Leukemia & Lymphoma

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Cardiac side effects of bruton tyrosine kinase (BTK)

inhibitors

Chloe Pek Sang Tang, Julie McMullen & Constantine Tam

To cite this article: Chloe Pek Sang Tang, Julie McMullen & Constantine Tam (2017):
Cardiac side effects of bruton tyrosine kinase (BTK) inhibitors, Leukemia & Lymphoma, DOI:
10.1080/10428194.2017.1375110

To link to this article: http://dx.doi.org/10.1080/10428194.2017.1375110

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Published online: 13 Sep 2017.

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 LEUKEMIA & LYMPHOMA, 2017
https://doi.org/10.1080/10428194.2017.1375110

REVIEW

Cardiac side effects of bruton tyrosine kinase (BTK) inhibitors

Chloe Pek Sang Tanga, Julie McMullenb and Constantine Tama
a
Department of Haematology, St Vincent’s Hospital Melbourne, Fitzroy, Australia; bBaker IDI Heart and Diabetes Institute, Melbourne,
Australia

ABSTRACT ARTICLE HISTORY

The development of bruton tyrosine kinase inhibitors (BTKi) has been a significant advancement Received 18 July 2017
in the treatment of chronic lymphocytic leukemia and related B-cell malignancies. As experience Revised 24 August 2017
in using ibrutinib increased, the first drug to be licensed in its class, atrial fibrillation (AF) Accepted 30 August 2017
emerged as an important side effect. The intersection between BTKi therapy for B-cell malignan-
KEYWORDS
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cies and AF represents a complex area of management with scant evidence for guidance. Bruton kinase inhibitor;
Consideration needs to be taken regarding the interplay of increased bleeding risk versus atrial fibrillation; ibrutinib
thromboembolic complications of AF, drug interactions between ibrutinib and anticoagulants
and antiarrhythmic agents, and the potential for other, as yet seldom reported cardiac side
effects. This review describes the current knowledge regarding BTKi and potential pathophysio-
logic mechanisms of AF and discusses the management of BTKi-associated AF. Finally, a review
of the second generation BTKi is provided and gaps in knowledge in this evolving field are
highlighted.

Background microenvironment are pivotal in the pathogenesis of

Mechanism of action of ibrutinib
Ibrutinib is an orally bioavailable bruton kinase inhibi-
tor (BTKi), which forms an irreversible covalent bond
to BTK at the Cysteine-481 residue [1,2]. However, its
binding profile is not restricted to BTK as it inhibits
other kinases such as ITK (interleukin-2-inducible T-cell
kinase), tec protein tyrosine kinase (TEC), BMX and epi-
dermal growth factor receptor (EGFR) [3]. It has proven
efficacy in several B-cell malignancies, including
chronic lymphocytic leukemia (CLL), mantle cell lymph-
oma (MCL), Waldenstrom’s macroglobulemia and mar-
ginal zone lymphoma, both in the upfront setting and
relapsed or refractory (R/R) setting [4–8]. Ibrutinib
induces apoptosis and reduces proliferation of malig-
nant CLL cells by downregulating B-cell receptor (BCR)
signaling and thwarts the supportive tissue microenvir-
onment for malignant cells by targeting chemokine-
controlled adhesion and migration of malignant cells
[9–11].
CLL is the most common form of adult leukemia
[12]. It is characterized by accumulation of malignant
mature B cells in the bone marrow, peripheral blood,
lymph node and spleen [13]. BCR-signaling pathways
and the interactions of the leukemic cells with its
the disease [14]. Autonomous BCR-signaling pathways
promote proliferation and survival of CLL cells [15].
The BCR is a multimer complex of membrane immuno-
globulin bound to heterodimers CD79a/CD79b.
Antigen ligation triggers the formation of BCR signalo-
some, consisting of protein tyrosine kinase (LYN),
spleen tyrosine kinase (SYK), BTK, phospholipase Cc2
(PLCc2) and phosphoinositide 3-kinase (PI3K)
(Figure 1). Phosphorylation of the signalosome results
in further activation of two main pathways: BTK and
PI3K-AKT [14].
BTK is a nonreceptor tyrosine kinase in the Tec fam-
ily of tyrosine kinases. BTK is primarily expressed in B
lymphocytes but not T lymphocytes and plasma cells
[16]. Following activation of BTK by SYK and LYN, BTK
in turn phosphorylates PLCc2 via B-cell linker protein
(BLNK). This subsequently leads to downstream
initiation of a signaling cascade consisting of nuclear
factor-jB (NF-jB), mitogen-activated protein kinase
(MAPK) and protein kinase Cb (PK Cb), resulting in cell
proliferation and transcriptional activation (Figure 1)
[17,18].
PI3Ks are divided into three classes (I, II and III) and
class I is further comprised of four isoforms (a, b, c, d).
The predominant form expressed by hematopoietic

