Chronic Lymphocytic Leukemia: A Review of Noncovalent BTK Inhibitors, Novel Agents, and Toxicity Management of BTK Inhibitors

Précis

This article discusses clinical data for noncovalent Bruton tyrosine kinase inhibitors (BTKis), novel strategies in chronic lymphocytic leukemia (CLL), and the practical management of BTKi toxicities.

Preamble

This article reviews the clinical data for noncovalent BTKis in CLL, BTK degraders, combination therapy, and other novel agents currently being studied in CLL. A review of BTKi toxicity management is also included. An article that discussed covalent BTKis in CLL and considerations when choosing between agents was published in the June 2024 edition of Pharmacy Practice in Focus: Oncology.

Introduction

The treatment landscape of chronic lymphocytic leukemia (CLL) has substantially changed with a greater understanding of the B-cell receptor pathway, specifically Bruton tyrosine kinase (BTK). BTK activation leads to increased production of transcription factors necessary for B-cell proliferation, differentiation, and survival.¹ BTK is also involved in B-cell migration and adhesion receptor signaling. The first-generation BTK inhibitor (BTKi) ibrutinib (Imbruvica; Janssen Biotech, Inc and Pharmacyclics LLC) has shown significantly improved survival outcomes in treatment-naive and relapsed/refractory (R/R) CLL in data across numerous clinical studies comparing ibrutinib with chemoimmunotherapy.^2-5 Although the survival benefits of ibrutinib were evident across all studied age groups in adults, numerous safety concerns were reported in clinical trials, including atrial fibrillation, bleeding, and infections.⁶

Second-generation BTKis with increased affinity for BTK were researched and subsequently approved in both treatment-naive and R/R CLL. Similarly, the survival benefits were apparent with acalabrutinib (Calquence; AstraZeneca Pharmaceuticals LP) and zanubrutinib (Brukinsa; BeiGene USA, Inc) vs chemoimmunotherapy.^7-9 Furthermore, data from head-to-head studies evaluating the progression-free survival (PFS) of second-generation BTKis vs ibrutinib reported noninferiority with acalabrutinib and superiority with zanubrutinib.^10,11 Safety outcomes were additionally improved, with second-generation BTKis demonstrating a reduced incidence of adverse events (AEs), including cardiovascular and bleeding events, vs ibrutinib.

Despite the improvements in efficacy and safety outcomes with first- and second-generation BTKis, some patients progress while on continuous therapy due to acquired resistance. Ibrutinib, acalabrutinib, and zanubrutinib are covalent BTKis that irreversibly bind to the C481 residue of BTK and block the ATP-binding pocket, preventing activation.^12,13 Patients can develop acquired resistance mutations to BTKis, most commonly a cysteine-to-serine mutation at position 481 (C481S), which can impair drug binding.¹² Additionally, mutations in the PLCG2 gene have been shown to confer resistance to BTKis by allowing B-cell proliferation independent of the BTK pathway.¹² The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology state BTK and/or PLCG2 mutation testing may be helpful in patients with disease progression or refractoriness while on BTKi therapy and do not recommend routine testing or therapy changes based on mutation results alone in patients who do not have evidence of progression.¹⁴ Noncovalent BTKis have been explored recently as pharmacologic agents able to overcome resistance that occurs as a result of BTK C481 mutations because these drugs do not require binding to the C481 residue. For this reason, some noncovalent BTKis have shown promise in wild-type and mutant BTK.¹³
There are numerous developments in the treatment of R/R CLL involving covalent BTKis with additional systemic therapies and monotherapy with noncovalent BTKis. In the current state, BTKi therapy is given continuously and therefore, the management of toxicities associated with this drug class is a particular topic of interest for clinicians. This review aims to highlight the clinical data supporting novel combination regimens and noncovalent BTKis while providing insights into the toxicity profile of BTKis.

