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Expert Review of Hematology

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BTK inhibitors: moving the needle on the

treatment of chronic lymphocytic leukemia

Alycia Hatashima & Mazyar Shadman

To cite this article: Alycia Hatashima & Mazyar Shadman (21 Aug 2024): BTK inhibitors: moving

the needle on the treatment of chronic lymphocytic leukemia, Expert Review of Hematology,

DOI: 10.1080/17474086.2024.2391097

To link to this article: https://doi.org/10.1080/17474086.2024.2391097

Published online: 21 Aug 2024.

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REVIEW

BTK inhibitors: moving the needle on the treatment of chronic lymphocytic

leukemia

Alycia Hatashima a and Mazyar Shadman a,b

a

Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA; b

Division of Hematology and Oncology, University of Washington,

Seattle, WA, USA

ABSTRACT

Introduction: Bruton’s tyrosine kinaseinhibitors (BTKis) changed the trajectory of upfront and relapsed/

refractory chronic lymphocytic leukemia (CLL) treatment. However, BTKis are plagued by a spectrum of

toxicities. Zanubrutinib was developed to circumvent challenges with prolonged tolerability by increasing BTK selectivity and maximizing efficacy through pharmacokinetic/pharmacodynamic optimization.

However, with the availability of ibrutinib, acalabrutinib, and zanubrutinib, limited data exists to guide

sequencing of BTKi therapy in the relapsed/refractory setting.

Areas covered: We review the first head-to-head trial (ALPINE) of zanubrutinib versus ibrutinib for the

treatment of relapsed/refractory CLL and compare zanubrutinib’s clinical efficacy and toxicities, including in patients with del(17p) and/or TP53 mutations to ibrutinib and acalabrutinib.

Expert opinion: Zanubrutinibrepresents one of the new standards of care for relapsed/refractory CLL

based on superior progression-free survival and response rates over ibrutinib. Whilezanubrutinib is

associated with fewer cardiac toxicities, similar rates of neutropenia and hypertension are noted.

Ongoing studies are pushing the envelope, utilizing targeted drug combinations and minimal residual

disease markers as well as receptor tyrosine kinase-like orphan receptor 1 inhibitors, chimeric antigen

receptor T-cells, and novel BTK degraders. However, zanubrutinibrepresents a strong contender in the

arsenal of treatment options for relapsed/refractory CLL.

ARTICLE HISTORY

Received 26 February 2024

Accepted 7 August 2024

KEYWORDS

ALPINE; BTK inhibitor;

chronic lymphocytic

leukemia; zanubrutinib;

Bruton’s tyrosine kinase

1. Introduction

Chronic lymphocytic leukemia (CLL) is a disease marked by the

accumulation of monoclonal CD5+ mature B cells in the blood,

bone marrow, lymph nodes, and spleen [1,2]. The initiation and

ongoing proliferation of CLL cells are driven by antigendependent and antigen-independent signaling [1–3].

Extracellular antigenic stimulation of the B-cell receptor (BCR)

initiates a cascade of phosphorylation events involving the Src

family kinases LYN, spleen tyrosine kinase (SYK), and phosphoinositide 3-kinase (PI3K) [1–5]. Constitutive activity and overexpression of LYN results in the acquisition of pro-survival

mechanisms and dysregulation of protein targets including

Src homology 2 domain-containing phosphatase 1 (SHP-1),

SHP-2, and protein phosphatase 2A [6]. In addition, Bruton’s

tyrosine kinase (BTK) is attracted to the cell membrane and fully

activated by trans-phosphorylation. BTK is largely responsible

for the phosphorylation of phospholipase C-γ2 and subsequent

propagation of downstream pathways lead to the upregulation

of transcription factors: extracellular signal-regulated kinase,

nuclear receptor of activated T cells and nuclear factor-κB are

upregulated, driving unhindered cell growth and survival. The

expansion of malignant clones is also facilitated by complex

signaling via chemokines and Toll-like receptors as well as costimulation by T-cells, nurse like cells, and other CLL cells within

the proliferation center microenvironment. Small lymphocytic

lymphoma is characterized by the same biology and treatment

remains identical to CLL; as such, the term CLL will refer to both

conditions hereafter.

2. Role of Bruton’s tyrosine kinase in CLL

BTK was identified over three decades ago based on its role in

defective B lymphocyte differentiation from pre-B to later B cell

stages in X-linked agammaglobulinemia [7]. It is one of the five

members of the tyrosine kinase expressed in carcinoma (TEC)

family of proto-oncogenes encoding non-receptor tyrosine

kinases: IL-2 inducible tyrosine kinase (ITK), resting lymphocyte

kinase, bone marrow-expressed kinase, and TEC and expressed

in all hematopoietic stem cell lineages apart from T lymphocytes

[3,5,8,9]. BTK was later discovered to play an integral role in the

BCR signal transduction pathway and consequently became an

attractive and important therapeutic target for the treatment of

B-cell leukemias and lymphomas, including CLL.

Prior to the advent of BTKis, patients who met criteria for

treatment were limited to corticosteroids, cytotoxic chemotherapy, and most recently chemoimmunotherapy (CIT) [2]. The

subset of patients with poor-risk disease features: del(17p),

TP53 mutation and unmutated immunoglobulin heavy-chain

variable (IGHV) status often accepted suboptimal outcomes.

The development and approval of BTK inhibitor (BTKi), ibrutinib,

ignited a new era spanning the last decade and indelibly changed the treatment trajectory for patients with CLL. Despite being

CONTACT Mazyar Shadman mshadman@fredhutch.org Fred Hutch Cancer Center, University of Washington, 1100 Fairview Ave. N, Seattle, WA 98109, USA

EXPERT REVIEW OF HEMATOLOGY

https://doi.org/10.1080/17474086.2024.2391097

© 2024 Informa UK Limited, trading as Taylor & Francis Group

the first-in-class BTKi, ibrutinib’s affinity for off-target kinases due

to a shared conserved cysteine residue results in a broad array of

toxicities limiting the long-term duration of therapy. The secondgeneration BTKis acalabrutinib and zanubrutinib were the results

of efforts to improve kinase selectivity and reduce adverse events

caused by ibrutinib.

With the January 2023 approval of zanubrutinib, the current armamentarium of BTK-targeted therapies for CLL

includes ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib (Tables 1 and 2). With the exception of pirtobrutinib which

recently gained approval in the United States for relapsed/

refractory (R/R) CLL, all aforementioned BTKis are indicated for

the treatment of newly diagnosed and R/R disease [10–14].

The majority of pivotal clinical trials leading to the aforementioned drug approvals compared BTKis to the previous standard of care, CIT; notably, ELEVATE-RR is one of the few studies

that compared BTKis in a head-to-head fashion [15]. Thus,

based on the available evidence, guidelines do not give preference to one BTKi based on efficacy, but do

recommend second-generation BTKis, acalabrutinib, and zanubrutinib, as preferred options in both the upfront and R/R

setting over ibrutinib due to safety concerns [16].

3. Ibrutinib

3.1. Treatment naïve

Ibrutinib has demonstrated improved efficacy over CIT in

patients spanning all age ranges, patient comorbidities and

those with high risk molecular characteristics: del(17p) and/or

TP53 mutations [17–28].

Article highlights

● Next-generation, potent, covalent BTKi, zanubrutinib, was designed

to optimize efficacy and tolerability through improved BTK specificity

and occupancy as well as favorable pharmacokinetic/pharmacodynamic characteristics.

● The ALPINE trial demonstrated superior progression-free survival and

response rates in patients with relapsed/refractory CLL treated with

zanubrutinib versus ibrutinib.

● Zanubrutinib is associated with a manageable toxicity profile: fewer cardiac complications, diarrhea, arthralgias, fatigue, balanced with slightly

higher rates of neutropenia and hypertension compared to ibrutinib.

● Zanubrutinib has been shown to be well tolerated and results in

stable or improved efficacy outcomes in patients who are intolerant

to ibrutinib and/or acalabrutinib.

● Robust data are lacking to guide BTKi sequencing, but zanubrutinib

represents a promising stand-alone treatment option and is currently

being evaluated in combination regimens as well as with novel

targeted agents in frontline and relapsed/refractory CLL.

Table 1. Phase III trials of BTK inhibitors for treatment naïve CLL.

