CME
Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™
Released: August 30, 2024
Expiration: August 29, 2025
First-Generation Covalent BTK Inhibitor Ibrutinib: Earlier Role as 1L Therapy for CLL
Jeremy S. Abramson, MD, MMSc: The management of CLL has been transformed in recent years. In the past, our only option for patients was chemoimmunotherapy (CIT). However, CIT is now rarely used in the United States due to the availability of highly efficacious targeted therapies.
This revolution in treatment started with trials evaluating ibrutinib for patients with relapsed/refractory 17p deleted disease, and trials comparing ibrutinib to CIT for relapsed/refractory CLL without 17p deletions. Following the success of these studies, randomized trials also found ibrutinib superior to chemoimmunotherapy as frontline treatment.. The 2 phase III studies shown on this slide—ECOG 1912 and NCRI FLAIR—demonstrated that ibrutinib is superior to fludarabine/cyclophosphamide/rituximab (FCR), our most potent CIT, in terms of overall survival and progression‑free survival (PFS).1,2
What about older patients? Historically, we would have recommended chlorambucil/obinutuzumab or bendamustine/rituximab. However, clinical trials comparing ibrutinib with either chlorambucil/obinutuzumab or bendamustine/rituximab showed dramatically improved efficacy in terms of PFS and overall survival with ibrutinib.3-5
Despite this, an interesting signal emerged when comparing ibrutinib with these CIT regimens, showing that ibrutinib is a very good drug, but not a harmless drug, with associated toxicities that can be significant, including atrial fibrillation, bleeding, bruising, arthralgias, diarrhea, and others. In the RESONATE‑2 trial comparing ibrutinib with chlorambucil, 41% of patients discontinued ibrutinib therapy with adverse events (AEs) being the most common reason for discontinuation. With ibrutinib, patients could have more severe AEs, like atrial fibrillation or bleeding, or problematic quality-of-life AEs, like arthralgias, myalgias, and bruising, which are important to consider with a drug that is designed to be taken every day until progression or intolerance.
Next-Generation Covalent BTK Inhibitors: Fewer AEs and Superior to CIT
Jeremy S. Abramson, MD, MMSc: The next question that emerges is, “Are there drugs that might be better tolerated than ibrutinib and preserve the efficacy with this agent?” We now know that the next-generation covalent BTK inhibitors acalabrutinib and zanubrutinib are superior to CIT—either chlorambucil/obinutuzumab or bendamustine/rituximab—for efficacy and have lower rates of toxicity and discontinuation due to AEs than these regimens.6,7 The discontinuation rate due to AEs is approximtely 10% with these agents, suggesting that we can maintain the benefit of a BTK inhibitor with less toxicity vs chemoimmunotherapy.
Safety With Acalabrutinib or Zanubrutinib vs Ibrutinib for R/R CLL
Jeremy S. Abramson, MD, MMSc: The ELEVATE-RR and ALPINE trials were head-to-head trials comparing acalabrutinib or zanubrutinib with ibrutinib for patients with previously treated CLL. Although these trials included patients with relapsed/refractory CLL, data from these trials can help inform treatment recommendations with the different available BTK inhibitors.
ELEVATE‑RR was a randomized phase III noninferiority trial comparing acalabrutinib with ibrutinib in 533 patients with relapsed/refractory CLL characterized by del(17p) or del(11q).8 In terms of median PFS, there was no difference between treatment arms. However, there was a difference in this trial in toxicity. With ibrutinib, higher rates of atrial fibrillation, hypertension, bleeding events, diarrhea, and arthralgias were observed vs acalabrutinib.
Based on these data, one should favor acalabrutinib over ibrutinib when considering these 2 options.
What about zanubrutinib? ALPINE was a randomized phase III trial comparing zanubrutinib with ibrutinib in 652 patients with relapsed/refractory CLL.9 This trial had a slightly different design vs ELEVATE-RR; it did not enrich exclusively for higher‑risk patients. ALPINE showed better PFS with zanubrutinib vs ibrutinib. Looking at toxicity, there was substantially less atrial fibrillation/flutter with zanubrutinib vs ibrutinib, but there was no difference between groups with regard to hypertension.
Let’s return to a question from earlier in the program.