CONTACT Constantine Tam Constantine.Tam@petermac.org 41 Victoria Parade, Fitzroy 3065, Victoria, Australia
ß 2017 Informa UK Limited, trading as Taylor & Francis Group
 2 C. P. S. TANG ET AL.
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Figure 1. B-cell receptor signalling pathways in chronic lymphocytic leukaemia. Abbreviations: BMSC: bone marrow stromal cells;
NLC: nurselike cell; FDC: follicular dendritic cell; NK cell: natural killer cell.
cells is the PI3Kd. PI3K forms PIP3 which in turns acti-
vates the Akt pathway by recruiting Akt to the plasma
membrane, thereby inhibiting apoptosis and promot-
ing cell survival by phosphorylating the proapoptotic
proteins Bad and FOX03a [19].
Both BTK and PI3K pathways regulate CLL cell
interactions with its tissue microenvironment [11,20].
CLL cells recirculate between peripheral blood, lymph
nodes and bone marrow within a tumor microenvir-
onment. This process of tissue homing and CLL traf-
ficking is a tightly regulated process whereby CLL
cells engage in crosstalk with a host of accessory
cells (e.g. nurse-like cells, T lymphocytes and bone
marrow stromal cells) in these proliferating compart-
ments. BTK and PI3K integrate signals from cell sur-
face receptors including CXCR4/5, CD40 and integrin,
enhancing chemostaxis to CXCL 12/13 expressed by
the accessory cells. These interactions serve to
improve CLL longevity and bypass immune-mediated
destruction [9,10,21].
Ibrutinib and CLL
Ibrutinib was first granted accelerated approval by the
US Food and Drug Administration (FDA) following the
pivotal trial published by Byrd et al. [4,22]. A total of
101 relapsed or refractory (R/R) patients received ibru-
tinib, with the majority of them being high-risk
patients (34% del (17p); 78% unmutated immuno-
globulin heavy chain (IGHV)). The overall response rate
(ORR) was 90% and estimated progression-free survival
(PFS) at 30 months was 69%. For patients with del
(17p) and del (11q), the median PFS was 28 months
and 38.7 months, respectively [4,22]. Subsequently,
several trials have validated the efficacy of ibrutinib
both in the upfront setting and in the R/R setting,
either as a single agent or as combination therapy
(Table 1). These studies heralded a paradigm shift for
the treatment of CLL patients, in particular those with
high-risk features such as TP53 dysregulation (deletion
or mutation), unmutated IGHV, those who are
 CARDIOTOXICITY OF BTK 3

conventionally refractory to fludarabine-based chemo-

97% and 79% for R/R

CR: complete response; mths: months; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; Pts: patients; RCT: randomized controlled trial; R/R: relapsed or refractory; TN: treatment naïve;
At 30mo, OS for TN was
therapy, as well as older or frail patients who may not

92.3 vs. 85 vs. 87.5

Not reached vs. 8.1 90 vs. 79 at 12 mo
84 vs 74 at 24 mo
tolerate toxicity related to standard chemotherapy
Not reached in

75% at 24 mo

83.8 at 18 mo
OS

both arms
[30]. High-risk patients treated with first-line chemo-

at 12 mo
95 vs. 84
therapy generally experienced abysmal outcomes with
reported median progression free survival for del 17p
and TP53 mutation of 19.2 months and 23.3 months

91 vs 80 at 24 mo
respectively [31]. Similarly, median overall survival was

75 at 12 mo
not reached

88.7 vs. 85 vs.

