Landscape of BCL2 Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory
Chronic Lymphocytic Leukemia Treated with Venetoclax
(739593 (European Union’s Horizon 2020 Research and Innovation Programme))
(BO/00125/22)
(ÚNKP-22-5-SE-7)
Az orvos-, egészségtudományi- és gyógyszerészképzés tudományos műhelyeinek fejlesztése(EFOP-3.6.3-VEKOP-16-2017-00009)
Támogató: EFOP-VEKOP
(TKP2021-EGA-24)
János Bolyai Research Scholarship of the Hungarian Academy of Sciences(TKP2021-NVA-15)
Szakterületek:
Klinikai orvostan
The oral, highly selective Bcl2 inhibitor venetoclax has substantially improved the
therapeutic landscape of chronic lymphocytic leukemia (CLL). Despite the remarkable
response rates in patients with relapsed/refractory (R/R) disease, acquired resistance
is the leading cause of treatment failure, with somatic BCL2 mutations being the predominant
genetic drivers underpinning venetoclax resistance. To assess the correlation between
disease progression and the most common BCL2 mutations G101V and D103Y, sensitive
(10−4) screening for the most common BCL2 mutations G101V and D103Y was performed
in 67 R/R CLL patients during venetoclax single-agent or venetoclax–rituximab combination
therapy. With a median follow-up time of 23 months, BCL2 G101V and D103Y were detected
in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with four patients harboring
both resistance mutations. Ten out of eleven patients carrying BCL2 G101V and/or D103Y
experienced relapse during the follow-up period, representing 43.5% of the cases (10/23)
showing clinical signs of disease progression. All BCL2 G101V or D103Y variants were
detected in patients receiving venetoclax as a continuous single-agent treatment while
these mutations were not observed during or after fixed-duration venetoclax therapy.
Targeted ultra-deep sequencing of BCL2 uncovered three additional variants in four
patient samples obtained at relapse, suggesting convergent evolution and implying
a cooperating role of BCL2 mutations in driving venetoclax resistance. This cohort
is the largest R/R CLL patient population reported to date in which BCL2 resistance
mutations were investigated. Our study demonstrates the feasibility and clinical value
of sensitive screening for BCL2 resistance mutations in R/R CLL.