CLL14: PFS and OS With First-line Obinutuzumab + Venetoclax or Chlorambucil
Jeremy S. Abramson, MD, MMSc: Venetoclax plus obinutuzumab is also an option as initial therapy for patients with CLL. This combination was compared to chlorambucil/obinutuzumab in the randomized phase III CLL14 trial.10 This trial showed that venetoclax/obinutuzumab substantially improved PFS over chlorambucil/obinutuzumab. What is remarkable about this is that venetoclax/obinutuzumab is given as 1 year of time‑limited therapy; if you look 6 years later, that dominant PFS benefit continues to be maintained.
CLL14: Most Frequent Grade ≥3 Adverse Events With Obinutuzumab Plus Venetoclax or Chlorambucil
Jeremy S. Abramson, MD, MMSc: Venetoclax/obinutuzumab can have potential AEs, most notably cytopenias, but most people tolerate this regimen very well. Venetoclax can cause tumor lysis syndrome (TLS), but by gradually increasing the venetoclax dose over 5 weeks, the risk of TLS is effectively abrogated, and there is evidence from this trial that the incidence of TLS was actually higher in the chlorambucil/obinutuzumab arm than it was with venetoclax/obinutuzumab, where it was only 1%.
Let’s return to a question from earlier in the program.
GAIA/CLL13: Time-Limited First-line Venetoclax + Anti-CD20 Ab ± Ibrutinib for CLL
Jeremy S. Abramson, MD, MMSc: The natural next question in previously untreated disease is, “Can we combine venetoclax, a covalent BTK inhibitor, and obinutuzumab?” This question was asked by the GAIA/CLL13 trial, in which patients with previously untreated CLL received ibrutinib plus venetoclax/obinutuzumab, venetoclax/obinutuzumab, venetoclax/rituximab, or CIT with FCR or bendamustine/rituximab (BR).11
GAIA/CLL13: Efficacy
Jeremy S. Abramson, MD, MMSc: What this trial showed was quite fascinating. First, obinutuzumab is a better antibody than rituximab in CLL in terms of PFS and undetectable measurable residual disease (MRD) findings; this is why we rarely use rituximab in CLL anymore.
This trial also showed that any of the regimens, including venetoclax plus ibrutinib, improved PFS and undetectable MRD rates vs CIT. Finally, this trial showed that adding ibrutinib to venetoclax/obinutuzumab did not substantially improve PFS compared with venetoclax/obinutuzumab alone.
Multiple other triplet therapy studies are ongoing using next-generation BTK inhibitors, but this study would suggest that the addition of ibrutinib is not necessarily the answer.
CAPTIVATE FD Cohort 4-Year Update: PFS and OS
Jeremy S. Abramson, MD, MMSc: The CAPTIVATE trial assessed the addition of ibrutinib to venetoclax as time‑limited therapy for previously untreated CLL.12 Patients received 1 year of fixed‑duration ibrutinib and venetoclax, and the outcomes were excellent. Among all treated patients, 79% receiving venetoclax and ibrutinib remain progression free at 4 years. These benefits are enjoyed similarly in patients with CLL with unmutated IGHV or del(17p). This regimen is listed in current national guidelines, but it does require giving ibrutinib where we have largely shifted to next-generation BTK inhibitors for this disease.13
Frontline Covalent BTK Inhibitors vs Venetoclax Plus Obinutuzumab: Factors to Consider
Jeremy S. Abramson, MD, MMSc: When thinking about frontline therapy for CLL, we now debate whether to start patients on a continuous BTK inhibitor or fixed‑duration venetoclax plus obinutuzumab. I tell my patients that either approach will lead to an excellent outcome. So how do we make that decision with our patients?
When selecting a covalent BTK inhibitor, I will typically choose acalabrutinib or zanubrutinib based on more favorable safety profiles vs ibrutinib. These strategies do require continuous dosing, but that is relatively easy. No TLS monitoring or dose ramp-up is required, and no visits for infusions are necessary. However, covalent BTK inhibitors can be associated with easy bruising, some increased risk for bleeding and atrial fibrillation, and other AEs we have discussed.
