REGULAR ARTICLE

Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment

for patients with chronic lymphocytic leukemia

Paul M. Barr,1 Carolyn Owen,2 Tadeusz Robak,3 Alessandra Tedeschi,4 Osnat Bairey,5 Jan A. Burger,6 Peter Hillmen,7
Steve E. Coutre,8 Claire Dearden,9 Sebastian Grosicki,10 Helen McCarthy,11 Jian-Yong Li,12 Fritz Offner,13 Carol Moreno,14
Cathy Zhou,15 Emily Hsu,16 Anita Szoke,16 Thomas J. Kipps,17 and Paolo Ghia18
1
Clinical Trials Office, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY; 2Division of Hematology & Hematological Malignancies, Tom Baker
Cancer Centre, University of Calgary, Calgary, AB, Canada; 3Department of Hematology, Medical University of Lodz, Copernicus Memorial Hospital, Lodz, Poland; 4Department
of Hematology, Azienda Socio Sanitaria Territoriali Grande Ospedale Metropolitano Niguarda, Milan, Italy; 5Department of Hematology, Rabin Medical Center, Petah Tikva, Israel;
6
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX; 7Department of Haematology, The Leeds Teaching Hospitals, St. James Institute of
Oncology, Leeds, UK; 8Hematology Clinic, Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA; 9Haemato-Oncology Department, The Royal Marsden
Hospital, London, UK; 10Department of Hematology and Cancer Prevention, School of Public Health, Silesian Medical University, Katowice, Poland; 11Haematology Department,
Royal Bournemouth General Hospital, Bournemouth, UK; 12Department of Hematology, Jiangsu Province Hospital, Nanjing, China; 13Department of Clinical Hematology,
Universitair Ziekenhuis Gent, Gent, Belgium; 14Department of Hematology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain;
15
Biostatistics, Pharmacyclics LLC, an AbbVie Company, South San Francisco, CA; 16Clinical Sciences, Pharmacyclics LLC, an AbbVie Company, South San Francisco, CA
17
Department of Medicine, University of California San Diego, Moores Cancer Center, San Diego, CA; and 18Department of Onco-Hematology, Universit
a Vita-Salute San
Raffaele and Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Milan, Italy

Key Points We report long-term follow-up from the RESONATE-2 phase 3 study of the once-daily
A
Bruton’s tyrosine kinase inhibitor ibrutinib, which is the only targeted therapy with
 Long-term
significant progression-free survival (PFS) and overall survival (OS) benefit in multiple
RESONATE-2 data
randomized chronic lymphocytic leukemia (CLL) studies. Patients ($65 years) with
show sustained PFS
previously untreated CLL, without del(17p), were randomly assigned 1:1 to once-daily
and OS benefits
ibrutinib 420 mg until disease progression/unacceptable toxicity (n 5 136) or
(medians not
reached) for first-line chlorambucil 0.5-0.8 mg/kg #12 cycles (n 5 133). With up to 8 years of follow-up
ibrutinib treatment (range, 0.1-96.6 months; median, 82.7 months), significant PFS benefit was sustained
in patients with CLL. for ibrutinib vs chlorambucil (hazard ratio [HR], 0.154; 95% confidence interval [CI],
0.108-0.220). At 7 years, PFS was 59% for ibrutinib vs 9% for chlorambucil. PFS benefit
 Forty-two percent B
was also observed for ibrutinib- vs chlorambucil-randomized patients with high-risk
of patients continued
ibrutinib for up genomic features: del(11q) (HR, 0.033; 95% CI, 0.010-0.107) or unmutated immunoglobulin
to 8 years; dose heavy chain variable region (HR, 0.112; 95% CI, 0.065-0.192). OS at 7 years was 78% with
management for AEs ibrutinib. Prevalence of adverse events (AEs) was consistent with previous 5-year
allowed patients follow-up. Ibrutinib dosing was held ($7 days) for 79 patients and reduced for 31
continue to benefit patients because of AEs; these AEs resolved or improved in 85% (67 of 79) and 90% (28 of
from ibrutinib. 31) of patients, respectively. With up to 8 years of follow-up, 42% of patients remain on
ibrutinib. Long-term RESONATE-2 data demonstrate sustained benefit with first-line
ibrutinib treatment for CLL, including for patients with high-risk genomic features. C
These trials were registered at www.clinicaltrials.gov as #NCT01722487 and
#NCT01724346.

Submitted 26 October 2021; accepted 28 February 2022; prepublished online on Blood The full-text version of this article contains a data supplement.
Advances First Edition 4 April 2022; final version published online 8 June 2022. DOI © 2022 by The American Society of Hematology. Licensed under Creative
10.1182/bloodadvances.2021006434. Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-
Requests for data sharing may be submitted to Paul M. Barr (paul_barr@urmc. ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other
rochester.edu.). rights reserved.