Noncovalent BTKis

Although primary resistance to BTKis is rare, secondary resistance can develop, most commonly due to acquisition of the C481S or PLCG2 mutation.^12,13 The C481S mutation affects the ability of BTKis to covalently bind to the cysteine binding site and has been reported in patients treated with ibrutinib, acalabrutinib, and zanubrutinib. Noncovalent agents reversibly inhibit BTK through alternative mechanisms and can therefore overcome C481 mutational resistance.¹⁵ Pirtobrutinib (Jaypirca; Eli Lilly and Company) is currently the only commercially available noncovalent BTKi. It exerts its action by blocking the ATP binding site of BTK with over 300-fold selectivity for BTK compared with 98% of other kinases.¹⁶ Nemtabrutinib (MK-1026; Merck & Co, Inc) is currently under investigation and forms hydrogen bonds with glutamic acid at position 475 and tyrosine at position 476, with additional activity against SRC and ERK signaling kinases.¹⁶

Pirtobrutinib

The BRUIN phase 1/2 study (NCT03740529) was a multicenter, open-label trial that assessed the safety and efficacy of pirtobrutinib in 323 patients with refractory B-cell malignancies.¹⁵ In phase 1, 203 patients were enrolled in a traditional 3+3 dose escalation design and received daily pirtobrutinib in 28-day cycles across 7 dose levels: 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg. Therapy continued until disease progression, unacceptable toxicity, or study withdrawal. In phase 2, 120 patients were allocated into 6 cohorts based on malignancy type, previous therapies, and BTK mutation status. The recommended dose for the phase 2 study was 200 mg (determined by phase 1 study results).

The median age of the total patient population was 68 years; 52.6% of the overall population had CLL or small lymphocytic lymphoma (SLL), 18.9% had mantle cell lymphoma, 8% had Waldenström macroglobulinemia, and 20.4% had other types of B-cell lymphomas. In the CLL or SLL subgroup, 86% of patients had received previous BTKi therapy, 82% had received prior chemotherapy, and 34% had received the BCL2 inhibitor venetoclax (Venclexta; AbbVie Inc), with a median of 3 prior lines of therapy. Prior BTKi therapy was discontinued due to disease progression as defined by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) in 71% of patients and due to toxicity or another reason in the remaining 29%. In patients with CLL who were evaluable for cytogenetic and molecular features, 71 of 81 evaluable patients (88%) had unmutated IGHV, 27 of 91 patients (30%) had mutated TP53, and 20 of 81 patients (25%) had deletion 17p (del[17p]). Additionally, 27% had a BTK C481 mutation.

The primary end point for the phase 1 study was to establish a maximum tolerated dose and phase 2 dose recommendation.¹⁵ Dose-limiting toxicities were not observed and thus the maximum tolerated dose was not established. Selection of the 200-mg dose was determined with pharmacokinetic data that corresponded with 96% target inhibition.

The primary end point for the phase 2 study was overall response rate (ORR).¹⁵ In 139 CLL or SLL patients, ORR was 63% (95% CI, 55%-71%). In those pretreated with BTKi therapy, the ORR was similar (62%; 95% CI, 53%-71%). ORR was similar between patients with resistance and those with intolerance to previous BTKi therapy (67% and 52%, respectively). Patients with a BTK C481 mutation had an ORR of 71% whereas those with BTK wild-type had an ORR of 66%. The ORR was 79% in high-risk patients with del(17p) or a TP53 mutation or both. Of the 88 patients with CLL or SLL who responded to pirtobrutinib therapy, all but 4 remained progression free at the time of data cutoff after a median follow-up of 6 months.

Secondary end points included safety, tolerability, and PFS.¹⁵ The most common AEs observed in at least 10% of the safety population were fatigue (20%), diarrhea (17%), and contusion (13%). Neutropenia was the most common grade 3 or greater AE, reported in 10% of patients. Arrhythmia was reported in 2 patients (< 1%). Grade 3 hemorrhage was observed in 1 patient in the setting of mechanical trauma. Permanent discontinuation due to drug-related AEs was observed in 5 patients (1%).