The combination of venetoclax plus obinutuzumab is generally administered as 1 year of time‑limited therapy. It does require weekly visits for the first 2 months of treatment for initial doses and dose ramp-up, but after that, visits shift to once a month for treatment. After 6 months, treatment with obinutuzumab ends. Remissions with this regimen are often durable. This is often a preferred therapy, particularly for young, fit patients who don’t mind making the frequent trips to the clinic in the first couple of cycles. For an older, frailer patient where travel is more difficult, or if venetoclax is contraindicated, I would certainly prefer a BTK inhibitor, but I always have this discussion with my patients.
Shuo Ma, MD, PhD: It is often a long discussion with the patient. In addition to the approved options, of course, we now also have a lot of clinical trials to consider, so when it is time for discussion of treatment options, it is always a long visit. I do spend a lot of time with the patient laying out the data in terms of efficacy, PFS, and toxicity. When it comes to individual patients, I think several factors matter. I look at the patient in terms of their baseline comorbidities, whether they have significant cardiac disease, significant arrhythmia, or difficult-to-control hypertension. I also consider bleeding tendency, including whether they are taking medications that might increase their risk of bleeding, such as anticoagulation or antiplatelets. In the presence of those things, my recommendation may move away from a BTK inhibitor, but the decision is case by case. For example, BTK inhibitors are not contraindicated for patients who are taking baby aspirin or a small molecule anticoagulant. However, if a patient recently had a cardiac stent and they’re on 2 antiplatelet agents, then I would be more concerned about potential risk of bleeding with a BTK inhibitor.
On the flip side, if the patient has significant kidney dysfunction, for example, I would be worried about their ability to handle TLS. In that case, I might swing away from the venetoclax‑based therapy if they have a high tumor burden.
I also look at their tumor features. If a patient has an extremely high risk of TLS, very bulky adenopathy, and very high white blood cell count, I will communicate this to them and let them know they will likely need to be admitted to the hospital for venetoclax-based therapy initiation, which might not be appealing for some patients.
In most patients, however, I would say a BTK inhibitor or venetoclax-based regimen would both be optimal. Both are likely to give them quite a long time of disease control. The most common factor for choosing therapy is often patient preference—whether they would like an easy start with a BTK inhibitor and are OK with the long‑term oral medication, or whether they are more willing to invest more time upfront with the venetoclax‑based limited‑duration therapy and enjoy a treatment‑free period after that.
Key Questions in CLL Panel Discussion: Prognostic Markers
Farrukh Awan, MD: How do we prognosticate patients in the current era? How are you managing prognostic markers in the upfront setting and then also in the relapse setting?
Jeremy S. Abramson, MD, MMSc: That is an important question. For my patients, I check IGHV mutational status, a FISH panel and karyotype, and an NGS panel at diagnosis. I include in that FISH panel cyclin D1 to make sure there is not an occult mantle cell lymphoma. The next-generation sequencing panel primarily looks for TP53 mutations, but also for other recurring mutations, including SF3B1, NOTCH1, and others.
The presence of 17p deletion or a TP53 mutation is the most important in making treatment decisions. Patients with CLL who have these alterations progress earlier after time‑limited therapy with venetoclax/obinutuzumab.10 Their median PFS is still over 50 months, so still very good, but I do think they are very likely to need additional therapy. The presence of these alterations will sway me toward thinking about a BTK inhibitor upfront.
A patient with IGHV unmutated CLL will also progress slightly earlier after time‑limited therapy with venetoclax/obinutuzumab, although most will still achieve a 5-year remission, which is great, and I think there is a benefit to being off therapy and removed from the treatment side effects.
So other than a TP53 mutations/17p deletion, there are no alterations that factor into my frontline treatment decision-making today.
Farrukh Awan, MD: There are a couple of things that I would add to this. Once an IGHV mutation is present, it is always present. Findings with FISH can evolve, especially post therapy, so it is ideal that you test with this modality before starting next‑line therapy, or at least that is our standard practice.
Also, a del(17p) detected by FISH is different than a TP53 mutation on a polymerase chain reaction and next-generation sequencing assay. Having access to both pieces of the puzzle rather than just the FISH is helpful, because you may be missing a few patients with higher-risk CLL by just limiting yourself to the FISH.
Lastly, another way that I use IGHV: if a patient has unmutated CLL and I am seeing them for the first time, I tend to see them sooner compared to the patients with IGHV mutated CLL, for whom I can prolong the follow-up time maybe 6 months or a year.