3440 14 JUNE 2022 • VOLUME 6, NUMBER 11

 Introduction End points and assessments
End points included PFS, overall response rate (ORR), improvement
Prior to the introduction of novel targeted agents, the standard-of-care in hematologic parameters, and safety. Per follow-up, OS is
for patients older than 65 years with chronic lymphocytic leukemia/ reported here only for patients randomly assigned to ibrutinib.
small lymphocytic lymphoma (CLL/SLL) included the chemotherapy Long-term response was investigator-assessed per International
chlorambucil.1 Primary results from the pivotal RESONATE-2 phase Workshop on CLL 2008 criteria.14 PFS and OS were analyzed
A 3 study demonstrated superior efficacy and tolerability of ibrutinib, a according to the Kaplan-Meier method. Hazard ratios (HRs) were
once-daily Bruton’s tyrosine kinase (BTK) inhibitor, vs standard-of-care estimated using a stratified Cox regression model with treatment as
chemotherapy, and supported the initial approval in the United States the only covariate; stratification factors used in the model were East-
and European Union2 for patients with CLL/SLL treated in the first- ern Cooperative Oncology Group score (0-1 vs 2) and Rai stage
line setting.3 Additionally, ibrutinib is the only therapy to demonstrate (0/I/II vs III/IV) at baseline. Long-term safety data are reported for
both a significant progression-free survival (PFS)3-8 and overall survival patients receiving ongoing treatment in the ibrutinib arm only. Stan-
(OS)3,4,7,8 benefit in multiple randomized phase 3 studies for patients dardized Medical Dictionary for Regulatory Activities queries from
with first-line CLL/SLL. MedDRA version 24.0 were used to assess adverse effects (AEs)
of clinical interest: major hemorrhage (terms included vitreous hem-
Evidence from RESONATE-2 also showed that patients with high- orrhage, gastrointestinal hemorrhage, postprocedural hemorrhage,
risk genomic features, such as chromosome 11q deletion (del[11q]) subdural hematoma, traumatic hematoma, cerebral hemorrhage,
or unmutated immunoglobulin heavy chain variable region (IGHV), subarachnoid hemorrhage, hematuria) and hypertension (narrow;
that predict inferior outcomes with chemotherapy and chemoimmu- terms included blood pressure increased, hypertension).15
notherapy, experienced significantly improved long-term efficacy out-
comes with single-agent ibrutinib vs chlorambucil.9 At the last Results
update for RESONATE-2, the median PFS for ibrutinib was not
reached with a median follow-up of 5 years; 70% of patients Patients
with CLL treated with first-line ibrutinib remained progression-free In RESONATE-2, 269 patients were randomly assigned to receive
and alive.9 ibrutinib (n 5 136) or chlorambucil (n 5 133; supplemental
Long-term data on targeted agents in the treatment of patients with Figure 1). Baseline patient characteristics were well matched
CLL/SLL are limited. Therefore, reporting extended follow-up data between treatment arms (supplemental Table 1).3 Among enrolled
on patient outcomes and safety is essential to inform clinical deci- patients, 53% (143 of 269) had 1 or more high-risk genomic fea-
sion making. Currently, ibrutinib is the BTK inhibitor with the longest tures (TP53 mutation, del[11q], and/or unmutated IGHV). Of evalu-
follow-up data in first-line CLL/SLL and other B-cell malignan- able patients with available data, 22% (54 of 251) had del(11q)
cies.9-13 Herein we report up to 8 years of efficacy and safety data and 58% (118 of 204) had unmutated IGHV.
for patients with previously untreated CLL/SLL from the phase 3 At the current median follow-up of 7.4 years (88.5 months; range,
RESONATE-2 study. 0.1-96.6) for patients in the ibrutinib arm, 57 patients (42%) contin-
ued first-line ibrutinib treatment (supplemental Table 2). One patient
Methods (,1%) randomly assigned to chlorambucil continues to be followed
for PFS. Seventy-eight patients (59%) treated with chlorambucil
Study design and population subsequently crossed over to receive second-line ibrutinib treatment
RESONATE-2 is a phase 3, open-label, multicenter, international, after PD (1 patient crossed over to receive ibrutinib without docu-
randomized study (PCYC-1115/PCYC-1116; #NCT01722487 and mented PD).
#NCT01724346) comparing the efficacy and safety of ibrutinib vs
chlorambucil in first-line CLL/SLL. Detailed methods have been pre- PFS and OS
viously reported.3 Previously untreated patients aged $ 65 years With up to 8 years of follow-up, the median PFS has not yet been
requiring therapy per the 2008 International Workshop on CLL crite- reached for patients in the ibrutinib arm (95% confidence interval
ria14 for CLL/SLL and without chromosome 17p deletion [del(17p)] [CI], 82.1 months-not estimable [NE]) and was 15 months (95%
were randomly assigned 1:1 to once-daily ibrutinib 420 mg until CI, 10.2-19.4) for patients in the chlorambucil arm (Figure 1A). Ibru- B
progressive disease (PD) or unacceptable toxicity or to up to 12 tinib treatment led to an 85% reduction in risk of PD or death vs
cycles of chlorambucil 0.5 mg/kg, increased up to 0.8 mg/kg as tol- chlorambucil (HR, 0.154; 95% CI, 0.108-0.220). At 7 years, 59%
erated, on days 1 and 15 of each 28-day cycle. Patients randomly of ibrutinib-randomized patients were estimated to be progression
assigned to chlorambucil were eligible to cross over to second-line free and alive vs 9% of chlorambucil-randomized patients. Thirty-one
treatment with ibrutinib after confirmed PD. After a median follow-up patients (23%) in the ibrutinib arm progressed at any point during
of 5 years, the protocol was amended to provide up to 10 years of study follow-up, but only 18 patients (13%) progressed while on
PFS follow-up for both arms; up to 10 years of OS follow-up were active ibrutinib treatment, and the remaining 13 patients (10%) pro-
planned for the ibrutinib arm only. gressed after drug discontinuation.
This study was conducted according to principles of the Declaration Sustained benefit for ibrutinib vs chlorambucil was maintained
of Helsinki and the International Conference on Harmonization across subgroup analyses of baseline clinical characteristic factors
Guidelines for Good Clinical Practice, and it was approved by the such as advanced stage and bulky disease (Figure 2). A significant
institutional review boards of participating institutions. All patients PFS benefit with ibrutinib was also observed for patients with high-
provided written informed consent. risk genomic features, that is, TP53 mutation, del(11q), and/or