Trial

Treatment Regimen

(n)

Median

Follow-Up PFS OS Response

Discontinuation due

to adverse events Reference

RESONATE-2 Ibrutinib (n = 136) 8 years Median: NR

7-year: 59%

Median: NR

7-year: 78%

ORR: 92%

CR: 34%

24% [17–19]

Chlorambucil

(n = 133)

Median: 15 months

7-year: 9%

Not reported ORR: 37%

CR: not reported

Not reported

Alliance North

American Intergroup

(A041202)

Ibrutinib (n = 182) 55 months 4-year: 76% 4-year: 85% ORR: 93%

CR: 7%

Not reported [20,21]

Ibrutinib + rituximab

(n = 182)

4-year: 76% 4-year: 86% ORR: 94%

CR: 21%

Bendamustine +

rituximab

(n = 183)

4-year: 47% 4-year: 84% ORR: 81%

CR: 26%

ECOG 1912 Ibrutinib + rituximab

(n = 354)

70 months 5-year: 78% 5-year: 95% ORR: 96%

CR: 17%

22% [22,23]

FCR (n = 175) 5-year: 51% 5-year: 89% ORR: 81%

CRR: 30%

Not reported

iLLUMINATE Ibrutinib + rituximab

(n = 113)

45 months Median: NR

42-month: 74%

Median: NR ORR: 91%

CR: 42%

Ibrutinib: 22%

Obinutuzumab:

9%

[24,25]

Chlorambucil +

obinutuzumab

(n = 116)

Median: 22 months

42-month: 33%

Median: NR ORR: 81%

CR: 17%

Chlorambucil: 9%

Obinutuzumab:

13%

ELEVATE-TN Acalabrutinib

(n = 179)

75 months Median: NR

72-month: 62%

Median: NR

72-month: 76%

ORR: 90%

CR: 11%

18% [33–35]

Acalabrutinib +

obinutuzumab

(n = 179)

Median: NR

72-month: 78%

Median: NR

72-month: 84%

ORR: 96%

CR: 31%

21%

Chlorambucil +

obinutuzumab

(n = 177)

Median: 28 months

72-month: 17%

Median: NR

72-month: 75%

ORR: 83%

CR: 13%

47-month: 15%

SEQUOIA (without del

(17p))

Zanubrutinib

(n = 241)

44 months Median: NR

42-month: 82%

Median: NR

42-month: 89%

ORR: not reported

CR: 17%

15% [65,66]

Bendamustine +

rituximab

(n = 238)

Median: 42 months

42-month: not

reported

Median: NR

42-month: 88%

ORR: not reported

CR: 22%

SEQUOIA (with del

(17p))

Zanubrutinib

(n = 111)

48 months Median: not

reported

42-month: 79%

Median: not

reported

42-month: 90%

ORR: not reported

CR: 15%

14%

BTK: Bruton’s tyrosine kinase; n: number of patients; PFS; progression free survival; OS: overall survival; NR: not reached; ORR: objective response rate; CR: complete

response; ECOG: Eastern Cooperative Oncology Group; FCR: fludarabine, cyclophosphamide, rituximab.

2 A. HATASHIMA AND M. SHADMAN

RESONATE-2, the initial trial leading to ibrutinib’s United

States Food and Drug Administration (FDA) approval, compared oral ibrutinib to chlorambucil in an international,

phase III trial of patients 65 years and older [17]. The results

from the original analysis were confirmed with long-term

follow-up demonstrating that the PFS and OS rates were

superior with ibrutinib compared to chlorambucil [17–19].

The median PFS was not reached (95% confidence interval

(CI): 82.1 months-not estimable (NE)) in the ibrutinib arm and

significantly longer than the 15 months (95% CI: 10.2–19.4

months) in the chlorambucil arm; the median OS was not

reached in the ibrutinib group. The median OS in the chlorambucil cohort was reported to be 89 months (HR 0.453; 95%

CI: 0.276–0.743). However, following the 5-year follow-up, OS

was not documented for chlorambucil patients who experienced disease progression. Patients treated with ibrutinib

achieved an objective response rate (ORR) of 92% versus

37% with chlorambucil. Response in the ibrutinib arm was

primarily driven by partial responses (PRs) and only 11%

reached a complete response (CR) at the time of the primary

analysis. However, CRs with ibrutinib deepened over time to

30% and 34% at the five and seven year analysis.

Subsequent trials evaluating ibrutinib monotherapy or in

combination with an anti-CD20 monoclonal antibody revealed

similar benefits of ibrutinib over the comparator arms.

However, efficacy required indefinite treatment and CR rates

remained low [20–26].

3.2. Relapsed/refractory

Ibrutinib was also found to be efficacious in the R/R setting

following its accelerated approval based on impressive

response rates in the phase Ib/II PCYC-1102 trial [29]. A large

phase III study of ibrutinib versus ofatumumab administered

for up to 24 weeks reported a significantly higher 5-year PFS

rate of 40% with ibrutinib compared to 3% with ofatumumab

as well as longer median PFS (p < 0.001) and OS in patients

treated with ibrutinib [30–32]. Consistent with response seen

in the upfront setting, initial response rates were 43% and 4%

in the ibrutinib and ofatumumab groups and fully driven by

PRs. With 5-years of follow-up, the CR and CR with incomplete

bone marrow recovery increased to roughly 11% of the

patients treated with ibrutinib.

4. Acalabrutinib

4.1. Treatment naïve

Acalabrutinib alone and in combination with obinutuzumab

has been compared to the CIT regimen of chlorambucil plus

obinutuzumab [33–35]. Similar to ibrutinib-containing studies,

acalabrutinib with or without obinutuzumab demonstrated

higher PFS rates, and the median PFS was not reached in

either acalabrutinib arm compared to 27.8 months with chlorambucil plus obinutuzumab (p < 0.0001) [35]. The median OS

was not reached in any arm but was significantly longer in

patients treated with acalabrutinib plus obinutuzumab versus

chlorambucil and obinutuzumab (HR 0.62; p = 0.0349). The 72-

month OS rates were numerically higher in the acalabrutinib

containing groups. Also consistent with ibrutinib data, CR

rates were low and predominantly PRs. However, acalabrutinib

paired with obinutuzumab yielded the highest CR or CRi at

37% of the patients. In patients with del(17p) and/or TP53

mutated disease, favorable outcomes were achieved among

those who received acalabrutinib-containing regimens.

However, the addition of obinutuzumab to acalabrutinib did

not improve PFS or OS in this high-risk subset.

4.2. Relapsed/refractory

THE ASCEND trial was the first of two notable phase III

randomized studies to assess the efficacy and safety of acalabrutinib in the R/R setting [36–38]. The median PFS with

acalabrutinib monotherapy was not reached and significantly

longer than the PFS of 16.2 months (p < 0.001) and 18.6

months (p < 0.001) reported in patients who received

Table 2. Phase III trials of BTK inhibitors for relapsed/refractory CLL.

Trial

Treatment Regimen

(n)

Median FollowUp PFS OS Response

Discontinuation due to adverse

events Reference

RESONATE Ibrutinib (n = 195) 74 months Median: 44 months

60-month: 40%

Median: 68 months ORR: 91%

CR: 11%

16% [30–32]

Ofatumumab

(n = 196)

Median: 8 months

60-month: 3%

Median: 65 months Not reported 4%

ASCEND Acalabrutinib

(n = 155)

47 months Median: NR

42-month: 62%

Median: NR

42-month: 78%

ORR: 83%

CR: 5%

23% [36–38]

IdR (n = 119)

OR

BR (n = 36)

Median: 17 months

42-month: 23%

Median: NR

42-month: 65%

ORR: 84%

CR: 5%

IdR: 67%; BR: 17%

ELEVATERR

Acalabrutinib

(n = 268)

41 months Median: 38 months Median: NR ORR: 81%

CR: 3%

15% [15]

Ibrutinib (n = 265) Median: 38 months Median: NR ORR: 77%

CR: 4%

21%

ALPINE Zanubrutinib

(n = 327)

36 months Median: not

reported

36-month: 66%

Median: not

reported

36-month: 83%

ORR: 85%

CR: 10%

20% [68–70]

Ibrutinib (n = 325) Median: not

reported

36-month: 54%

Median: not

reported

36-month: 80%

ORR: 75%

CR: 7%

25%

BTK: Bruton’s tyrosine kinase; n: number of patients; PFS; progression free survival; OS: overall survival; NR: not reached; ORR: objective response rate; CR: complete

response; IdR: idelalisib + rituximab; BR: bendamustine + rituximab.

EXPERT REVIEW OF HEMATOLOGY 3

idelalisib plus rituximab and bendamustine plus rituximab

(BR), respectively. The 3-year PFS rate was significantly higher

in the acalabrutinib arm. The 3-year OS rate and response

rates were not significantly different between the groups.

Encouragingly, favorable PFS outcomes remained true in

patients with del(17p) mutations.

Prior to the ELEVATE-RR trial, data comparing one BTKi to

another was lacking [15]. This phase III, randomized, noninferiority trial selected for patients with del(17p) and/or del(11q) R/R

CLL. The median PFS was 38.4 months in both the acalabrutinib

(95% CI: 33.0–38.6) and ibrutinib arm (95% CI: 33.0–41.6; HR 1.00;

95% CI, 0.79–1.27). The median OS was not reached in either

group (HR 0.82; 95% CI: 0.59–1.15). Response rates as assessed by

the independent review committee were also similar at 81%

(95% CI: 75.8–85.2) and 77% (95% CI: 71.5–81.6) in patients

who received the acalabrutinib and ibrutinib. CR rates were low

and reported in 1.9% and 3% of acalabrutinib and ibrutinib

patients, respectively. Consequently, in treatment exposed

patients with del(17p) and/or del(11q), the choice of acalabrutinib or ibrutinib may not be a decision of efficacy but instead

dictated by patient-specific comorbidities and drug toxicity

profiles.

