Preamble
This article discusses the clinical data for covalent BTK inhibitors in CLL in the front-line setting and considerations when choosing initial BTK inhibitor therapy. A future article that discusses noncovalent BTK inhibitors, management of BTK inhibitor toxicity, and future directions in the treatment landscape is projected to be published in a future issue.
Introduction
Chronic lymphocytic leukemia (CLL) is the most common chronic leukemia in adults, and the median patient age at diagnosis is 70 years.1 This type of leukemia is characterized by an accumulation of mature B lymphocytes in the peripheral blood, bone marrow, and/or lymphoid tissue and is often diagnosed after an incidental finding of lymphocytosis on routine bloodwork.2 Small lymphocytic leukemia (SLL), on the other hand, is characterized by lymphadenopathy or extranodal involvement and a monoclonal B-cell count of less than 5 x 109/L, with immunophenotypic features characteristic of CLL; it is treated similarly to CLL.2
Indications for treatment of CLL include severe fatigue, weight loss, night sweats, fever without infection, end-organ dysfunction, progressive bulky disease, and/or steroid-refractory autoimmune cytopenia.2,3 Most patients with CLL do not meet criteria for treatment at the time of diagnosis, and approximately 30% never require initiation of CLL-directed therapy.2 Risk assessment scoring via indices such as the CLL International Prognostic Index can be used to provide prognostic information on survival and may be helpful to anticipate time to first treatment; however, these prognostic tools were largely developed in the chemoimmunotherapy era.4
Mutations in TP53 or NOTCH1 genes and/or unmutated IGHV are known adverse prognostic factors.3,4 Cytogenetic analysis findings of deletions in the short arm of chromosome 17 (del[17p]), deletions in the long arm of chromosome 11 (del[11q]), or complex karyotype also confer unfavorable risk.3 Favorable risk factors include mutated IGHV as well as del(13q) if it is the sole cytogenetic abnormality.4
Treatment options for patients who require CLL-directed therapy have substantially changed during the past decade. Chemoimmunotherapy was the mainstay of CLL management for many years, but the advent of novel targeted agents rapidly transformed the treatment paradigm and improved clinical outcomes. Further understanding of the B-cell receptor pathway and its importance in the pathogenesis of CLL was paramount in the development of these medications.5
When the B-cell receptor is activated, downstream signaling leads to activation of Bruton tyrosine kinase (BTK). BTK activation leads to increased production of transcription factors necessary for B-cell proliferation, differentiation, and survival. First-generation BTK inhibitor (BTKi) ibrutinib (Imbruvica; Pharmacyclics LLC) and second-generation BTKis acalabrutinib (Calquence; AstraZeneca Pharmaceuticals LP) and zanubrutinib (Brukinsa; BeiGene USA Inc) are covalent BTKis. These agents covalently bind with cysteine residue 481 at the adenosine triphosphate–binding pocket of BTK, which inhibits kinase activity and leads to BTK degradation. This irreversible binding leads to prolonged BTK inhibition.6
In 2014, ibrutinib became the first BTKi approved by the FDA for use in patients with CLL who had received at least 1 prior line of therapy.7 Since then, ibrutinib and the second-generation BTKis have been evaluated and incorporated into the therapeutic armamentarium for CLL, including as first-line therapy. This review provides a comprehensive overview of the clinical data supporting the utility and FDA approval of covalent BTKis for patients with CLL.
First-Generation BTKI As Frontline Therapy
RESONATE trial
The first-generation BTKi ibrutinib was initially granted accelerated FDA approval in February 2014 for patients with CLL who had received at least 1 prior therapy. The approval was based on overall response rate (ORR) data from a phase 1b/2 study.8 As required by the accelerated approval process, a phase 3 trial confirming clinical benefit was initiated.
The open-label, randomized, phase 3 RESONATE trial (NCT01578707) in patients with relapsed or refractory (R/R) CLL was shown to significantly improve progression-free survival (PFS), overall survival (OS), and ORR, including durable responses, compared with the anti-CD20 monoclonal antibody ofatumumab (Kesimpta; Novartis Pharmaceuticals Corporation).8 These promising results led to the evaluation of ibrutinib in earlier lines of therapy.