14 JUNE 2022 • VOLUME 6, NUMBER 11 EIGHT-YEAR FOLLOW-UP OF IBRUTINIB IN RESONATE-2 3441

A
A 100 |

90
80

Progression-free survival, %
70
Ibrutinib
60
50
Chlorambucil Ibrutinib
40 Median PFS, mo 15.0 NE
HR (95% CI) 0.154 (0.108–0.220)
30
20
Chlorambucil
10
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Months
B Patients at risk
Ibrutinib: 136 129 124 121 112 108 104 99 92 88 81 76 67 65 57 17 1
Chlorambucil: 133 88 69 57 41 33 30 25 19 16 12 6 5 5 4 1 0

B 100
90
Ibrutinib, with del(11q)
80
Progression-free survival, %

70
Ibrutinib, without del(11q)
60
With del(11q) Without del(11q)
50 Ibr Chl Ibr Chl
7 year PFS 52% 0 61% 12%
40 Median PFS, mo 88 9.0 NR 18.4
HR (95% CI) 0.033 (0.010–0.107) 0.193 (0.128–0.289)
30
20 Chlorambucil, without del(11q)
10 Chlorambucil, with del(11q)
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Months
Patients at risk
Ibrutinib, without del(11q): 101 94 89 87 80 76 73 70 64 61 57 55 48 47 43 13 0
Ibrutinib, with del(11q): 29 29 29 29 28 28 27 25 24 23 20 18 16 16 12 2 0
Chlorambucil, without del(11q): 96 64 54 45 35 29 25 21 17 15 12 6 5 5 4 1 0
Chlorambucil, with del(11q): 25 15 8 6 3 1 1 1 0

C 100
90
80
Progression-free survival, %

Ibrutinib, mutated IGHV

70 Ibrutinib, unmutated IGHV
60
Unmutated IGHV Mutated IGHV
50 Ibr Chl Ibr Chl
7 year PFS 58% 2% 68% 17%
40 Median PFS, mo NR 9.3 NR 16.7
HR (95% CI) 0.112 (0.065–0.192) 0.174 (0.089–0.342)
30
Chlorambucil, mutated IGHV
20
10 Chlorambucil, unmutated IGHV

0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Months
Patients at risk
Ibrutinib, mutated IGHV: 40 37 34 34 32 30 30 29 27 26 25 22 19 19 16 6 1
Ibrutinib, unmutated IGHV: 58 57 56 53 49 48 46 43 42 41 36 35 32 30 27 10 0
Chlorambucil, mutated IGHV: 42 32 25 21 18 15 14 12 11 8 8 5 4 4 3 0 0
Chlorambucil, unmutated IGHV: 60 33 23 19 11 8 6 5 3 3 2 1 1 1 1 1 0

Figure 1.