5. Zanubrutinib

As the newest covalent next-generation BTKi for CLL, zanubrutinib, formerly BGB-3111, was developed to optimize

kinase selectivity paired with a favorable pharmacokinetic

(PK)/pharmacodynamic (PD) profile relative to its predecessors. Identical to ibrutinib and acalabrutinib, zanubrutinib

exerts its therapeutic effect by forming an irreversible, covalent bond at the Cys481 residue in the adenosine triphosphate

(ATP) binding pocket of BTK [39]. Using a structure–activity

relationship methodology for drug development, zanubrutinib

was designed to achieve improved oral bioavailability and

maximize BTK target occupancy at low doses compared to

ibrutinib. In mouse models, zanubrutinib exhibited 3-fold

greater potency in both peripheral blood mononuclear cells

(PBMC) and spleen and 3-fold higher plasma concentrations at

the same dose levels relative to ibrutinib. Furthermore, to

improve selectivity and minimize off-target kinase inhibition,

zanubrutinib’s molecular configuration was chosen due to its

reduced affinity for and inhibition of cysteine residues in

structurally related kinases: ITK, Janus kinase 3 (JAK3), ERBB2/

HER2, epidermal growth factor (EGFR), TEC, and Src family

kinases.

5.1. Pharmacokinetics

Zanubrutinib’s clinical activity and safety was first validated in

a global, first-in-human, multicenter, open-label phase I trial

conducted in patients with B-cell malignancies [40–42]. Data

from the initial dose finding cohort determined that zanubrutinib exhibits linear and dose proportional maximum

observed plasma concentrations (Cmax) and area under the

plasma concentration-time curve (AUC) at doses from 40 mg

to 320 mg daily [43,44]. Regardless of the dosing schedule,

zanubrutinib 320 mg administered once daily or as a split

dose twice daily, achieved comparable plasma exposures.

PK analyses demonstrated that zanubrutinib is rapidly

absorbed with a median Cmax of 2 hours post oral administration. Zanubrutinib is readily eliminated with a mean terminal elimination half-life of approximately 2–4 hours [43,44].

Following repeated doses of zanubrutinib, the mean accumulation ratio was found to be close to one, indicating limited

systemic accumulation.

Approximately 94% of zanubrutinib is bound to plasma

proteins [13,44]. This is in contrast with ibrutinib and acalabrutinib which both exhibit roughly 97% plasma protein binding, resulting in half the available unbound drug available to

elicit a pharmacological response [11,12]. After adjusting for

protein binding, the free drug exposure of zanubrutinib 320

mg daily is 6- to 8-times higher than ibrutinib 560 mg daily

and 2- to 3-times higher than that achieved with acalabrutinib

100 mg twice daily [40,44–46]. Zanubrutinib’s free drug exposure remains above the half maximal inhibitory concentration

(IC50) required for BTK inhibition (0.5 nM) throughout both the

160 mg twice daily and 320 mg daily dosing intervals and

trough concentrations are 7- and 2-fold higher than the IC50,

respectively [47]. Thus, regardless of the dosing schema, zanubrutinib maintains concentrations above what is required for

full BTK inhibition. Exposure-response analyses suggest that

the PK differences between the two zanubrutinib dosing schemas are unlikely to yield meaningful differences in efficacy

and/or safety [44,47]. In addition, PK studies suggest that

zanubrutinib’s PK parameters are consistent regardless of

intrinsic and extrinsic factors including age, sex, race, and

creatinine clearance [43,44,48].

Zanubrutinib undergoes extensive hepatic metabolism primarily via cytochrome P450 3A (CYP3A); nearly 87% is

excreted in feces (38% as unchanged drug) and 8% in the

urine (<1% as unchanged drug) [49]. Zanubrutinib’s metabolism does not yield major active metabolites. In contrast, both

ibrutinib and acalabrutinib have pharmacologically active

metabolites which achieve approximately double the systemic

exposure compared to their parent molecules [12,50–53].

While ibrutinib’s active metabolite, PCI-45227, and acalabrutinib’s M27 are less potent against BTK, they retain kinase

selectivity mirroring the parent compounds potentially contributing to off-target toxicities. A post-hoc analysis of ibrutinib,

acalabrutinib, M27, and zanubrutinib at 100× IC50 (BTK) concentrations profiled against 370 kinases confirmed zanubrutinib’s kinase selectivity; zanubrutinib was found to inhibit

seven off-target kinases, significantly fewer than ibrutinib,

acalabrutinib, and M27 which inhibited 17, 15, and 23 kinases,

respectively [54].

First-pass metabolism plays a prominent role in the clearance of zanubrutinib and reduced serum albumin concentrations due to hepatic impairment alter levels of circulating

unbound drug [49,50]. Compared with matched healthy subjects, zanubrutinib’s PK parameters are not significantly

altered in individuals with mild or moderate hepatic impairment (Child-Pugh class A or B). However, patients with severe

hepatic impairment experienced total and unbound plasma

AUCs of zanubrutinib increased by 1.6- and 2.9-fold, respectively. It is recommended that a 50% dose reduction to zanubrutinib 80 mg twice daily be applied in patients with severe

hepatic dysfunction [13].

4 A. HATASHIMA AND M. SHADMAN

5.2. Clinically relevant drug–drug interactions

Similar to other covalent BTKis, zanubrutinib is vulnerable to

drug–drug interactions (DDIs), most commonly due to medications that exert inhibitory or inducible effects on the CYP3A

pathway. To this end, a DDI study evaluated the interaction

potentials of strong CYP3A inhibitor, itraconazole, and strong

CYP3A inducer, rifampin, on zanubrutinib [55]. Concomitant

use of itraconazole resulted in 2.6- and 3.8-fold increases in

the Cmax and plasma exposure ofzannubrutinib, whereas

rifampin significantly reduced the bioavailability and accelerated the clearance of zanubrutinib evidenced by a 12.6- and

13.5-fold reduction in the Cmax and measured exposure of

zanubrutinib. Additional studies showed similar PK outcomes

with other strong CYP3A inhibitors, voriconazole and clarithromycin, as well as moderate CYP3A inhibitors, albeit to a lesser

magnitude, fluconazole and diltiazem, and moderate CYP3A

inducer, rifabutin [56–59]. Consequently, dose adjustments are

recommended based on the potency of the CYP3A inhibitor or

inducer [13].

In vitro studies were conducted to evaluate the potential

for zanubrutinib to affect hepatic CYP isoforms. At a total daily

dose of 320 mg, zanubrutinib exhibited minimal to no effect

on the activity of CYP2B6, CYP2C8, and CYP2C9; however,

zanubrutinib reduced the systemic exposure of CYP3A4 and

CYP2C19 substrates by a mean reduction of less than 50%

[59,60]. Furthermore, data suggests that zanubrutinib is unlikely to be impacted by transporter-mediated drug interactions

as it is minimally involved in the activity of human breast

cancer resistance protein (BCRP) and P-glycoprotein (P-gp)

and is not a substrate of BCRP, organic anion transporting

polypeptide (OATP)1B1/1B3, organic cation transporter (OCT)

2, or OAT1/3 [58,60]. However, zanubrutinib may be

a substrate of the efflux transporter P-gp.

5.3. Pharmacodynamic properties

Assessments of BTK occupancy in PBMCs and lymph nodes

demonstrated that zanubrutinib achieves complete or near

complete (>95%) and sustained binding across blood and

tissue compartments [40,41,44]. The median BTK occupancy

in PBMCs was > 95% starting at 40 mg daily to the highest

dose level of 320 mg daily (or divided twice daily). In 30 paired

samples of nodal tissue, the median BTK occupancy was 94%

(range: 82.4–100%) and 100% (range: 86.3–100%) in patients

who received 320 mg daily and 160 mg twice daily (p =

0.0189), respectively. Furthermore, a higher percentage of

patients achieved nodal BTK occupancy greater than 95% in

the cohort who received zanubrutinib 160 mg twice daily

versus 320 mg daily (50% vs 89%; p = 0.0342) ultimately determining the target dose for future investigations.

5.4. Early phase clinical trials using zanubrutinib

Phase I of the multicenter, open-label AU-003 trial as previously described, determined the maximum tolerated dose

and recommended phase II dose (RP2D) of zanubrutinib 160

mg twice daily among patients with B-cell malignancies [44].

The expansion study enrolled disease-specific cohorts including a total of 123 patients with treatment naïve (TN) (n = 22) or

R/R (n = 101) CLL treated with zanubrutinib indefinitely until

unacceptable toxicity or disease progression [44,61,62]. Forty

patients initially received zanubrutinib 320 mg daily until the

RP2D was established, 28 of whom voluntarily switched to the

160 mg twice daily dosing schedule. The study included

patients with adverse disease characteristics including patients

with del(17p), TP53 mutation, unmutated IGHV, and Rai stage

≥ III; patients with R/R disease received a median of two prior

therapies (range: 1–10), none of which were alternative BTKis.

Antiplatelet or anticoagulant therapies were allowed.

At a median follow-up of 13.7 months, 89 of 94 patients

(94.7%) remained on study; of the 78 evaluable patients, two

patients (2.6%) achieved a complete response (CR), 63 patients

(80.8%) achieved a PR and 10 patients (12.8%) achieved a PR

with lymphocytosis (PR-L) [44]. All 16 patients with del(17p)

and TP53 mutation responded to zanubrutinib. The estimated

1-year progression-free survival (PFS) was 100%. Zanubrutinib

was well tolerated with the majority of adverse events (AEs)

grade 1 or 2, and approximately 36% were grade 3 or 4 in

severity. The most common grade ≥ 3 AEs were neutropenia

(n = 6), pneumonia (n = 2), hypertension (n = 2), and anemia (n

= 2). No deaths were reported. Notable AEs included one

patient with grade 2 atrial fibrillation and one patient experienced a grade 3 subcutaneous hemorrhage while also receiving concomitant aspirin.