63% at 24 mo
23% for TN and 96% at 30 mo

78% at 18 mo
poor for del (17p) and TP53 mutation patients, at 19.2
PFS

months and 30.2 months, respectively [31]. The

89 vs. 84
13.3 vs.

updated result of the CLL8 trial suggests that FCR (flu-

darabine, cyclophosphamide and rituximab) chemoim-
munotherapy may represent the optimal first-line
0 vs. 5 vs. 0
2.8 vs. 10.4

7% for R/R

treatment for young and fit patients without adverse

8 vs 2
18 vs
8%
CR

8 high-risk features, especially in the era whereby min-

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imal residual disease (MRD) negativity may signify a

curative possibility [32,33]. However, for the older or
100 vs. 84 vs. 75
67.8 vs. 82.7

frail patients, the high morbidity from infections (13%)

92 vs. 36

97 vs. 80

63 vs. 4
83%
89%
ORR

and prolonged neutropenia (4%) of fludarabine-based

95

chemotherapy may prove to be intolerable [32].

Most of the longer-term outcomes from recent trials
as illustrated in Table 1 suggest that ibrutinib is very
32 vs. 33
Del 17p
0

100%
27

100%

44

40

well tolerated with a rapid and durable response. The

most common side effects from ibrutinib treatment
Follow-up

are diarrhea (59%), upper respiratory tract infection

Table 1. Trials demonstrating efficacy of ibrutinib in both upfront and relapsed or refractory CLL.

(mths)

28.6

12.5

16.8
9.4
17

28
36

24

(47%), bruising (51%) and fatigue (33%) [34]. These

events were predominantly mild (grade 1–2) in nature.
(yrs; median)

AF and bleeding are emerging as notable grade 3 side

Age

effects that warrant vigilant monitoring and AF will be

64

64
68

73

62

67
64

63

the focus of this review.

Bendamustine þ rituximab (BR)þ

Ibrutinib and mantle cell lymphoma (MCL)

placebo vs BR þ Ibrutinib

In 2013, ibrutinib first gained accelerated approval

Comparator

from FDA following pilot data published by Wang

et al. In this phase-2 study, 111 patients with relapsed
Ofatumumab
Chlorambucil

or refractory mantle cell lymphoma received a daily

dose of 560 mg and were followed up for a median
None
None

None

None

None

duration of 15.3 months. An overall response rate of

60% was achieved of which 21% achieved complete
ibrutinib and rituximab,
40 Phase-2, single-arm with
145 Phase-2, single-arm, R/R
132 Phase-2, single-arm, TN

85 Phase-2, single-arm, TN

remission. The estimated progression-free survival was

71 Phase-1b/2, single-arm,
R/R ibrutinib þ of
Study Design

13.9 months and overall survival was 58% at 18

months [35]. More recently, the updated data from
R/R and TN
atumumab

this cohort of patients with median follow-up of 26.7

and R/R

and R/R
578 RCT, R/R

391 RCT, R/R

269 RCT, TN

months showed a durable response with an overall

response rate of 67%, 24-month progression-free
survival and overall survival rate of 31% and 47%,
No.
pts

respectively [6].
Jaglowski 2015 [28]
Farooqui 2015 [26]

The efficacy of ibrutinib in treating R/R advanced

O’Brien 2016 [24]

Burger 2014 [29]

Byrd 2014 [27]

MCL was further validated by a phase-3, randomized,

Byrd 2015 [4]
Chanan-Khan
2016 [23]

2016 [25]

open-label trial comparing ibrutinib with temsirolimus.

Barr et al.,

yrs: years.

The ibrutinib arm demonstrated superior progression-

Trial

free survival (14.6 months vs. 6.2 months) and less

 4 C. P. S. TANG ET AL.

Table 2. Rate of detection of AF in ibrutinib trials.

Trial No of patients Study design Median follow-up Rate of AF AF grade 3 Discontinuation rate from AF
Coutre 2017 [45] 94 Phase–1b/2, Single arm 44mo 6% 6%
Chanan-Khan 2016 [23] 578 RCT 17 mo 7% Not reported 1%
O’Brien 2016 [24] 144 Phase-2, single arm 27.6mo 7% 6% 7% had dose reduction
Jain 2016 [46] 40 Phase-2, single arm (IR) 47 mo 7% 2%
Barr 2015 [25] 269 RCT 28.5 10% 6%
Farooqui 2015 [26] 85 Phase-2, single arm 24mo 2% 0%
Byrd 2015 [4] 132 Phase-2, single arm 36mo 6% 6%
Jaglowski [28] 71 Phase-1b/2, single arm 12.5mo 8.5% 3%
Byrd 2014 [27] 391 RCT 9.4mo 5% 3%
AF: atrial fibrillation; mo: months; RCT: randomized controlled trial.

