Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Comparison
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Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Piotr Smolewski.

Chronic lymphocytic leukemia (CLL) is an indolent form of B-cell lymphoid malignancy that predominantly affects older individuals. Bruton’s tyrosine kinase (BTK) is a member of the TEC kinase family. It plays an important role in treatment of malignant B lymphocyte proliferation and improvement of survival of patients with CLL.

  • CLL
  • BTK
  • BTK inhibitors
  • ibrutinib
  • acalabrutinib
  • zanubrutinib
  • spebrutinib
  • tirabrutinib
  • orelabrutinib
  • TG-1701
  • DTRMWXHS-12
  • pirtobrutinib
  • vecabrutynib
  • fenebrutinib
  • nemtabrutinib

1. Introduction

Chronic lymphocytic leukemia (CLL) is an indolent form of B-cell lymphoproliferative disease, the most common type of leukemia in Western countries. It is predominantly diagnosed in older individuals, with a median age at diagnosis of 72 years [1][2]. It is the most common type of leukemia in Western countries, with a median age at diagnosis of 72 years. CLL is responsible for approximately 40% of all adult leukemias and 11% of all hematological malignancies. The incidence of the disease is 3.5 cases per 100,000 inhabitants per year [3]. In addition, the World Health Organization (WHO) also recognizes small lymphocytic lymphoma (SLL) as a disease entity. Its cells exhibit the same immunophenotype (CD5+/CD19+ and CD5+/CD23+) and morphology as in CLL but does not primarily involve the bone marrow; as such, small lymphocytic lymphoma (SLL) is classified as a combined lymphoproliferative disease, i.e., as SLL/CLL [4]. Consequently, many clinical trials have considered CLL and SLL in the same group of malignancies. In a recent study, relative survival improved significantly for CLL patients diagnosed between 1985 and 2015 [4]. However, despite these findings and recent changes in therapeutic strategies in CLL, the disease remains incurable in the majority of patients. Most of the patients will relapse sooner or later, and some will be resistant to the treatment available. Bruton’s tyrosine kinase (BTK) is a member of the TEC kinase family [5]. It plays an important role in malignant B lymphocyte proliferation and survival in CLL [6]. BTK inhibitors (BTKis) have become very important targets in the treatment of inflammatory reactions and autoimmune diseases, as well as of B-cell malignancies, including CLL. These agents have transformed CLL management in both previously untreated and relapsed/refractory (R/R) patients [7][8][9][10][11][12]. BTKis are classified into two categories: irreversible (covalent) inhibitors and reversible (non-covalent) inhibitors (Table 1) [13]. Ibrutinb, acalabrutinib, and zanubrutinib are irreversible BTKis, binding covalently to the Cys481 residue in the ATP binding pocket of BTK [14]. However, most patients develop resistance to treatment with currently approved BTKis, and novel therapies are urgently needed. Ibrutinib is a first-in-class, irreversible, oral, administrated once-daily BTKi approved for the treatment of CLL/SLL. As a single agent, ibrutinib has led to prolonged progression-free survival (PFS) and overall survival (OS) in patients with previously treated CLL [15]. Of the remaining irreversible BTKis, acalabrutinib and zanubrutinib are the most advanced in clinical trials. Both have been investigated in randomized clinical trials in CLL patients, some of which have made direct comparisons with ibrutinib [16][17].
Table 1. Irreversible and reversible Brutton tyrosine kinase inhibitors approved or in clinical trials in chronic lymphocytic leukemia.

BTKi

Binding

T1/2

[hours]

IC50 [nM]

Dosing

Clinical Trials in CLL

Ibrutinib

(PCYC-1102)

Covalent irreversible C481

4–8

0.5

420 mg

NCT04771507

NCT03513562

NCT02912754

Acalabrutinib

(ACP-196)

Covalent irreversible C481

0.9

5.1

100 mg

twice a day

NCT04008706

NCT04930536

NCT04722172

Zanubrutinib

(BGB-3111)

Covalent

irreversible C481

2–4

0.5

160 or 320 mg

twice a day

NCT04116437

NCT04458610

NCT03824483

NCT04282018

NCT04515238

NCT03336333

Spebrutinib

(CC-292)

Covalent irreversible C481

8–24

<0.5

1000 mg

NCT02031419

Tirabrutinib

(ONO/GS-4059)

Covalent irreversible C481

NA

5.6

80 mg

NCT03740529

NCT03162536

Orelabrutinib (ICP-022)

Covalent irreversible C481

~1.5–4 h

1.6

150 mg

NCT03493217

NCT04014205

SHR1459

(TG-1701)

Covalent irreversible C481

NA

3

300 mg

NCT03671590; NCT04806035

DTRMWXHS-12 (DTRM-12)

Covalent irreversible C481

~4

NA

200 mg

NCT02900716

NCT04305444

Pirtobrutinib

(LOXO-305)

Non-covalent reversible

NA

0.85

200 mg

NCT05023980

NCT04965493

NCT05024045

NCT04666038

Vecabrutinib

(SNS-062)

Non-covalent reversible

6.6-8

24

25 mg escalated to 500 mg

NCT03037645

Fenebrutinib

(GDC-0853)

Non-covalent reversible

2.2

0.91

200 mg twice a day

NCT01991184

Nemta

brutinib

(ARQ 531)

Non-covalent reversible

NA

0.85

65-100 mg

NCT04728893

NCT03162536

Abbreviations: BTKi—Bruton tyrosine kinase inhibitor, NA—not available.