The updated analysis of 123 patients reported ORRs and CRs

of 100% (95% CI: 84.6–100) and 22.7% in TN and 95% (95% CI:

88.8–98.4) and 17.8% in R/R CLL patients after a median followup of 54.1 months and 43.7 months, respectively [61].

Encouragingly, responses deepened with time and remained

durable. Among patients with del(17p) or TP53 mutations, objective responses were seen in 100% (95% CI: 47.8–100) and 84.2%

(95% CI: 60.4–96.6) of patients with TN and R/R disease. The

median PFS was not reached (95% CI: 41.4 months-NE) and

estimated to be 61.4 months (95% CI: 50.4-NE) for the TN and

R/R cohorts. The 3-year PFS and OS rates were 83% (95% CI: 74–

89) and 91% (95% CI: 84.4–95.2), respectively. Forty-six patients

discontinued zanubrutinib of whom 26 patients (21.1%) terminated treatment due to progressive disease and 12 (9.8%) discontinued due to AEs. Almost three-fourths of patients

experienced a grade ≥ 3 AE and 62.6% experienced a serious

AE. Common AEs mirrored those reported with other BTKis:

infections, bruising/minor bleeding and diarrhea. The incidence

of grade 3 and above infection (15.4%), neutropenia (15.4%),

hypertension (4.1%), and major hemorrhage (1.6%) decreased

over time. Cardiac AEs including atrial fibrillation or flutter

remained consistently low.

Additional phase I/II trials demonstrated zanubrutinib’s efficacy and safety in Chinese patients with R/R CLL [43,63]. The

phase I trial reported an ORR of 100% (95% CI: 66.4–100; n = 9)

and 33% CR rate (95% CI: 7.5–70.1%), respectively [43].

Similarly, among 91 evaluable patients 84.6% (95% CI: 75.5–

91.3) achieved a response which was also achieved in 86% of

the patients with del(17p)/TP53 mutation, 82% with unmutated IGHV, and 83% with refractory CLL [63]. With a median

follow-up of 12.9 months, the 1-year estimated PFS and OS

EXPERT REVIEW OF HEMATOLOGY 5

rates were 87.2% and 95.6%, respectively. Congruent with

zanubrutinib’s reported safety profile, the frequently reported

all grade AEs included neutropenia (69.2%), upper respiratory

tract infection (45.1%), thrombocytopenia (41.8%), hematuria

(39.6%), and petechiae/purpura/contusion (35.2%); the most

common grade ≥ 3 events included infection (38.5%), neutropenia (44%), and thrombocytopenia (15.4%). Eight patients

(9%) discontinued treatment due to AEs. Results from

a pooled post-hoc analysis of 211 patients further validated

the promising clinical outcomes and tolerability of zanubrutinib [43,44,63,64].

Phase II data demonstrated similar efficacy and safety profiles between zanubrutinib 320 mg daily and 160 mg twice

daily, affirming a previous hypothesis generated from exposure-response analyses in mantle cell lymphoma patients

[47,54]. Among 25 patients who received daily dosing once,

the ORR and disease control rate (DCR) were 54.2% (95% CI:

32.8–74.5%) and 91.7% (95% CI: 73–99%), respectively [54].

Similarly, patients who received zanubrutinib 160 mg twice

daily achieved an ORR of 70% (95% CI: 53.5–83.4%) and DCR

of 95% (95% CI: 83.1–99.4). Regardless of the dosing regimen,

almost all patients experienced at least one adverse event.

Grade ≥ 3 and serious AEs were reported in 32% and 16% of

the patients treated with daily zanubrutinib compared to 29%

and 10% of the patients who received split dose zanubrutinib.

Treatment-related discontinuations occurred in three patients

in the once daily group and two patients in the twice daily

dosing group. However, a higher proportion of patients who

received split dose zanubrutinib developed neutropenia (n = 8;

19%) versus once daily dosing (n = 2; 8%).

5.5. Treatment naïve

The SEQUOIA trial was a key phase III, multicohort study

comparing zanubrutinib with BR in older patients or patients

with comorbidities and TN CLL without del(17p) [65,66]. The

primary analysis demonstrated that patients without del(17p)

treated with zanubrutinib achieved a superior median PFS

compared to BR (95% CI: 0.28–0.63; HR 0.42; p < 0.0001 [65].

The 24-month PFS by the independent review committee was

85.5% (95% CI: 80.1–89.6) in the zanubrutinib arm versus

69.5% (95% CI: 62.4–75.5%; HR 0.42; p < 0.0001) in the BR

arm. The ORRs and CRs per the independent review committee were 94.6% and 7% versus 85.3% and 15% in the zanubrutinib and BR cohorts, respectively. The median OS was not

reached in either group, but there was no difference in the 24-

month OS rates (HR 1.07; 95% CI: 0.51–2.22; p = 0.87). The

extended follow-up showed sustained PFS benefit regardless

of IGHV mutation status [66]. At a median follow-up of 43.7

months, the median PFS was NE in patients treated with

zanubrutinib and 42.2 months in patients who received BR

(HR 0.3; 95% CI: 0.21–0.43; p < 0.0001). The 42-month PFS

was 82.4% in the zanubrutinib arm compared to 50% in the

BR arm. The response rates also deepened over time with

17.4% and 21.8% of the patients achieving a CR/CRi in the

zanubrutinib and BR groups, respectively. The 42-month OS

was similar between the two cohorts.

A separate cohort of patients with del(17p) was evaluated

in a single-arm study of zanubrutinib due to data suggesting

inferior outcomes with CIT in this patient population [65,66].

With a median follow-up of 30.5 months, the median PFS was

not reached, and the estimated 24-month PFS was 88.9% (95%

CI: 81.3–93.6). The 24-month OS was 93.6% (95% CI: 87.1–

96.9). Longer follow-up of approximately four years revealed

continued benefit with zanubrutinib in this historically difficult

to treat population; the 42-month PFS and OS rates were

79.4% and 89.5%, respectively. Similar to the cohort without

del(17p), the response rate was high at 90% (95% CI: 82.8–

94.9) although primarily PRs. Six percent of patients achieved

a CR at the time of the primary analysis, but the CR/CRi

improved to 14.5% with extended follow-up.

6. ALPINE trial

The results of the ALPINE trial confirmed zanubrutinib’s efficacy and safety for the treatment of CLL leading to its U.S. FDA

approval in both the upfront and R/R setting on

19 January 2023 [67].

ALPINE was a phase III, randomized, international, openlabel trial directly comparing zanubrutinib to ibrutinib in adult

patients with R/R CLL. Patients were randomized 1:1 to zanubrutinib 160 mg by mouth twice daily or ibrutinib 420 mg by

mouth once daily until disease progression or unacceptable

toxicity [68–70].

The interim analysis demonstrated that the primary endpoint of investigator-assessed ORR was superior in patients

treated with zanubrutinib (78.3%; 95% CI: 72–83.7) compared

to ibrutinib (62.5%; 95% CI: 55.5–69.1, p = 0.0006).

Zanubrutinib also demonstrated improved efficacy in patients

with del(17p)/TP53 mutation with response rates of 80.5%

(95% CI: 65.1–91.2) and 50% (95% CI: 33.4–66.6%) in the

zanubrutinib and ibrutinib arms, respectively. Responses

determined by blinded independent central review (ICR)

were consistent with the investigators. The final analysis confirmed the benefit of zanubrutinib with investigator-assessed

response rates of 83.5% (95% CI: 79–87.3) and 74.2% (95% CI:

69–78.8) and similarly encouraging responses of 81.3% (95%

CI: 70.7–89.4) and 64% (95% CI: 52.1–74.8%) among patients

with del(17p)/TP53 mutation.

With a median follow-up of 29.6 months, the median PFS

was not reached in patients who received zanubrutinib and

34.2 months (95% CI: 33.3-NE) in patients treated with ibrutinib. Further, the PFS per investigator assessment was superior

in the zanubrutinib compared to ibrutinib arms (HR 0.65; 95%

CI: 0.49–0.86; p = 0.002). The 12-month PFS rate was significantly higher in the zanubrutinib (94.9%) versus ibrutinibtreated patients (84%; HR 0.4; 95% CI: 0.23–0.69, p = 0.0007)

and continued to favor zanubrutinib (78.4%) over ibrutinib

(65.9%; HR 0.54, 95% CI: 0.49–0.86; p = 0.002) at 24 months.

Among the high-risk subgroup of patients with del(17p)/TP53

mutated disease, the 12- and 24-month PFS rates remained

numerically higher at 91.5% and 72.6% compared to 74.4%

and 54.6% in the zanubrutinib and ibrutinib arms, respectively.

The median OS was not reached in either group at the time

of data cutoff. However, fewer deaths were reported in the

zanubrutinib group (n = 48) versus the ibrutinib group (n = 60)

with a hazard ratio for death of 0.76 (95% CI: 0.51–1.11).

