CME
Physicians: Maximum of 0.50 AMA PRA Category 1 Credit™
Released: August 10, 2023
Expiration: August 09, 2024
Introduction
In this module, Catherine C. Coombs, MD, MS, of UCI Health and Toby Eyre, MBChB, MD, of the University of Oxford review key data from the 2023 European Hematology Association (EHA) Congress on the use of BTK inhibitors in chronic lymphocytic leukemia (CLL).
The key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset that can be found here or downloaded by clicking any of the slide thumbnails in the module alongside the expert commentary.
Clinical Care Options plans to measure the educational impact of this activity. Several questions will be asked twice: once at the beginning of the activity and then once again after the discussion that informs the best choice. Your responses will be aggregated for analysis, and your specific responses will not be shared.
Before continuing with this educational activity, please take a moment to answer the following questions.
Phase II Trial of Time-Limited Acalabrutinib Plus Obinutuzumab in Untreated CLL
Toby Eyre, MBChB, MD:
The first study from EHA 2023 that we will discuss is a phase II trial that evaluated the combination of the second-generation BTK inhibitor acalabrutinib plus obinutuzumab given for a fixed period of time. This therapy is currently approved as continuous therapy,1 but this combination could have potential benefits as fixed-duration therapy.
Catherine C. Coombs, MD, MS:
The goal of this trial was to determine if treatment with a fixed duration of acalabrutinib plus obinutuzumab would result in a deep enough remission such that patients could have a period of time off therapy. The trial included 20 patients who needed therapy per the International Workshop on Chronic Lymphocytic Leukemia criteria. They received a lead-in of 2 cycles of acalabrutinib, after which obinutuzumab was introduced monthly for 6 months. Patients could then receive an additional 6 doses of obinutuzumab if they had not attained a complete response by cycle 8. In total, patients received 24 cycles of therapy. The primary outcome was the number of patients still in remission 6 months after completing the 24 cycles of treatment. Secondary outcomes were durability of treatment-free remissions and efficacy of retreatment after relapse.2
Time-Limited Acalabrutinib Plus Obinutuzumab in Untreated CLL: Treatment Outcomes
Catherine C. Coombs, MD, MS:
There was 1 death during the study due to presumed bacterial pneumonia, but otherwise the remaining patients were progression free at follow-up. Only 1 patient appeared to have had more than a brief time off treatment, so a longer follow-up of this study is necessary to investigate changes during the treatment free intervals.2
Time-Limited Acalabrutinib Plus Obinutuzumab in Untreated CLL: Survival
Catherine C. Coombs, MD, MS:
Both progression-free survival (PFS) and overall survival (OS) were excellent, with estimated rates of 94.4% for both.2
Time-Limited Acalabrutinib Plus Obinutuzumab in Treatment-Naive CLL: Response
Catherine C. Coombs, MD, MS:
The investigators found very high rates of complete response, although it is unclear from the study results whether these data represent patients who received only the 6 cycles of obinutuzumab or if those who may have opted in for an additional 6 cycles are included. Only 6 patients were evaluated at 2 year follow-up, but 4 had remained in complete response, which is higher than what we would expect with a 2 year course of just a BTK inhibitor.
There was also quite a significant debulking of the amount of CLL in bone marrow.2
Time-Limited Acalabrutinib Plus Obinutuzumab in Untreated CLL: Impact on Practice
Catherine C. Coombs, MD, MS:
I was excited to see this trial. I think perhaps it is somewhat an injustice to their development that BTK inhibitors were never studied as time limited options. Now we have obinutuzumab, which is quite an effective antibody, and we can see patients get to undetectable minimal residual disease (MRD) when it is paired with BTK inhibitors. I think this is an opportunity to see if we can use these combinations to get patients to deep enough remissions to have time off therapy. I would not say it is a practice changing study—it was only 20 patients—but I think it is very interesting conceptually, and we are clearly going to need more follow-up.
Toby Eyre, MBChB, MD:
I agree. I think it is conceptually a very interesting study. We know that obinutuzumab improves MRD negativity rates, historically combined with chemotherapy and venetoclax in terms of its approval, but certainly with acalabrutinib it does seem to be an attractive combination. It will be interesting to see the long term follow up of this study.