2. Mechanism of Action

B-cell receptor (BCR) signaling is an essential component of the development and survival of normal and malignant B cells [18]. In a CLL-like mouse model, BTK deficiency significantly delayed development and reduced leukemia infiltration but still resulted in the development of lymphogenesis. In vivo BTK inhibition abolished tumor formation, while BTK overexpression increased cancer incidence and overall mortality [19].
The BCR signaling pathway includes several elements, the most important of which is BTK. This kinase consists of several regions, including the pleckstrin homology (PH) domain, the Tec homology (TH) domain, the Src homology (SH3) domain, the SH2 domain, and the C-terminal region with kinase activity. BCR signaling can be tonic or chronically activated. It is initiated by the antigen binding to the surface immunoglobulin, followed by autophosphorylation of the CD79A/CD79B heterodimer by kinases from Src family [20]. It has been also demonstrated that the Src kinase Lyn plays a pivotal role in the pathogenesis of CLL, mainly due to its constitutive phosphorylation. In CLL cells, constitutive phosphorylation of phospholipase C-γ2 (PLC-γ2), spleen tyrosine kinase (Syk), protein kinase C (PKC)-β, BTK, and phosphoinositide 3′-kinase (PI3K) resulted in the activation of the nuclear factor kappa B (NF-κB) pathway [21]. This process may interact with microenvironmental stimuli and thus initiate the maintenance of survival, proliferation, or migration of CLL cells [6][11]. Targeting the BCR pathway via the inhibition of BTK has evolved the treatment of some B-cell malignancies, including CLL. Most BTKis target the ATP binding site of BTK, which contains cysteine (C481), known to target several irreversible inhibitors. C481 in BTK can act as a nucleophile and form a covalent bond with the inhibitor.
BTKis are the most advanced targeted drugs in B-cell lymphoid malignancies. Their characteristics are presented in Table 1. The majority of currently approved BTKis are irreversible inhibitors. Three of them, ibrutinib, acalabrutinib, and zanubrutinib, have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of B cell neoplasms and graft-versus-host disease (GVHD).
These three approved BTKis have been found to demonstrate certain similarities. All irreversibly covalently bind to cysteine 481 in the ATP binding pocket of BTK. Biochemical binding kinetics indicate that ibrutinib is the most potent BTKi of the three, followed by zanubrutinib and acalabrutinib, but differences in biochemical potency were partially obscured in cellular assays using human peripheral blood mononuclear cells or human white blood cells (all below 10 nM). Of the three drugs, the highest selectivity and the lowest off-target ratio were demonstrated by acalabrutinib [22]. These observed differences will of course influence the dosage, efficacy, and side effects of their use in clinical practice. For example, when administered once a day, acalabrutinib had a shorter half-life than ibrutinib; in addition, twice-daily dosing yielded higher BTK load than once-daily dosing (95.3% vs. 87.6%). These results suggest that acalabrutinib requires two doses per 24 h [23]. Moreover, acalabrutinib was found to have an inhibitory effect on epidermal growth factor receptor (EGFR), which can be associated with rash and severe diarrhea [24]. Additionally, ibrutinib can trigger TEC kinase, which contributes to platelet dysfunction and increases the risk of bleeding [25]. BTKis can be combined with other targeted agents known to be active in CLL. They have demonstrated synergistic effects with anti-CD20 monoclonal antibodies in inducing apoptosis in tumor cells [26][27]. In addition, the combination of ibrutinib and a BCL-2 antagonist showed additive or more than additive cytotoxicity in vitro against CLL cells from patients treated with ibrutinib [28]. These findings suggest that combinations of BTKis, BCL-2 antagonists, and/or anti-CD20 monoclonal antibodies should be tested clinically against CLL to increase antileukemic efficacy and reduce the risk of acquired resistance. The mechanism of action of BTKis is summarized in Figure 1.
/media/item_content/202203/622eb8a389a1fcancers-14-00771-g001.png
Figure 1. Signaling pathways involved in the mechanisms of action of Bruton kinase inhibitors in chronic lymphocytic leukemia (CLL) cells. Abbreviations: AKT—protein kinase B, BCR—B-cell receptor, BLNK—B-cell linker protein BTK: Bruton’s tyrosine kinase, CTLA-4: cytotoxic T lymphocyte-associated antigen-4, C481—cysteine residue, CXCL12—C-X-C motif chemokine ligand 12, CXCR4—C-X-C chemokine receptor type 4, EGFR: epidermal growth factor receptor, ERK1/2—extracellular signal-regulated kinases 1 and 2, Gα, G β, Gϓ: G protein subunits, ITK—IL2-inducible T-cell kinase, Lyn—member of the Src kinase family, NF-κB—nuclear factor kappa B, PI3K—phosphoinositide 3-kinase, PLCG2—phospholipase gamma 2, PKCB—protein kinase C beta, PKCB: protein kinase C beta, PD-1—programmed death-ligand 1, PIP1, PIP2—phosphatidylinositols 1 and 2, Syk—spleen tyrosine kinase, TEC—tyrosine kinase expressed in hepatocellular carcinoma.