3442 BARR et al 14 JUNE 2022 • VOLUME 6, NUMBER 11

unmutated IGHV (HR, 0.098; 95% CI, 0.060-0.161). A similar ben- Safety
efit was observed when del(11q) and unmutated IGHV were The median duration of ibrutinib treatment was 74 months (range,
assessed individually. Patients with del(17p) were excluded from
0.7-96.6 months; supplemental Table 2), and median relative dose
the study, and the small numbers of patients with TP53 mutation
intensity was 98% at current follow-up. Chlorambucil safety data
(ibrutinib, n 5 11; chlorambucil, n 5 3) precluded meaningful PFS
are unchanged as reported previously3 with respect to that limited-
comparison and analysis.
duration treatment. The most frequent AEs of any grade with ibruti-
Ibrutinib led to a 97% reduction in risk of PD or death in patients nib were diarrhea (50%), cough (37%), and fatigue (37%). The
with del(11q) and 81% for those without del(11q) vs chlorambucil most common any-grade and grade $ 3 AEs over time are shown
(Figure 1B). At 7 years, PFS rates were higher for ibrutinib vs chlor- in Figure 5.
ambucil for patients with del(11q) (52% vs 0%) and without
For AEs of clinical interest, the prevalence rates of hypertension for
del(11q) (61% vs 12%). PFS follow-up was complete for all
the current follow-up (grades 1-3; no grade 4 or 5 events occurred)
chlorambucil-randomized patients with del(11q) (n 5 25) as of
were 25%, 23%, and 25% of patients in years 5-6, 6-7, and 7-8,
4 years on study, including 3 patients with censored observations.
respectively (Figure 6). Overall, grade 3 hypertension occurred in
PFS was similar in ibrutinib-randomized patients with and without
17 (12%) patients. Prevalence rates of atrial fibrillation (grades 1-3;
del(11q) (HR, 1.228; 95% CI, 0.672-2.241). Ibrutinib also led to an
no grade 4 or 5 events occurred) over time were 9%, 7%, and 7%
89% reduction in the risk of PD or death in patients with unmutated
of patients in years 5-6, 6-7, and 7-8, respectively (Figure 6). Over-
IGHV and 83% for patients with mutated IGHV vs chlorambucil
all, grade 3 atrial fibrillation occurred in 8 (6%) patients. No patients
(Figure 1C). At 7 years, PFS rates were higher for ibrutinib vs chlor-
had any-grade major hemorrhage events in years 5-6 and 6-7;
ambucil for patients with unmutated IGHV (58% vs 2%) or with
3% of patients had any-grade major hemorrhage events in years
mutated IGHV (68% vs 17%). Importantly, PFS was similar
7-8 (Figure 6). Overall, grade 3 major hemorrhage occurred in 10
in ibrutinib-randomized patients with mutated vs unmutated IGHV
(7%) patients, grade 4 in 1 (,1%) patient, and no grade 5 events
(HR, 0.858; 95% CI, 0.437-1.686).
occurred. Two of the 10 patients (20%) with grade 3 major hemor-
Median OS was not reached for ibrutinib-randomized patients, and rhage were also taking concomitant anticoagulation medications.
the 7-year survival estimate was 78% (Figure 3; HR vs chlorambu- With up to 8 years of follow-up, fatal cardiac events occurred in 4
cil: 0.453; 95% CI, 0.276–0.743). Patients with the high-risk (3%) patients: cardiac failure (n 5 2), myocardial infarction (n 5 1),
genomic features TP53 mutation, del(11q), and/or unmutated IGHV and cardiopulmonary failure (n 5 1).
had improved OS with ibrutinib treatment consistent with the
intent-to-treat population (HR vs chlorambucil: 0.461; 95% Discontinuations and dose management with
CI, 0.236–0.900). ibrutinib treatment
Overall response The primary reason for discontinuation was AEs for 32 patients
(24%). Treatment discontinuations because of AEs generally
With this extended follow-up, the proportion of ibrutinib-randomized decreased over time, with 7% of patients (9 of 135) discontinuing
patients with a best response of complete response (CR) or CR in years 0 to 1, 6% (7 of 121) in years 1 to 2, 5% (6 of 111) in
with incomplete bone marrow recovery (CRi) continued to increase years 2 to 3, 6% (6 of 99) in years 3 to 4, 1% (1 of 88) in years 4
up to 34% from 30% observed at 5-year follow-up (Figure 4). ORR to 5, 3% (2 of 79) in years 5 to 6, no patients in years 6 to 7, and
was 92% for patients randomly assigned to ibrutinib (including par- 2% (1 of 60) in years 7 to 8 (supplemental Figure 2A). AEs leading
tial response with lymphocytosis) and 37% for patients randomly to discontinuations occurring in .1 patient were atrial fibrillation
assigned to chlorambucil, which is consistent with prior follow-ups. (n 5 5), pneumonia (n 5 3), and palpitations (n 5 2; supplemental
Responses with ibrutinib treatment were durable, with the median Table 2).
duration of response not reached (95% CI, 83.8 months-NE)
compared with chlorambucil treatment (29.7 months; 95% CI, Thirty-one patients (23%) had dose reductions on study because of
15.2-40.4). The median duration of CR was not reached (95% CI, AEs; 28 of these patients (90%) had improvement or resolution of
NE) with ibrutinib and was 48.8 months (95% CI, 3.3-NE) with the AE following dose reduction. The rate of dose reductions
chlorambucil. For ibrutinib-randomized patients who had attained because of AEs was highest in years 0 to 1 (9%, 12 of 135) and
CR/CRi (n 5 46), the median PFS was not reached (95% CI: NE); lower in subsequent years: 5% (6 of 121) in years 1 to 2, 5%
the median PFS was 85 months (95% CI: 63.3 months-NE) for (5 of 111) in years 2 to 3, 4% (4 of 99) in years 3 to 4, 5% (4 of
those who had PR (nodular PR, PR, and/or PR with lymphocytosis; 88) in years 4 to 5, 4% (3 of 79) in years 5 to 6, 4% (3 of 70) in
n 5 79 patients; HR, 0.291; 95% CI, 0.141-0.604). For ibrutinib- years 6 to 7, and no patients (0 of 60) in years 7 to 8 (supplemental
randomized patients, ORR was similar in patients with vs without Figure 2B). Ibrutinib discontinuation following dose reduction
del(11q) (100% vs 90%, respectively), whereas the CR/CRi rate occurred in 20 patients because of AEs (n 5 12; 2 patients had
was slightly higher for patients with del(11q) vs without del(11q) dose reduction and subsequent discontinuation because of the
(45% vs 31%). ORR and CR/CRi rates were similar for ibrutinib- same AE) or because of study withdrawal (n 5 4), PD (n 5 3), or
randomized patients with mutated vs unmutated IGHV (ORR: 88% physician decision (n 5 1). AEs leading to dose reduction in .1
vs 95%; CR: 33% vs 34%, respectively). patient were thrombocytopenia (n 5 3) and anemia, arthralgia,

Figure 1 (continued) Investigator-assessed PFS. (A) PFS with single-agent ibrutinib vs chlorambucil in first-line CLL/SLL in the intent-to-treat population. PFS by
(B) del(11q) status and (C) IGHV mutational status. Survival analyses are from randomization until event or censoring at last evidence of non-PD; vertical tick marks indicate
censored patients. NE, not estimable; NR, not reached.