Longer follow-up results from the BRUIN study were recently published and included additional patients with R/R CLL/SLL.¹⁷ An updated efficacy analysis was conducted in 247 patients who had previously received a BTKi and enrolled in both phase 1 (n = 86) and phase 2 (n = 161) of the BRUIN study, with 85% receiving at least 1 recommended dose of pirtobrutinib at 200 mg once daily. The median age was 69 years. Bulky disease measuring 5 cm or greater was present in 32% of patients, 53% of patients had Rai stage 0 to II disease, and 41.3% had Rai stage III to IV disease. Similar to the earlier analysis, patients had received a median of 3 (range, 1-11) previous therapies. The most common prior therapies were anti-CD20 monoclonal antibodies (87.9%), chemotherapy (78.9%), BCL2 inhibitors (40.5%), and PI3K inhibitors (18.2%). Most patients discontinued previous BTKi therapy due to disease progression per iwCLL (76.9%). Toxicity or other reasons (not specified) was the reason for discontinuation in 23.1%. Additionally, 84% of patients had unmutated IGHV, 39% had mutated TP53, 29% had del(17p), and 42% had a complex karyotype; 37.8% of patients had a BTK C481 mutation.

The primary end point of ORR in patients previously treated with a BTKi was 73% (95% CI, 67%-79%), and increased to 82% (95% CI, 77%-87%) when patients with partial response with lymphocytosis were included.17 Notably, ORR was similar across most subgroups with the exception of those harboring a PLCG2 mutation. Patients with a PLCG2 mutation had a numerically lower ORR (56%) compared with other subgroups (range, 77%-95%).

Secondary efficacy end points included PFS and overall survival (OS).¹⁷ At a median follow-up of 19.4 months, the median PFS was 19.6 months (95% CI, 17-22). In patients who had received prior BTKi, BCL2 inhibitors, PI3K inhibitors, and chemoimmunotherapy, median PFS was 13.8 months (95% CI, 10.3-not estimable). In patients with a BTK C481 mutation, median PFS was 18.2 months (95% CI, 13.9-22.1) vs 17.5 months (95% CI, 10.7-20) in those without the mutation. Median PFS was 16.9 months (95% CI, 13.8-19.6) in patients with del(17p) or a TP53 mutation compared with 22.3 months (95% CI, 18.4-27.4) in those without these genetic markers. The 18-month OS in the overall population was 81% (95% CI, 75%-85%) at a median follow-up of 22.6 months. Safety data were reported among all 317 CLL/SLL patients who received pirtobrutinib with a median duration of treatment of 16.5 months.¹⁷ The most common AEs were infections (71%), bleeding (43%), and neutropenia (33%). AEs of special interest include hypertension (14%), major hemorrhage (21%), and atrial fibrillation or flutter (4%). Further, 12 patients died while receiving pirtobrutinib due to infection or infection-related complications and 4 died due to other causes. Dose reductions due to treatment-related AEs were reported in 5% of patients, with permanent discontinuation of pirtobrutinib in 3%.

Pirtobrutinib was granted accelerated approval by the FDA in CLL/SLL in patients who have received at least 2 prior lines of therapy including a BTKi and a BCL2 inhibitor based on results from the BRUIN phase 1/2 study.¹⁸ In addition to the third-line setting, NCCN guidelines include pirtobrutinib as a therapeutic option in the second-line setting after resistance or intolerance to prior covalent BTKi therapy in certain circumstances.¹⁴

Nemtabrutinib

The safety and efficacy of nemtabrutinib are being evaluated in the ongoing open-label, single-arm, phase 1/2 BELLWAVE-001 study (NCT03162536).¹⁹ In the interim analysis, 112 patients were enrolled, 57 of whom had CLL/SLL. All patients received nemtabrutinib at 65 mg daily. Of the patients with CLL, the median age was 66 years, 95% received prior BTKi therapy, and 42% received prior BTKi and BCL2 inhibitor therapy; 63% of patients had a BTK C481 mutation, 32% had mutated TP53, 33% had del(17p), and 53% had unmutated IGHV.