3. Irreversible Covalent BTK Inhibitors

3.1. Ibrutnib

Ibrutnib (PCYC-1102, Imbruvica®, Pharmacyclics LLC, Sunnyvale, CA, USA) was discovered in 2007 as an irreversible inhibitor for BTK [29]. The drug was approved by the FDA in 2013 for the treatment of mantle cell lymphoma (MCL) and in 2014 for R/R CLL. Subsequently, ibrutinib was approved for Waldenström’s macroglobulinemia (WM), GVHD, and marginal zone lymphoma (MZL). Ibrutinib binds to the cysteine 481 (C481) residue of BTK, irreversibly inhibiting phosphorylation of downstream kinases in the BCR signaling pathway and blocking B-cell activation. However, ibrutinib can also block other kinases, including EGFR, ErbB2, ITK, and TEC (Figure 1) [30]. Ibrutinib treatment can result in adverse events (AEs) such as bleeding and cardiac arrhythmia due to its off-target activity [31].

3.2. Acalabrutinib

Acalabrutinib (ACP-196, Calquence®, AstraZeneca Pharmaceuticals LP) is a novel second-generation oral, potent, highly selective, covalent BTKi, designed by Acerta Pharma. It is possible for acalabrutinib to covalently bind to the C481 residue in BTK via a reactive butinamide group. The new compound demonstrates different properties of ibrutinib, which reduce off-target binding: for example, acalabrutinib does not inhibit EGFR or ITK.

3.3. Zanubrutinib

Zanubrutinib (BGB-3111, Brukinsa®, BeiGene USA, Inc., San Mateo, CA, USA) is a next-generation irreversible inhibitor of BTK developed by BeiGene in 2012 for the treatment of B-cell malignancies [32][33][34][35][36]. It was designed to offer greater BTK occupancy and lower off-target inhibition of TEC- and EGFR-family kinases. Zanubrutinib demonstrates greater selectivity than ibrutinib for BTK compared to other receptor tyrosine kinases, which may result in a lower incidence of off-target toxicities and reduced severity [32][34]. Moreover, zanubrutinib is similar to acalabrutinib, with less activity on TEC and ITK [35]. Like ibrutinib, zanubrutinib forms H bonds with the residues of the E475 and M477 regions. The drug favorably alters the immune microenvironment by lowering the level of checkpoint molecules on suppressor cells and reducing the number of adhesion/homing receptors on B-cells [36].

3.4. Other Irreversible BTK Inhibitors

Several other irreversible BTKis have recently been developed and are under clinical investigation in lymphoid malignancies and autoimmune disorders. These include pebrutinib, evobrutinib, olmutinib, tirabrutinib, elsubrutinib (ABBV-105), and tolebrutinib (SAR 442168).

3.4.1. Spebrutinib

Similar to ibrutinib, spebrutinib (CC-292, AVL-292, Avila Therapeutics/Celgene) inhibits BTK activity by binding covalently with high affinity to the same cysteine 481 in BTK [37][38]. In preclinical studies, spebrutinib blocked BCR-dependent B-cell activation. In a first-in-human study performed in healthy volunteers, spebrutinib led to near-complete BTK occupancy for 8–24 h. Spebrutinibat doses up to 1000 mg/day were investigated in a phase 1 study in 84 patients with R/R CLL/SLL [39][40]. The patients included 21.4% with del(11q), 23.8% with del(17p), and 53.6% with unmutated IGVH. CC-292 was well tolerated, with two patients experiencing grade 4 thrombocytopenia, one patient with grade 3 drug-related pneumonitis, and one patient with grade 3 reversible mental-status changes. Common non-hematologic AEs of any grade were diarrhea (68%), fatigue (45%), nausea (35%), cough (27%), pyrexia (27%), and headache (25%). The median response duration was 11.0 months for the 750 mg once daily group and 5.6 months for the 1000 mg once daily, while this value was not yet reached for the 375 mg twice daily and 500 mg twice daily groups. This study indicates that spebrutinib was well tolerated and resulted in dose-dependent responses in R/R CLL/SLL patients, including those with high-risk cytogenetics. However, its clinical activity was lower than that observed in patients with ibrutinib or acalabrutinib.