RESONATE-2 trial
The phase 3 RESONATE-2 trial (NCT01722487) enrolled 269 patients with previously untreated CLL and evaluated the efficacy and safety of first-line ibrutinib vs chlorambucil. Patients were randomly assigned 1:1 to receive either once-daily ibrutinib 420 mg until disease progression or toxicity or chlorambucil 0.5 mg/kg on days 1 and 15 of each 28-day cycle for up to 12 cycles. Crossover was permitted for patients with disease progression on chlorambucil. The median age of participants was 73 years, and 70% were 70 years or older. Forty-five percent had Rai stage III or IV disease, 20% had del(11q), and approximately 44% had unmutated IGHV. Patients with del(17p) were ineligible.9
After a median follow-up of 18.4 months, the median PFS was not reached in the ibrutinib group vs 18.9 months in the chlorambucil group (HR, 0.16; 95% CI, 0.09-0.28; P < .001), demonstrating an 84% reduced risk of disease progression or death with ibrutinib compared with chlorambucil and meeting the trial’s primary end point of PFS. The 18-monthPFS rate was 90% in the ibrutinib arm compared with 52% in the chlorambucil arm, and the PFS benefit in the ibrutinib arm was observed regardless of age, Rai stage, presence of del(11q), and unmutated IGHV status.9
Ibrutinib also significantly prolonged OS; at 24 months, OS with ibrutinib was 98% vs 85% with chlorambucil (HR, 0.16; 95% CI, 0.05-0.56; P = .001), translating to an 84% lower relative risk of death with ibrutinib. Similarly, the ORR was significantly higher at 86% in the ibrutinib group vs 35% in the chlorambucil group.9
A similar portion of patients in both groups experienced a grade 3 or greater adverse event (AE), but the type of AEs varied. The incidence of grade 3 or greater hematological AEs was higher in the chlorambucil group compared with the ibrutinib group and included neutropenia (18% vs 10%, respectively), anemia (8% vs 6%), and thrombocytopenia (6% vs 2%). However, patients who received ibrutinib compared with those who received chlorambucil experienced a higher rate of cardiovascular AEs, such as any-grade hypertension (14% vs 0%, respectively), major hemorrhage (4% vs 2%), and any-grade atrial fibrillation (6% vs < 1%). In the ibrutinib arm, some of the most common any-grade AEs were diarrhea, fatigue, and nausea; in the chlorambucil arm, they were nausea, fatigue, and neutropenia. A greater percentage of patients in the chlorambucil group discontinued therapy due to toxicity.9
Based on the positive results from the RESONATE-2 trial, in 2016, the FDA approved an expanded indication for ibrutinib as initial treatment for patients with CLL or SLL.10 However, the benefit of ibrutinib compared with chemoimmunotherapy, a cornerstone of frontline treatment for CLL at the time, was still an important clinical question to address.
A041202 trial
The question of ibrutinib vs chemoimmunotherapy led to the randomized, phase 3 A041202 trial (NCT01886872) that compared the efficacy of ibrutinib alone or in combination with rituximab (Rituxan; Genentech) vs chemoimmunotherapy in patients 65 years or older with untreated CLL. In this 1:1:1 study, 547 patients were randomly assigned to receive chemoimmunotherapy with bendamustine and rituximab (BR), ibrutinib monotherapy, or ibrutinib plus rituximab (IR). Treatment was administered in 28-day cycles as follows11:
- Arm 1: The BR group received 6 cycles of bendamustine 90 mg/m2 on days 1 and 2 of each 28-day cycle plus rituximab 375 mg/m2 on day 0 of cycle 1 and then 500 mg/m2 on day 1 of cycles 2 through 6. Patients with disease progression could cross over to ibrutinib monotherapy within 1 year of progression.
- Arm 2: The ibrutinib monotherapy group was given 420 mg daily until unacceptable toxicity or disease progression.
- Arm 3: The IR group was administered ibrutinib as in arm 2 plus rituximab 375 mg/m2 weekly for 4 weeks starting on day 1 of cycle 2 and then on day 1 of cycles 3 through 6.
