P1836

Risk of Hypertension in Patients With CLL/SLL Who Participated in ALPINE: A Post Hoc Analysis
Dulce Ramirez,1 Lipeng Chen,2 Jun Zhang,1 Wassim Aldairy,1 William B. White3
BeiGene USA, Inc, San Mateo, CA, USA; 2BeiGene (Beijing) Co, Ltd, Beijing, China; 3Cardiology Center, University of Connecticut Health Center, Canton, CT, USA

1RESULTS• Ibrutinib, the first-generation BTK inhibitor, is associated with anincreased risk of cardiovascular events, including hypertension1• At baseline, patient characteristics were generally balanced
between the zanubrutinib and ibrutinib arms (Table 1)• This post hoc analysis evaluated the risk of developing
hypertension with zanubrutinib vs ibrutinib in ALPINE based on
initiation of antihypertensive therapy

METHODS• Time to first event of hypertension and rates of antihypertensive
medication use in the zanubrutinib (n=324) and ibrutinib (n=324)
arms of ALPINE were assessed (Figure 1)• Concomitant antihypertensive drugs were defined by theWHODrug medicinal information dictionary Standardized DrugGroupings• Concomitant antihypertensive drugs were adjudicated by anindependent hypertension specialist who was blinded to BTK
inhibitor assignment• Time-to-onset endpoints were analyzed using the log-rank test
Figure 1. Study DesignIbrutinib(n=324)Age, median (range), years

67.0 (35-90)

67.5 (35-89)

212 (65)

231 (71)

Male sex, n (%)
Race, n (%)

Zanubrutinib (n=324)

261 (81)

Asian2(NCT03734016)

Hemoglobin, g/L
Neutrophil count, 10⁹/L
Platelet count, 10⁹/L

Type 2 diabetes mellitus, n (%)
Zanubrutinib Ibrutinib(n=324)(n=324)
Assessed forTime to first eventof hypertension(based on narrow SMQ)

Rate of antihypertensive
medication use(based on SDG)

Rate of patients initiating
new antihypertensive druga

Rate of patients initiating
new antihypertensive drugin a new classb

Antihypertensive SDG:
• Antihypertensives• Beta-blocking agents• Calcium channel blockers• Agents acting on therenin-angiotensin system

44 (14)27.2 (4.9)

27.1 (4.6)

121.6 (21.9)
4.1 (2.5)
139.1 (65.5)
72.8 (17.8)
67 (21)120.5 (20.3)
4.2 (4.8)

70.2 (17.8)

25

157 (48)150 (46)b• Among patients not on an antihypertensive medication atbaseline, 21% of zanubrutinib-treated patients and 29% ofibrutinib-treated patients initiated antihypertensive therapy during
the study (Figure 3)

26

20

1720

• In patients with CLL/SLL from the ALPINE study,

initiation of a new antihypertensive drug or a
new class of antihypertensive drug occurred lessfrequently with zanubrutinib vs ibrutinib• Initiation of antihypertensive therapy occurred sooner
with ibrutinib compared with zanubrutinib• These findings should be considered when initiating
BTK inhibitor therapy in patients with CLL/SLL who
have an elevated cardiovascular risk
Figure 4. Kaplan-Meier Curve of Time to Initiation of First New
Antihypertensive Drug
5040Ibrutinib
Zanubrutinib
CensoredHR, 0.77; P=.071

31230
20
10090

No. of patients at risk
Ibrutinib
324
271
Zanubrutinib 324
289

6 months

12 months

18 months

3576.2 (11.7)

127.3 (15.1)[92-187]2830 months

36 months

Figure 3. Summary of Antihypertensive Therapy in ALPINE

76.9 (10.7)• Overall, the rates for time to first event of hypertension weresimilar in both the zanubrutinib and ibrutinib arms (Figure 2)

Time to initiation of first new
antihypertensive drug in
a new classb by KM method

10Heart rate, mean (SD), bpm

128.9 (16.0)[92-187]291230Baseline systolic blood pressure,mean (SD) [range], mmHg

161580 (25)162 (50)202095 (29)165 (51)

2625063 (19)Hypertension SMQ narrow, n (%)

Ibrutinib (n=324)

5132.1 (57.1)

Data cutoff: August 8, 2022.
BMI, body mass index; bpm, beats per minute; eGFR, estimated glomerular filtration rate; SMQ, Standardized MedDRA Query.