3.4.2. Orelabrutinib

Orelabrutinib (ICP-022, Biogen/Innocare Pharma) is an orally available, second-generation BTKi being developed for the treatment of B cell malignancies and autoimmune diseases. In a KINOMEscan assay conducted in parallel against numerous kinases at a 1 μM drug concentration, Orelabrutinib was more selective than ibrutinib [41]. 2020 In this study, BTK was the only kinase targeted by orelabrutinib (with >90% inhibition). It is currently being investigated in clinical trials for lymphoid malignancies and autoimmune disorders [42][43]. In December 2020, orelabrutinib received initial approval in China for the treatment of patients with MCL and CLL/SLL who have received at least one prior treatment [43].

3.4.3. Tirabrutinib

Tirabrutinib ((Velexbru®, ONO/GS-4059, Ono Pharmaceutical, Gilead Sciences) is another very potent and specific BTKi targeting BTK C481. It demonstrates greater selectivity than ibrutinib. The drug demonstrated potent activity in patients with CLL/SLL. Walter et al. report the results of an initial phase 1 study involving 90 RR patients with various B-cell malignancies [44]. In the CLL group, 96% (24/25) of patients achieved objective responses within the first three months of therapy. Elsewhere, a Japanese study examined its safety, efficacy, pharmacokinetics, pharmacodynamics, and prognostic biomarkers in patients with R/R primary central nervous system lymphoma (PCNSL) [45]. The most common AE was found to be mild diarrhea, occurring in 18% of the cases. In the CLL cohort, 14.3% of patients experienced drug-related grade 3 or 4 AE, with the most common being hematological toxicity. Further studies of tirarutinib with other targeted drugs are ongoing [46].

3.4.4. SHR1459

SHR1459 (TG 1701, EBI-1459; Reistone Biopharma, Jiangsu Hengrui Medicine Co., Lianyungang, China) is a second-generation, covalently bound, and irreversible second-generation BTKi currently under clinical development. This agent has been found to demonstrate superior selectivity to BTK compared to ibrutinib in in vitro kinase screening [47]. SHR1459 therapy, alone or in combination with ublituximab and umbralisib, is currently under clinical development in phase 1 trial in patients with R/R mature B cell neoplasms or CLL (NCT03671590; NCT04806035) [48].

3.4.5. DTRMWXHS-12

DTRMWXHS-12 (DTRM-12) (NCT02900716) is a pyrazolo-pyrimidine derivative irreversible BTKi currently under phase 1 and phase 2 clinical trials for CLL and NHL [49]. DTRMWXHS-12, used alone and in combination with everolimus and pomalidomide, has yielded encouraging findings in several high-risk, multirefractory CLL and NHL patients, including those previously treated with ibrutinib, in simultaneous phase I studies [50]. DTRM-12 monotherapy was well tolerated across B cell malignancies and CLL in both studies. No dose-limiting toxicity (DLT) was observed, and MTD was not identified. PK studies demonstrate adequate target drug exposures at all dose levels. A phase II expansion cohort study of DTRMWXHS-12 in combination with everolimus and pomalidomide in patients with refractory or relapsed CLL and NHL is ongoing (NCT04305444).

4. Reversible BTK Inhibitors

Reversible BTKis, such as pirtobrutinib and vecabrutinib, bind BTK non-covalently and do not require C481 to be present [51], thus overcoming this resistance mechanism. They can therefore inhibit BTK in the presence of the C481S mutation, and non-selective reversible BTK-i, including MK1026, may also overcome mutations within PLCG2 [52]. Results from ongoing studies of alternative BTKis will help define their role in CLL therapy as single drugs or in combination.

4.1. Pirtobrutinib

Pirtobrutinib (LOXO-305, Loxo Oncology/Lilly) is a highly selective, next generation BTKi that blocks the ATP binding site of BTK by noncovalent, non-C481-dependent binding, thus overcoming acquired resistance to covalent BTKis [53]. Recently, the results of the BRUIN phase 1/2 study of pirtobrutinib performed in mature B-cell lymphoid malignancies has been reported, with promising results [54]. The study enrolled 323 patients, including 170 with heavily pretreated R/R CLL. Among them, 25% of patients had 17p deletion, 30% TP53 mutation, 19% 11q deletion, and 88% unmutated IGHV. The median number of previous lines of therapy was three (range 2–5). Moreover, 86% of patients had previously been treated with a BTKi, and 34% with venetoclax. In the total population of CLL patients, overall response rate (ORR) was 63% including 79% in del(17p) and/or TP53 mutated patients. In patients previously treated with other BTKis, ORR was 62%. Moreover, ORR was similar in patients who previously discontinued another BTKi for progression (67%) or toxicity (52%). Importantly, in patients with a BTK C481 mutation, ORR was 75%. The reported most common adverse events included fatigue (20%), diarrhea (17%), contusion (13%), and grade 3 or higher neutropenia (10%). Importantly, grade 3 atrial fibrillation/flutter were not observed, and only one patient with major bleeding was reported, caused by mechanical trauma. Only 1% discontinued treatment due to adverse events. Currently, pirtobrutinib is being compared to investigator’s choice in a phase 3 global, randomized, open-label study in CLL/SLL patients treated with at least a covalent BTKi. The choice consists of either idelalisib + rituximab or bendamustine + rituximab (BRUIN CLL-321, NCT04666038).