The median age of patients was 71 years (range, 65-89). Six percent of patients had del(17p), 19% had del(11q), 10% had a TP53 mutation, 29% had complex karyotype, and 61% had unmutated IGHV.11
The primary end point of PFS was assessed in the 524 patients who met eligibility criteria. The estimated 2-year PFS rate was 74% (95% CI, 66%-80%) in the BR arm, 87% (95% CI, 81%-92%) in the ibrutinib monotherapy arm, and 88% (95% CI, 81%-92%) in the IR arm. PFS was significantly improved with ibrutinib monotherapy vs BR (HR, 0.39; 95% CI, 0.26-0.58; 1-sided P < .001) and with IR vs BR (HR, 0.38; 95% CI, 0.25-0.59; 1-sided P < .001). However, no significant difference in PFS was seen between the IR group and the ibrutinib monotherapy group (HR, 1.00; 95% CI, 0.6-1.62; 1-sided P = .49). The PFS benefit in the ibrutinib arms was seen across all prespecified subgroups, including del(17p), del(11q), and modified Rai stage (intermediate vs high).11
At 2 years, the OS rate was 95% (95% CI, 91%-98%) with BR, 90% (95% CI, 85%-94%) with ibrutinib alone, and 94% (95% CI, 89%-97%) with IR, with no significant OS difference between the 3 arms (P ≥ .65 for all comparisons). The ORR was 81% with BR, 93% with ibrutinib alone, and 94% with IR.11
Grade 3 or greater hematologic AEs were more commonly observed in the BR group (61%) compared with the ibrutinib monotherapy (41%) and IR (39%) groups. Nonhematologic grade 3 or greater AEs occurred more often in the ibrutinib-containing arms than in the BR arm (74% vs 63%, respectively). Any-grade atrial fibrillation occurred in 3% of the BR group, 17% of the ibrutinib monotherapy group, and 14% of the IR group. Hypertension (grade ≥ 3) was seen in 14%, 29%, and 34%, respectively.11
Overall, the ibrutinib-containing treatment arms had a longer PFS compared with the BR arm, but there was no significant difference in OS between the 3 arms. The study results also showed that the addition of rituximab to ibrutinib did not significantly improve PFS.11
E1912 trial
The randomized, phase 3 E1912 trial (NCT02048813) compared IR to 6 cycles of the chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab (FCR),12 but unlike A041202, it enrolled patients younger than 70 years and did not include an ibrutinib monotherapy arm.
E1912 findings reported an improved PFS with IR vs FCR (HR, 0.35; 95% CI, 0.22-0.56; P < .001).12 This benefit was not seen in the initial results for the subgroup of patients with mutated IGHV (HR, 0.44; 95% CI, 0.14-1.36),12 but it was seen after long-term follow-up (HR, 0.27; 95% CI, 0.11-0.62; P < .001).13 Whereas the A041202 trial findings did not show an OS benefit when comparing ibrutinib monotherapy or IR with chemoimmunotherapy,11 the E1912 trial findings showed a sustained OS improvement in the IR group (HR, 0.47; 95% CI, 0.25-0.89; P = .018).13
Any-grade atrial fibrillation occurred in 7.4% of patients in the IR group compared with 3.2% of the FCR group. Hemorrhagic events (grade ≥ 3) were experienced in 1.1% of the IR group and in 0% of the FCR group.12
In an article published in Blood in 2022 about the long-term outcomes of the trial, Shanafelt et al wrote, “In conclusion, with a median follow-up of approximately 6 years, the long-term results of the E1912 trial continue to demonstrate superior PFS and OS for IR therapy relative to FCR in patients with mutated or unmutated IGHV.”13
Of note
Based on the results of these studies, ibrutinib established its place as a first-line oral agent for CLL. Because the addition of rituximab to ibrutinib did not provide a PFS or ORR benefit compared with ibrutinib monotherapy in the A041202 trial,11 the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology list the combination of ibrutinib and rituximab as a category 2B, other recommended regimen.3
Although improved outcomes were seen with ibrutinib compared with chemotherapy (RESONATE-2 trial) and with chemoimmunotherapy (A041202 and E1912 trials), significant toxicities with ibrutinib limit its long-term use.6 Because of the indefinite nature of BTKi therapy, ensuring tolerability and adherence is of paramount importance. In a real-world analysis of 616 patients with CLL treated with ibrutinib, at a median follow-up of 17 months, approximately 41% had discontinued ibrutinib.14 Ibrutinib toxicity was the most common reason for discontinuation in all settings, accounting for 63.1% and 50.2% of discontinuations in treatment-naive patients and patients with R/R disease, respectively.14 Toxicity is likely caused by off-target effects due to ibrutinib’s nonselective binding to other kinases,6 which led to greater interest in developing second-generation BTKis with reduced affinity for offtarget kinases.