The median follow-up for patients with CLL was 8.1 months. An objective response was seen in 32 patients, conferring an ORR of 56% (95% CI, 42%-69%).¹⁹ In responders, the median duration of response (DOR) was 24.4 months and median PFS was 26.3 months. In patients with prior BTK and BCL2 inhibitor therapy, the ORR was 58%, median DOR was 8.5 months, and median PFS was 10.1 months. In those with a BTK C481 mutation, the ORR was 58%, median DOR was 24.4 months, and median PFS was 26.3 months. Patients with del(17p) had an ORR of 53%, a median DOR of 11.2 months, and a median PFS of 10.1 months. Lastly, patients with unmutated IGHV had an ORR of 50%, a median DOR of 24.4 months, and a median PFS of 15.9 months.

In all 112 patients enrolled, the most common anygrade AEs were dysgeusia (21%), decreased neutrophils (20%), fatigue (13%), nausea (12%), decreased platelets (12%), diarrhea (10%), and hypertension (10%).19 The most common grade 3 or greater AEs were decreased neutrophils (17%), decreased platelets (5%), and lymphocytosis (5%).

The ongoing BELLWAVE-008 phase 3 trial (NCT05624554) will compare nemtabrutinib with chemoimmunotherapy as first-line therapy in patients without TP53 mutations. Additionally, the BELLWAVE-011 trial (NCT06136559) will compare nemtabrutinib with investigator’s choice of acalabrutinib or ibrutinib in the frontline setting, and the BELLWAVE-010 trial (NCT05947851) will compare nemtabrutinib plus venetoclax with rituximab (Rituxan; Genentech, Inc) plus venetoclax in the second-line setting.

BTKi Plus Venetoclax Combinations

Although BTKis have been established as the standard of care for treatment-naive CLL due to response and survival benefits over chemoimmunotherapy, a major point of consideration is the indefinite nature of BTKi therapy. Another category 1 recommended frontline therapeutic option per NCCN guidelines is the combination of the BCL2 inhibitor venetoclax with the anti-CD20 monoclonal antibody obinutuzumab.¹⁴ With this regimen, treatment consists of twelve 28-day cycles followed by an active surveillance period and has been shown to elicit deep, durable responses, which may be predicted based on undetectable minimal residual disease (MRD).^20,21 Venetoclax plus obinutuzumab is particularly an attractive option in patients who desire time-limited therapy. The combination of ibrutinib and venetoclax was found to have a synergistic effect in data from preclinical studies, likely due to BTKi mobilization of CLL cells into the peripheral blood and increased dependence of CLL cells on BCL2 for proliferation.21 The combination of a BTKi and venetoclax may provide the first all-oral, time-limited therapeutic option.²²

The CAPTIVATE trial (NCT02910583) was a phase 2, open-label, single-arm study of adult patients 70 years or younger with previously untreated CLL.^1,21 Patients received 3 cycles of ibrutinib 420 mg daily as a lead-in followed by twelve 28-day cycles of ibrutinib 420 mg daily plus venetoclax. The dosage of venetoclax was initiated at 20 mg and was ramped up over 5 weeks to a target dose of 400 mg daily as currently approved by the FDA for CLL/SLL. The study included 2 separate cohorts: MRD-guided randomized treatment discontinuation and fixed duration (FD).

The MRD cohort consisted of 164 patients.²¹ Patients with undetectable MRD, which was measured with 8-color flow cytometry with a detection sensitivity of 10–4, confirmed on 2 assessments at least 3 months apart after completion of ibrutinib and venetoclax (n = 86) were randomly assigned 1:1 to placebo or ibrutinib, and those with detectable MRD (n = 63) were randomly assigned 1:1 to ibrutinib or ibrutinib and venetoclax. The maximum overall duration of venetoclax was 2 years. The median age was 58 years. Bulky disease was present in 35% of patients, 20% had either del(17p) or a TP53 mutation, and 60% had unmutated IGHV.

The primary end point in the MRD cohort was 1-year disease-free survival rates in those with undetectable MRD after randomization, which was 95% in the placebo arm vs 100% in the ibrutinib arm.¹ The secondary end point of ORR in the overall population was achieved in 97% (95% CI, 93-99), with complete response (CR) or CR with incomplete hematologic recovery (CRi) in 46%. The 30-month PFS rates were 95% and 100% in the placebo and ibrutinib arms, respectively. In those who had detectable MRD, 30-month PFS rates were 95% in the ibrutinib alone arm and 97% in the ibrutinib and venetoclax arm. After patients with detectable MRD were randomly assigned, rates of MRD negativity increased from 32% to 42% via bone marrow assessment for the ibrutinib arm and remained at 45% when assessed via peripheral blood. For those randomly assigned to ibrutinib and venetoclax, rates of MRD negativity increased from 50% to 69% via peripheral blood and 31% to 66% via bone marrow assessment.