14 JUNE 2022 • VOLUME 6, NUMBER 11 EIGHT-YEAR FOLLOW-UP OF IBRUTINIB IN RESONATE-2 3443

 Favor ibrutinib Favor chlorambucil N HR 95% CI

All patients 269 0.164 (0.116, 0.232)

Age
70 80 0.101 (0.046, 0.221)
t70 189 0.185 (0.125, 0.273)
Gender
Male 169 0.184 (0.123, 0.275)
Female 100 0.118 (0.059, 0.236)
Rai stage at baseline
Stage 0–II 137 0.216 (0.135, 0.345)
Stage III–IV 132 0.125 (0.075, 0.210)
ECOG at baseline
0 112 0.183 (0.110, 0.305)
1–2 157 0.152 (0.095, 0.245)
Bulky disease
5 cm 170 0.154 (0.097, 0.245)
t5 cm 94 0.130 (0.073, 0.230)
Cytopenias at baseline
Yes 145 0.142 (0.088, 0.230)
No 124 0.197 (0.119, 0.326)
High genomic risk (TP53 mut/
del(11q)/unmut IGHV)
Yes 142 0.098 (0.060, 0.161)
No 127 0.236 (0.142, 0.394)
E2-microglobulin at baseline
d3.5 mg/L 74 0.276 (0.140, 0.545)
!3.5 mg/L 174 0.119 (0.077, 0.183)

0.0 0.5 1.0 1.5 2.0

HR

Figure 2. Subgroup analysis of PFS. Forest plot of PFS in baseline factor subgroups of interest. ECOG, Eastern Cooperative Oncology Group.

diarrhea, fatigue, and palpitations (n 5 2 each). After dose reduc- antiplatelet agents were frequently used (73% and 54%) during
tions related to AEs (lasting a median of 92 days), the ibrutinib dose treatment with ibrutinib and chlorambucil, respectively, as were anti-
was re-escalated back to the previous dose in 8 of the 31 patients hypertensive medications (73% and 61%), including agents acting
with dose reduction (26%). Re-escalated ibrutinib treatment contin- on the renin-angiotensin system (56% and 42%), and medications
ued for a median of 731 days (24.0 months). to treat acid-related disorders (64% and 41%), including proton
pump inhibitors (56% and 36%). The rate of neutrophil growth
Ibrutinib dose-holds (for $7 consecutive days) because of AEs of factor use was similar between the arms (10% and 12%). In
any grade were reported for 79 patients, with most patients (85%, ibrutinib-treated patients who received concomitant medications for
67 of 79) having improved or resolved AEs following their dose- acid-related disorders, the estimated proportion of patients who
hold. For the 79 patients with dose-holds, the median duration were progression free and alive at 7 years (any anti-acid agent,
between first dose-hold of ibrutinib to study treatment discontinua- 61%; proton pump inhibitors, 61%) was similar to that observed in
tion or last known date alive for those still on treatment was 49 all ibrutinib-randomized patients (59%; supplemental Figure 3).
months (maximum, 921 months). Following dose-hold, ibrutinib was
restarted at the same dose in 50 of 79 patients (63%) and at a Outcomes after ibrutinib discontinuation
reduced dose in 23 of 79 patients (29%). For patients who discontinued ibrutinib because of AEs (n 5 32),
OS estimate rate at 7 years from the time of randomization was
Concomitant medications
60%. Discontinuations of ibrutinib because of PD occurred in 18
Concomitant medication data were summarized during the treat- patients. As previously reported,9 this included 2 patients with
ment period, which was a median of 74 months for ibrutinib and a Richter’s transformation. Of patients who discontinued because of
median of 7 months for chlorambucil. Concomitant medications of PD, 72% (13 of 18) remain alive or had exited the study with no
clinical interest are shown in Table 1. Anticoagulants and/or known death as of data cutoff. The median OS following

3444 BARR et al 14 JUNE 2022 • VOLUME 6, NUMBER 11

 100

90

80
Ibrutinib

70 Chlorambucil
Overall survival, %

60
OS was not captured for
50 chlorambucil arm for patients
with PD after median 5 years
of follow-up
40

30

20
Ibrutinib Chlorambucil
10 Median OS, mo NR 89
HR (95% CI) 0.453 (0.276–0.743)
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Months
Patients at risk
Ibrutinib: 136 131 131 127 121 117 113 112 107 101 98 95 91 89 86 27 1
Chlorambucil: 133 124 116 106 98 97 93 90 86 79 74 50 20 13 10 2 0

Figure 3. Long-term OS. OS with single-agent ibrutinib vs chlorambucil in first-line CLL/SLL for intent-to-treat population. Brackets indicate that OS was not captured for
chlorambucil arm of patients with PD after the median 5 years of complete follow-up. Survival analyses are from randomization until event or censoring at last follow-up;
vertical tick marks indicate censored patients. NR, not reached.

100
1%
4% 7% 8% 10% 13% 15% 20% 24% 26% 27% 30% 31% 32% 32% 34%
90 1% 1%
1% 1% 1%
2%
80 2%

70 4% 4% 5%
6% 6% 6% 6%
Response rate, %

60 6%

50 51% 68% 74% 77% 75% 76% 74% 69% 63% 62% 60% 55% 54% 54% 53% 52%

40 21%

30

20 10%

22% 5%
10 3% 3%
13% 1% 1% 1% 1% 1% 1% 1% 1%
2% 2% 2%
9% 7% 7% 4% 4% 4% 4% 4% 4% 4% 4% 4% 4% 4%
0
6 9 12 15 18 24 30 36 42 48 54 60 66 72 78 84
Months

CR/CRi nPR PR PR-L SD

Figure 4. Investigator-assessed ORR. Cumulative best response over time in all ibrutinib-randomized patients. Percentages of patients in each category of response may
not add up to the overall proportion with a response because of rounding. nPR, nodular partial response; PR-L, partial response with lymphocytosis; SD, stable disease.