Second-Generation BTKIs As Frontline Therapy
The second-generation BTKis acalabrutinib and zanubrutinib were FDA approved for CLL in 2019 and 2023, respectively,15,16 based on data from the following 2 landmark trials. These second-generation agents are more selective and exhibit fewer off-target effects than firstgeneration BTKi ibrutinib.17-19
ElevateTN trial
ElevateTN (NCT02475681) was a phase 3, randomized, open-label study of 535 patients with treatment-naive CLL that compared the efficacy and safety of acalabrutinib with or without obinutuzumab (Gazyva; Genentech) with chemoimmunotherapy. The results from this trial—along with those from the ASCEND trial (NCT02970318)—led to the FDA approval of acalabrutinib for adults with CLL or SLL.15
The trial’s primary end point was PFS. Enrolled patients were 65 years or older or those aged 18 to 64 years with specific comorbidities17 and were randomly assigned to 1 of 3 arms: acalabrutinib monotherapy, acalabrutinib plus obinutuzumab (A + O), or obinutuzumab plus chlorambucil (O + Clb). Treatment was administered in 28-day cycles as follows17:
- Patients in the acalabrutinib monotherapy group received twice-daily oral acalabrutinib 100 mg until unacceptable toxicity or disease progression.
- Patients in the A + O group received acalabrutinib as dosed above plus intravenous obinutuzumab 100 mg on day 1, 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15 of cycle 2 as well as 1000 mg on day 1 of cycles 3 through 7.
- Patients in the O + Clb arm were administered intravenous obinutuzumab 100 mg on day 1, 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15 of cycle 1 as well as 1000 mg on day 1 of cycles 2 though 6. They also received oral chlorambucil 0.5 mg/kg on days 1 and 15 of each cycle for 6 cycles. Crossover to acalabrutinib monotherapy was permitted for patients in this group who experienced disease progression.
Most patients had either high-risk or very high-risk CLL at 69% and 12%, respectively, including 9% with del(17p) and 11% with a TP53 mutation. IGHV was unmutated in 63% of patients.17
At a median follow-up of 28.3 months, the median PFS was not reached in the A + O arm and was 22.6 months in the O + Clb arm (HR, 0.10; 95% CI, 0.06-0.17; P < .0001), translating to a 90% reduced risk of disease progression or death in the A + O arm. Patients in the acalabrutinib monotherapy arm also had improved PFS vs patients in the O + Clb arm (HR, 0.20; 95% CI, 0.13-0.30; P < .0001). In subgroup analyses, the benefit seen with acalabrutinib monotherapy or A + O compared with O + Clb was consistent across all prespecified patient subgroups, including those with del(17p), mutated TP53, unmutated IGHV, and bulky disease. Updated results after a median follow-up of 58.2 months showed continued benefit from acalabrutinib monotherapy or A + O vs O + Clb, with the median PFS not reached with acalabrutinib monotherapy or A + O vs 27.8 months for O + Clb.18
The ORR at a median of 28.3 months was 94% for A + O, 86% for acalabrutinib monotherapy, and 79% for O + Clb.17 Complete response with or without bone marrow recovery was seen more frequently in patients receiving A + O (14%) compared with acalabrutinib monotherapy (1%) and O + Clb (5%),17 and it increased to 32%, 14%, and 14%, respectively, after 5 years of follow-up.18 At the 5-year update, median OS was not reached in any treatment arm and was significantly longer in the A + O arm compared with the O + Clb arm (HR, 0.55; P = .0474).18 Estimated 5-year OS rates in the A + O, acalabrutinib monotherapy, and O + Clb arms were 90%, 84%, and 82%, respectively.18
Grade 3 or greater AEs were experienced by 70.2%, 49.7%, and 69.8% of patients in the A + O, acalabrutinib monotherapy, and O + Clb arms, respectively. The most common grade 3 or greater AEs in all 3 groups were neutropenia (A + O: 29.8%; acalabrutinib: 9.5%; O + Clb: 41.4%), thrombocytopenia (8.4%, 2.8%, and 11.8%), and anemia (5.6%, 6.7%, and 7.1%). Among the obinutuzumab-containing arms, grade 3 or greater tumor lysis syndrome (TLS) and infusion-related reactions (IRRs) were more common in the O + Clb arm (TLS: 8%; IRRs: 5%) than in the A + O arm (TLS: 1%; IRRs: 2%).17
Any-grade atrial fibrillation occurred in 3%, 4%, and 1% of patients in the A + O, acalabrutinib monotherapy, and O + Clb arms, respectively.17 Bleeding AEs of any grade were more common in the acalabrutinib-containing arms (43% with A + O and 39% with acalabrutinib monotherapy vs 12% with O + Clb) and were most commonly contusions or petechiae.17 Grade 3 or greater infections occurred in 21% of patients receiving A + O, 14% of patients receiving acalabrutinib monotherapy, and 8% of patients receiving O + Clb.17 No new safety signals were seen in the 5-year follow-up.18
The ElevateTN trial findings showed superior efficacy with acalabrutinib-containing therapy compared with O + Clb, with the safety and tolerability of acalabrutinib consistent with its known profile. The investigators concluded, “After a 5-year follow-up, efficacy and safety of A + O and [acalabrutinib] monotherapy were maintained, with significantly longer OS in the A + O arm compared with O + Clb.”18
SEQUOIA trial
Zanubrutinib is the newest approved covalent BTKi, and its approval was based on data from the randomized, open-label, multicenter, phase 3 SEQUOIA study (NCT03336333) of 590 patients with untreated CLL.16,19 The study examined the clinical effectiveness and safety of zanubrutinib vs standard chemoimmunotherapy as frontline therapy.