The FD cohort consisted of 159 patients.²¹ All patients received 3 cycles of ibrutinib lead-in followed by ibrutinib and venetoclax. If patients had progressive disease after completing the regimen, they could be re-treated with ibrutinib with or without venetoclax. The median age of the patients was 60 years. Bulky disease was present in 33% of patients, 17% had del(17p) or mutated TP53, 56% had unmutated IGHV, and 19% had complex karyotype.

The primary end point in the FD cohort was CR rate, which was 55% (95% CI, 48%-63%) in the overall population.²¹ In patients with either del(17p) or a TP53 mutation, the CR rate was 56% (95% CI, 37%-74%). The ORR was 96% in the overall population, which was the same in those with del(17p) or mutated TP53. Those with nonbulky disease had higher CR rates than those with bulky disease of 5 cm or greater (66% vs 31%). Those with unmutated IGHV also had higher CR rates than those with mutated IGHV (62% vs 47%).

MRD was undetectable in 77% of all patients when assessed via peripheral blood and in 60% in the bone marrow.²¹ In the population with del(17p) or a TP53 mutation, MRD negativity rates were 81% and 41% in the peripheral blood and bone marrow, respectively. Rates of unmeasurable MRD in the bone marrow were similar across other evaluable subgroups, including those with bulky disease, unmutated IGHV, and those who were 65 years or older. An additional secondary end point was 24-month PFS, which was 95% in the overall population and 84% in those with del(17p) or a TP53 mutation.

The most common grade 3 or greater toxicities in both studies were neutropenia (35% in MRD and 33% in FD), hypertension (8% in MRD and 6% in FD), thrombocytopenia (5% in MRD and 13% in FD), and diarrhea (5% in MRD and 3% in FD).^1,21 Atrial fibrillation was seen in 7% of the MRD cohort (grade ≥ 3: 2%) and 4% of the FD cohort (grade ≥ 3: 1%). No clinical tumor lysis syndrome was seen in either study.

The combination of BCL2 inhibitors and BTKis show promising efficacy with a favorable safety profile and may allow for an additional time-limited therapeutic option in patients with CLL after data from further studies confirm these results. The use of MRD-directed therapy may provide clinicians with a potential monitoring tool to allow them to maximize efficacy and limit toxicity of this doublet therapy.

Management of BTKi Toxicities

The AE profile of BTKis has been linked to their on-target effects on BTK as well as off-target effects on various kinases including tyrosine-protein kinase (Tec), EGFR, and interleukin-2-inducible T-cell kinase.²³ In a post hoc analysis of 358 patients from the ELEVATE-TN study (NCT02475681), which compared acalabrutinib with or without obinutuzumab to chlorambucil with obinutuzumab, data showed that patients who discontinued acalabrutinib within the first year (13%) had inferior survival compared with the 75% of acalabrutinib-treated patients who did not require dose reductions or interruptions for more than 14 days (HR, 8.39; 95% CI, 3.96-17.8).²⁴ Those who had dose reductions or interruptions for more than 14 days but did not discontinue therapy (12%) had a similar survival to those who did not require dose reductions or interruptions. The most common reason for treatment discontinuation in this analysis was AEs. Given the current indefinite nature of BTKi therapy and frequency of adverse effects experienced in clinical trials (Table), it is of paramount importance to ensure that patients, caregivers, and the health care team are aware of BTKi-associated AEs and how to manage them. Pharmacists specifically can play a vital role in managing patients with CLL through patient education and toxicity management.

