CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Nurses: 1.00 Nursing contact hour
Released: September 29, 2021
Expiration: September 28, 2022
We will turn now to key safety data on BTK inhibitors from influential studies of clinical trial and real-world populations. Because ibrutinib has been available since 2013 and thus has the longest follow-up, most of these analyses focus on ibrutinib rather than the newer BTK inhibitors.
First, how does the incidence of AEs with ibrutinib change over time? A 2019 analysis evaluated the time course of grade ≥3 AEs of clinical interest in the phase III RESONATE trial, which compared the safety and efficacy of ibrutinib vs ofatumumab in 391 patients with relapsed/refractory (R/R) CLL/SLL with a median follow-up of up to 6 years.35,36 The key takeaway from this analysis was that when you follow patients over time, the incidence of AEs decreases.
These findings underline that BTK inhibitors have a tolerable safety profile, with a relatively low rate of AEs for patients who continue therapy beyond the first year.
Turning now to real-world patients, a large, multicenter, retrospective analysis of patients with CLL evaluated ibrutinib intolerance.37 More than 600 patients who were treated in routine clinical practice and clinical trials were enrolled, and the discontinuation rate was 42% after a median follow-up of 17 months.
The most common reasons for discontinuation differed for patients who were treated in the frontline vs relapsed setting. Among patients receiving frontline therapy, the most common reasons for discontinuation were arthralgias (42%), atrial fibrillation (25%), and rash (16%). In the relapsed setting, the most common reasons for discontinuation were atrial fibrillation (12%), infections (11%), pneumonitis (10%), bleeding (9%), and diarrhea (7%). The most likely reasons for these differences are, first, that patients in the relapsed setting may have cytopenias related to prior therapies that put them at an increased risk for infection. Second, patients in the relapsed setting are likely to be older and thus have other comorbidities and/or risk factors that contribute to the risk of atrial fibrillation.
Historically, physicians have been more likely to prematurely discontinue ibrutinib when AEs occur vs trying to manage the AE. For example, among patients in the frontline setting, 2 of the most common reasons for discontinuation in this analysis were arthralgias and rash. Both AEs can be managed with supportive care and common medications such as acetaminophen or occasionally a dose of steroids. If necessary, the drug also can be held and then restarted as opposed to completely discontinuing. If symptoms return, physicians also may try a dose reduction.
Unfortunately, there are no current data on real-world discontinuation rates with acalabrutinib or zanubrutinib, the newer agents. We also lack good, real-world data on BTK inhibitor discontinuation rates in patients with MCL.
Shown here are data from both real-world and clinical trial patients on the risk of atrial fibrillation with ibrutinib. In 2017, Wiczer and colleagues38 performed a large, single-institution, retrospective analysis of 582 patients with hematologic malignancies who were receiving ibrutinib. The graph depicts the cumulative incidence of atrial fibrillation with ibrutinib over time and shows that atrial fibrillation risk is significantly higher for patients with a history of atrial fibrillation vs those with no history of atrial fibrillation (P <.01).38 At 2 years, the estimated cumulative incidence was 10.3% in patients with a history of atrial fibrillation vs 5.9% in patients without.
A separate study by Brown and colleagues39 helped establish the utility of the Shanafelt risk score system for categorizing patients’ risk of developing atrial fibrillation. This scoring system assigns points based on the presence of 4 risk factors: age (65-74 years or 75 years and older), male gender, valvular heart disease, and hypertension. In this study of pooled data from 1505 clinical trial participants receiving ibrutinib, there was a marked difference in the 5-year rate of atrial fibrillation based on Shanafelt risk category score. In patients without a history of atrial fibrillation, the estimated 5-year atrial fibrillation rate was 17.9% in those with a risk score ≥5 vs 0.40% in those with a risk score of 0-1.
As mentioned earlier, hypertension and other major adverse cardiovascular events have been observed with ibrutinib. In an analysis of 562 real-world patients with lymphoid malignancies receiving ibrutinib between 2009 and 2016, the cumulative incidence of new hypertension reached 50% at a median follow-up of 4.2 months.40 These events typically occur relatively early after the start of BTK inhibitor therapy and then plateau with a very gradual increase.
When looking at the risk of bleeding with ibrutinib among clinical trial patients, this analysis by Brown and colleagues41 observed approximately 50 bleeding events per 1000 patient-months. The majority were minor bleeding events. When major hemorrhage did occur, it was more common among those with concomitant use of anticoagulation or antiplatelet therapy.
How does the safety profile of BTK inhibitors change when given in combination regimens? The combination of ibrutinib plus rituximab is currently recommended by the National Comprehensive Cancer Network for first-line treatment of younger, fit patients with CLL without del(17p)/TP53 mutation and for second-line and subsequent treatment of patients with MCL.21,42 This recommendation in the setting of previously untreated CLL was based on the randomized phase III trials ECOG 1912 (E1912) and A041202.
E1912 compared first-line ibrutinib plus rituximab vs fludarabine, cyclophosphamide, and rituximab (FCR) in 529 patients with CLL aged 70 years or younger.43,44 The trial met its primary endpoint by demonstrating a significantly improved progression-free survival (PFS) with ibrutinib plus rituximab vs FCR (3-year PFS rate: 89.4% vs 72.9%; HR: 0.35; 95% CI: 0.22-0.56; P <.001).