Cohort 1 included patients without del(17p), but did allow patients with TP53 mutations. Patients in cohort 1 were randomly assigned 1:1 to receive either zanubrutinib 160 mg twice daily in 28-day cycles (group A: n = 241) or chemoimmunotherapy with BR (group B: n = 238). Patients in group B with disease progression could cross over to group A. Cohort 2 included patients with del(17p). Patients in cohort 2 all received treatment with zanubrutinib (group C: n = 111) because of the known inferiority of chemoimmunotherapy in this population.19
The median age for the total patient population was 70 years, with 24% of patients 75 years or older. In cohort 1, 29% of patients had Binet stage C disease and 30% had bulky disease. In cohort 2, 35% had Binet stage C disease and 40% had bulky disease. Of the patients with evaluable results, approximately 53% in cohort 1 and 60% in cohort 2 had unmutated IGHV status. Approximately 6% had mutated TP53 in cohort 1 and 43% in cohort 2.19
The trial met its primary end point (PFS in cohort 1). After a median follow-up of 26.2 months, the median PFS was not reached in group A or B of cohort 1. However, group A (zanubrutinib monotherapy) experienced a significantly longer PFS than group B (chemoimmunotherapy with BR) (HR, 0.42; 95% CI, 0.28-0.63; P < .0001). The 24-month PFS was 85.5% in group A vs 69.5% in group B. The PFS benefit with zanubrutinib compared with BR was observed regardless of age, Binet stage, and presence of bulky disease. However, the difference in PFS was not seen in patients with IGHV or TP53 mutation.19
The ORR was 94.6% in group A and 85.3% in group B. Median duration of response was not reached in group A and was 30.6 months in group B.19
The secondary end point of OS in groups A and B was not met (HR, 1.07; 95% CI, 0.51-2.22; P = .87). The median OS was not reached in group A or group B at the time of data cutoff, and the estimated 24-month OS was similar between the 2 groups (94.3% vs 94.6%, respectively).19
After a median follow-up of 30.5 months in group C, median PFS was not reached. The estimated 24-month PFS and OS rates were 88.9% and 93.6%, respectively, and ORR was 90%. Median duration of response was not reached.19
The overall incidence of grade 3 or greater AEs in groups A, B, and C were 53%, 80%, and 55%, respectively. The most common grade 3 or greater AE was neutropenia (11% in group A, 51% in group B, and 15% in group C). Grade 3 or greater infection occurred in 16% of patients in group A and 19% in group B. Any-grade atrial fibrillation was seen in 3% of patients in groups A and B and 4.5% in group C. Major bleeding events occurred in 5% of group A, 2% in group B, and 7% in group C.19
Ultimately, the SEQUOIA trial findings showed that zanubrutinib significantly improved PFS compared with BR chemoimmunotherapy and had a manageable safety profile. Patients with mutated TP53 also responded to zanubrutinib therapy.19 Findings from this trial further confirmed the superiority of BTKis compared with chemoimmunotherapy approaches.
Of note
Although findings from these 2 studies helped establish the role of second-generation covalent BTKis in CLL, comparisons between agents were limited to retrospective studies. Despite these limitations, the lower rates of cardiovascular AEs seen in findings from the ElevateTN and SEQUOIA trials vs the rates reported in findings from the RESONATE-2, A041202, and E1912 trials were promising.