Catherine C. Coombs, MD, MS:
Another aspect of this study that perhaps I will apply indirectly to some of my patients is that acalabrutinib plus obinutuzumab does have FDA approval in the United States as frontline therapy, but some patients end up discontinuing therapy due to intolerance. I see acalabrutinib intolerance less frequently than ibrutinib intolerance, but I think if these patients do well and I do have a patient with intolerance to acalabrutinib, perhaps this could provide more confidence in how long of a remission such a patient may have.
Phase III CLL12 Trial: Ibrutinib vs Placebo in Asymptomatic Previously Untreated Early-Stage CLL
Catherine C. Coombs, MD, MS:
The CLL12 trial was initiated approximately 10 years ago and was designed to evaluate a potential benefit to early intervention with ibrutinib. The primary endpoint of the study was event-free survival, which previously was demonstrated to be superior with ibrutinib compared with placebo. This longer-term assessment provided an update on secondary outcomes, including treatment-free survival, PFS, and OS, which is arguably the most important outcome in an asymptomatic patient population.
The population enrolled in the study underwent a risk assessment using the German CLL Study Group score,3 which includes numerous clinical and laboratory components. Low-risk patients were instructed to watch and wait and were not part of the randomized cohort receiving either ibrutinib or placebo. Patients who had increased risk were randomized 1:1 to receive either ibrutinib at the standard dose of 420 mg/day or placebo. It is worth noting that approximately two thirds of the enrolled patients were classified as having increased risk according to their German CLL Study Group scores (NCT02863718).4
CLL12: AEs
Catherine C. Coombs, MD, MS:
The number of adverse events (AEs) was similar between the ibrutinib and placebo arms when looking at events of any grade. However, when comparing AEs of clinical interest, a higher incidence of events that are typically observed with ibrutinib occurred in patients receiving therapy, which included bleeding, cardiac arrhythmias, and hypertension.4
CLL12: Treatment and Response
Catherine C. Coombs, MD, MS:
Among the patients on the placebo arm, only approximately one half (48.5%) discontinued over the study follow-up period because of progressive disease, which suggests that perhaps a large number of patients were included who did not actually have high-risk disease. Ultimately, 81% of patients on the placebo arm discontinued early; this was because of AEs in only 28.7% of patients. Conversely, a much higher percentage of patients receiving ibrutinib discontinued because of AEs (72.4%).4
CLL12: EFS and PFS
Both event-free survival and PFS were significantly improved with ibrutinib vs placebo.4
CLL12: TTNT and PFS2
Catherine C. Coombs, MD, MS:
This study also revealed a difference in the time until the next subsequent treatment for patients receiving ibrutinib vs placebo, which is not an unexpected finding given that the patients receiving ibrutinib likely attained therapeutic benefit in terms of their CLL and thus did not need subsequent treatment for a longer period compared with patients receiving placebo.4
CLL12: OS Outcomes
Catherine C. Coombs, MD, MS:
No difference in OS was found between patients receiving ibrutinib vs placebo. The authors concluded that for patients with asymptomatic CLL who do not have an indication for therapy, the best course of action is to watch and wait.4
Phase III CLL12 Trial: Impact on Practice
Catherine C. Coombs, MD, MS:
The findings of this study are certainly interesting, but they are not practice changing, in my opinion. At this time, even for our highest risk patients with CLL, if there is no indication for therapy, I believe watch and wait remains the best approach unless there is a clinical trial. This trial, however, does not end the discussion on whether early intervention with novel agents is needed.
In the United States, the EVOLVE CLL/SLL study (SWOG S1925/NCT04269902) is evaluating early vs delayed intervention with venetoclax and obinutuzumab, which I think may be a more attractive therapy to give patients for whom we have advised watch and wait because it is time limited. The other advantage of that study is that it focuses on a relatively higher risk subgroup. It uses the CLL‒International Prognostic Index score,5 so patients have to be either high risk or very high risk or have complex karyotype. So, instead of being approximately two thirds of patients who walk in the door, it ends up being a little closer to one third. We hope that, of the patients randomized, we will see a higher proportion in the watch-and-wait group progressing and needing therapy, as opposed to this group, where only one half of the patients on the placebo arm ultimately progressed; this suggests that perhaps we are overtreating a certain amount of patients with ibrutinib on the experimental arm who may not have actually needed it for some time.