4.2. Vecabrutinib

Vecabrutinib (SNS-062, SNSS) is a selective, reversible, non-covalent, nanomolar potency and mutant BTKi [55]. In vitro studies have found it to demonstrate antitumor activity, even in cells that carry BTK Cys481Ser mutation. This dual activity is believed to result from vecabrutinib binding to the C481-independent BTK domain and suggests that it may have therapeutic potential in both covalent BTK relapse inhibitor disease and treatment-naive patients. Due to its very promising preclinical profile, this drug is being evaluated in 1b/2 phase study in patients with various B cell malignancies including CLL (NCT03037645) to potentially overcome ibrutinib resistance [56].

4.3. Fenebrutinib

Fenebrutinib (GDC-0853, Roche/Chugai Pharmaceutical) is another selective, reversible, non-covalent inhibitor of BTK that does not require interaction with the Cys481 residue for its activity [57]. Structural analyses have identified unique fenebrutinib-BTK interactions, which may explain its selectivity. The in vitro activity of the compound was also preserved towards BTK demonstrating single and double lesions of C481S, T474A, and T474S/C481S, respectively [58]. In addition to autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis [59], studies are currently examining the therapeutic potential of fenebrutinib in 24 R/R patients with B-cell malignancies, 14 of whom with CLL. Of the latter, six had been previously treated with BTK and were C481S-positive [60]. The findings indicate an ORR of around 30% with only one complete response (CR). The most common grade 3 or higher AE was anemia (12.5%); however, fatigue (38%), nausea (33%), diarrhea (29%), thrombocytopenia (25%), and headache (21%) were also reported. Three fatalities were reported: one from pneumonia, another from H1N1 infection, and another due to disease progression.

4.4. Nemtabrutinib

Nemtabrutinib (MK1026, ARQ 531; ArQule, Inc./Merck Sharp and Dohme) is able to reversibly inhibit of both wild-type and ibrutinib-resistant C481S-mutant BTK. It has a distinct selectivity profile with regard to kinases and has been found to demonstrate strong inhibition against a number of known key oncogenic factors, including those from the TEC, Trk, and Src kinase families. In two murine engraftment models of CLL (Eμ-TCL1 and Eμ-MYC/TCL1) resembling Richter transformation, nemtabrutinib was found to bestow increased survival compared to ibrutinib [61][62]. Nemtabrutinib was also observed to inhibit CLL cell survival and BCR-mediated activation of C481S BTK and PLCγ2 mutants; these are known to foster clinical resistance to ibrutinib. It also demonstrated greater efficacy in prolonging survival in animal models than ibrutinib and displayed in vitro activity in CLL cells with the ibrutinib resistance mutations BTKC481S or PLCγ2 [62]. Preliminary findings from a phase 1 escalation trial suggest that nemtabrutinib also has clinical activity against R/R B-cell lymphoid malignancies [62]. Overall, 14 out of the 47 patients treated with nemtabrutinib had PRs and additional 10 patients had stable disease. Responses were observed in patients with CLL, Richter’s transformation, diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL).