Cardiovascular Toxicity

BTKis are known to cause cardiac events. The first-generation BTKi ibrutinib has been shown in data from clinical studies to cause fatal and serious cardiac arrhythmias and cardiac failure. Grade 3 or greater ventricular tachyarrhythmias were reported in 0.2% of 4896 patients who received ibrutinib in clinical trials; grade 3 or greater atrial fibrillation was reported in 3.7% of patients and grade 3 or greater cardiac failure was reported in 1.3% of patients.25 Grade 1 or 2 atrial fibrillation was reported in 12% to 15% of patients. Older patients may be at higher risk of developing atrial fibrillation due to increased likelihood of comormid conditions at baseline.

The prevalence of grade 3 or greater atrial fibrillation was higher in the A041202 study (NCT01886872) in which the median age of patients was 71 years (6%) compared with the E1912 study (NCT02048813) in which the median age was 58 years (2.9%).^4,5 The prevalence of atrial fibrillation with ibrutinib was highest within 3 months of starting therapy.

In contrast with ibrutinib, second-generation BTKis have demonstrated improved cardiac safety profiles, likely due to reduced off-target effects. Data from the ALPINE study (NCT03734016) showed a reduced incidence of any-grade atrial fibrillation (5.2% vs 13.3%) and grade 3 or greater atrial fibrillation (2.5% vs 4.0%) with zanubrutinib compared with ibrutinib.¹¹ The ELEVATE-RR study (NCT02477696) reported a reduced incidence of any-grade atrial fibrillation with acalabrutinib compared with ibrutinib (9.4% vs 16.0%), although it should be noted that the incidence of grade 3 or greater atrial fibrillation was slightly higher (4.9% vs 3.8%).¹⁰

The mechanism of atrial fibrillation due to BTKi is unknown. It is hypothesized to be due to the PI3K-Akt pathway, which plays a major role in cardiac protection and is regulated by BTK and Tec.²⁶ Reduction in PI3K-Akt activity increased susceptibility of developing atrial fibrillation in animal models, and ibrutinib was found to significantly reduce PI3K-Akt activity in cardiac cells in animal myocytes.

Prior to initiating BTKi therapy, risk factors for the development of atrial fibrillation should be assessed. If atrial fibrillation develops, the BTKi may be continued at a reduced dose or interrupted until symptoms resolve, depending on severity.^27,28 Successful resumption of ibrutinib after atrial fibrillation has been reported and permanent discontinuation is often not required. In a retrospective study, more patients who discontinued ibrutinib after developing atrial fibrillation had disease progression compared with those who continued at full or reduced dose without interruption.²⁹ The rate of persistent atrial fibrillation was similar in those who continued on full compared with reduced dose. Additionally, as mentioned throughout this review, rates of atrial fibrillation are lower with acalabrutinib and zanubrutinib. In patients with disease control on ibrutinib who develop atrial fibrillation that is not medically controllable, clinicians can consider switching to acalabrutinib or zanubrutinib.¹⁴ In patients who develop atrial fibrillation while on BTKi therapy, rate control with β-blockers is the recommended treatment option given numerous drug-drug interactions.27 All available BTKis are major substrates of CYP3A4 and several rhythm control agents interact through this pathway. For example, agents such as diltiazem, verapamil, and amiodarone inhibit CYP3A4, and may increase ibrutinib toxicity. Additionally, depending on the patient’s thromboembolic risk per standard available models (eg, CHA2DS2-VASc), anticoagulation may be warranted.³⁰ This must be balanced with the increased risk of bleeding seen with BTKis. If anticoagulation is indicated, direct oral anticoagulants are preferred.³⁰ Warfarin should be avoided as there was an increased risk of major hemorrhage in early ibrutinib studies in patients receiving warfarin and thus these patients were excluded from all subsequent BTKi trials.³⁰

Bleeding

Fatal bleeding events have been reported in patients receiving ibrutinib, with major hemorrhage (grade ≥ 3 bleeding, serious bleeding, intracranial hemorrhage, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) occurring in 4.2% of patients and fatalities in 0.4% across 27 clinical trials involving 2838 patients. Bleeding events, including bruising and petechiae, occurred in 39%, and excluding these, in 23% of patients. Concomitant use of anticoagulant or antiplatelet agents with ibrutinib increases the risk of major hemorrhage. Major hemorrhage occurred in 3.1% of 2838 patients without these agents, increasing to 4.4% with antiplatelet therapy and to 6.1% with anticoagulant therapy.²³