6 A. HATASHIMA AND M. SHADMAN

Following an extended overall study follow-up of 36.3

months, updated efficacy results demonstrated sustained

response rates, PFS and OS in patients treated with zanubrutinib

over ibrutinib in the R/R setting [70]. With a median treatment

duration of 34.7 months and 31.5 months, ORRs remained significantly higher at 85% in the zanubrutinib cohort compared to

74.8% (p = 0.001) in patients treated with ibrutinib, driven by

deepening rates of CR/CRi and PR-L or better. PFS continued to

favor zanubrutinib, including patients with del(17p)/TP53

mutated disease where 36-month PFS rates were 64.9% and

58.6% in the zanubrutinib group compared to 54.8% (HR 0.68;

95% CI: 0.53–0.86; p = 0.0011) and 41.3% (HR 0.52; 95% CI: 0.32–

0.83; p = 0.0047), respectively. The authors performed sensitivity

analyses for PFS. In these models that (1) only included progressions that occurred while on treatment, (2) censored patients

who switched to other therapies in the absence of progressions

and (3) after censoring death due to COVID-19, the PFS remained

significantly superior in the zanubrutinib arm compared to the

ibrutinib arm. OS was similar (HR 0.75; 95% CI: 0.54–1.05; p =

0.098) with 36-month OS rates of 82.5% and 79.6% in the zanubrutinib and ibrutinib arms.

7. Zanubrutinib efficacy following other BTKi

One of the current unknowns in CLL treatment is the optimal

sequencing of BTKi therapy. Preliminary efficacy results of

patients intolerant to ibrutinib and/or acalabrutinib demonstrated continued and in some patients improved response

rates with zanubrutinib [54,71]. With a median zanubrutinib

exposure of 11.6 months and 9.8 months, 36 previously ibrutinib

intolerant patients and five previously ibrutinib and/or acalabrutinib intolerant patients experienced a disease response resulting

in an ORR of 64.1% (95% CI: 51.1–75.7%) [54]. Approximately 94%

of the patients achieved clinical benefit with zanubrutinib. If

patients who were ineligible for a PR due to low baseline disease

burden were excluded, the ORR improved to 73.2% (95% CI:

59.7–84.2%). The 18-month PFS was 83.8% (95% CI: 62.6–

93.6%), and the median PFS was not reached.

An extended follow-up of 27 acalabrutinib intolerant patients,

13 of whom were also ibrutinib intolerant, reasserted the efficacy

of zanubrutinib in this patient population [71]. Seventy percent

of patients had a diagnosis of CLL. Nineteen patients received

zanubrutinib 160 mg twice daily and the remaining patients

received 320 mg once daily. With a median time on zanubrutinib

of 11.4 months, 24 of 25 efficacy-evaluable patients achieved

disease control and 16 patients achieved a minor response or

better. Among the 17 efficacy-evaluable patients with CLL, PR-L

or better was reported in 12 patients.

8. Safety

8.1. Ibrutinib

At present, the duration of BTKi therapy remains indefinite and

efficacy is predicated on long-term drug tolerability. An analysis

of low- and moderate-AEs from the E1912 trial highlighted the

impact of grade 1 and 2 BTKi-related AEs raising the odds of

higher treatment side effect bother as well as the association of

grade ≥ 2 AEs with increased odds of treatment discontinuation

[72]. In addition, grade ≥ 2 symptomatic AEs differentially contributed to increased side-effect bother compared to asymptomatic AEs, thus emphasizing the significance of and perhaps

underappreciation for seemingly low grade toxicities.

As the first-in-class irreversible, covalent BTKi, ibrutinib’s

toxicity profile has been extensively described in the literature

and increasingly well appreciated in clinical practice.

Prolonged ibrutinib therapy is plagued by on- and off-target

adverse effects: bleeding, infections, diarrhea, rash, arthralgias,

hypertension, and cardiac toxicities, most notably atrial fibrillation and ventricular arrhythmias [18,32,73]. A recent posthoc safety analysis of the ELEVATE-RR trial demonstrated

higher exposure-adjusted incidence rates of diarrhea, arthralgia, muscle spasms, urinary tract infections, and dyspepsia in

patients treated with ibrutinib [74]. The exposure-adjusted

incidence rates of all grade atrial fibrillation, hypertension,

and bleeding were 2.0-, 2.8-, and 1.6-fold higher with ibrutinib

and contributed to worse AE burden. Ventricular arrhythmias

and sudden cardiac death were rare but reported in three and

one patient, all of whom were in the ibrutinib arm.

While efforts have been made to guide clinicians to manage

ibrutinib induced side effects, patients struggle to remain adherent to therapy [73,75,76]. Discontinuation rates due to toxicities

have been noted to range from 12 to 42% in clinical trials

[18,26,31,72,77–79]. Further, real-world analyses report ibrutinib

treatment discontinuation of 63% in the frontline and up to 50%

in the relapse/refractory settings [80–82]. To prevent cessation of

therapy, treatment interruptions and dose reductions have been

utilized with mixed conclusions on the impact of these strategies

on clinical outcomes [81,83–86].

8.2. Acalabrutinib

While associated with overlapping AEs, acalabrutinib is associated with an improved safety profile compared to ibrutinib,

largely due to its increased selectivity for BTK. Given the

importance of treatment adherence, it is worthwhile to recognize that acalabrutinib discontinuation rates due to AEs are

relatively low, ranging from 9% to 21% [15,37,87].

Relative to ibrutinib, acalabrutinib is associated with

a milder cardiac toxicity profile versus ibrutinib. When compared head-to-head the rate of all-grade atrial fibrillation has

been shown to be significantly lower with acalabrutinib and

despite extended treatment durations, the annual incidence

rates of atrial fibrillation did not increase with time [15,74,87].

Infections while on BTKi therapy are common and reported

at similar incidences between acalabrutinib and ibrutinib [74].

All-grade infections may occur in over 70% of patients with

grade ≥ 3 infections ranging from 15% to 30% [15,34,36,87].

Major and minor bleeding as well as hypertension are class

effects of BTKis that are seen with acalabrutinib, albeit at reduced

frequencies compared to ibrutinib [15,87]. Consistently across

trials, all grade and grade ≥ 3 bleeding and hypertension events

occurred less often with acalabrutinib compared to ibrutinib.

Similarly, arthralgias, rash, and diarrhea are observed with

reduced frequencies in acalabrutinib treated patients compared

to ibrutinib.

Unique to acalabrutinib, headaches are reported with

increased frequency compared to ibrutinib [74]. In a pooled

EXPERT REVIEW OF HEMATOLOGY 7

analysis, 38% of the patients experienced headaches, the

majority of which were grade 1 or 2 [87]. Clinical trial data

have reported the incidence of headaches from 35% to 51%

[15,33,88]. Headaches most often occur within the first three

weeks of therapy and self-resolve with continued acalabrutinib

exposure.

8.3. Zanubrutinib

Zanubrutinib’s optimized PK/PD profile and targeted kinase

selectivity aimed to reduce the toxicity burden and lower the

barrier to sustained compliance as compared to ibrutinib and

acalabrutinib. Consistent with the safety data from pooled

analyses, the ALPINE trial reaffirmed zanubrutinib’s improved

tolerability compared to ibrutinib [69,89,90]. Discontinuation

rates due to treatment-emergent AEs from studies of

patients with B-cell malignancies ranged from 7% to 12%

[54,89,90].

Phase III data from the SEQUOIA trial were congruent with

pooled data showing similar discontinuation rates of 8% and

14% with zanubrutinib and BR, respectively [65]. However,

after a median treatment duration of 28.4 months in the zanubrutinib and 24.3 months in the ibrutinib arm, the ALPINE trial

noted 53 patients (16.2%) and 74 patients (22.8%) discontinued treatment due to adverse events [69]. With extended

follow-up, zanubrutinib discontinuation rates due to drug tolerability remained lower with zanubrutinib (20.2%) compared

to ibrutinib (24.9%) [70]. Fatal adverse events occurred in 33

patients (10.2%) and 36 patients (11.1%) in the zanubrutinib

and ibrutinib treated groups, respectively.

The incidence of any grade cardiac adverse events was

noted to be higher in patients who received ibrutinib

(29.6%) versus zanubrutinib (21.3%) and lead to treatment

discontinuation in 14 patients (4.3%) in the ibrutinib group

compared to one patient (0.3%) in the zanubrutinib group

[69]. Notably, any grade and grade 3 or higher atrial fibrillation/flutter were reported 4% and 2.5% and 13.3% and 5.2% of

patients in the zanubrutinib and ibrutinib cohorts, respectively. With extended follow-up, fewer cardiac complications

including atrial fibrillation were seen with zanubrutinib compared to ibrutinib (6.2% vs 16%; p < 0.001) [70]. All six deaths

due to cardiac events occurred in the ibrutinib arm [69,70].

At the time of the original analysis of the ALPINE trial, anygrade infection rates were similar between the two arms

(71.3% vs 73.1%), but COVID-19 and upper respiratory tract

infections occurred more frequently in the zanubrutinib group

and remained higher after 36 months of follow-up [69].

Further, higher incidences of grade 3 or higher neutropenia

and hypertension occurred in 16% and 14.8% of the patients

in the zanubrutinib arm and 13.9% and 11.1% in the ibrutinib

arm, which remained consistent with extended follow-up [70].