Key Questions in CLL Panel Discussion: Role of MRD Findings
Farrukh Awan, MD: What do you think is the role for MRD testing in managing CLL? Do you think MRD makes a difference when you are selecting a BCL-2 inhibitor or BTK inhibitor?
Jeremy S. Abramson, MD, MMSc: Not officially, and it is not something that I think there is a mandate to check. The CLL14 trial stopped therapy in everybody, regardless of whether they were MRD detectable or not. I check MRD because knowledge is power. We do know that the majority of patients become MRD undetectable with venetoclax/obinutuzumab.10,11 Very few, if any, patients become MRD undetectable with a single‑agent BTK inhibitor14 and that is why BTK inhibitors are recommended as continuous therapy and why venetoclax/obinutuzumab induces deeper remissions and can be time‑limited therapy. We do know that the small proportion of patients who are MRD detectable at the end of their 1 year of venetoclax/obinutuzumab are more likely to progress than those patients who are MRD undetectable.10
Farrukh Awan, MD: You could argue that it might increase the anxiety level for a patient knowing that they are MRD positive at the end of therapy.
Jeremy S. Abramson, MD, MMSc: That is correct. I think for patients who are MRD positive at the end of 1 year of venetoclax/obinutuzumab, we can do exactly what the data would tell us to do, which is to stop therapy and observe or, and I have this discussion with my patients, say, “You’re tolerating venetoclax like a rock star. You’re having zero side effects. We know that you’re at high risk of progression if we stop therapy and we could continue it.” That of course negates the benefit of time‑limited therapy. Thankfully, this is not a common event. I typically have that discussion with the patient, but it is not a frequent one.
Farrukh Awan, MD: For patients with del(17p)/TP53 mutated CLL, a lot of us would have a bias towards continuing venetoclax after 1 year despite MRD. So what role does MRD have? That is an ongoing discussion. At this point, many major academic centers do check MRD for most patients routinely, either by flow or by the clonoSEQ assay.
Cases in CLL
Jeremy S. Abramson, MD, MMSc: Now that we have discussed some of the key factors in selecting frontline therapy for patients with CLL, let’s return to the case from the beginning of the activity, and we will discuss how our panelists might approach this patient in their clinics.
Case Discussion (I)
Jeremy S. Abramson, MD, MMSc: For our first case above, I would recommend continuous treatment with acalabrutinib or zanubrutinib. This patient told us he did not want to make a whole lot of trips and visits to the treating center, and venetoclax/obinutuzumab requires numerous visits upfront, and so a second-generation BTK inhibitor would be a great option.
Farrukh Awan, MD: This patient does have CLL with del(17p), and that might sway us away from venetoclax/obinutuzumab here as well, although it would not be wrong to recommend this therapy. With hypertension, diabetes, and chronic kidney disease, any bias toward 1 second-generation BTK inhibitor vs another?
Jeremy S. Abramson, MD, MMSc: I wouldn’t say so. In phase III trials, acalabrutinib appeared to have less hypertension compared with ibrutinib, while with zanubrutinib, rates were similar vs ibrutinib. I think either zanubrutinib or acalabrutinib would be entirely reasonable.
Farrukh Awan, MD: In collaboration with Jennifer R. Brown, MD, PhD; Nicole Lamanna, MD; Sameer A. Parikh, MBBS; and Jennifer A. Woyach, MD, I assisted CCO in creating an online treatment decision support tool to educate healthcare professionals on making optimal treatment choices for patients with CLL. To use the tool, HCPs enter their patients’ characteristics and intended treatment plan; expert recommendations based on those same characteristics as then provided. This tool can be found here.
When we enter the characteristics of this patient into the tool, all CLL experts would recommend a second-generation BTK inhibitor.
Jeremy S. Abramson, MD, MMSc: Let’s have a look at another case.
Case Discussion (II)
Jeremy S. Abramson, MD, MMSc: For this second case, I would be most likely to recommend venetoclax plus obinutuzumab, as this patient is younger and lives close to her treatment center, with CLL with no high-risk features, and desires a deep remission, which venetoclax/obinutuzumab is likeliest to provide.
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