Treatment Selection in CLL Broadens Beyond Discussions of Efficacy

Alexey V. Danilov, MD, PhD

BTK inhibitors and BCL-2 inhibitors have led to a paradigm shift in the treatment of patients with chronic lymphocytic leukemia (CLL) and is one that requires comprehensive discussions regarding patient preferences, comorbidities, concurrent medications, and potential drug-drug interactions, according to Alexey V. Danilov, MD, PhD.

“The choice that we currently have for frontline therapy is either a BTK inhibitor, such as ibrutinib [Imbruvica] or acalabrutinib [Calquence], or the BCL-2 inhibitor venetoclax [Venclexta] in combination with obinutuzumab [Gazyva],” said Danilov. “If patients concurrently take anticoagulants or have poorly controlled atrial fibrillation or hypertension, then BTK inhibitors could be a more difficult choice. Also, BTK inhibitors are continued indefinitely right now, whereas the combination with venetoclax is given for a finite duration. All of these factors play into the final decision of what treatment is chosen.”

In an interview with OncLive®, Danilov, an associate professor of medicine, Program in Molecular and Cellular Biology, Cancer Biology Graduate Program, Oregon Health & Science University School of Medicine, discussed current treatment strategies for patients with CLL in the era of novel therapeutics.

OncLive®: What factors should be considered when choosing a frontline therapy for patients with CLL?

Danilov: This is a very important question. In the era of novel therapies, there has been quite a shift in the paradigm in terms of how we approach [frontline treatment]. Disease biology is among the key factors to consider. I strongly recommend testing all patients with fluorescence in situ hybridization [FISH] to identify any abnormalities. In my practice, I also conduct next-generation sequencing [NGS] to identify gene mutations such as TP53, NOTCH1, and SF3B1 mutations, which can be associated with inferior prognosis. IGHV mutational status is becoming a little less important in the era of novel therapies. However, it’s still prognostic with treatments, such as venetoclax as we saw from recent updates of the CLL14 study.

There are of course, patient factors [that we have to consider] in terms of their comorbidities, concurrent medications, and potential drug-drug interactions. In this era, we rarely use chemoimmunotherapy, at least at our center, and specialized treatment centers for CLL. It’s still being used in the community. Therefore, I would strongly encourage the community to test for IGHV mutations on NGS or FISH if they plan to use chemoimmunotherapy. There is really a group of patients, such as those with del(17p) and del(11q), and arguably patients with unmutated IGHV, where the use of chemoimmunotherapy is probably not as appropriate as for patients with low-risk disease.

If patients concurrently take anticoagulants or have poorly controlled atrial fibrillation, or poorly controlled hypertension, then BTK inhibitors could be a more difficult choice. However, it’s not impossible. However, if patients live far, they have difficulty monitoring tumor lysis syndrome (TLS), coming back for labs, then venetoclax might become more of a “logistical nightmare,” due to the need to monitor TLS quite frequently in the first month during the dose ramp up. That’s the sort of conversation with the patient. What is their preference? What are they trying to achieve with this treatment?

BTK inhibition is continued indefinitely right now, whereas the combination with venetoclax is given for a finite duration. All of these factors play into the final decision of what treatment is chosen. The final factor, which I shouldn’t admit, is coronavirus disease 2019. The combination of venetoclax and obinutuzumab is associated with more frequent visits compared with BTK inhibitors. Therefore, how comfortable we feel, or how the patient feels about visits to the clinic during the pandemic, does play a role as well.

When it comes to BTK inhibitors, should they be used alone or in combination with an anti-CD20 antibody?

I typically do not combine ibrutinib with CD20-directed antibodies. However, some of my colleagues do, so there is some difference of opinion there. Findings from an ALLIANCE study, which randomized patients to ibrutinib; ibrutinib/rituximab [Rituxan]; or bendamustine-based therapy, showed that both ibrutinib regimens were better than bendamustine. However, neither regimen was superior to the other, meaning that rituximab didn’t seem to add much in terms of PFS benefit. Similarly, a study conducted at The University of Texas MD Anderson Cancer Center arrived at the same conclusion, of which the addition of rituximab did not improve PFS in patients on ibrutinib. Therefore, at this point, we have enough data to suggest that rituximab doesn’t add much to ibrutinib long-term and doesn’t improve PFS. Therefore, if I’m about to use ibrutinib, I use it by itself.

In terms of the combination of acalabrutinib and obinutuzumab vs acalabrutinib alone, the ELEVATE-TN study suggested that they may be different, but the study was not powered to compare those 2 arms. The comparison really was with chemoimmunotherapy. We need longer follow-up to understand if there is a true difference. Plus, there are more adverse effects [AEs] on the acalabrutinib/obinutuzumab arm compared with acalabrutinib alone. 

How might the use of proton pump inhibitors affect treatment decisions?

The proton pump inhibitors are important because, in particular, acalabrutinib has a drug-drug interaction with proton pump inhibitors. I certainly ask about them if I’m about to start someone on acalabrutinib. It is important to talk to patients about this because some of these drugs are over the counter, so they may not be listed [on a patient’s history], but they may be taking them. Some patients take the drug because it was prescribed to them and they don’t remember why, and sometimes we are able to stop it.