Overall, lower incidences of diarrhea, arthralgias, rash, fatigue, and muscle spasms occurred in patients who received

zanubrutinib [69]. Adverse events of special interest including

all-grade hemorrhage (42.3% vs 41.4%), neutropenia (29.3% vs

24.4%), and hypertension (23.5% vs 22.8%) were observed at

similar or slightly increased frequencies in patients treated

with zanubrutinib versus ibrutinib. Consistent with the

ALPINE trial, the rate of all grade bleeding in the SEQUOIA

trial was similar at 49%; however, all-grade neutropenia was

significantly lower at 17% [66]. The SEQUOIA trial also

reported a lower rate of all-grade hypertension of 18% in

patients who received zanubrutinib which was comparable

to those treated with BR. However, the hypertension rate in

the zanubrutinib arm of the ASPEN trial was not different from

the ALPINE trial and slightly lower in the ibrutinib arm among

patients with Waldenstrom Macroglobulinemia [91].

Similar to early phase trials, rates of infections, neutropenia

and hemorrhage tended to plateau or trend down over time

[61,89,90]. In addition, the risk of atrial fibrillation/flutter does

not appear to be temporally related to zanubrutinib exposure.

The absence of new safety signals with prolonged treatment

duration supports zanubrutinib as a potent yet well-tolerated

treatment option.

8.3.1. Zanubrutinib for ibrutinib or acalabrutinib

intolerance

Shadman and colleagues recently published data from an

ongoing phase II study evaluating zanubrutinib in patients

who were intolerant of ibrutinib alone (cohort 1; n = 57) or

intolerant of both ibrutinib and acalabrutinib (cohort 2; n = 27)

[57,58]. Patients with CLL accounted for the majority of represented disease states in each group: 78% (cohort 1) and 70%

(cohort 2). A total of 62 patients experienced 115 ibrutinib

intolerance events, and 27 patients experienced 40 acalabrutinib intolerance events. Following a median zanubrutinib

exposure of approximately 11.5 months in each cohort, 60%

of the ibrutinib-intolerant patients did not report a recurrence

of their intolerance event which accounted for 70% of ibrutinib intolerance events. Ibrutinib intolerance events that

recurred most commonly included fatigue, arthralgia, rash,

and hemorrhage. Sixty-three percent of patients did not report

recurrence of their acalabrutinib intolerant event representing

70% of acalabrutinib intolerance events.

Of the 34 ibrutinib and 12 acalabrutinib recurrent events,

none recurred at a higher grade with zanubrutinib. Twentyseven (79%) of ibrutinib intolerance events and five (13%) of

acalabrutinib intolerance events recurred at lower severities.

No patients who experienced a recurrent ibrutinib intolerance

event discontinued treatment while two patients with acalabrutinib intolerance events discontinued zanubrutinib due to

recurrent myalgias and diarrhea.

8.4. Quality of life

Due to the necessity for prolonged treatment durations,

patient reported outcomes to assess health-related quality of

life (HRQoL) associated with BTKi use are paramount to understand barriers to compliance and inform clinical decisionmaking. Prior evidence suggests that BTKis may improve

HRQoL over chemoimmunotherapy [18,92–94]. However,

covalent BTKis are responsible for a spectrum of undesirable

on- and off-target side effects, potentially diminishing the

positive effects of treatment and resulting in poor HRQoL.

Patient reported outcomes were evaluated in the ALPINE

trial to assess the impact of zanubrutinib versus ibrutinib

monotherapy on HRQoL indicators [95]. Patients treated with

zanubrutinib experienced clinically meaningful improvements

8 A. HATASHIMA AND M. SHADMAN

in global health status as well as physical and role functioning

compared to ibrutinib through the first year of treatment.

When evaluating symptom-specific parameters, patients

experienced clinically meaningful improvements in fatigue

and pain at 6 months and 12 months after starting zanubrutinib; however, patients did not report a clinically meaningful

improvement in diarrhea from baseline and nausea/vomiting

remained stable.

Improvements in patient reported outcomes among

patients without del(17p) treated with zanubrutinib are further

corroborated by a similar QoL analysis from the SEQUOIA trial

[94]. Patients were asked to complete HRQoL assessments at

weeks 12 and 24 of treatment; zanubrutinib maintained or

improved patients’ functional abilities and symptom scores

at both timepoints with the exception of pain. Furthermore,

by week 24, patients in the zanubrutinib group reported significant improvements in overall global health status/QoL

scores compared to the BR group.

In addition, Levy and colleagues conducted a qualityadjusted time without symptoms of disease and toxicity

(Q-TWiST) analysis within the ALPINE trial to elucidate the

impact of zanubrutinib and ibrutinib on quality-adjusted survival [96]. With a median duration of follow-up of 29.6 months,

patients with del(17p) and/or TP53 mutated CLL experienced

a relative Q-TWiST gain of 9.14% and an estimated difference

in mean Q-TWiST gain of 2.4 months (95% CI: 1.9–2.9; p <

0.001) favoring zanubrutinib. Taken together, zanubrutinib

appears to be associated with a reduced toxicity burden and

favorable duration and quality of survival relative to ibrutinib

[95,96].

9. Resistance mechanisms with zanubrutinib

Aside from BTKi intolerance, the Achilles heel of ongoing covalent BTKi efficacy remains drug resistance. Acquired mutations,

first identified in patients treated with ibrutinib, predominantly

occur at the Cys481 residue in the ATP binding pocket of BTK

[43,54,77,97–100]. However, mutational analyses have shown

that alterations at BTK Cys481, non-Cys481 mutations, and

downstream gain-of-function mutations in PCLγ2 have been

implicated at times of disease progression with ibrutinib, acalabrutinib, and zanubrutinib [43,54,100–103].

Contrary to ibrutinib and acalabrutinib, the genetic mechanisms of resistance to zanubrutinib are less well described. In

order to characterize resistance mutations to zanubrutinib and

ibrutinib, Brown and colleagues performed next generation

sequencing on peripheral blood samples of patients enrolled

in the ALPINE trial who progressed on either therapy [100]. Of

the 52 patients included in the analysis, nine patients (17.3%)

acquired a BTK or PCLγ2 mutation. Baseline BTK mutations were

not detected in any patients, but one patient in each arm was

found to have a baseline PCLγ2 mutation. Eight patients

acquired a BTK mutation, five treated with zanubrutinib and

three with ibrutinib; two patients both in the ibrutinib group

had PCLγ2 mutations. One patient had both BTK and PCLγ2

mutations. Single nucleotide variants (SNV) at C481 were the

most common mutation in BTK, comprising 11 and three out of

18 total SNVs in patients who received zanubrutinib and ibrutinib, respectively. Non-C481 and L528W mutations were less

common and occurred in three (12.5%) and two patients (8%)

who progressed on zanubrutinib.

However, previous reports have elucidated the potential

clinical importance and increased prevalence of BTK L528W

mutation in patients progressing on zanubrutinib over ibrutinib [43,100,103]. Mutational analyses from the BRUIN trial also

identified BTK L528W as a co-occurring mutation at the time

of pirtobrutinib progression, suggesting that this ‘kinase-dead’

mutation contributed to secondary pirtobrutinib resistance

[104,105]. As the L528W mutation was not prevalent with

earlier covalent BTKi, the emergence of L528W mutations

with zanubrutinib and subsequent enrichment of the same

variant over time with pirtobrutinib use may be suggestive of

cross-resistance between the two inhibitors [102].

In addition to zanubrutinib’s shared resistance mutation, it

should be noted that T474× gatekeeper mutations have been

identified as mutations conferring resistance to pirtobrutinib

as well as acalabrutinib [104–107]. Acquired T474× mutations

were identified in 26% of the patients enrolled in the BRUIN

trial and the most common BTK mutation identified in patients

who progressed on pirtobrutinib [104]. However, despite frequent baseline BTK mutations, pirtobrutinib demonstrated

efficacy in patients with heavily pretreated disease, prone to

developing new resistance mechanisms, and achieved

response in 83% of the patients.

10. Combination regimens with zanubrutinib

Regimens including zanubrutinib coupled with other proven

targeted therapies are being explored to capitalize on potential synergistic mechanisms of inhibition for enhanced efficacy.

Early phase data have yielded promising results propelling

zanubrutinib’s inclusion in many ongoing trials for both treatment naïve and R/R CLL patients (Table 3).

10.1. Zanubrutinib + venetoclax ± obinutuzumab

The original analysis from the multicenter, phase II trial of zanubrutinib, obinutuzumab and venetoclax (BOVen) was previously

published [108]. In brief, BOVen was an MRD-driven discontinuation study of patients with TN CLL; zanubrutinib 160 mg twice

daily was initiated with cycle 1 followed by obinutuzumab administered cycles 2 through 8 and venetoclax starting with cycle 3

for a duration of 8–24 cycles. Starting with cycle 7, if patients

achieved undetectable MRD (uMRD; <10−4) in PB and BM, treatment was discontinued. If patients met criteria for retreatment or

experienced biopsy-proven disease progression, zanubrutinib

and venetoclax were resumed. Eighty-five percent of patients

with the intention of treating the population achieved the primary endpoint of uMRD in both peripheral blood and bone

marrow. All patients responded to treatment at a median time

of uMRD in BM of 8 months; twenty-one patients (57%) achieved

a CR or CR with incomplete marrow recovery. Eighty-nine percent of patients were able to meet the prespecified MRD criteria

to discontinue treatment at which time 45% of the patients had

a PR and 55% had a CR or CR with incomplete marrow recovery.