14 JUNE 2022 • VOLUME 6, NUMBER 11 EIGHT-YEAR FOLLOW-UP OF IBRUTINIB IN RESONATE-2 3445

 A n=11
n=57
n=13
Diarrhea n=9
n=8
n=7
n=4
n=1
n=26
n=13
n=12
Cough n=9
n=11
n=10
n=5
n=2
n=38
n=27
n=21
Fatigue n=19
n=18
n=15
n=11
n=8
n=27
n=9
n=5
Nausea n=3
n=4
n=4
n=3
n=2
n=17
n=8
n=10
URTI n=10
n=7
n=7
n=3
n=2
n=23
n=17
n=13
Peripheral edema n=12
n=10
n=9
n=9
n=5
n=20
n=8
n=7
n=6
Pyrexia n=6
n=4
n=2
0
n=22
n=12
n=9
Anemia n=9
n=6
n=5
n=4
n=3
n=24
n=16
n=11
Arthralgia n=6
n=15
n=9
n=9
n=7
n=10
n=8
n=4
Pneumonia n=6
n=6
n=6
n=5
n=2
n=12
n=11
n=9
UTI n=11
n=5
n=5
n=8
n=3
n=16
n=5
n=7
n=3
Vomiting n=1
n=2
0
0
n=17
n=15
n=11
Constipation n=6
n=7
n=3
n=2
n=3
n=13
n=10 0–1 years (n=135)
n=12
n=13 1–2 years (n=123)
Muscle spasms n=12
n=13 2–3 years (n=111)
n=10
n=7 3–4 years (n=100)
n=13 4–5 years (n=89)
n=5
n=6 5–6 years (n=79)
Weight loss n=6
n=6 6–7 years (n=70)
n=7
n=8 7–8 years (n=60)
n=6

0 20 40 60 80 100
Patients, %

Figure 5.

3446 BARR et al 14 JUNE 2022 • VOLUME 6, NUMBER 11

 B n=7
n=3
n=3
n=4
Pneumonia n=2
n=3
n=3
n=2

n=11
n=4
n=1
n=1
Neutropenia 0
n=1
0
0
n=8
n=1
n=1
0
Anemia 0
n=1
0
0

n=1
n=1
n=1
n=1
Cataract n=3
n=3
n=1 0–1 years (n=135)
0 1–2 years (n=123)
2–3 years (n=111)
n=3
n=3 3–4 years (n=100)
0 4–5 years (n=89)
0
Hyponatremia n=1 5–6 years (n=79)
0 6–7 years (n=70)
0
0 7–8 years (n=60)

0 20 40 60 80 100
Patients, %

Figure 5 (continued) Summary of AEs for ibrutinib-treated patients. The most common any-grade (A) and grade $ 3 AEs (B) are shown by yearly interval. Prevalence
was determined by the proportion of patients with a given AE (existing event or new onset of an event) during each yearly interval. Multiple onsets of the same AE term within a
specific yearly interval were counted once, and the same AE term continuing across several yearly intervals was counted in each of the intervals. Atrial fibrillation and hypertension
are shown in Figure 6. URTI, upper respiratory tract infection; UTI, urinary tract infection.

discontinuation of ibrutinib because of PD (n 5 18) was not provide important data for informed decision making in the current
reached (95% CI, 3.3 months-NE). treatment landscape. With up to 8 years of follow-up, the median
PFS was not reached for patients in the ibrutinib arm, and the
First subsequent therapy after ibrutinib discontinuation was reported
majority of patients remain progression free. Only 18 patients have
for 22 patients and included chemoimmunotherapy (n 5 9; includ-
had PD with continuous long-term use of single-agent ibrutinib to
ing fludarabine plus cyclophosphamide and rituximab, bendamustine
date, and rates of CR/CRi continue to increase with further follow-
plus rituximab, vincristine plus rituximab, and obinutuzumab plus
up (34%) compared with 11% at primary analysis with a median
chlorambucil), chemotherapy (n 5 3; chlorambucil, bendamustine), follow-up of 18 months.3 This is similar to what was observed previ-
novel agents (n 5 7; including 4 patients on venetoclax), immuno- ously with long-term follow-up in the phase 1b/2 PCYC-1102/1103
therapy (n 5 1), investigational agent (n 5 1), and radiation (n 5 1). study: previously untreated patients achieved a CR/CRi rate of 35%
Thirteen patients had the best overall response to the first subse- with up to 8 years of follow-up.11
quent drug reported, with 9 who responded, 2 who had stable dis-
ease, and 2 who had PD. At the current data cut, of the 22 patients Ibrutinib continues to be effective for patients with 1 or more high-
with subsequent therapy, 13 remained on study follow-up, 3 risk genomic features (TP53 mutation, del[11q], and/or unmuta-
patients withdrew consent, 4 patients died, and 2 patients exited ted IGHV), with a 90% reduction in the risk of progression or
the study at PCYC-1115 closure. In the second or later line of ther- death overall compared with chlorambucil treatment. Of note,
apy after ibrutinib, 3 patients received venetoclax or venetoclax plus RESONATE-2 excluded patients with del(17p), and as such, the
rituximab. population with TP53 mutation is limited. del(11q) and unmutated
IGHV have been shown to be predictors of poor outcomes,16 par-
ticularly for patients treated with chemotherapy or chemoimmuno-
Discussion therapy.17-19 At 7 years, RESONATE-2 patients with del(11q) or
These unprecedented long-term data among phase 3 studies of a unmutated IGHV who were randomly assigned to ibrutinib had a
targeted agent in the first-line treatment of patients with CLL/SLL significant benefit, with PFS rates of 52% and 58% of patients,