grade 3 or higher adverse events (68% vs. 87%) after a Table 3. Rate of AF in phase-3 trials.
median follow-up of 20 months [36]. Trial Ibrutinib arm (%) Comparator arm (%)
Byrd 2014 (RESONATE) [27] 3 0
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Burger 2015 (RESONATE-2) [5] 6 1

Ibrutinib and Waldenstrom’s macroglobulinemia
(WM)
Waldenstrom’s macroglobulinemia (WM) is an IgM-
secreting lymphoplasmacytic lymphoma (LPL) [37]. The
L265P mutation in MYD88 is the most common acti-
vating somatic mutation in WM, present in more than
90% of patients [38,39]. Ibrutinib induces apoptosis of
WM cells by inhibiting the activation of nuclear factor-
jB (NF-jB) via the bruton tyrosine kinase’s pathway.
Following the landmark study published by Treon
et al., ibrutinib was approved for use in WM patients.
Significant improvement in overall response rate
occurred in all genomic subgroups. In particular,
responses occurred more rapidly in patients with a
MYD88L265P mutation and wild-type CXCR4, as CXCR4
mutation may confer resistance to ibrutinib. In CXCR4
wild-type patients, the ORR was 100%. Comparatively,
patients with both MYD88L265P and CXCR4 mutations’
had lower ORR of 85.7%. The two-year progression-
free survival and overall survival among all patients
were 69.1% and 95.2%, respectively [7]. A further study
of patients with rituximab-refractory WM confirmed
the high single-agent activity of ibrutinib in WM [40].
Ibrutinib and AF
Evidence from trials
Ibrutinib has proven to be highly efficacious with
remarkable depth of response in B-cell malignancies
with an acceptable toxicity profile. However, AF
appears to be a significant treatment-emergent side
effect that warrants closer inspection. Interestingly,
this phenomena is not seen in patients with X-linked
agammaglobulinemia (XLA), a primary immunodefi-
ciency disease characterized by BTK deficiency second-
ary to BTK gene mutations, implying that other
kinases may be involved in the pathophysiology of
Chanan-Khan 2016 (HELIOS) [23] 7 2
Dreyling 2015 [36] 3 1
ibrutinib-induced AF [41]. In a recent meta-analysis of
20 studies investigating the impact of AF in ibrutinib-
treated patients, the pooled rate of AF was 3.3 per
100 person-years over a median follow-up of 26
months. This was comparatively higher than the noni-
brutinib-treated patients and age-matched general
population (0.84 per 100 person-years and 0.55 per
100 person-years, respectively) [42]. Similarly, Shanafelt
et al. reported 10-year retrospective data on the preva-
lence of AF in 2292 newly diagnosed patients on ibru-
tinib without prior history of AF and found an
incidence rate of 6.1% [43]. Another study reported
figures as high as 16% after a median follow-up of 28
months [44]. Data from long-term follow-up studies
suggest that most of these AF events are of grade 3
and would have warranted either treatment reduction
or cessation (Table 2). All major phase–3 trials
evidently showed that AF rates were unequivocally
elevated compared to the control arms (Table 3). The
true prevalence of AF may be underrepresented in
these trials, as systematic AF surveillance was not
conducted.
Implications of AF
The implications of the link between ibrutinib and AF
are multifold. Firstly, the most common reason for
ibrutinib discontinuation was treatment-related
toxicity, with AF being the most common cause of
toxicity-related treatment discontinuation [47].
Discontinuation rate has been reported as high as 32%
from several pivotal studies [46,48,49]. Although the
outcomes of patients who discontinued treatment due
to treatment intolerance appeared to be superior com-
pared to those due to Richter transformation (RT) or