At a median 15.8 months of post-treatment surveillance, 31

patients (94%) had sustained uMRD in PB.

EXPERT REVIEW OF HEMATOLOGY 9

A recent update reported results from 50 efficacy evaluable

CLL patients after a median follow-up of 40 months [109].

Ninety-six percent and 92% of the patients had uMRD in PB

and PB plus BM following a median duration of therapy of 10

cycles. Of the patients who met the criteria to stop treatment,

the MRD-free survival was 29.8 months. Further, supporting

the potential importance of ΔMRD400, defined as ≥ 400-fold

reduction in PB MRD at C5D1, of the patients with uMRD in PB,

those who met the definition of ΔMRD400 benefited from

a significantly longer MRD-free survival versus patients who

did not (not reached vs 18.1 months; p = 0.003). The signal of

ΔMRD400 as a predictive biomarker has led to a future phase II

trial using ΔMRD400-guided treatment duration to improve

uMRD duration and theoretically survival outcomes.

10.2. Zanubrutinib + obinutuzumab

Zanubrutinib is an attractive pairing with obinutuzumab

owing to its improved kinase specificity; relative to ibrutinib,

zanubrutinib spares off-target ITK inhibition of Fc receptor

stimulated NK cell function and consequently retains antiCD20 monoclonal antibody-dependent cellular cytotoxicity

[110]. A phase Ib/II trial evaluated the combination of zanubrutinib plus obinutuzumab in TN and R/R CLL patients [111].

Phase Ib assessed the tolerability of zanubrutinib 320 mg daily

and 160 mg twice daily with intravenous obinutuzumab for 6

total cycles per FDA labeling. This cohort included 12 patients,

five of whom were diagnosed with CLL; since a dose limiting

was not identified, both zanubrutinib dosing schemas were

considered acceptable for phase II. The efficacy evaluable

phase II cohort of CLL patients included five from part I and

an additional 40 patients, 20 of whom were TN and 25 with R/

R disease. The ORR and CR rates were 100% and 30% in

patients with TN CLL and 92% and 28% in patients with R/R

CLL. In the subset of patients with del(17p), 100% and 50% of

TN patients and 80% and 20% of R/R patients achieved an

objective response and CR, respectively. The estimated 24-

month event-free survival was 90.4% (95% CI: 76.5–96.3%),

and the median PFS was not reached. The combination zanubrutinib plus obinutuzumab was well tolerated as almost

three-fourths of patients remained on the study at data cutoff;

five patients stopped treatment due to disease progression

and four patients discontinued due to AEs.

10.3. Zanubrutinib + sonrotoclax (BGB-11417)

The combination of a BTKi plus B-cell lymphoma 2 (BCL2)

inhibitor is an attractive pairing based on synergistic activity

demonstrated in preclinical models. The combination of ibrutinib and venetoclax has demonstrated improved efficacy

compared to chlorambucil plus obinutuzumab in TN CLL

[112,113]. However, drug-induced toxicities may limit prolonged use.

Sonrotoclax is a second-generation, highly selective and

potent BCL2 inhibitor with encouraging in vitro efficacy

against BCL2 mutations [114]. BGB-11417-101 (NCT04277637)

is an ongoing phase I/II trial in patients with B-cell malignancies treated with sonrotoclax monotherapy, sonrotoclax plus

zanubrutinib and sonrotoclax plus obinutuzumab with or

without zanubrutinib. Tam and colleagues report results

from the cohort who received zanubrutinib plus sonrotoclax

in the upfront setting for CLL. Patients received zanubrutinib

320 mg once daily or 160 mg twice daily alone for 8 to 12

weeks prior to sonrotoclax initiation which was administered

according to a dose ramp-up schedule. Ninety-four patients

were enrolled and included 41 patients in the arm targeted to

receive sonrotoclax 160 mg daily and 53 patients in the arm to

received sonrotoclax 320 mg daily. However, 15 patients did

not progress to sonrotoclax and received zanubrutinib alone.

Despite a short follow-up of 8.5 months, no progression events

or deaths occurred and response was seen in all patients. CR

was achieved in nine patients (36%) in the sonrotoclax 160 mg

group and six patients (19%) in the sonrotoclax 320 mg group.

As an exploratory endpoint, peripheral blood uMRD was noted

in at least 50% of the evaluable patients who received sonrotoclax at weeks 24 and 48.

Table 3. Ongoing studies evaluating zanubrutinib in treatment naïve and relapsed/refractory CLL.

Clinical Trial

Number Phase Intervention Key Efficacy Endpoints

Treatment naïve

NCT04277637 I/II Zanubrutinib + Sonrotoclax (BGB-11417) Safety, MTD, RP2D

Sonrotoclax (BGB-11417) alone; Sonrotoclax (BGB-11417) +

Obinutuzumab ± Zanubrutinib

NCT04458610 II Zanubrutinib + Rituximab Treatment-free remission 6 months after discontinuation

of zanubrutinib

NCT05650723 II Zanubrutinib + Venetoclax ± Obinutuzumab consolidation for MRD

positivity

uMRD in PB & BM at cycle 16

NCT05718869 II Zanubrutinib + Tafasitamab Safety, CR rate

NCT05287984 II Zanubrutinib + FCR/BR MRD negative rate of patients with CR at the end of

cycle 16

NCT06073821 III Zanubrutinib + Sonrotoclax (BGB-11417) PFS

Venetoclax + Obinutuzumab

Relapsed/refractory

NCT05665530 I Zanubrutinib + PRT2527 Safety, MTD, RP2D

NCT05168930 II Zanubrutinib + venetoclax uMRD at the end of cycle 15

NCT05020392 III Zanubrutinib + Fludarabine-based chemotherapy + CD19-directed CAR-T

cells

Treatment-related AEs

Fludarabine-based chemotherapy + CD19-directed CAR-T cells

N/A: not applicable; MTD: maximum tolerated dose; RP2D: recommended phase 2 dose; uMRD: undetectable minimal residual disease; PB: peripheral blood;

BM: bone marrow; CR: complete response; PFS: progression free survival; CAR-T: chimeric antigen receptor T-cells; AE: adverse events.

10 A. HATASHIMA AND M. SHADMAN

The combination of sonrotoclax with zanubrutinib, regardless of the sonrotoclax dose, was well tolerated with the most

common treatment emergent AEs including neutropenia, diarrhea, and contusion. Grade 3 or higher neutropenia was

reported in 13 patients. Tumor lysis syndrome was not seen

in any patients on the weekly or daily sonrotoclax ramp-up

schedule. Based on these promising results, an open-label,

phase III trial (NCT06073821) is recruiting to evaluate sonrotoclax plus zanubrutinib against venetoclax plus obinutuzumab

in patients with TN CLL.

11. Noncovalent BTKi in CLL

11.1. Pirtobrutinib

Noncovalent, reversible BTKi, pirtobrutinib has emerged as an

attractive treatment option, especially as it retains activity

against wild-type and mutated C481S in BTK. The phase I/II

BRUIN trial evaluated the efficacy and safety of pirtobrutinib in

heavily pre-treated R/R CLL patients who progressed or were

intolerant to an alternative BTKi [115]. Patients had received

a median of three prior therapies (range: 1–11) and high risk

molecular features – del(17p) and/or TP53 mutation, complex

karyotype, and unmutated IGHV were common. The primary

endpoint of the overall response occurred in 73.3% (95% CI:

67.3–78.7) with four (1.6%) CRs. In a subset of patients who

received prior BTKi and BCL2 inhibitor, response was seen in

70% (95% CI: 60–78.8) of patients. An extended analysis with

more than two years of follow-up reported an overall response

rate of 72% (95% CI: 66.4–77.1%) in all patients who were

previously treated with a covalent BTKi [116]. In the subgroup

of patients who received a covalent BTKi in the first-line setting and pirtobrutinib as second-line treatment, the ORR

including PR-L was 89.5%.

At a median follow-up of 27.5 months, the median PFS was

19.4 months (95% CI: 16.6–22.1); the median PFS in patients

who received a BTKi but not BCL2 inhibitor was 23 months

and patients who received both therapies prior to pirtobrutinib had a median PFS of 15.9 months. The median OS was not

estimable for the entire cohort as well as the subgroups who

did or did not receive a prior BCL2 inhibitor. The 12-month,

18-month, and 24-month OS rates were 86% (95% CI: 81–

89.8%), 80.5% (95% CI: 74.8–85%), and 73.2% (95% CI: 67.4–

78.2), respectively.

The results from the BRUIN trial in R/R CLL patients revealed

that pirtobrutinib maintained efficacy regardless of prior BCL2

inhibitor exposure. Pirtobrutinib had an acceptable safety profile with only slightly higher rates of grade ≥ 3 neutropenia in

patients who previously received a BCL2 inhibitor and low

treatment discontinuation rates. Pirtobrutinib thus remains

an important next line of therapy particularly when deciding

to sequence therapies inhibiting the BTK pathway.