Second-Generation BTKIs vs Ibrutinib in R/R CLL
The ELEVATE-RR and ALPINE trials were conducted with acalabrutinib and zanubrutinib, respectively, to prospectively compare the safety and efficacy of second-generation BTKis with ibrutinib.
ELEVATE-RR trial
The efficacy and safety of acalabrutinib compared with ibrutinib were evaluated in the randomized, multicenter, open-label, noninferiority, phase 3 ELEVATE-RR trial (NCT02477696). It enrolled 533 patients with previously treated CLL who had confirmed del(17p) and/or del(11q). Patients were randomly assigned 1:1 to receive acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until disease progression or toxicity.
Overall, the median age was 66 years (range, 28-89 years), with approximately 16.3% of patients 75 years or older. Approximately 49.7% of patients had Rai stage III or IV disease, 49.5% had bulky disease, 45.2% had del(17p), and 64.2% had del(11q). IGHV was unmutated in 82.1% of patients in the acalabrutinib arm and 89.4% of patients in the ibrutinib arm. The most common previous therapies were alkylating agents (90.4%), anti-CD20 monoclonal antibodies (85.6%), and purine analogues (61.9%). Both treatment arms had a median of 2 prior therapies (overall range, 1-12).20
At a median follow-up of 40.9 months, the primary end point of noninferiority with acalabrutinib in PFS was met, with a median PFS of 38.4 months in both the acalabrutinib (95% CI, 33.0-38.6) and ibrutinib arms (95% CI, 33.0-41.6; HR, 1.00; 95% CI, 0.79-1.27). The investigators noted that median PFS was “generally comparable” across prespecified subgroups and regardless of the number of prior therapies.20
OS was a secondary end point of the trial, and the median OS was not reached in either arm (HR, 0.82; 95% CI, 0.59-1.15). At the time of data cutoff, 63 deaths (23.5% of patients) had occurred with acalabrutinib vs 73 (27.5%) with ibrutinib. ORRs were similar between groups: 81% with acalabrutinib (95% CI, 75.8%-85.2%) and 77% with ibrutinib (95% CI, 71.5%-81.6%).20
The median duration of treatment exposure was 38.3 months with acalabrutinib and 35.5 months with ibrutinib, and the most common any-grade AEs differed by treatment arm. The acalabrutinib arm had a higher incidence of any-grade headache (34.6% vs 20.2% with ibrutinib) and cough (28.9% vs 21.3%). Conversely, ibrutinib had a higher incidence of any-grade diarrhea (46% vs 34.6% with acalabrutinib), arthralgia (22.8% vs 15.8%), hypertension (22.8% vs 8.6%), contusions (18.3% vs 11.7%), urinary tract infections (13.7% vs 8.3%), back pain (12.9% vs 7.5%), muscle spasms (13.3% vs 6%), and dyspepsia (12.2% vs 3.8%).20
The overall incidence of grade 3 or greater AEs was lower with acalabrutinib (68.8%) compared with ibrutinib (74.9%). Patients in the acalabrutinib arm also had lower rates of bleeding events vs patients in the ibrutinib arm (38% vs 51.3%, respectively) but had similar rates of major bleeding (4.5% vs 5.3%).20
Notably, significantly fewer incidences of any-grade atrial fibrillation (a secondary end point) were reported with acalabrutinib than with ibrutinib (9.4% vs 16.0%; P = .02), with acalabrutinib reducing the cumulative risk of atrial fibrillation by 48% (HR, 0.52; 95% CI, 0.32-0.86). Additionally, the median time to any-grade atrial fibrillation/atrial flutter was longer with acalabrutinib than with ibrutinib (28.8 vs 16.0 months). No patients in the acalabrutinib arm discontinued treatment due to atrial fibrillation vs 7 patients (2.7%) in the ibrutinib group.20
Acalabrutinib was “generally better tolerated” in patients with higher-risk R/R CLL, according to the investigators, with fewer patients on acalabrutinib requiring discontinuation of treatment due to AEs compared with ibrutinib (14.7% vs 21.3%, respectively).20
ALPINE trial
Zanubrutinib was similarly studied in a head-to-head trial vs ibrutinib. ALPINE (NCT03734016) was an open-label, randomized, phase 3 trial that compared the efficacy, safety, and tolerability of zanubrutinib with ibrutinib in 652 adult patients with R/R CLL. Patients who had previously received a BTKi were excluded.