In this younger population of patients with CLL, there were significantly higher rates of grade ≥3 treatment-related atrial fibrillation with ibrutinib plus rituximab vs FCR (2.9% vs 0%, respectively; P <.05) and grade ≥3 treatment-related hypertension (7.4% vs 1.9%; P <.05).
Data on this combination in an older population with CLL come from the A041202 trial, which compared first-line ibrutinib vs ibrutinib plus rituximab vs rituximab plus bendamustine in patients with CLL aged 65 years or older.45-47 The rates of grade ≥3 atrial fibrillation and hypertension were comparable between the ibrutinib vs ibrutinib plus rituximab arms and higher than observed with bendamustine plus rituximab. Grade ≥3 atrial fibrillation occurred in 9% vs 6% vs 3%, respectively (P = .05) and grade ≥3 hypertension in 29% vs 34% vs 14% (P <.001).
Although it is difficult to compare clinical trials and populations, the rates of high-grade atrial fibrillation and hypertension reported with ibrutinib plus rituximab in E1912 and A041202 were generally similar to those reported with ibrutinib alone for R/R CLL in the RESONATE trial, which we discussed earlier.
Turning now to acalabrutinib, the second BTK inhibitor approved by the FDA, we do have some follow-up data since its approval in 2017.
An informative analysis of select AEs over time with acalabrutinib comes from the phase I/II ACE-CL-001 trial, which evaluated acalabrutinib in 99 previously untreated patients with CLL.48-50 As was seen in the analysis of AEs with ibrutinib over time, AEs were much more common in the first year compared with subsequent years of acalabrutinib treatment. For example, in the first year, diarrhea was observed in 33% of patients, headache in 44%, and arthralgias in 22%. At 1-2 years, the rates for diarrhea dropped to 17%, headache to 6%, and arthralgias to 6%; these rates continued to decline through Years 3-4. One exception is hypertension, which after an initial drop from 12% in Year 1 to 1% in Years 1-2 rose to 5% in Years 3-4.
Given that there are some differences in both the selectivity and safety profiles of acalabrutinib vs ibrutinib, it is useful to consider how acalabrutinib is tolerated in patients with ibrutinib intolerance.
As shown on this slide, Awan and colleagues51 performed an analysis of the ACE-CL-001 trial, which included an ibrutinib-intolerant cohort of 33 patients with CLL who were heavily pretreated and unable to continue ibrutinib treatment because of AEs. These patients received acalabrutinib and remained on treatment for a median duration of 19 months. Most (72%) of the ibrutinib-related AEs associated with intolerance did not recur with acalabrutinib, 11% recurred at the same grade, and 13% recurred at a lower grade. Only 3% of AEs recurred at a higher grade with acalabrutinib than was previously experienced with ibrutinib.
Another informative analysis comes from a phase II trial specifically evaluating efficacy and safety of acalabrutinib in 60 patients with R/R CLL and ibrutinib intolerance.52 Ibrutinib intolerance was defined as having experienced a grade 2 treatment-related AE that persisted for ≥2 weeks or recurred at least twice, despite dose modifications and supportive care, or having discontinued ibrutinib due to grade 3/4 AEs persisting despite supportive care. In this phase II trial, the median duration of acalabrutinib exposure was 32 months. Acalabrutinib was associated with efficacy in this ibrutinib-intolerant population, with an investigator-associated overall response rate (ORR) of 73%.
Overall, 10 patients (16.7%) discontinued acalabrutinib due to AEs; 4 out of 10 of these AEs were deemed related to acalabrutinib. Only 1 discontinuation was due to the same AE—diarrhea—that had led to ibrutinib discontinuation. When looking at recurrence of AEs, 24 out of 60 patients experienced 27 recurrent AEs. Most events (67%) were lower grade with acalabrutinib, 30% were the same grade, and 1 event (4%) was a higher grade.
In 2021, results from the important comparative phase III ELEVATE-RR trial were presented at the 2021 American Society of Clinical Oncology Virtual Annual Meeting and subsequently published in the Journal of Clinical Oncology by Byrd and colleagues.53,54 This trial compared acalabrutinib vs ibrutinib in 533 patients with previously treated CLL and del(17p) or del(11q). The trial met its primary endpoint by demonstrating the noninferiority of PFS for acalabrutinib vs ibrutinib.
As shown here, there were important differences in rates of AEs in the acalabrutinib vs ibrutinib arm. Those that were significantly lower (P <.05) with acalabrutinib vs ibrutinib were any-grade diarrhea (34.6% vs 46.0%), arthralgia (15.8% vs 22.8%), hypertension (8.6% vs 22.8%), contusion (11.7% vs 18.3%), atrial fibrillation (9.0% vs 15.6%), urinary tract infection (8.3% vs 13.7%), back pain (7.5% vs 12.9%), muscle spasms (6.0% vs 13.3%), and dyspepsia (3.8% vs 12.2%). Grade ≥3 diarrhea also was significantly less common with acalabrutinib vs ibrutinib (1.1% vs 4.9%), as was grade ≥3 hypertension (4.1% vs 8.7%).
