• Patients treated with next generation BTKi therapy acalabrutinib still see a >8 fold risk of ventricular arrhythmia and sudden death events.

  • Ventricular arrhythmias may be a class effect of BTKi therapy, and vigilance is needed.

Acalabrutinib, a next-generation Bruton’s tyrosine kinase inhibitor (BTKi), associates with dramatic efficacy against B-cell malignancies. Recently, unexplained ventricular arrhythmias (VAs) with next-generation BTKi-therapy have been reported. Yet, whether acalabrutinib associates with VAs in long-term follow-up is unknown. Leveraging a large-cohort of 290 consecutive B-cell malignancy patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence of VAs. The primary-endpoint was incident VA development (ventricular fibrillation, ventricular tachycardia, and symptomatic premature ventricular contractions). Probability-scores were assessed to determine likelihood of acalabrutinib-association. Incident rates as function of time-on-therapy were calculated. Weighted average observed incidence rates were compared with expected population rates using relative-risks. Absolute excess risk (AER) for acalabrutinib-associated VAs was estimated. Over 1063 person-years of follow-up, there were 8 cases of incident-VAs, including 6 in those without coronary disease (CAD) or heart failure (HF) and 1 sudden-death; median time-to-event 14.9 months. Among those without prior ibrutinib-use, CAD, or HF, the weighted average incidence was 394 per 100 000 person years compared with a reported incidence of 48.1 among similar-aged non–BTKi-treated subjects (relative risk, 8.2; P < .001; AER, 346). Outside of age, no cardiac or electrocardiographic variables associated with VA development. Collectively, these data suggest VAs may be a class-effect of BTKi therapies.

1.
Byrd
JC
,
Harrington
B
,
O’Brien
S
, et al
.
Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia
.
N Engl J Med
.
2016
;
374
(
4
):
323
-
332
.
2.
Wang
M
,
Rule
S
,
Zinzani
PL
, et al
.
Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial
.
Lancet
.
2018
;
391
(
10121
):
659
-
667
.
3.
Sharman
JP
,
Egyed
M
,
Jurczak
W
, et al
.
Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial
.
Lancet
.
2020
;
395
(
10232
):
1278
-
1291
.
4.
Byrd
JC
,
Woyach
JA
,
Furman
RR
, et al
.
Acalabrutinib in treatment-naive chronic lymphocytic leukemia
.
Blood
.
2021
;
137
(
24
):
3327
-
3338
.
5.
Woyach
JA
,
Blachly
JS
,
Rogers
KA
, et al
.
Acalabrutinib plus obinutuzumab in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia
.
Cancer Discov
.
2020
;
10
(
3
):
394
-
405
.
6.
Herman
SEM
,
Montraveta
A
,
Niemann
CU
, et al
.
The bruton tyrosine kinase (BTK) inhibitor acalabrutinib demonstrates potent on-target effects and efficacy in two mouse models of chronic lymphocytic leukemia
.
Clin Cancer Res
.
2017
;
23
(
11
):
2831
-
2841
.
7.
Byrd
JC
,
Hillmen
P
,
Ghia
P
, et al
.
Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial
.
J Clin Oncol
.
2021
;
39
(
31
):
3441
-
3452
.
8.
Fazal
M
,
Gomez
S
,
Cheng
P
,
Rhee
JW
,
Baykaner
T
.
Tyrosine kinase inhibitor associated polymorphic ventricular tachycardia
.
J Am Coll Cardiol CardioOnc
.
2022
;
4
(
suppl 1
):
S4
-
S5
.
9.
Guha
A
,
Derbala
MH
,
Zhao
Q
, et al
.
Ventricular arrhythmias following ibrutinib initiation for lymphoid malignancies
.
J Am Coll Cardiol
.
2018
;
72
(
6
):
697
-
698
.
10.
Lampson
BL
,
Yu
L
,
Glynn
RJ
, et al
.
Ventricular arrhythmias and sudden death in patients taking ibrutinib
.
Blood
.
2017
;
129
(
18
):
2581
-
2584
.
11.
Sirichand
S
,
Killu
AM
,
Padmanabhan
D
, et al
.
Incidence of idiopathic ventricular arrhythmias: a population-based study
.
Circ Arrhythm Electrophysiol
.
2017
;
10
(
2
):
e004662
.
12.
National Cancer Institute
.
Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0
. Accessed 11 April 2022. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50.
13.
Naranjo
CA
,
Busto
U
,
Sellers
EM
, et al
.
A method for estimating the probability of adverse drug reactions
.
Clin Pharmacol Ther
.
1981
;
30
(
2
):
239
-
245
.
14.
Wiczer
TE
,
Levine
LB
,
Brumbaugh
J
, et al
.
Cumulative incidence, risk factors, and management of atrial fibrillation in patients receiving ibrutinib
.
Blood Adv
.
2017
;
1
(
20
):
1739
-
1748
.
15.
Xiao
L
,
Salem
JE
,
Clauss
S
, et al
.
Ibrutinib-mediated atrial fibrillation attributable to inhibition of C-terminal Src kinase
.
Circulation
.
2020
;
142
(
25
):
2443
-
2455
.
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