Hemorrhagic events, including major hemorrhagic events, occurred with similar frequency among the patients in both the zanubrutinib group and ibrutinib group.¹¹ Acalabrutinib demonstrated a lower frequency of bleeding events (38.0%) compared with ibrutinib (51.3%). However, rates of major bleeding events were comparable between acalabrutinib (4.5%) and ibrutinib (5.3%).¹⁰

The mechanism of bleeding is complex and thought to be related to on- and off-target kinase inhibition.²⁷ BTK and other Tec family kinases help mediate collagen-induced platelet activation.²³ When inhibited, coagulation is impaired. Reduced platelet adhesion to von Willebrand factor–coated surfaces, which reduces platelet aggregation, has been observed in vitro.³¹ Management of bleeding depends on the severity. For minor bleeds, holding the BTKi for 2 or 3 days is reasonable.²³ As an added precaution, it is recommended to hold BTKis for 3 to 7 days pre- and post-procedures depending on the bleed risk.

Infection

The inherent disease state of CLL increases the risk of infection through dysregulation of the innate and adaptive immune system including T-cell dysfunction, impaired T-cell stimulation, reduced natural killer (NK) cell activity, and complement pathway dysfunction.³² Additionally, hypogammaglobulinemia is common in patients with CLL and may further increase the risk of infection. BTKis have also been demonstrated to decrease the function of T cells, NK cells, monocytes, and macrophages. Grade 3 or higher infections were reported in 21% of ibrutinib patients,²⁵ 19% of acalabrutinib patients,³³ 24% of zanubrutinib patients,³⁴ and 17% of pirtobrutinib patients,³⁵ with respiratory tract infections being the most common among all BTKis. Fungal infections have been rarely reported with ibrutinib,³⁶ acalabrutinib,³⁷ and zanubrutinib,³⁸ but if suspected, are most commonly attributed to Aspergillus species. Infection with Pneumocystis jirovecii pneumonia (PJP) occurs with an incidence ranging between 0% and 5.6% and thus the role of PJP prophylaxis is unclear.^39-41 Prior to initiating BTKi therapy, it is important to evaluate each patient’s risk of opportunistic infections. Prophylaxis against PJP and varicella zoster virus may be considered in patients deemed to be high risk. All patients should be screened for hepatitis B and HIV.³² A thorough vaccination history should be completed. Patients should receive vaccination against influenza, Streptococcus pneumoniae, herpes zoster, and COVID-19.¹⁴ Live vaccines should be avoided.

Other Toxicities

Additional BTKi AEs include headache, most commonly with acalabrutinib, which typically resolves with time on treatment and is responsive to caffeine. Rash may occur and is typically responsive to topical steroids with or without dose interruptions.²³ Arthralgias and myalgias are most commonly associated with ibrutinib but can be seen with any BTKi and may be difficult to manage. Changes to treatment may include dose reductions and/or dose holds for arthralgias or myalgias that affect activities of daily living. Autoimmune cytopenias, which occur in up to 10% of patients, are a manifestation of CLL and improve with CLL-directed therapy. Grade 3 or greater neutropenia occurred at a rate of 22% to 24% across clinical trials of all available BTKis.^25,33-35 Anemia and thrombocytopenia are less common. Lymphocytosis, a key feature of CLL, is also commonly seen after initiation of BTKi therapy and does not confer disease progression.⁴² This class effect is caused by reduced binding of CLL cells to adhesion molecules after exposure to BTKis and increased efflux from tissue compartments into peripheral blood, with no increased blood viscosity or risk of leukostasis.⁴³ The reported onset of lymphocytosis occurs within the first month of BTKi initiation with median time to resolution of 12 to 14 weeks.⁴²

Future Directions in the Treatment Landscape of CLL

The treatment landscape of CLL continues to expand with a focus on MRD-guided treatment strategies; novel combination regimens with BTKis, BCL2 inhibitors, and/or anti-CD20 monoclonal antibodies; and development of new pharmacologic drug classes such as BTK degraders and chimeric antigen receptor (CAR) T-cell therapy.