5. Resistance to BTK Inhibitors

Acquired resistance to covalent inhibitors is observed in approximately 60% of long-term treated patients with CLL [63][64]. In most cases, BTK resistance is caused by the development of clones with mutated cysteine (C481) in the ibrutinib binding site [65][66]. Among CLL/SLL patients who progressed after ibrutinib administration, mutations were found in the BTK Cys481, SH2 (BTK Thr316), and BTK Thr474 binding domains of BTK. Cysteine-to-serine mutations at the C481 site allow further signaling, including activation of PLCγ2 and CARD11, thus bypassing inactive BTK and promoting the activation of distal BCR signaling. These changes result in cancer cell proliferation and migration.
In CLL, the mechanism of acalabrutinib resistance is similar to that of ibrutinib and is related to BTK mutation [67]. In a study of 103 patients with CLL treated with acalabrutinib and routinely screened for BTK mutation, 22 were found to develop mutations. The median time from acalabrutinib initiation to mutation detection was 31.6 months. Among 16 patients with CLL progression, 11 (69%) demonstrated BTK C481 mutations, including C481S in 10 patients, C481R in one and C481Y in another. Four patients demonstrated additional mutations to BTK C481S, including BTK T474I in one, BTK C481R in another, and PLCG2 in two others. All these mutations had previously been identified in patients with ibrutinib resistance.
Several strategies for overcoming resistance to BTK have been investigated [64]. In particular, the third-generation, reversible, noncovalent BTKis display inhibitory activities against both BTK and BTKC481 mutants and have the potential to overcome resistance to covalent inhibitors caused by BTKC481 mutation [68]. Noncovalent binding BTKis such as pirtobrutinib, vecabrutinib, and MK1026 continue to inhibit BTK in the presence of the C481S mutation and have been found to be effective against C481 mutants [69]. Vecabrutinib and pirtobrutinib are more specific and inhibit wild-type and C481S-mutated BTK. Nemtabrutinib inhibits additional targets and has demonstrated activity in the presence of mutated PLCG2 [70]. Sequencing and combination therapies can also overcome BTKi resistance. Venetoclax is an active drug in CLL patients relapsed after ibrutinib [71]. PI3K inhibitors, such as idelalisib, duvelisib, or umbralisib, have also demonstrated therapeutic activity in CLL patients, previously treated with BTKis, who developed progression on treatment [72]. CD3×CD19 bispecific antibodies can mediate effective killing of CLL cells regardless of IGVH and TP53 mutational status, irrespective of sensitivity to ibrutinib. Recent studies have also found CD3×CD19 bispecific antibodies to be effective in killing ibrutinib-resistant CLL cells [73]. Chimeric antigen receptor-modified T (CAR-T) cell therapy has been investigated in CLL patients refractory to ibrutinib and showed promising activity. In the TRANSCEND CLL 004 phase 1/2 study, performed in R/R CLL patients failing on previous ibrutinib therapy, patients received CD19-directed CAR-T therapy; one-half of the patients had previously failed on both ibrutinib and venetoclax [74][75]. In addition, another new strategy for overcoming BTKi resistance is proteolysis-targeting chimera (PROTAC)-induced degradation of BTK. PROTAC has been found to be effective in a mouse model of the BTK C481S mutation [76].

6. Adverse Events

BTKis have unique toxicities that require monitoring. As such, it is essential to provide optimal management to achieve the best possible outcomes for patients [77][78]. The most common reason for discontinuing ibrutinib is toxicity, particularly the AEs specific for this group of drugs, such as atrial fibrillation (AF), bleeding events, arthralgias, rash, diarrhea, and cytopenias [79]. Ibrutinib discontinuation caused by AEs, mainly AF, arthralgias, rash, diarrhea, and bleeding events, was observed in 4–26%. Acalabrutinib and zanubrutinib are selective next-generation covalent BTKis, with less off-target activity than ibrutinib and better tolerability. The most common AE associated with acalabrutinib with acalabrutinib is headache, observed in 22–51% of patients. The incidence of AF is lower than for ibtrutinib. In patients treated with zanubrutinib, the most common grade ≥3 AEs were neutropenia and infections. The following section summarizes the key BTKi-related AEs in patients with CLL and strategies for their management.

6.1. Bleeding and Bruising

Bleeding and bruising are frequently observed AEs in patients treated with BTKis [80]. In a systematic review and pooled analysis of four randomized controlled trials, ibrutinib treatment was associated with an increase in all-grade bleeding (4.85% vs. 1.55%, RR = 2.93, p = 0.03) compared to control treatments. This is believed to be partly due to the off-target TEC kinase inhibition and platelet inhibitory mechanisms [81][82]. Acalabrutinib did not induce the platelet dysfunction or inhibition of platelet aggregation observed with ibrutinib [83]. However, bleeding complications were also observed in patients treated with acalabrutinib. In a pooled safety analysis of zanubrutinib monotherapy in patients with B-cell malignancies, bruising occurred in 25% of patients and major hemorrhage in 4% [84]. The risk of bleeding and bruising is more common in patients simultaneously treated with antiplatelet drugs and anticoagulants; in these patients, serious life-threatening bleedings were observed. The ibrutinib-associated risk of bleeding can decrease by prohibiting the use of oral anticoagulants and by avoiding CYP3A4 drug–drug interactions [85]. It is therefore recommended to stop BTKi treatment for three days before and after any minor invasive procedure, and for seven days before and after a major surgical procedure, to decrease the risk of bleeding. Patients considered to receive BTKis should be advised to stop aspirin treatment or reduce the dose to 81 mg if necessary. However, patients with episodes of bleeding or bruising should not receive anticoagulation treatment if possible. Achieving optimal anticoagulation therapy in patients with atrial fibrillation during BTKi treatment is a difficult challenge. For patients with new AF, anticoagulation should be recommended to decrease the risk of stroke. Apixaban is usually suggested following an analysis of the risks and benefits. However, the need for BTKi continuation should be considered.