Table 4. Rate of major bleeding from major ibrutinib trials.
Major bleeding
Trial Study design (grade 3) rate
Chanan-Khan (HELIOS) [88] RCT 4%
Byrd et al. 2015 [4] Phase-2, single arm 8%
Barr (RESONATE 2) [90] RCT 6%
Byrd (RESONATE) [62] RCT 1%
Wang et al. 2015 [6] Phase-2, single arm 6%
Dreyling 2016 [29] RCT 10%
disease progression, they still collectively performed
worse than patients who did not have treatment inter-
ruption or cessation [50,51]. In a retrospective study
highlighting the impact of AF on patients receiving
ibrutinib, patients whose treatment was interrupted
had inferior progression-free survival compared to
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those who proceeded with full dose or dose reduction
(median 19 months vs. 27 months) [52]. Jain et al ana-
lyzed survival outcomes for 320 patients after ibrutinib
discontinuation based on the cause of discontinuation.
The median time to discontinuation was 15 months
and after a median follow-up of 38 months, the
median survival was 33 months for ibrutinib intoler-
ance, 16 months for disease progression and 2 months
for RT [48].
Secondly, AF is associated with increased stroke
risk, cardiomyopathy and mortality [52,53]. The median
time from initiation of treatment to onset of AF was
3.8 months and in the majority of events, medical
therapy failed to prevent recurrence of AF [52]. This
contrasts with Byrd’s reporting of no detectable events
of AF after 2 years of treatment, although this may
just reflect the high dropout rate (only 17% of patients
remained on treatment after 3 years) [4]. Shanafelt
et al. identified older age, male sex, valvular heart dis-
ease and hypertension as risk factors for the develop-
ment of AF in this unique group [43]. Very recently,
baseline (preibrutinib) left atrial abnormality on elec-
trocardiogram (i.e. ‘p mitrale’), prolonged PR interval
and lead V1-biphasic P wave were found in a retro-
spective case–control study to be associated with a
6.6-fold increase in the risk of AF arising during ibruti-
nib therapy [54]. This hypothesis generating study
underscores the need for closer evaluation of baseline
cardiac investigations in order to develop predictive
models to identify high AF risk patients.
More concerningly, there have been reports of sud-
den cardiac deaths and ventricular arrhythmias associ-
ated with ibrutinib use [55,56]. Retrospective review of
FDA Adverse Event Reporting System (FAERS) from
2013 to 2015 identified a total of 11 cases of ventricu-
lar arrhythmias including ventricular tachycardia (VT)
and ventricular fibrillation (VF) and six cases of sudden
cardiac deaths [55]. The median age of these patients
CARDIOTOXICITY OF BTK 5
was 61 years and the median time from initiation of
ibrutinib to these cardiac events was 65 days. Thirteen
of 17 of these patients had no previous cardiac history.
Extensive cardiac workup in patients who developed
ventricular arrhythmia revealed no other provoking
factor apart from ibrutinib in 10 out of 11 patients.
Five patients stopped their ibrutinib permanently and
two patients resumed their ibrutinib but had recur-
rence of ventricular arrhythmia despite antiarrhythmic
agents. In a pooled data of published clinical trials, the
incidence rates of sudden cardiac death was 788
events per 100,000 person-years for patients on ibruti-
nib compared to 200–400 events per 100,000 person-
years for the age-matched general population [55].
With increasing use of ibrutinib in the future, we will
likely encounter more of these cardiac events. The
exact pathophysiology of ventricular arrhythmia and
sudden cardiac death is unknown. It will be interesting
to explore if AF and ventricular arrhythmias secondary
to ibrutinib arise from a common mechanism. The true
prevalence of these events will need to be determined
in prospective trials utilizing systematic cardiac
surveillance.
Pathophysiology of AF
In light of the magnitude and impact of AF and poten-
tial for cardiomyopathy for patients treated with ibruti-
nib, it is imperative that the exact pathophysiology by
which ibrutinib contributes to cardiac side effects be
elucidated. McMullen et al. hypothesized that ibrutinib
causes AF by inhibiting the PI3K–Akt pathway in the
heart [57]. There is evidence from other cell types of
crosstalk between BTK and TEC and the PI3K–Akt path-
way [58]. Reduced PI3K signaling in the heart can lead
to an increased susceptibility to AF [59]. BTK and TEC
transcripts are present in human heart tissue, and
increased expression was identified in patients with
AF, which may signify a cardioprotective role in the
heart in preventing both AF and stress-induced cardio-
myopathy [57]. Ibrutinib was found to inhibit PI3K–Akt
signaling in isolated rat neonatal cardiac myocytes
[57]. In another study, ibrutinib prolonged and trig-
gered abnormal action potentials in isolated adult
mouse and rabbit cardiac myocytes. These defects
were reversed by increasing PI3K by adding PIP3 to
the patch pipette [60]. The role of PI3K in ibrutinib-
induced AF is further reinforced by the fact that idela-
lisib, being a PI3K inhibitor (inhibiting PI3Kd as
opposed to ibrutinib, which affects PI3Ka), does not
cause cardiotoxicity [61,62]. Clearly, further in-depth
understanding of the mechanism of ibrutinib-induced