Patients were randomly assigned 1:1 to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or toxicity. The median age of enrolled patients was 67 years. A total of 23% of patients had a TP53 mutation, del(17p), or both; 73% had unmutated IGHV; 27% had del(11q); and 19% had complex karyotype. The median number of prior lines of therapy was 1 (range, 1-12), with chemoimmunotherapy being the most common (80% in the zanubrutinib group and 76% in the ibrutinib group).21
The primary end point was ORR, which was higher in the zanubrutinib group (83.5%) than in the ibrutinib group (74.2%). ORR in prespecified subgroups (eg, those with del[17p], TP53 mutation, or both; those with unmutated IGHV) favored zanubrutinib. The duration of response was not reached in the zanubrutinib group compared with 33.9 months in the ibrutinib group.21
A key secondary end point was PFS, which was first assessed to determine whether zanubrutinib was noninferior to ibrutinib; when zanubrutinib’s noninferiority was established, the superiority of zanubrutinib was tested. At a median follow-up of 29.6 months, disease progression or death was lower with zanubrutinib compared with ibrutinib (87 vs 118 occurrences; HR, 0.65; 95% CI, 0.49-0.86), demonstrating superiority of zanubrutinib. Zanubrutinib was also found to improve 18-month and 24-month PFS compared with ibrutinib (83.3% vs 75%, respectively, at 18 months and 78.4% vs 65.9% at 24 months). Median PFS was not reached with zanubrutinib and was 34.2 months with ibrutinib. Similar to the ORR benefit, the PFS benefit was also seen across high-risk subgroups.21
The median duration of treatment was 28.4 months with zanubrutinib and 24.3 months with ibrutinib. The most common any-grade AEs were COVID-19 (23.1% with zanubrutinib vs 17.9% with ibrutinib), neutropenia (22.8% vs 18.2%), hypertension (21.9% vs 19.8%), diarrhea (16% vs 24.1%), anemia (15.1% vs 15.7%), arthralgias (14.5% vs 16.4%), and thrombocytopenia (13% vs 15.4%). A higher proportion of patients treated with ibrutinib developed any-grade atrial fibrillation (13.3%) compared with those treated with zanubrutinib (5.2%), and the rate of hemorrhagic events was similar between the 2 arms (approximately 42%), with major hemorrhage in 4% of patients.21
Fewer deaths occurred in the zanubrutinib arm compared with the ibrutinib arm (48 vs 60, respectively), but OS was not different between the 2 arms (HR for death, 0.76; 95% CI, 0.51-1.11) despite the 29.6-month follow-up, prompting investigators to note, “Longer follow-up is warranted to determine any differences between the treatments with respect to survival.”21
Of note
Due to the improved outcomes with acalabrutinib and zanubrutinib vs ibrutinib demonstrated in findings from these trials, acalabrutinib and zanubrutinib are recommended in the NCCN guidelines as category 1, preferred treatment options for first- or second-line therapy, whereas ibrutinib is a category 1, other recommended regimen.3
Considerations in the Selection of BTKI Therapy
In general, second-generation BTKis are preferred over ibrutinib based on results from the ELEVATE-RR and ALPINE studies. Although both trials were conducted in R/R CLL, the favorable toxicity profiles of acalabrutinib and zanubrutinib support their designation as preferred options for first-line therapy in the NCCN guidelines.
Zanubrutinib and acalabrutinib have not been compared head-to-head prospectively, but a matched-adjusted indirect comparison (MAIC) between the 2 agents suggests similar efficacy and incidence of AEs. Acalabrutinib, however, demonstrated a lower risk of grade 3 or greater hypertension, any-grade hemorrhage, and dose reduction due to AEs. Given the unmeasurable extent of bias with MAICs and unobserved variables or variables reportedby only 1 study, Kittai et al noted that the “limitations of MAIC analyses mean these results should be seen as hypothesis generating” and should be confirmed with prospective trials.22
Therefore, when choosing a BTKi for initial therapy, it is prudent to consider the patient’s comorbid conditions and the toxicity profile of each BTKi. For instance, in patients with atrial fibrillation, acalabrutinib or zanubrutinib may be preferred due to the lower rates of atrial fibrillation seen in findings from the ELEVATE-RR and ALPINE studies, respectively.20,21 For those with hypertension, acalabrutinib may be preferred because it demonstrated a lower rate of hypertension vs ibrutinib in the ELEVATE-RR trial findings20 and because zanubrutinib had a similar rate of hypertension compared with ibrutinib in the ALPINE trial findings.21 And for patients who have frequent headaches, acalabrutinib may exacerbate the frequency and/or severity.20
For patients who require anticoagulation, use caution with all BTKis. Minor bleeding happened more frequently with ibrutinib (51.3%) than acalabrutinib (38%) in the ELEVATE-RR trial findings,20 similar to zanubrutinib in the ALPINE trial findings (42% in both groups),21 whereas major bleeding was rare in findings from both studies (≤ 5%).20,21 However, the inherent bleed risk is present regardless of the BTKi chosen. In findings from all recent BTKi studies, patients receiving warfarin were excluded due to the increased risk of major hemorrhage seen in findings from early ibrutinib studies3; therefore, BTKi therapy is not recommended for patients on warfarin.