New antihypertensive therapy is defined as any new medications for hypertension taken after the first dose of study drug. New class ofantihypertensive is defined as any new medications for hypertension in a new class taken after the first dose of study drug.
KM, Kaplan-Meier; SDG, Standardized Drug Grouping; SMQ, Standardized MedDRA Query.
a45 (14)30

Hyperlipidemia, n (%)

Prior antihypertensive druguse, n (%)

Time to initiation of first new
antihypertensive druga
by KM method

264 (81)

Key hematologic parameters,mean (SD)eGFR, mean (SD), ml/min
per 1.73 m²

ALPINE

Figure 2. Cumulative Event Rate of Hypertension Over Time
35

WhiteBMI, mean (SD), kg/m

• The cumulative event rates for initiation of a new antihypertensive
drug or a new class of antihypertensive drug were consistently
lower with zanubrutinib compared with ibrutinib at each time point(Figures 4 and 5)

CONCLUSIONS

Cumulative event rate, %– However, in the phase 3 ALPINE study, patients with relapsed/refractory (R/R) CLL/SLL had similar hypertension TEAE rates
with zanubrutinib and ibrutinib,4 which is not consistent withother clinical studies5,6Characteristic

Zanubrutinib(n=324)• Fewer patients in the zanubrutinib arm initiated a new class ofantihypertensive drugs (Figure 3) and had a statistically significant
delay in initiation vs the ibrutinib arm (Figure 5; HR, 0.72; P<.05)

Cumulative event rate, %• Results from a pooled safety analysis showed that zanubrutinib
is generally well tolerated and has lower rates of hypertension
compared with ibrutinib3

Table 1. Baseline Demographics

Proportion of patients, %• Zanubrutinib is a potent and selective next-generation BTK
inhibitor designed to maximize BTK occupancy and minimize offtarget effects2• Fewer patients in the zanubrutinib arm initiated new
antihypertensive therapy (Figure 3) and initiation was latercompared with the ibrutinib arm (Figure 4; hazard ratio [HR], 0.77;
P=.071)5032292928242140109151821242730

33

36

115
149

85
120

76
106

5980

2633

Time, months
238
268

220
250

208
238

189
225

169
214

150
198

Ibrutinib
Zanubrutinib
CensoredHR, 0.72; P<.05

31230
20
100

156Figure 5. Kaplan-Meier Curve of Time to Initiation of First
Antihypertensive Drug in a New Class
Cumulative event rate, %INTRODUCTION0

No. of patients at risk
Ibrutinib
324
277
Zanubrutinib 324
295

6915

18

21

24

27

30

33

36

127
157

94
125

84
109

67
83

28
35Time, months
246
276

227
264

216
252

197
238

179
225

162
208

5REFERENCES0Patients who initiatednew antihypertensive therapy
among those withoutbaseline antihypertensive therapy
Zanubrutinib (n=169)

Ibrutinib (n=178)

Patients with new
Patients with new
antihypertensive therapy antihypertensive therapy
in a new drug class
Zanubrutinib (n=324)

Ibrutinib (n=324)

1. Quartermaine C, et al. JACC CardioOncol. 2023;5(5):570-590.
2. Guo Y, et al. J Med Chem. 2019;62(17):7923-7940.
3. Tam CS, et al. Blood Adv. 2022;6(4):1296-1308.

4. Brown JR, et al. N Engl J Med. 2023;388(4):319-332.
5. Tam CS, et al. Blood. 2020;136(18):2038-2050.
6. Tam CS, et al. Lancet Oncol. 2022;23(8):1031-1043.

DISCLOSURESDR, WA: Employment, leadership and stock options: BeiGene. LC, JZ: Employment and stock options: BeiGene. WBW: Consultant: BeiGene.

ACKNOWLEDGMENTS

The authors thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers. This study wassponsored by BeiGene, Ltd. Medical writing support was provided by Brittany Gifford, PharmD, of Nucleus Global, an Inizio company, and supported byBeiGene.

Presented at the EHA2024 Hybrid Congress; June 13-16, 2024; Madrid, Spain