Toby Eyre, MBChB, MD:
I agree that it is a very interesting concept, potentially moving to fixed-duration therapy for asymptomatic patients with high-risk disease. Knowing how large or small to make that intervention group in terms of the ultimate impact on the watch-and-wait strategy is clearly a challenge. I was very struck by the number of AEs that occurred on the placebo arm. I think it speaks not only to the fact that all patients with CLL do get AEs, but also to some of our reporting procedures and the fact that we report a lot of low grade AEs, which may or may not be clinically relevant—certainly something to consider.
Phase I/II BRUIN Trial: Genomic Analysis of Pirtobrutinib in Pretreated CLL/SLL
Catherine C. Coombs, MD, MS:
Among the 279 patients with pretreated CLL/small lymphocytic lymphoma who received pirtobrutinib in the phase I/II BRUIN trial, the genomic analysis included 49 patients with progressive disease who had available longitudinal samples. The investigators performed next-generation sequencing on paired baseline and progression samples from these patients using a targeted panel of 74 genes, including BTK, PLCG2, and TP53.6
BRUIN: Baseline Characteristics
Catherine C. Coombs, MD, MS:
At baseline, the sampled patients were heavily pretreated, similar to the overall cohort, with a median of 4 prior lines of systemic therapy. Most (90%) had received prior ibrutinib, which was comparable to the overall cohort (88%). Only 20% of the sampled patients had previously received acalabrutinib, and only 2% had prior zanubrutinib. Almost all (81.6%) had received prior chemotherapy, and 45% had prior BCL2 inhibitor treatment.6
BRUIN: Response Rates
Catherine C. Coombs, MD, MS:
There was a similar response rate between the sampled patients with progressive disease and the overall cohort of 80% and 82%, respectively.6
BRUIN: Baseline Genomics and Pirtobrutinib Efficacy
Catherine C. Coombs, MD, MS:
At baseline, approximately one half (51%) of the sampled patients had BTK mutations, the most common of which was the C481S mutation, with a smaller number of patients making up the other C481 mutations.6
BRUIN: Characteristics of Acquired Resistance to Pirtobrutinib
Catherine C. Coombs, MD, MS:
The investigators found that 55% of the sampled patients had the emergence of new BTK mutations that were not at detectable levels prior to treatment with pirtobrutinib. The most common was the gatekeeper T474 mutation in 22% of patients, followed by what is referred to as the kinase-dead or kinase impaired L528 mutation in 11% of patients.6
BRUIN: Characteristics of Acquired BTK Mutations
Catherine C. Coombs, MD, MS:
Almost all patients who had a C481 mutation at baseline had a significant decline in the clone, either becoming smaller or completely cleared upon progression while receiving pirtobrutinib. However, new BTK mutations did emerge, most commonly T474 or L528. Approximately 29% of the cohort had no mutations upon progression, suggesting the possibility of alternate mechanisms of resistance to pirtobrutinib that have yet to be determined. Whether that is related to cytogenetic changes, expression data, etc, is yet to be determined.6
BRUIN: Presence of Non-C481 BTK Mutations Preexisting at Low Levels at Baseline
Catherine C. Coombs, MD, MS:
Patients who had these mutations emerge still responded to treatment with pirtobrutinib. When the investigators revisited the expression of mutations that were below the level of detection at baseline, 24% of patients had some of the mutations associated with pirtobrutinib resistance that were preexisting at baseline at low variant allele frequencies of approximately 1% to 3%, including patients who had received ibrutinib and/or acalabrutinib. Fortunately, these patients still responded to pirtobrutinib; therefore, it appears that having these low- to very low–frequency resistance mutations did not preclude patients from response to pirtobrutinib for a median treatment duration of almost 1 year.6
BRUIN Genomic Analysis: Impact on Practice
Catherine C. Coombs, MD, MS:
It is good to see that patients who did have the emergence of BTK mutations still had response to pirtobrutinib. Even those with acquired non-C481 BTK mutations at the time of progression that also were found to be present at baseline at low variant allele frequencies still saw a benefit with pirtobrutinib, with a median time on treatment of 11.2 months.