AEs that were significantly more frequent (P <.05) with acalabrutinib vs ibrutinib were any-grade headache (34.6% vs 20.2%) and cough (28.9% vs 21.3%). Grade ≥3 headache also was significantly more common with acalabrutinib (1.5% vs 0% with ibrutinib), as was grade ≥3 fatigue (3.4% vs 0%).
Of note, there were no significant differences in the rates of upper respiratory tract infection, cytopenias, rash, and myalgia.
The rate of deaths due to AEs was numerically lower with acalabrutinib vs ibrutinib (10.5% vs 12.5%, respectively), with infections and infestations representing the most common cause of death for each treatment arm.
When we focus on select AEs of clinical interest in the ELEVATE-RR trial, we see that several were significantly less frequent with acalabrutinib vs ibrutinib.54 Any-grade atrial fibrillation occurred in 9.4% of patients with acalabrutinib vs 16.0% with ibrutinib, bleeding events in 38.0% vs 51.3%, and interstitial lung disease/pneumonitis in 2.6% vs 6.5% (all P <.05).
Regarding the most recently approved BTK inhibitor, zanubrutinib, we have comparative data in the settings of CLL and WM. The data on CLL come from the international, randomized phase III ALPINE trial, which was presented at the European Hematology Association Virtual Congress 2021.55,56 This trial compared zanubrutinib vs ibrutinib in 652 patients with R/R CLL, with the primary endpoint assessing noninferiority and superiority of ORR. At the interim analysis, the trial met its primary endpoint by demonstrating a significantly improved ORR with zanubrutinib vs ibrutinib (78.3% vs 62.5%; superiority 2-sided P = .0006; prespecified α = 0.0099).
The rate of atrial fibrillation or flutter was significantly lower with zanubrutinib vs ibrutinib (2.5% vs 10.1%, respectively; P = .0014; α = .0099). The rate of cardiac disorders leading to treatment discontinuation also was numerically lower with zanubrutinib vs ibrutinib (0% vs 3.4%), consistent with the lower rate of cardiac disorders of any grade (13.7% vs 25.1%).
Additional comparative data on zanubrutinib vs ibrutinib come from the ongoing multicohort phase III ASPEN trial.57 The trial enrolled 199 patients with MYD88L265P-mutated WM requiring treatment into cohort 1. These patients could have either R/R disease or be previously untreated and unsuitable for standard immunochemotherapy. After a median follow-up of 19.4 months, there was a numerical improvement in the primary endpoint of patients in cohort 1 achieving a complete response/very good partial response with zanubrutinib vs ibrutinib (28% vs 19%, respectively; P = .09).
As shown here, the rates of AEs of interest were generally lower with zanubrutinib vs ibrutinib. Of note, all-grade bleeding and atrial fibrillation/flutter, as well as grade ≥3 atrial fibrillation/flutter, were significantly less frequent with zanubrutinib vs ibrutinib (all P ≤.05). By contrast, neutropenia was significantly more common (all P ≤.05), but this did not translate into a higher rate of infections. The rate of dose reduction due to AEs was lower with zanubrutinib vs ibrutinib (23% vs 14%), as was the rate of treatment discontinuation due to AEs (9% vs 4%).
Based on supportive results from cohort 1 and cohort 2, which enrolled patients with wild-type or unknown MYD88 status, the FDA approved zanubrutinib for treatment of adults with WM in August 2021.11,58
Zanubrutinib was approved for R/R MCL based on positive results from the phase II BGB-311-206 trial, which evaluated zanubrutinib in patients with R/R MCL who had received ≥1 prior therapy.59-61 The primary endpoint was ORR, which was 84%.
In this trial, 41.9% of patients experienced grade ≥3 AEs. AEs led to treatment discontinuation in 9.3% of patients, and 6 patients (7.0%) died due to AEs. Grade ≥3 AEs of special interest included infections, which were experienced by 14% of patients; hypertension in 3.55%; and major hemorrhage in 1.2%. Of note, there were no cases of grade ≥3 atrial fibrillation/flutter in this trial.
To summarize, BTK inhibitors are important therapies for patients with CLL, MCL, MZL, and WM. Ibrutinib, a first-generation BTK inhibitor, is indicated for CLL, MCL, MZL, and WM. The next-generation BTK inhibitor acalabrutinib is approved for CLL and MCL, and zanubrutinib is now approved for MCL.
These agents are generally well tolerated, but they can be associated with treatment-associated AEs. The most common are diarrhea, bleeding, and rash, with important but less common events including atrial fibrillation. Because treatment with BTK inhibitors is often long-term, management of AEs is important to ensure adherence and the best patient outcomes, with many AEs being manageable simply with supportive care. In some instances, dose reductions or switching to more selective BTK inhibitors may help mitigate intolerance.
Selecting the optimal BTK inhibitor therapy for a patient should be based on the efficacy, the indication, and the safety profile, as well as patient comorbidities and preferences.
Back