cardiac toxicity is warranted.
 6 C. P. S. TANG ET AL.
Management of patients with BTK inhibitor
induced AF
Balancing thrombosis versus bleeding risk
In the general population, the risk of cardioembolic
stroke from AF may be estimated with the widely
used model CHA2DS2VASc. Contemporary guidelines
recommend therapeutic anticoagulation for
CHA2DS2VASc of 2 or greater [63]. However, as dis-
cussed below, patients receiving ibrutinib are at a
heightened bleeding risk due to the combination of
antiplatelet effect of ibrutinib, the disease (CLL) itself,
baseline thrombocytopenia and concomitant anti-
coagulant use.
Platelets express both BTK and TEC which help to
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activate platelet aggregation by regulating phospho-
lipase C!2 downstream of the collagen receptor glyco-
protein VI (GPVI) [64]. Ibrutinib possesses potent
antiplatelet effects due to inhibition of collagen and
von Willebrand factor-dependent platelet functions
downstream of GPVI [65]. The degree of reduction of
in vitro collagen-mediated platelet aggregation in
blood from ibrutinib-treated patients was correlated
with the frequency of bleeding, which was reversible
following addition of untreated platelets and drug ces-
sation [65,66].
In clinical trials, ibrutinib was associated with
approximately 50% risk of bleeding, albeit the majority
being grade 1–2 bleeds consisting of petechiae and
contusion [4,6,26,28]. Major bleeding (grade 3)
ranged from 1–10% in major trials (Table 4). Notably,
secondary analysis from two studies of single-agent
ibrutinib trials (PCYC-1102 and RESONATE) showed
that anticoagulant (11%) and antiplatelet agents (34%)
use were frequent amongst ibrutinib patients and that
3% of this population had major bleeding events
[22,27,67]. Most of these events tended to occur early
during treatment (within 3–6 months of therapy) and
led to drug discontinuation in 1% of patients [67].
However, Thompson et al. reported the risk of grade
3–4 bleeding in patients who are anticoagulated for
ibrutinib-induced AF was much higher (14%).
Furthermore, CLL itself induces platelet dysfunction by
impairing both adenosine diphosphate (ADP) and col-
lagen-mediated platelet dysfunction [68].
Choice of anticoagulant
There is a paucity of safety data regarding the opti-
mal choice of anticoagulation in ibrutinib patients
who develop AF with elevated embolic stroke risk
[69]. Most of the trials involving ibrutinib prohibited
concurrent use of warfarin following observations of
major hemorrhage in patients using warfarin [57].
The United States and European regulatory agencies
provide contradictory recommendations regarding
the concomitant use of ibrutinib and warfarin.
Concomitant warfarin use is contraindicated by
European Medicines Agency but is acceptable by FDA
[70,71]. Other forms of anticoagulation (most com-
monly low-molecular-weight heparin) and antiplatelet
agents have been used in trials with acceptable
bleeding risk [67].
Direct oral anticoagulants (DOAC) may be the pre-
ferred therapy of choice due to the ease of administra-
tion and reduced major and fatal bleeding compared
to warfarin. In a meta-analysis and systematic review
of clinical trials performed in noncancer settings,
DOAC significantly reduced the rate of major bleeding
(relative risk 0.72) and fatal bleeding (relative risk 0.53).
In the absence of similar trials performed in cancer set-
tings, it may not be unreasonable to extrapolate this
data to our patient population [72]. Caution must be
exercised though due to potential clinically significant
drug–drug interactions. Ibrutinib is predominantly
metabolized by hepatic cytochrome P450 3A4
(CYP3A4) and to a lesser extent CYP2D6.
Coadministration of CYP3A perpetrators (i.e. CYP3A
inducers or inhibitors) can cause significant drug–drug
interactions (DDI), which may alter the toxicity and
efficacy of the medications [73,74]. Even though both
apixiban and rivaroxaban are substrates of CYP3A4,
the clinical relevance of coadministration of both sub-
strates is not established, unless there is possibility of
enzyme saturation (which is uncommon for this group
of drugs). A personalized, risk-adapted approach
should be taken when selecting an anticoagulant, sup-
plemented by tools such as HAS-BLED (hypertension,
abnormal renal/liver function, stroke, bleeding history
or predisposition, labile international normalized ratio
(INR)) for patients who were on warfarin or HAS-BED
for treatment naïve patients (hypertension, abnormal
renal/liver function, stroke, bleeding history or predis-
position, elderly, drugs/alcohol) [75–77]. Factor Xa
inhibitors may be the preferred choice of anticoagu-
lant in the elderly patient cohort with multiple comor-
bidities. Conversely, it is feasible to continue warfarin
for patients who were taking warfarin with stable INR
prior to commencement of ibrutinib [78]. Although
firm evidence is lacking, it may be reasonable to lower
the dose of ibrutinib in those patients who develop
bleeding manifestations while on concurrent anticoa-
gulation. Improved awareness of medications that may
impact the CYP3A4, especially when anticoagulation is
taken in combination is needed. Alarmingly, a recent
report showed that a significant proportion of patients