Toby Eyre, MBChB, MD:
I am intrigued by the fact that the C481 clones declined, and I suppose there is an open question about whether you can reexpose somebody to a covalent BTK inhibitor at progression on pirtobrutinib, which could be an intriguing concept to explore in clinical studies.
CAPTIVATE: 4-Year Follow-up Analysis From Fixed-Duration Cohort of First-line Ibrutinib Plus Venetoclax for CLL/SLL
Toby Eyre, MBChB, MD:
This presentation was a 4-year update of the CAPTIVATE trial examining a fixed-duration cohort of patients who received a lead-in of 3 cycles of ibrutinib 420 mg/day followed by 12 cycles of the combination of ibrutinib and venetoclax 400 mg/day (following a 5-week ramp-up). Patients with progression during follow-up were eligible for retreatment with single-agent ibrutinib or the combination of ibrutinib and venetoclax if they had a durable response. The primary endpoint was the complete remission/complete remission with incomplete bone marrow recovery rate per investigator assessment.7
CAPTIVATE Fixed-Duration Cohort 4-Year Update: Response
Catherine C. Coombs, MD, MS:
Overall response remained excellent, and many patients on the trial appeared to have had sustained response over time. However, a bit of separation between the patients with the highest risk markers and the overall cohort has begun to emerge. Patients with del(17p) and/or TP53 mutations appear to have had the largest drop in response rate over the 4-year follow-up period.7,8
CAPTIVATE Fixed-Duration Cohort 4-Year Update: PFS and OS
Catherine C. Coombs, MD, MS:
The majority of patients in the CAPTIVATE trial were still progression free at the 4-year follow-up, and a median PFS has not yet been reached. Most progression events occurred in the highest-risk patient group—those with del(17p)/TP53 mutations—which is not an unexpected finding.7,8 Some healthcare professionals may prefer a continuous therapy in these higher-risk patients vs a time-limited treatment because of results with other approaches, such as with the time-limited venetoclax/obinutuzumab combination.9 Historically, when such patients were treated exclusively with chemoimmunotherapy, they would have quite poor outcomes in terms of progression following completion of therapy, or they may have progressed while still receiving therapy.
Another notable finding is how well the patients with unmutated IGHV did—PFS was similar to that of the entire cohort. A few more relapse events might have occurred among that patient group, but they appeared to be continuing to do quite well during this longer-term follow-up.
OS in all patient groups has been phenomenal.
The CAPTIVATE trial enrolled younger, more fit patients with CLL compared with the GLOW trial,10 which enrolled relatively older, unfit patients. This could perhaps explain the better outcomes observed in the CAPTIVATE study.7,8
CAPTIVATE Fixed-Duration Cohort 4-Year Update: PFS by MRD Status and Time to Next Treatment
Catherine C. Coombs, MD, MS:
Results from the CAPTIVATE trial suggest a correlation between PFS and attainment of undetectable MRD. The landmark PFS rate at the 4-year follow-up was 90% in patients who achieved undetectable MRD compared with 66% in patients who had detectable MRD.7,8
CAPTIVATE Fixed-Duration Cohort 4-Year Update: Retreatment With Ibrutinib
Toby Eyre, MBChB, MD:
As of August 2022, 19 patients with progressive disease were retreated with ibrutinib, and nearly all of these patients responded to reexposure therapy.
CAPTIVATE Fixed-Duration Cohort 4-Year Update: Impact on Practice
Catherine C. Coombs, MD, MS:
This is a good update. Of interest, this is one of the very few drug combinations that is approved in Europe but not in the United States. So, this is not a regimen that I have been using with any frequency given that it is not approved by the FDA. Dr Eyre, given that it is approved where you are practicing, what are your thoughts on this data and some scenarios where you may use this combination?
