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 * BTK mutation prevalence
 * Kinase-dead and kinase-proficient mutations
 * BTK mutations and the BCR signaling pathway
 * Additional resources
 * Stay up to date





WHEN IT COMES TO BTK MUTATIONS,


KNOW THE DIFFERENCES

BTK mutation
prevalence
Kinase-dead and
kinase-proficient mutations
BTK mutations and
the BCR signaling pathway
Additional resources
BTK mutation prevalence
Kinase-dead and kinase-proficient mutations
BTK mutations and the BCR signaling pathway
Additional resources
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IN CLL PATIENTS WHO PROGRESSED WHILE ON A BTKI, UP TO ~80%
(14-83%) HAD A BTK ± PLCG2 MUTATION PRESENT1-6

IN PATIENTS WHO PROGRESSED ON A BTKi1:

 1. .
 2. .
 3. .
 4. .
 5. .

.

~20%

no mutations
(wild-type BTK/PLCG2)

<10%

PLCG2 mutation

20%-30%

BTK and PLCG2 mutation

~50%

BTK mutation



Image adapted from Ahn IE, Brown JR. Front Immunol. 2021;12:687458.

 * Of the patients participating in clinical trials who were reported to have ≥1
   BTK mutation (sample size ranged from 6-57), C481S was the most common
   mutation in patients who progressed on a BTKi2-5


BTK MUTATIONS MAY BE CLASSIFIED AS EITHER
KINASE-PROFICIENT OR KINASE-DEAD7

Kinase proficient

c481s
t474i

Kinase-proficient mutations maintain the enzymatic activity of the BTK, which
may help continue function of BTKis7,8

Kinase dead

l528w
a428d

Kinase-dead mutations may reduce the enzymatic activity of the BTK, but retain
downstream signaling of the B-cell receptor by bypassing the BTK7,9

 * BTK mutations may alter the kinase domain, impeding the ability of BTKis to
   bind to the kinase1

Preclinical Studies


KINASE-DEAD MUTATIONS MAY HAVE REDUCED KINASE ACTIVITY
COMPARED TO BTK WILD TYPE IN PRECLINICAL STUDIES7

KINASE ACTIVITY OF SELECT
KINASE-PROFICIENT VS KINASE-DEAD
MUTATIONS VS BTK WILD TYPE



Image adapted from Montoya S, Bourcier J, Thompson MC, et al. Blood.
2022;140(Suppl 1):1811-1813.

Kinase activity MAY BE SUBSTANTIALLY reduced
with kinase-dead mutations7

Preclinical Studies


KINASE-DEAD MUTATIONS SUCH AS L528W AND A428D MAY
PREVENT BTKIS FROM BLOCKING BTK ENZYMATIC ACTIVITY8

CHOOSE MUTATION

 1. BCR Signaling pathway
 2. Kinase-dead mutation




Images adapted from Ahn IE, Brown JR. Front Immunol. 2021;12:687458. Images are
schematic representations of possible BCR signaling pathways.

BCR signaling may bypass
BTK activity in the case of
kinase-dead mutated BTK7,9

Preclinical Studies


RELATED RESOURCES





ASTRAZENECA IS COMMITTED TO BETTER
UNDERSTANDING THE SCIENCE OF MUTATIONS

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ADP=adenosine diphosphate; ATP=adenosine triphosphate; BCR=B-cell receptor;
BTKi=Bruton tyrosine kinase inhibitor; CLL=chronic lymphocytic leukemia;
PLCG2=phospholipase C gamma 2.

References: 1. Ahn IE, Brown JR. Front Immunol. 2021;12:687458. 2. Maddocks KJ,
Ruppert AS, Lozanski F, et al. JAMA Oncol. 2015;1(1):80-87. 3. Woyach J, Furman
R, Liu TM, et al. N Engl J Med. 2014;370:2286-94. 4. Woyach J, Ruppert AS, Guinn
D, et al. J Clin Oncol. 2017;35(13):1437-1443. 5. Woyach J, Huang Y, Rogers K,
et al. Blood. 2019;134(Suppl 1):504. 6. Flaherty C. OncLive. Published December
14, 2023. Accessed March 4, 2024. https://www.onclive.com/conference/ash 7.
Montoya S, Bourcier J, Thompson MC, et al. Blood. 2022;140(Suppl 1):1811-1813.
8. Wang E, Mi X, Thompson M, et al. N Engl J Med. 2022;386:735-743. 9. Blombery
P, Thompson ER, Lew TE, et al. Blood Adv. 2022;6(20):5589-5592.

ADP=adenosine diphosphate; ATP=adenosine triphosphate; BCR=B-cell receptor;
BTKi=Bruton tyrosine kinase inhibitor; CLL=chronic lymphocytic leukemia;
PLCG2=phospholipase C gamma 2.

References: 1. Ahn IE, Brown JR. Front Immunol. 2021;12:687458. 2. Maddocks KJ,
Ruppert AS, Lozanski F, et al. JAMA Oncol. 2015;1(1):80-87. 3. Woyach J, Furman
R, Liu TM, et al. N Engl J Med. 2014;370:2286-94. 4. Woyach J, Ruppert AS, Guinn
D, et al. J Clin Oncol. 2017;35(13):1437-1443. 5. Woyach J, Huang Y, Rogers K,
et al. Blood. 2019;134(Suppl 1):504. 6. Flaherty C. OncLive. Published December
14, 2023. Accessed March 4, 2024. https://www.onclive.com/conference/ash 7.
Montoya S, Bourcier J, Thompson MC, et al. Blood. 2022;140(Suppl 1):1811-1813.
8. Wang E, Mi X, Thompson M, et al. N Engl J Med. 2022;386:735-743. 9. Blombery
P, Thompson ER, Lew TE, et al. Blood Adv. 2022;6(20):5589-5592.

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US-81471 Last Updated 3/24

The clinical significance of the presence or absence of BTK mutations has not
been established. Information on BTK
mutations does not imply any clinical safety or efficacy aspects related to BTK
inhibitors.