(64%) on ibrutinib were on concurrent medications
that may alter its metabolism [79]. Concurrent adminis-
tration of CYP3A4 inhibitors in this instance may lead
to clinically significant bleeding.
For patients with intermediate stroke risk
(CHA2DS2VASc of 1), the addition of antiplatelet agent
for younger patients with few comorbidites may not
be unreasonable as even though ibrutinib has antipla-
telet properties, it is unclear if it confers protective
role against cardioembolic stroke. Further studies are
required to enable physicians to make informed deci-
sions regarding anticoagulation in patients who are on
ibrutinib.
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Management of arrhythmia and heart failure
The complexity of management of ibrutinib-induced
AF and heart failure is further compounded by the
lack of evidence-based guidelines regarding the (1)
utility and method of surveillance, (2) choice between
pharmacological treatment or interventional therapy
such as direct current cardioversion and (3) safety and
efficacy regarding ibrutinib cessation or dose reduc-
tion. Thompson et al. retrospective study found that in
the majority of cases, AF persisted despite stopping or
reducing the dose of ibrutinib [52]. Historically, both
rate control and rhythm control confer similar efficacy
in the reduction of mortality, heart failure and rate of
hospitalizations from AF in the noncancer patient
population [80,81]. We usually select rate control with
beta blockers for patients with ibrutinib-induced AF, as
the majority of antiarrhythmic agents used in pharma-
cological cardioversion are pro-arrhythmic in nature.
Secondly, pertinent drug interactions occur between
ibrutinib and several antiarrhythmic agents (amiodar-
aone, verapamil and diltiazem) via CYP3A4 hepatic
metabolism. Pharmacovigilance among physicians
again is mandated. Electrical cardioversion may be
prudent for symptomatic persistent or permanent AF
failing rate control with beta blockers. Inevitably, there
are patients in whom we need to cease or interrupt
their ibrutinib treatment when they develop grade
3 AF which fails to respond to pharmacological or
interventional therapy. Barr et al showed that sus-
tained treatment adherence was associated with better
PFS, higher ORR and a trend toward improved ORR,
irrespective of del 17p or TP53 mutation. Treatment
interruption for just 1 week was associated with
increased PFS events [82]. This growing group of
patients is particularly difficult to manage due to
decreased ibrutinib efficacy and a relative paucity of
alternate treatment options [48,51].
CARDIOTOXICITY OF BTK 7
Future directions
The potency of ibrutinib in treating B-cell malignancies
is unquestionable. However, the risk of AF is not negli-
gible and complicated by management issues such as
balancing bleeding versus clotting risk and pharmaco-
logical drug interactions. Notwithstanding the net
benefit of therapy, the critical issues of AF need to be
addressed ideally with general consensus guidelines.
Closer collaboration between hematologists and cardi-
ologists is needed in both clinical trial designs and
adjudicating cardiovascular end points. A risk-adapted
approach needs to be employed in therapy selection,
especially in the front-line setting taking into consider-
ation patient demographics, cardiovascular risk factors
and nature of disease. Several second-generation BTK
inhibitors are also on the horizon with the potential
promise of improved efficacy and safety profile.
Acalabrutinib (ACP-196)
Similar to ibrutinib, acalabrutinib is an irreversible BTK
inhibitor that binds covalently to the cysteine-481 resi-
due. Contrary to ibrutinib, it has enhanced selectivity
to BTK with potential improvement of potency and
less off-target activity on EFGR, TEC and ITK, which
may result in less untoward side effects such as bleed-
ing, severe diarrhea and rash, and possibly AF [83,84].
In a phase 1–2 trial involving 61 heavily relapsed or
refractory patients (median of 3 previous therapies)
and majority of high risk patients (31% had TP53 dys-
regulation and 75% had unmutated IGHV), the overall
response rate was 95% after a median follow-up of
14.3 months. Encouragingly, the ORR for the subset of
patients with chromosome 17p13.1 deletion was
