Table 1 Incidence and characteristics of BTK and PLCG2 mutations in patients with CLL both within and outside clinical trials.

Reference (PMID/PMCID/DOI)	Type of study	Drug(s)	Disease setting	BTK mutations	PLCG2 mutations
34019713	Observational studies	IBR	RR	80% (32/40) only BTK^C481S was assessed	Not assessed in all patients 1 in a patient without BTK mutations
• 28418267 • (PCYC1102, PCYC1109, PCYC1113 RESONATE)	Clinical trial^a	IBR	RR	78.3% (36/46)	15.2% (7/46) 4 in patients without BTK mutations
38754046 (ELEVATE-RR)	Clinical trial^b	IBR, ACA	RR	ACA: 66% (31/47) IBR: 37% (11/30)	ACA: 6% (3/47)^c IBR: 20% (6/30)^c
• 30508305	Observational studies	IBR, ACA	NA	65.6% (19/29)	0% (0/29)
• 36696464	Observational studies	IBR	TN & RR	61.2% (30/49) 6 detected only with ddPCR	28.5% (14/49) 2 in patients without BTK mutations
• 32726539	Clinical trial^d	IBR	TN	50% (6/12)	58.3% (7/12) 4 in patients without BTK mutations
• 38313250	Observational studies	IBR, ACA PIR, VEC	TN & RR	−IBR, & ACA: 41.7% (15/36) PIR & VEC: 83.3% (5/6)	−IBR, & ACA: 8.3% (3/36)^e PIR & VEC: 33.3% (2/6)
• 37314786 • (PCYC1122e, RESONATE, RESONATE-2, RESONATE-17 iLLUMINATE)	Clinical trial^f	IBR	TN & RR	−25% (3/12) in TN pts 49% (22/45) in RR pts	−8% (1/12) in TN pts 13% (6/45) in RR pts
https://doi.org/10.1182/blood-2023-173547 (ALPINE)	Clinical trial^g	IBR, ZANU	RR	ZANU: 20.8% (5/24) IBR: 10.7% (3/28)	ZANU: 0% (0/24) IBR: 7.1% (2/28)^h
PMC10428413 (BRUIN)	Clinical trialⁱ	PIR	RR	55.5% (27/49)	8% (4/49)

IBR ibrutinib, ACA acalabrutinib, PIR pirtobrutinib, VEC vecabrutinib, RR relapsed/refractory, TN treatInaive, NA not available, ddPCR Droplet Digital polymerase chain reaction.
^aNCT01105247 (phase 2), NCT01217749 (phase 2), NCT01589302 (phase 2), NCT01578707 (phase 3); ^bNCT02477696 (ELEVATE-RR, phase 3); ^c2 in patients without BTK mutations in each arms.
^dNCT01500733 (phase 2 trial); ^eAll co-occurred with BTK mutations; ^fNCT01500733 (phase 2), NCT01722487 (RESONATE-2, phase 3), NCT02264574 (iLLUMINATE, phase 3), NCT01744691 (phase 2), NCT01578707 (RESONATE, phase 3); ^gNCT03734016 (ALPINE, phase 3); ^hOne patient without BTK mutations; ⁱNCT03740529 (BRU½ phase 1/2).

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