14 JUNE 2022 • VOLUME 6, NUMBER 11 EIGHT-YEAR FOLLOW-UP OF IBRUTINIB IN RESONATE-2 3447

 At 7 years, ibrutinib-randomized patients in RESONATE-2 demon-
n=18 strated an unprecedented OS rate of 78%, confirming the long-term
n=14
n=16 value of first-line ibrutinib treatment, including for patients with high-
n=17
Hypertensiona n=20 risk disease features. OS benefit for ibrutinib vs chlorambucil was
n=20 previously established in analyses both with and without censoring
n=16
n=15 for crossover, with HRs of 0.376 (95% CI, 0.180-0.786) and 0.450
n=8 (95% CI, 0.266-0.761), respectively.9 However, these analyses are
n=4
n=10 confounded by the high number of patients in the chlorambucil arm
n=8
Atrial fibrillation n=7 who crossed over to receive ibrutinib (n 5 78), with ibrutinib use
n=7
n=5 likely prolonging survival of the patients who crossed over consistent
n=4 0–1 years (n=135) with data in relapsed/refractory populations.10 After a median follow-
n=5 1–2 years (n=123) up of 5 years, patients in the chlorambucil arm who had experienced
n=3 2–3 years (n=111)
n=1
3–4 years (n=100)
PD were exited from the study, and a protocol amendment to extend
n=4
Major hemorrhagea n=2 4–5 years (n=89) the study to 10 years focused on PFS for both arms and OS for ibru-
0
0
5–6 years (n=79) tinib only. Eligible exiting patients could continue ibrutinib in a long-
n=2 6–7 years (n=70)
term extension study (PCYC-1145-LT; #NCT03229200).
7–8 years (n=60)

0 20 40 60 80 100
In terms of concomitant medications, the use of neutrophil growth
factor was similar between the 2 treatment arms despite a longer
Patients, %
reporting period for patients in the ibrutinib arm vs the chlorambucil
arm. In patients treated with ibrutinib, the use of antithrombotic
Figure 6. AEs of clinical interest for ibrutinib-treated patients. Any-grade
AEs of clinical interest are shown by yearly interval. Prevalence was determined by
agents was frequent (73%); however, major hemorrhage events
the proportion of patients with a given AE (existing event or new onset of an event)
were generally rare and decreased over time. Recently, analyses of
during each yearly interval. Multiple onsets of the same AE term within a specific
fatal cardiac events evaluated the impact of cardiovascular disease
yearly interval were counted once, and the same AE term continuing across several
or angiotensin-converting enzyme inhibitor use in patients treated
yearly intervals was counted in each of the intervals. aCombined terms.
with ibrutinib plus rituximab in the FLAIR study.22 By contrast, the
safety profile of ibrutinib has now been well established with up to
8 years of follow-up, and although use of agents acting on the
respectively. Importantly, patients in the ibrutinib arm who had renin-angiotensin system (angiotensin-converting enzyme inhibitors
del(11q) or unmutated IGHV experienced PFS benefits similar to or angiotensin II receptor antagonists) was frequent (56%) in
those in patients without del(11q) or with mutated IGHV, respec- ibrutinib-treated patients on RESONATE-2, the incidence of cardiac
tively. Taken together, our results continue to demonstrate ibrutinib’s events was consistent with previous reports.23,24 Furthermore, more
effectiveness regardless of genomic risk status. This confirms prior than half of patients in this study received medications for acid-
analyses demonstrating that high-risk prognostic risk factors such related disorders while on study treatment, including proton pump
as del(11q) or unmutated IGHV have less prognostic significance inhibitors, with no apparent impact on PFS in ibrutinib-treated
with ibrutinib treatment.20,21 patients. Ibrutinib co-administration with acid-altering medications is
not contraindicated. Absorption of the BTK inhibitor acalabrutinib is
impacted by co-administration with these classes of medications,25
Table 1. Concomitant medications of clinical interest and thus use should be avoided in such patients, an important con-
Ibrutinib, Chlorambucil, sideration for treatment selection.26
n 5 135 n 5 132
Ibrutinib remains well tolerated, with no new safety signals observed
Antithrombotics, n (%) 99 (73) 71 (54)
with long-term follow-up. Indeed, nearly half of patients remain on
Antiplatelets 82 (61) 67 (51) ibrutinib at up to 8 years of follow-up. The rate of discontinuation
Anticoagulants 49 (36) 13 (10) because of AEs was most frequent during the first year of ibrutinib
Antihypertensives, n (%) 98 (73) 80 (61) treatment and generally decreased over time, which is consistent
Agents acting on the renin-angiotensin system 76 (56) 55 (42) with previously published studies.27,28 Overall, with longer follow-up,
rates of discontinuation because of AEs remain low. Active dose
b-Blocking agents 62 (46) 45 (34)
management (dose-holds and reductions) to address AEs enabled
Calcium channel blockers 49 (36) 15 (11)
most patients who required such dose management to continue
Other* 15 (11) 6 (5) benefiting from ibrutinib treatment, and dose re-escalation after AE
Acid-related disorders, n (%) 87 (64) 54 (41) resolution was feasible. Real-world evidence indicates that practic-
H2-receptor antagonists 23 (17) 10 (8) ing dose management (using dose reductions or modifications)
Proton pump inhibitors 75 (56) 47 (36) resulted in improvement or resolution of AEs without evident impact
on disease outcomes.29
Other† 17 (13) 3 (2)
Neutrophil growth factors, n (%) 13 (10) 16 (12) The breadth of experience with targeted agents is still expanding;
*Excluding agents acting on the renin-angiotensin system, b-blocking agents, and
however, ibrutinib has the longest demonstrated efficacy across multi-
calcium channel blockers. ple phase 3 studies,6,7 whereas other targeted agents, including
†Excluding proton pump inhibitors or H2-blockers. follow-on BTK inhibitors approved or in development for CLL, lack
comparable long-term data.30-32 Here we demonstrated in the