100%. There were no reports of dose-limiting toxicities,
major hemorrhage and AF. Severe bleeding occurred
in less than 2% of patients. Only 19% of patients
experienced grade 3–4 toxicities (most commonly
hypertension). The most common side effects
were headache, diarrhea and weight gain [85]. No
cases of AF have been publically reported for acalabru-
tinib to date.
BGB-3111
BGB-3111 is a second-generation BTKi which is equipo-
tent against BTK compared to ibrutinib with less
inhibitory effect on EGFR, TEC, ITK, HER 2 and JAK 3. In
a phase-1 study involving 45 patients with R/R CLL, of
which 15% had del 17p, only 1 case of AF (grade 2)
and major bleeding (grade 3 purpura) was reported
out of the 29 patients who were available for analysis.
 8 C. P. S. TANG ET AL.
The most common side effects were mild (grade 1/2)
and comprised of bruising/bleeding, diarrhea and
upper respiratory infections. After a median follow-up
of 7.5 months, the ORR was 90% and there was no
reported disease progression or Richter’s transform-
ation [86]. This drug has also demonstrated high clin-
ical activity in WM. In a recent phase 1–2 study
involving 24 patients who were either treatment naïve
or R/R, the ORR was 92%, with 33% achieving very
good partial response (33%) after a median follow-up
of 7.6 months. There were two cases of AF (grade 1–2)
and no reports of grade 3 bleeding [87].
ONO/GS 4059
Downloaded by [Imperial College London Library] at 04:49 14 September 2017
ONO/GS 4059 is another second-generation BTK inhibi-
tor that forms an irreversible covalent bond to a cyst-
eine residue at the BTK active site. It has high oral
bioavailability with high selectivity for BTK compared
to ibrutinib but has less inhibitory effect on EGFR and
ITK [88]. Walter et al. performed a phase 1–2 single-
arm study with ONO/GS 4059 on 28 R/R high genetic
risk (del 17p 36%; TP53 mutation 52%; unmutated
IGHV 84%) CLL patients. Anticoagulation was allowed
for this study; 6/28 patients were on anticoagulant
therapy. At a median follow-up of 32.5 months, 39.3%
(11) of patients dropped out of the study (3 due to
disease progression; 3 due to death and 4 due to tox-
icities). The estimated median progression-free survival
was 38.5 months and median overall survival was 44.9
months. Overall response rate was 96%. There were no
new treatment emergent side effects on the updated
data. The use of anticoagulants in this cohort was not
associated with increased risk of bleeding. There was 1
case of grade-3 bleeding (spontaneous psoas hema-
toma), but this patient was not on anticoagulation.
One case of AF was reported, but it was provoked by
pneumonia. Overall, the treatment was well tolerated
with the most common side effects being bruising
(35.7% all grades), neutropenia (35.7% all grades) and
anemia (32.1%) [89].
Clearly, it is still premature to determine if these
newer BTK inhibitors are comparable if not more
superior to ibrutinib with better safety profiles. It is
hoped that the ongoing ELEVATE trial, which is a
phase-3 noninferiority trial comparing ibrutinib and
acalabrutinib in treating high-risk, relapsed/refractory
CLL patients will shed more light in this area in the
very near future [90]. Currently, in the absence of
head-to-head trial outcomes, it may be difficult to
draw precise conclusions, but it will be tantalizing to
see if these newer agents deliver the same durable
high response with less toxicity in longer-term follow-
up reports.
Conclusions
Ibrutinib is undoubtedly an effective therapy for B-cell
malignancies but results in an increased rate of AF
with consequences of potentially excessive bleeding
risk and discontinuation of treatment. The manage-
ment of this cohort of patients is truly an area of
unmet needs, which mandates urgent exploration in
future prospective studies involving both hematolo-
gists and cardiologists especially since it will be used
increasingly in the upfront setting. Vigilance is needed
among treating physicians with regards to the nuances
of the treatment for these patients.
Potential conflict of interest: Disclosure forms pro-
vided by the authors are available with the full text of
this article online at https://doi.org/ 10.1080/10428194.
2017.1375110.
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