6.2. Cardiovascular Complications

Cardiotoxicity is an important complication of treatment with ibrutinib and other BTKis. A pooled analysis of four randomized controlled clinical trials found ibrutinib to be associated with an increased risk of AF and flutter compared to other treatments (3.03% vs. 0.80%, RR = 3.80, p = 0.003 [86]. In another study of 178 patients with CLL, those who discontinued ibrutinib-based therapy gave AF as the most common reason for discontinuation [87]. Long-term data indicate that approximately 20% of ibrutinib-treated patients develop incidences of arrhythmia [88][89].
A review of the Food and Drug Administration Adverse Event Reporting System (FAERS) database by Grewel et al. examined the cardiovascular complications associated with novel agents in CLL, including ibrutinib and acalabrutinib [90]. A total of 6074 cardiac adverse events were identified. Of the examined agents, ibrutinib was found to have the highest risk of cardiac adverse events (4832/36581; 13.2%). The ibrutinib group also demonstrated a higher frequency of AF (41.5%) than in the group treated with acalabrutinib (age-adjusted OR = 2.21, 95% CI = 1.25–3.90, p = 0.005). A pooled safety analysis of zanubrutinib monotherapy in a group of 779 patients with B-cell malignancies found AF to occur in 3%; for such patients, multidisciplinary care is indicated to optimize anticoagulant treatment and cardiac management. Ibrutinib is associated with a significantly increased risk of hypertension [91]. In an early-phase study of ibrutinib in CLL, 23% of patients developed new or worsened existed hypertension, and follow-up data suggest a continual increase in the incidence of hypertension over time [92][93]. In a recent analysis by Dickerson et al., 78.3% of patients treated with ibrutinib developed new or worsened hypertension over a median observation period of 30 months [94]. Hypertension developed in 71.6% of patients, with a time to 50% cumulative incidence of 4.2 months. In addition, 17.7% of the patients developed high-grade hypertension with blood pressure above 160/100 mm Hg. Taken together, these findings suggest that ibrutinib treatment results in a higher risk of hypertension and greater severity, as well as an increased risk of cardiotoxic events; however, acalabrutinib treatment is associated with a lower burden of hypertension than ibrutinib. Grade ≥3 hypertension was also observed in 5% of patients with lymphoid malignancies treated with zanubrutinib [94].

6.3. Cytopenias

Cytopenias are relatively frequent AEs in patients treated with BTKis, but they are usually not serious and are typically managed with supportive care and/or treatment interruption. Severe cytopenias are rarer in CLL patients treated with BTKis than other antileukemic drugs and usually do not warrant dose reduction. Among patients treated with zanubrutinib, grade ≥3 neutropenia was observed in 23%, thrombocytopenia in 8%, and anemia in 8% [95]. BTKi treatment should be withheld from patients demonstrating grade ≥3 neutropenia and infection or fever until resolution to baseline or grade 1; following this, the treatment can be restarted at a reduced dose. In addition, patients demonstrating grade 3 thrombocytopenia with bleeding or grade 4 thrombocytopenia should not receive BTKi treatment until resolution to baseline or grade 1, following which, BTKi treatment can be restarted at a reduced dose. If cytopenia occurs for a fourth time, the BTKis should be discontinued. Treatment-emergent autoimmune cytopenias were observed in 1% of patients during ibrutinib therapy [96]. In a phase 2 study evaluating acalabrutinib monotherapy in 134 R/R CLL patients, only one case of autoimmune hemolytic anemia (AIHA) recurrence was noted among 11 patients with a history of autoimmune cytopenia. In addition, ibrutinib induces rapid and durable responses when used to treat AIHA developed in CLL patients [96].

6.4. Infections

BTK plays an important role in immunity, participating in numerous pathways including B cells, T cells, and macrophages. It is therefore a driving factor in both lymphoproliferative disorders and response to infection [97][98]. BTKis are considered less immunosuppressive and safer than other chemotherapeutic drugs and have been proposed as useful agents for reconstituting humoral immunity and protecting against infection in patients with CLL [99]. In addition, ibrutinib can inhibit inflammation induced by bacterial infections.
However, several clinical trials indicate an increased risk of infection, including upper respiratory tract infection, pneumonia, cellulitis, and sepsis [93][100][101][102]. In a recent retrospective, single-center study of patients treated with ibrutinib, 11.4% of the patients developed serious infections requiring hospitalization or parenteral therapy, including 4.2% with invasive fungal infections [100]. In another study, the incidence of one or more serious infections in patients with hematologic malignancies receiving ibrutinib therapy was 18.0%; most (16.1%) were bacterial in nature and 4.3% multiple infections [101]. In a pooled analysis of 1476 ibrutinib-exposed patients, the incidence of Grade ≥3 infection was 21%. Grade ≥3 infection was observed in 27% patients receiving zanubrutinib. This value is similar to that reported in a pooled analysis from ibrutinib-exposed patients.
Mauro et al. analyzed the risk factors of infections in 494 CLL patients treated with ibrutinib [103]. They found pneumonia, grade 3 or higher non-opportunistic infections, and opportunistic infections in 32% of patients, with an overall incidence rate per 100 person-year of 15.3%. Infections also caused the permanent discontinuation of ibrutinib in 9% of patients. Severe infection in the year before starting ibrutinib, chronic obstructive pulmonary disease, and two or more prior treatments were associated with a two to threefold increase in the rate of infections.
At present, the individual contribution of BTKis to the risk of serious infection is unclear. A body of evidence indicates that this risk is influenced by various additional factors such as concurrent steroid use, neutropenia, and prior chemo- or immunochemotherapy. In patients with multiple risk factors, targeted antimicrobial prophylaxis may reduce the risk of infection associated with BTKi use. Vaccinations (e.g., against influenza, COVID-19, and pneumococcus) are recommended before treatment initiation [104][105]. Recombinant, adjuvanted varicella-zoster virus vaccine should be also considered [106]. Intravenous immunoglobulin supplementation is also useful for patients with recurrent infections and hypogammaglobulinemia.

