is combined with obinutuzumab in first line, or when it's being combined with rituximab in the relapsed/refractory setting. But overall it is well tolerated. Another consideration is that venetoclax is daily dosing, which is a convenient factor for many patients.

Amy Goodrich

We've got some options here with venetoclax as well. In the first-line setting, venetoclax and obinutuzumab is 1 year of therapy, but in the relapsed/refractory setting, you can give venetoclax with rituximab for 2 years or you can just give it open-ended as monotherapy until progression or unacceptable toxicity.¹ As we discussed, BTK inhibitors are also indicated first-line and in relapsed/refractory CLL. So these patients truly have an ever-increasing number of treatment options. The bottom line here is that they are all, overall, tolerated very well and patients have similar rates of response and durations of response.

When you think about how you're going to choose these therapies, comorbidities definitely come into play. For some patients, the finite therapy is attractive but those involve infusions so if they have difficult IV access or transportation is difficult or they live a long way from your facility, then monotherapy with daily ibrutinib, twice-daily acalabrutinib, or daily venetoclax is also very effective. Carmen, what about holding, dose reducing, or discontinuing therapy? Because certainly that does happen.

Carmen Nobre

I think a valuable clinical pearl here is considering how to transition our patients. When we consider a patient who may be on a BTK inhibitor, one thing to be aware of is when we stop therapy, patients can experience a flare of their disease. This is seen in about 25% of patients when they stop ibrutinib.⁷ A recent study has shown that this same phenomenon may also happen when we have a temporary interruption of ibrutinib— whether that's due to side effects or if we're holding for procedures or other things of that nature. The takeaway is that it's important to minimize the time off of therapy, both in the setting of holding or having a dose interruption, or if we're transitioning off therapy to an alternative therapy.

Amy Goodrich

Right. We also think about treatment response when we're discussing oral therapies with these patients. If you look at ibrutinib, after 5 years, there was a continued 92% overall response rate.² If you look at acalabrutinib, an 86% overall response rate at 2 years was reported.³ And then not forgetting about venetoclax and obinutuzumab, an overall response rate of 85% with 88% progression-free survival at 2 years.⁶ These are really great, great numbers. So how does one choose therapy when you have so many wonderful options?

Carmen Nobre

Knowing they're all very effective does really help us to individualize treatment a bit more, like we've been talking about, just considering the patient’s cytogenetics, some of the side-effect profiles, the patient’s comorbidities, and the patient's preference.  That shared clinical decision-making between the provider and the patients is key here. We have so many good options now, and with the many ongoing clinical trials we will have more options to choose from going forward.

Amy Goodrich

Yes. The bottom line is that most of these drugs are tolerated very well. Adherence may be an issue with these oral drugs, and there are significant toxicities to consider, so we always have to be monitoring and communicating with patients. For all of these drugs, there are dose interruptions, dose reductions, and even change of agent or change of drug class that may be appropriate. We know that patients will discontinue ibrutinib because of side effects, and then the majority go on to tolerate acalabrutinib with either resolution of the side effects or less severity of that same side effect.

In fact, in a large analysis of ibrutinib discontinuation rates in nine “real-world practice” studies in both the US and Europe, published in June 2020, the average discontinuation rate was 33.5%, with more than half of those discontinuations due to adverse events.⁸

And in November 2019 in Blood,⁹ there was an interesting small “real-world” retrospective analysis of CLL patients treated outside of clinical trials at nine US cancer centers, looking at treatment discontinuation with BTK inhibitors. They found 98% of patients (so, 46 patients) cited prior intolerance to ibrutinib as the reason for choosing acalabrutinib. The AEs leading to discontinuation of ibrutinib occurring in over 10% of patients were rash (in 22%); a-fib or flutter and arthralgia (each in 17%); and bleeding, infection, and fatigue (each in 13% of patients). Most (99%) of the ibrutinib-treated patients then switched to acalabrutinib.

The common AEs in over 10% of patients who switched to acalabrutinib in this analysis were fatigue and infection (each in 13%, or 9 patients each) and diarrhea/colitis in 10% (7 patients). Then in less than 10% of patients on acalabrutinib, common AEs reported were nausea/vomiting in 9%, headache and rash in 7% each, bleeding in 3%, and a-fib/flutter in 1%. At 5-month follow-up of the patients on acalabrutinb, 19% had discontinued therapy. ⁹

Clearly more research is needed in this area. Like you alluded to, Carmen, besides the “real-world” analyses that I just highlighted, there are a number of trials underway trying to describe changing BTK inhibitors when you have toxicity. And trying to develop drugs with less off-target effects is another big area of study. I think in the end, Carmen, this is a great time for our patients with CLL, particularly those with 17p deletion and TP53 mutations, where they used to have a 12-months life expectancy. Now we have 5-year data on folks on ibrutinib who are in remission. So, just the conversations we have with patients have really changed over time.

It's no longer a dismal conversation. There's so much more hope for our patients with CLL. And like you said, there are more drugs coming, more classes coming. It just gets more and more exciting every day for our patients, and for us too, because it's really nice to see patients coming back year after year after year.