3448 BARR et al 14 JUNE 2022 • VOLUME 6, NUMBER 11

longest follow-up to date from a phase 3 study of first-line novel with AbbVie, AstraZeneca, and Janssen and received research
agent therapy in patients with CLL/SLL that nearly half of patients funding from Janssen. J.A.B. has received honoraria from and has
with CLL/SLL were able to receive long-term continuous first-line had a consulting/advisory role with Janssen; received research
treatment with single-agent ibrutinib. With up to 8 years of follow-up, funding from AstraZeneca, BeiGene, and Pharmacyclics LLC, an
single-agent ibrutinib continues to confer sustained PFS benefit vs AbbVie Company; and has been on the speakers bureau for and
chlorambucil. This persistent efficacy extended to patients with the received travel expenses from Gilead, Janssen, Novartis, Pharma-
high-risk genomic features TP53 mutation, del[11q], and/or unmu- cyclics LLC, an AbbVie Company, and TG Therapeutics. P.H. has
tated IGHV. Superior benefit for ibrutinib vs chlorambucil was also had a consultancy/advisory role with AbbVie, AstraZeneca, and
maintained across subgroup analyses of baseline clinical characteris- Janssen; received research funding from AbbVie, AstraZeneca,
tic factors such as advanced stage and bulky disease. The tolerability Gilead, Janssen, Novartis/GSK, Pharmacyclics LLC, an AbbVie
and safety of ibrutinib observed with long-term follow-up was consis- Company, and Roche; has been on the speakers bureau for Abb-
tent with previous reports, and no new safety signals emerged. Vie, AstraZeneca, Janssen, and Roche; and received travel
expenses from AbbVie and Janssen. S.E.C. received honoraria
Acknowledgments from AbbVie, Janssen, and Pharmacyclics LLC, an AbbVie Com-
The authors thank the patients who participated in the study and pany; had a consultancy/advisory role with AbbVie, Adaptive,
their supportive families, as well as the investigators and clinical AstraZeneca, BeiGene, Celgene, Genentech, Janssen, Novartis,
research staff from the study centers. This study was sponsored and Pharmacyclics LLC, an AbbVie Company; received research
by Pharmacyclics LLC, an AbbVie Company. Editorial support funding from AbbVie, AstraZeneca, Janssen, and Pharmacyclics
was provided by Emily Chastain, PhD, an employee of Pharma- LLC, an AbbVie Company; and provided expert testimony for
cyclics LLC, an AbbVie Company. This study is in memory of Genentech and Janssen. H.M. received honoraria and travel
Steven Coutre, who died during the writing of the manuscript. expenses from Janssen and has had a consultancy/advisory role
with AbbVie and Janssen. C.M. has had consultancy/advisory role
with AbbVie, AstraZeneca, BeiGene, and Janssen and received
Authorship research funding from and sat on the speakers’ bureau for
Contribution: P.M.B. designed the study in collaboration with the AbbVie and Janssen. C.Z. E.H., and A.S. are employed by
study sponsor; C.O., T.R., A.T., O.B., J.A.B., P.H., S.E.C., C.D., S.G., Pharmacyclics LLC, an AbbVie Company, and received stock
H.M., J.-Y.L., F.O., C.M., T.J.K., and P.G. contributed to data collec- ownership in AbbVie. T.J.K. has had a consultancy/advisory
tion; C.Z. performed the data analyses; A.S., E.H., and C.Z. con- role with AbbVie, Celgene, Genentech-Roche, Gilead, and
firmed the accuracy of the data and compiled it for analysis; and all Pharmacyclics LLC, an AbbVie Company, and received research
authors had access to the data and were involved in the interpreta- funding from AbbVie, Genentech-Roche, Oncternal Therapeutics,
tion of data, contributed to manuscript review and revisions, and and Pharmacyclics LLC, an AbbVie Company. P.G. received
approved the final version for submission. honoraria from and had a consultancy/advisory role with AbbVie,
Conflict-of-interest disclosure: P.M.B. has had a consultancy/ Acerta/AstraZeneca, ArQule/MSD, Celgene/Juno/Bristol Myers
advisory role with AbbVie, AstraZeneca, Bristol Myers Squibb, Squibb, Janssen, Lilly/Loxo, MEI Pharma, and Roche and received
Celgene, Genentech, Gilead, Janssen, MEI Pharma, Merck, Mor- research funding from AbbVie, AstraZeneca, Janssen, and
phosys, Pharmacyclics LLC, an AbbVie Company, Seattle Genet- Sunesis. The remaining authors declare no competing financial
ics, and TG Therapeutics and received research funding from interests.
AstraZeneca and TG Therapeutics. C.O. received honoraria from
ORCID profiles: P.M.B., 0000-0002-9733-401X; T.R., 0000-
AbbVie, AstraZeneca, Gilead, Incyte, Janssen, Merck, Roche, and
0002-3411-6357; J.A.B., 0000-0002-6177-7572; T.J.K., 0000-
Teva. T.R. received honoraria from AstraZeneca and Janssen and
0002-0064-4549; P.G., 0000-0003-3750-7342.
had a consultancy/advisory role with and research funding from
Acerta, AstraZeneca, and Janssen. A.T. has had a consultancy/ Correspondence: Paul M. Barr, Wilmot Cancer Institute, Uni-
advisory and speakers bureau role for AbbVie, AstraZeneca, Bei- versity of Rochester Medical Center, 601 Elmwood Ave, #704,
Gene, and Janssen. O.B. has had a consultancy/advisory role Rochester, NY 14642; e-mail: [email protected].

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