6.5. Arthralgias and Myalgias

The occurrence of arthralgias/myalgias is a common AE in CLL patients treated with ibrutinib in both upfront and R/R settings, with an increased risk observed at longer treatment durations [106][107]. In clinical trials and retrospective studies, arthralgias and myalgias were noted in 11–36% of patients [106][107][108][109][110][111]. In a recent analysis, 76 of 214 (36%) patients with CLL treated with ibrutinib, either as a single agent or in combination, developed arthralgias/myalgias during follow-up, with a median follow-up of 34.5 months [107]. Most patients (79%) had grade 1 or 2 toxicity, and 28% continued ibrutinib with resolution of symptoms. More effective toxicity management was observed for dose holds of ibrutinib than dose reduction. However, 63% of patients with grade 3 or higher toxicity discontinued ibrutinib treatment, indicating that this subgroup does not tolerate ibrutinib. For some patients, the use of non-steroidal anti-inflammatory drugs, acetaminophen, or corticosteroids can temporarily reduce symptoms; however, these drugs may exacerbate the risk of bleeding and should be used with caution [108]. The mechanisms behind of ibrutinib-induced arthralgias/myalgias remain unclear.
Additional studies are needed to determine the mechanism of ibrutinib-related arthralgias/myalgias and develop optimal management strategies. Rhodes et al. recommend continuing ibrutinib at the current dose in the case of grade 1 or 2 arthralgias/myalgias, as long as the symptoms do not interfere with activities of daily living, as most symptoms can resolve spontaneously [106]. If symptoms affect daily activities, dose reduction should be advised. If there is no improvement at a lower dose, further dose reduction or a dose hold until improvement in symptoms should be recommended. However, if symptoms recur with re-challenge after a dose hold, ibrutinib should be permanently discontinued, and the use of alternative CLL-directed therapies is recommended. In cases of grade 3 or higher arthralgias or myalgias, the dose hold should be maintained until resolution of symptoms. If the symptoms resolve, re-challenging can be performed with a lower dose. If the symptoms do not recur, it is advisable to continue with ibrutinib at a reduced dose, rather than attempting to escalate. If symptoms recur, ibrutinib should be discontinued, as well as other CLL-directed therapies, and BTKi considered. Replacing ibrutinib with acalabrutinib is a reasonable option, as acalabrutinib seems not cause myalgias. A recent study indicates that approximately two-thirds of patients with ibrutinib-induced arthralgias/myalgias did not experience recurrent symptoms following acalabrutinib treatment [111].

6.6. Dermatologic Complications

Approximately 20% of patients treated with ibrutinib or acalabrutinib demonstrate rashes, which have been associated with EGFR inhibition and infiltration of inflammatory cells [112][113]. Witholding the BTKi is usually recommended and if the rash resolves, the BTKi can be resumed. However, if the rash recurs, a dose reduction is indicated. In addition, erythema nodosum was observed in patients treated with ibrutinib. Both skin symptoms usually respond to corticosteroids or dose holds. Textural changes can also be observed in the hair and nails, with long-term ibrutinib therapy being associated with a higher incidence of brittle fingernails or toenails [114]. However, these manifestations tend to have a gradual onset, typically around nine months, and are not dose-limiting toxicities. Recommended treatments are biotin supplementation and nail oil application.

6.7. Headaches

Headaches are noted approximately in 40% of patients treated with acalabrutinib and are rarely observed in patients receiving ibrutinib [115]. Usually, headaches occur early after treatment initiation and the incidence decreases over time. This AE is usually a manageable toxicity and does not influence the continuation of BTKi treatment.

6.8. Diarrhea

Diarrhea is commonly observed AE in patients treated with BTKi. It is observed mainly in the first six months from beginning therapy, with a frequently observed self-limited course [115][116]. Similar incidence is observed between patients treated with ibrutinib and acalabrutinib [115][116]. Temporary drug holds should be considered in the case of grade ≥3 diarrhea.

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