Regarding anticoagulation in general and BTKi therapy, in findings from a retrospective study examining 64 patient exposures to ibrutinib and anticoagulation with either direct oral anticoagulants or low–molecular weight heparin, major bleeding was seen in 8% of exposures, higher than what has been reported in findings from other ibrutinib studies.23 The anticoagulation agents used were apixaban (n = 35, Eliquis; Bristol Myers Squibb), rivaroxaban (n = 17, Xarelto; Janssen Biotech, Inc), enoxaparin (n = 10, Lovenox; Winthrop US), and dabigatran (n = 2, Pradaxa; Boehringer Ingelheim). The highest rate of major bleeding was seen with rivaroxaban (18%), followed by apixaban (6%).23 No patient exposures to enoxaparin resulted in major bleeding events.23 Thirty-eight percent of patient exposures were to concomitant antiplatelet therapy with anticoagulation, with major bleeding occurring with 1 exposure (4%).23 Thus, although anticoagulation is not a contraindication to BTKi therapy, caution is warranted.24
Patients should also be instructed to avoid OTC medications or supplements that may further increase bleed risk, such as fish oil, vitamin E, and frequent use of nonsteroidal anti-inflammatory medications.24 For patients requiring dual antiplatelet therapy, it is recommended to consider alternative CLL treatment options.24 Other practical considerations for choosing between covalent BTKis include dosing frequency, pill burden, and drug interactions (Table).
About the Authors
Richa Shah, PharmD, BCOP, is a leukemia clinical pharmacy specialist at Memorial Sloan Kettering Cancer Center in New York, New York.
Rebecca Pokorny, PharmD, BCPS, BCOP, is a neuro-oncology clinical pharmacy specialist at Vanderbilt University Medical Center in Nashville, Tennessee.
Luisa Giannangelo, MBA, RPh, is a pharmacist and medical writer in High Point, North Carolina.
Cradesha Perry, PharmD, MBA, works as a science writer at Rose Li & Associates, Inc, a professional services firm located in Chevy Chase, Maryland.
Adina Kagan is a class of 2025 PharmD candidate at Touro College of Pharmacy in New York, New York.
Yuxi Lei is a class of 2024 PharmD candidate at Rutgers University Ernest Mario School of Pharmacy in Piscataway, New Jersey.
Rezarta Lako, PharmD, BCPS, is a board-certified clinical pharmacist at Strong Memorial Hospital at University of Rochester Medical Center in New York, with experience in inpatient, ambulatory, and specialty pharmacy services.
Jessie Modlin, PharmD, BCOP, is a clinical oncology pharmacist at St Luke’s Cancer Institute in Boise, Idaho.
Kevin Pang, PharmD, is a pharmacist at Cooper University Hospital in Camden, New Jersey, and is the manager of a clinical stage authoring group.
Conclusion
The advent of BTKis revolutionized CLL treatment, including for patients with high-risk features. Since the approval of ibrutinib, second-generation BTKis acalabrutinib and zanubrutinib have further improved outcomes compared with chemoimmunotherapy.
Acalabrutinib and zanubrutinib were shown to have similar efficacy compared with ibrutinib in findings from the ELEVATE-RR20 and ALPINE21 trials, respectively, with zanubrutinib also showing improved PFS.21 This, along with the improved tolerability of second-generation BTKis compared with ibrutinib,20,21 supports the preferential use of acalabrutinib and zanubrutinib in the frontline setting.
Although great advances have been made, disease progression may still occur with covalent BTKis due to the development of resistance, necessitating additional therapeutic options. Novel therapies that are emerging as potential treatments for CLL include noncovalent BTKis, doublet and triplet regimens, BTK degraders, and chimeric antigen receptor T-cell therapy.
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The authors have no disclosures.