Toby Eyre, MBChB, MD:
It is very important to see the longer term data from this cohort. We did see more toxicity with this combination in the GLOW trial in older, more unfit patients.10 Personally, I would feel comfortable administering this combination in a younger, more fit patient. I have concerns about using this combination in older, more frail patients with comorbidities.
I was somewhat disappointed with some of the progression events that we are starting to see, particularly in patients with TP53 mutations. Perhaps 15 months of therapy—12 months of combination therapy—in this study is not quite long enough. We have seen similar studies with doublet therapy that have administered treatment for slightly longer, including some that are MRD driven, that show patients with TP53 mutations achieving better outcomes.11 So, these are interesting data, and the debate will continue as to how you best treat patients with TP53 mutations—fixed duration vs continuous therapy. Of course, an important consideration is that PFS events do not necessarily equate to drug class resistance. We have some data on retreatment with ibrutinib—19 patients from the CAPTIVATE trial—showing that nearly all responded to reexposure to therapy, which I think conceptually is a very important point.
So, we have an increasing number of options, including this all oral fixed duration regimen, which is a unique aspect of this combination. For younger, more fit patients perhaps with unmutated disease, I would discuss this regimen. Certainly, different healthcare professionals have different perspectives on this, but that is the group for whom I would consider using it.
Catherine C. Coombs, MD, MS:
I think one view is that the patients with del(17p)/TP53 mutations did not do well, but I still think there is a real benefit for these younger patients to have time off therapy. I think the missing piece of data is how long they respond to rechallenge. In theory, they should not be resistant, but I think the first-line therapy is the main chance these patients are going to have to get any treatment free remission. So, I think if they have good, sustained responses to rechallenge of ibrutinib or even ibrutinib plus venetoclax, it still may be a win to me. I think that the follow-up is immature with respect to retreatment.
Toby Eyre, MBChB, MD:
Yes. Also, we have only 27 patients out of 159 who have a TP53 mutation or del(17p), so the retreatment data for those patients is going to be relatively limited. However, I agree it will be a very conceptually important point to evaluate moving forward.
SEQUOIA: Updated Analysis of Frontline Zanubrutinib vs Bendamustine/Rituximab in Patients With Previously Untreated CLL/SLL
Toby Eyre, MBChB, MD:
An updated analysis of the phase III SEQUOIA trial was presented. Cohort 1 included patients without del(17p) who were randomized to receive zanubrutinib vs bendamustine/rituximab (BR). Cohort 2 included patients with del(17)p who received zanubrutinib (NCT03336333).12,13
SEQUOIA: PFS in Cohort 1
Catherine C. Coombs, MD, MS:
The results of SEQUOIA have been previously published,14 but we now have updated data with a median follow-up of 43.7 months. The key finding was that zanubrutinib continued to outperform BR with regard to PFS. BR reached its median PFS at approximately 42 months, which is not unexpected, but by comparison, 82% of patients receiving zanubrutinib were still progression free and alive at 42 months.12,13
SEQUOIA: OS in Cohort 1
Catherine C. Coombs, MD, MS:
There still is no OS benefit with zanubrutinib.12,13
SEQUOIA: PFS and OS in Cohort 2
Catherine C. Coombs, MD, MS:
The study also had a separate arm of patients with del(17p), as it would not have been ethical to randomize these patients to receive BR. PFS for these patients at 42 months was 79.4%, which also was quite excellent.
SEQUOIA: AEs
Catherine C. Coombs, MD, MS:
Toxicities reported in the SEQUOIA update were in line with expectations. With additional follow-up, a slight increase in the rate of atrial fibrillation occurred. This still compares quite favorably with what has been reported for earlier BTK inhibitors, specifically ibrutinib. Hypertension occurred in 17.5% of patients receiving zanubrutinib in cohort 1, which suggests that hypertension may need to be monitored in patients receiving zanubrutinib, but overall cardiac safety appeared quite favorable.
SEQUOIA Updated Analysis: Impact on Practice
Toby Eyre, MBChB, MD:
Zanubrutinib provides a very nice treatment option for patients in this setting. The benefit now looks like it is in patients with both mutated and unmutated disease, as well, which is another interesting and important finding.
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