12. Conclusion

The promise of zanubrutinib rested in its favorable PK/PD to

maximize BTK occupancy throughout the entirety of the dosing interval and minimize sequelae associated with off-target

kinase inhibition. ALPINE was a pivotal, head-to-head trial of

zanubrutinib and ibrutinib in patients with R/R CLL [69]. To

date, this is the first and only trial to demonstrate the superiority of one BTKi over another. The primary analysis reported

higher investigator assessed ORR of 83.5% and 74.2% in the

zanubrutinib and ibrutinib arms, respectively. Superior investigator assessed PFS was also noted with 87 occurrences of

disease progression or death with zanubrutinib compared to

118 occurrences with ibrutinib (HR 0.65; 95% CI: 0.49–0.86; p =

0.002). The PFS benefit was upheld in the high-risk subgroup

of patients with del(17p) and/or TP53 mutation. Following

approximately three years of follow-up, the initial results

demonstrating improved outcomes with zanubrutinib

remained true. Reassuringly, complete responses deepened

with time and resulted in CR/CRi rates of 10.1% and 7.4% in

the zanubrutinib and ibrutinib arms, respectively [70].

Furthermore, phase II data using zanubrutinib in patients

with R/R B-cell malignancies showed that zanubrutinib retains

efficacy and can deepen responses after ibrutinib and/or acalabrutinib discontinuation due to treatment-related toxicities

[54,71].

The safety profile of zanubrutinib aligned with previous

trials: relative to ibrutinib, zanubrutinib spared cardiac toxicities including atrial fibrillation/flutter while any grade and

grade ≥ 3 infection rates remained comparable. However,

zanubrutinib-associated grade ≥ 3 neutropenia and hypertension were reported with increased frequencies. Lower rates of

dose interruption, reduction, and discontinuation due to AEs

were noted in the zanubrutinib arm. Albeit, drug-related treatment discontinuation was higher in zanubrutinib arm of the

ALPINE trial than prior reports.

Covalent BTKi resistance is a significant obstacle. The C481S

mutation originally described in ibrutinib-related resistance is

shared with zanubrutinib and an effective strategy for CLL

cells to escape leukemic control [90,100]. Non-C481S mutations in the BTK and PCLγ2 mutations also contribute to

resistance with a noteworthy mention of L528W which may

confer cross resistance to pirtobrutinib, significantly impacting

the potential sequencing of therapies and available options

after progression on a covalent BTKi. However, additional

studies are needed to fully elucidate the mechanisms of resistance to zanubrutinib and to compare and contrast mutational

frequencies with other covalent and noncovalent BTKis.

13. Expert opinion

The ALPINE trial continues to forge a path forward for zanubrutinib, building on the therapeutic groundwork laid by years

of trials and tribulations utilizing established covalent BTKis

and navigating the short- and long-term sequelae of BTKi

therapy.

Nonetheless, a notable hurdle remains: the toxicity of BTKi

therapy is not only restricted to its side effect profile but also

by its impact contributing to the financial burden of CLL

treatment as BTKi therapy is lifelong or until disease progression. A health-economic model using efficacy data from the

ALPINE trial was constructed to evaluate the economic impact

of zanubrutinib compared to ibrutinib [117]. The number

needed to treat the model showed that for every eight

patients treated with zanubrutinib one event of progression

EXPERT REVIEW OF HEMATOLOGY 11

or death would be spared compared to ibrutinib. Furthermore,

the relative cost savings per person using zanubrutinib over

ibrutinib was reported to be $59,593 suggesting not only

favorable clinical but also financial benefit of utilizing zanubrutinib in the R/R setting. While this data may provide temporary solace, the financial toxicities of treatment continues to

be a sobering reminder that much progress remains toward

the development of finite duration and novel treatment

options.

The list of FDA approved treatments either alone or in

combinations is relatively limited compared to the landscape

of investigational therapies for patients with R/R CLL. The most

pressing challenges to the current armamentarium of treatment options, namely covalent BTKis, are overcoming BTKi

AEs, combating drug resistance and preparing for the increasing prevalence of double exposed/double-refractory patients

[118,119]. Patients who are double-refractory as opposed to

those who are double exposed but not refractory have been

shown to have short PFS and OS, respectively. With each

subsequent line of therapy, survival outcomes diminish and

the population of double-refractory patients and beyond

represent an urgent unmet need.

In order to expand treatment options and improve on

outcomes with monotherapy inhibitors, many trials aim to

capitalize on dual mechanisms of action using a BTKi plus

BCL2 inhibitor with or without an anti-CD20 monoclonal antibody and resources are heavily invested in elucidating the

optimal combination of agents to prolong remission using

time-limited therapy and uMRD as a prognostic indicator

[120–123].

Second generation BCL2 inhibitors, sonrotoclax and lisaftoclax,

have also gained traction alone or in combination with existing

CLL therapies. Sonrotoclax may be of particular interest as it has

been shown to overcome the BCL2 G101V mutation conferring

resistance to venetoclax [124]. Thus, results of ongoing trials evaluating sonrotoclax monotherapy (NCT05479994) and sonrotoclax

plus zanubrutinib against venetoclax plus obinutuzumab

(NCT06073821) will be eagerly awaited. Similarly, lisaftoclax

showed early stage response and survival benefits in heavily pretreated CLL patients with primary toxicities including hematologic

and hypertriglyceridemia [125]. A global phase III trial of lisaftoclax

plus a BTKi versus BTKi monotherapy in previously treated CLL/SLL

patients is actively recruiting (GLORA study; NCT06104566) and

lisaftoclax plus acalabrutinib compared to CIT in TN CLL patients

(NCT06319456) is slated to open in the near future.

While recent fan fair has largely surrounded BTKis and

BCL2-targeted treatments, PI3K inhibitors, duvelisib, and idelalisib plus rituximab remain the FDA approved options and

are recommended in the guidelines after prior BTKi- and

venetoclax-based regimens [16,126–128]. However, a drug

class that was once a promising for R/R CLL has now fallen

out of vogue, especially following the withdrawal of FDA

approval of idelalisib monotherapy and umbralisib [129,130].

The burgeoning arsenal of novel BCR-targeted therapies, nextgeneration BTKis, and BCL-2 inhibitors as well as bi-specific

antibody drugs and cellular therapies may leave little promise

for PI3K inhibitors in the future of CLL treatment.

Targeting alternative drivers of CLL proliferation with agents

such as receptor tyrosine kinase-like orphan receptor 1 (ROR1)

monoclonal antibodies, oral BTK degraders, and CD19-directed

chimeric antigen receptor T-cell therapy have also ignited interest in patients with R/R disease [131–135]. Although in its

infancy, anti-ROR1 monoclonal antibody, cirmtuzumab, has

been shown to have activity in CLL cells without dose limiting

adverse effects, encouraging the pursuit of phase Ib/II studies

evaluating cirmtuzumab with ibrutinib (NCT03088878) and in

combination with venetoclax as consolidation therapy

(NCT04501939) [131]. Additionally, a first-in-human phase

I study of a ROR1-targeted bispecific T-cell engager, NVG-111,

is ongoing to evaluate the safety and PK/PD properties of this

novel antibody drug conjugate in patients with R/R ROR1+

malignancies including CLL (NCT 04763083).

First-in-human, phase I/Ia evaluations of BTK degraders, NX2127-001 (NCT04830137) and NX-5948-301 (NCT05131022), represent early advancements in small molecule therapies for patients

with R/R B-cell malignancies [132,133]. While limited in numbers

and duration of follow-up, among the efficacy evaluable CLL

patients who received one of the aforementioned BTK degraders,

the majority achieved PR or stable disease. In addition, encouraging results from the TRANSCEND CLL 004 trial using lisocabtagene maraleucel showed sustained and deepening CR/CRis

among patients with double refractory CLL after almost two

years of follow-up [134,135].

The exciting development of investigation drugs has capitalized on advancements in drug design, novel targeting pathways and cellular therapies, and demonstrates the tireless

ongoing work to continue the momentum of the last two

decades of CLL treatment. While the future is bright, the CLL

community must await mature results from BTKi combination

regimens and novel targeted therapies proving substantial

efficacy and toxicity benefits over available therapies. Until

that time, the ALPINE trial has shown that zanubrutinib

alone remains a promising potent, next-generation BTKi in

the R/R setting.

Funding

This paper was not funded.

Declaration of interest

M Shadman has acted as a consultant and has taken part in advisory

boards, steering committees, or data safety monitoring committees for

Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene,

Bristol Myers Squibb, Morphosys/Incyte, TG Therapeutics, Innate Pharma,

Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune,

Mustang Bio, Regeneron, Merck, Fate therapeutics, MEI pharma, and Atara

Biotherapeutics; and has received research funding from Mustang Bio,

Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, AbbVie,

TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics,

Genmab, and Morphosys/Incyte. The authors have no other relevant

affiliations or financial involvement with any organization or entity with

a financial interest in or financial conflict with the subject matter or

materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One reviewer has served as a consultant for Abbvie, Roche, and Sandoz;

and has received honoraria and research funding from Abbvie,

AstraZeneca, BeiGene, Amgen, Gilead, Celgene, and Janssen. Peer

12 A. HATASHIMA AND M. SHADMAN

reviewers on this manuscript have no other relevant financial relationships

or otherwise to disclose.

ORCID

Alycia Hatashima http://orcid.org/0000-0002-2978-3366

Mazyar Shadman http://orcid.org/0000-0002-3365-6562

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