Other times we are able to replace with H2 blockers. Sometimes you can’t get away from them in which case I would not use acalabrutinib because of this drug-drug interaction. That’s where it becomes important. It’s less important with some other medications, such as ibrutinib, venetoclax, and such.

How do you approach subsequent treatment in a patient with ibrutinib intolerance?

It depends on the intolerance. There are some AEs with ibrutinib, which are less common with second-generation BTK inhibitors. Rashes, for example, I find are less common. Arthralgias, I find are less common with second-generation drugs. If it’s atrial fibrillation, which I can’t control on ibrutinib, then I would hesitate to go to acalabrutinib. By that point, I’d probably go to venetoclax and maybe later, think of a second-generation BTK inhibitor. Hypertension can typically be controlled. Sometimes you do have to stop ibrutinib, there’s no other way. Then it is reasonable to try acalabrutinib.

However, with some of the other AEs, such as arthralgias and myalgias, fatigue, and diarrhea, which can lead to discontinuation of ibrutinib, I find that they do improve with acalabrutinib. But, as I said, if I’m about to start a BTK inhibitor, I do favor a second-generation drug. A lot of the AEs do happen early in the course of BTK inhibitor therapy, so I honestly see fewer AEs because of this.

Are cardiovascular AEs a concern with BTK inhibitors?

I do think they are a prominent issue; it’s a class effect of the drugs. A few publications, which came out in the past 3 to 4 years, highlight that. A publication identified risk factors for atrial fibrillation. In patients older than 70 or 75 years, as well as males with hypertension, atrial fibrillation was shown in up to 15% to 16% of patients treated with ibrutinib. [Another data set] showed that patients with a history of atrial fibrillation have a 30% to 40% risk of atrial fibrillation reemerging on ibrutinib.

[We also have data] on hypertension and the major cardiovascular events on ibrutinib, which essentially was great even though they defined hypertension very stringently. Be that as it may, about two-thirds of patients experienced an elevation in blood pressure. I believe close to 10% of patients had some major event, such as myocardial infarction or stroke, which is not insignificant. Those are real issues with BTK inhibitors. The hope is that with second-generation inhibitors, they will be less frequent, and there are emerging data to support that. However, we will have to wait for the randomized trial results to say definitively that that’s the case. 

How do the options change upon progression?

The options do change a little bit in the relapsed/refractory setting. Luckily, we have really good results with BTK inhibitors. I certainly have patients who have stayed on BTK inhibitors for 5 to 6 years, even with high-risk disease with complex phenotype and TP53 mutations. With chemoimmunotherapy, so many of these patients progress after 1 year, whereas with BTK inhibitors, we really delay when we have to start talking about relapsed/refractory disease. There is the question of how patients progress. If patients are intolerant of ibrutinib, there’s good data to suggest that acalabrutinib can be used in those patients. I do favor selective second-generation BTK inhibitors compared with ibrutinib. There are enough data to support the use [of these agents]. We have data from a pooled analysis, with substantial follow-up at this point in time.

If patients progress following venetoclax, we do have options of retreating with venetoclax, or giving a BTK inhibitor. Emerging data from a multicenter analysis and also anecdotal evidence from clinical trials suggest that BTK inhibitors are effective in patients who progress on venetoclax after treatment with venetoclax and vice versa. The phase 2 study of venetoclax in patients progressing on BTK inhibitors did demonstrate an overall response rate of over 60% and a median progression-free survival of longer than 2 years.

It doesn’t seem like a “home run.” However, those patients also have received multiple chemotherapy drugs before they went on BTK inhibitors. The hope is that as our patients have not been exposed to so much chemotherapy in the past, they may actually have better responses, even if they progress on BTK inhibitors.

Where should future research efforts be focused in this area?

There are certain unmet medical needs which still exist in CLL. The first one is genetic high-risk disease—so patients with P53 aberrations. Those patients are still going to be the first ones to progress on BTK inhibitors and BCL-2 inhibitors. We do need to know who those patients are. That’s a clear indication to continue testing and make plans, particularly for younger patients for allogeneic stem cell transplant or CAR T-cell therapy.

The second area of unmet need is doubly refractory patients. Patients who progress on BTK and BCL-2 inhibitors have very limited options at this stage. Noncovalent BTK inhibitors have shown promise in the setting. LOXO-305, for example, has been very promising in patients with the BTK C481S mutation. Nevertheless, PI3K inhibitors may also show efficacy. These are patients for patients for whom we need more definitive therapies.

[We also have to] understand how cellular therapies work in this context. CAR T-cell therapy has shown very promising data in this doubly refractory patient population may fill some of this unmet medical need.

Patients with comorbid conditions still do less well with BTK inhibitors. We published a study a couple of years ago, showing that discontinuation rates are much higher in patients who had comorbidities based on [certain] risk scale scores. Those patients have significantly shorter overall survival by about 20% or so over 2 years. These patients have quite an inferior prognosis and remain an unmet medical need as well.

Another area is Richter’s transformation. We still don’t know how to handle that. It’s rare, but that also makes it a bit difficult to study. We haven’t come to a “home run” in that group of patients. Again, CAR T cells could be promising. We have 2 trials at City of Hope evaluating novel therapies, which may be effective in that setting.

Finally, immune deficiencies in CLL is still something we have to tackle. The novel agents have very interesting but poorly understood immunomodulatory effects, which can be harnessed to further help patients and improve their survival as many of these patients die because of infectious complications.