MRD negativity, defined as the presence of less than 1 CLL cell of 10,000 leukocytes (10–4) has been shown to predict outcomes in patients receiving chemoimmunotherapy.^44,45 Recent and ongoing clinical trials now often include MRD assessment to further elucidate the role of this monitoring parameter in clinical decision-making and the potential for time-limited therapy in CLL treatment.

Trials evaluating combining novel oral agents, such as second-generation BTKis and venetoclax, are underway. In addition to the CAPTIVATE trial involving ibrutinib, the phase 3 randomized MAJIC study (NCT05057494) will compare acalabrutinib plus venetoclax with venetoclax plus obinutuzumab (Gazyva; Genentech, Inc) as frontline therapy.⁴⁶

Time-limited triplet therapy using BTKis, venetoclax, and the CD20-targeting monoclonal antibody obinutuzumab is also being explored. Frontline ibrutinib with venetoclax and obinutuzumab (GIVe regimen) was evaluated in 41 patients with CLL with del(17p) and/or a TP53 mutation.⁴⁷ With a median follow-up of 38.4 months, 3-year PFS was 79.9% and 3-year OS was 92.6%. At final restaging (cycle 15), 78% and 65.9% of patients had undetectable MRD in the peripheral blood and bone marrow, respectively.⁴⁸ Notable grade 3 or greater AEs included neutropenia (48.8%), infection (19.5%), hypertension (4.9%), and atrial fibrillation (2.4%).⁴⁷ Additionally, a study (NCT03836261) of frontline acalabrutinib, venetoclax, and obinutuzumab vs acalabrutinib with venetoclax vs chemoimmunotherapy in patients without del(17p) or a TP53 mutation is ongoing.

The investigational agent NX-2127 is a BTK degrader that has been shown to degrade wild-type and C481-mutated BTK in high-risk (defined as presence of del[17p]) or standard-risk (defined as del[13p] only) CLL cells. A phase 1 clinical trial (NCT04830137) evaluating the safety and efficacy of NX-2127 in R/R B-cell malignancies, including CLL, after at least 2 prior lines of therapy is ongoing.

Lisocabtagene maraleucel (liso-cel), a CAR T-cell product, is being evaluated in patients with R/R CLL for whom BTKi and BCL2 inhibitor therapy was not successful. In the phase 1/2 TRANSCEND CLL 004 study (NCT03331198) of 117 patients with CLL who received liso-cel, 49 were treated with the dose level of 100 x 106 CAR T cells, of whom 9 patients (18%) achieved CR/CRi. In all 117 patients who received liso-cel, grade 3 cytokine release syndrome and neurologic events were seen in 9% and 18% of patients, respectively.⁴⁹ Liso-cel is currently FDA approved for use in R/R large-B cell lymphoma and was recently granted accelerated approval under priority review for R/R CLL.⁵⁰

Conclusion

Covalent and noncovalent BTKis have been studied in numerous clinical trials and have demonstrated clear survival benefits for patients with CLL. As worsened outcomes have been seen in patients who stop BTKi therapy due to toxicity, prompt identification and management of AEs is of paramount importance. In the frontline setting, the novel combination of ibrutinib with venetoclax has early clinical data suggesting that patients may further benefit from early therapy intensification, which may allow for time-limited treatment. In the R/R setting, new combinations and pharmacologic drug classes are being developed to further improve outcomes. Noncovalent BTKis, such as pirtobrutinib and nemtabrutinib, have demonstrated an alternative mechanism of action and can overcome resistance arising from BTK C481 mutations. Patients with advanced disease who have relapsed on covalent BTK inhibitors may now initiate pirtobrutinib therapy, although the pharmaceutical agent currently has accelerated approval and needs additional data to fully support its clinical utility. CAR T cells and BTK degraders may present as valuable pharmacologic classes for patients whose disease is refractory to or who have relapsed after currently available treatment options, with studies ongoing. Additional research is needed into the targetable biomarkers and pharmaceutical agents to further improve outcomes for patients with CLL.

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The authors have nothing to disclose.