TY - JOUR
T1 - Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients
AU - Zhao, Shuangtao
AU - Kanagal-Shamanna, Rashmi
AU - Navsaria, Lucy
AU - Ok, Chi Young
AU - Zhang, Shaojun
AU - Nomie, Krystle
AU - Han, Guangchun
AU - Hao, Dapeng
AU - Hill, Holly A.
AU - Jiang, Changying
AU - Yao, Yixin
AU - Nastoupil, Loretta
AU - Westin, Jason
AU - Fayad, Luis
AU - Nair, Ranjit
AU - Steiner, Raphel
AU - Ahmed, Sairah
AU - Samaniego, Felipe
AU - Iyer, Swaminathan P.
AU - Oriabure, Onyeka
AU - Chen, Wendy
AU - Song, Xingzhi
AU - Zhang, Jianhua
AU - Badillo, Maria
AU - Moghrabi, Omar
AU - Aranda, Jorge
AU - Tang, Guilin
AU - Yin, C. Cameron
AU - Patel, Keyur
AU - Medeiros, Leonard Jeffrey
AU - Li, Shaoying
AU - Vega, Francisco
AU - Thirumurthi, Selvi
AU - Xu, Guofan
AU - Neelapu, Sattva
AU - Flowers, Christopher R.
AU - Romaguera, Jorge
AU - Fowler, Nathan
AU - Wang, Linghua
AU - Wang, Michael L.
AU - Jain, Preetesh
N1 - Publisher Copyright:
© 2020 Wiley Periodicals, Inc.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Venetoclax is effective in relapsed patients with mantle cell lymphoma (MCL). Mechanisms of resistance to venetoclax in MCL are poorly understood. We describe the clinical outcomes and genomic characteristics of 24 multiply relapsed patients (median of five prior lines of therapy) who received venetoclax-based therapies; 67% had progressed on BTK inhibitors (BTKi) and 54% had blastoid or pleomorphic histology. Median follow up after venetoclax treatment was 17 months. The overall response rate was 50% and complete response (CR) rate was 21%, 16 patients had progressed and 15 died. The median progression free, overall and post venetoclax survival were 8, 13.5 and 7.3 months respectively. Whole-exome sequencing (WES) was performed on samples collected from seven patients (including five pairs; before starting venetoclax and after progression on venetoclax). The SMARCA4 and BCL2 alterations were noted only after progression, while TP53, CDKN2A, KMT2D, CELSR3, CCND1, NOTCH2 and ATM were altered 2-4-fold more frequently after progression. In two patients with serial samples, we demonstrated clonal evolution of novel SMARCA4 and KMT2C/D mutations at progression. Mutation dynamics in venetoclax resistant MCL is demonstrated. Our data indicates that venetoclax resistance in MCL is predominantly associated with non-BCL2 gene mutations. Further studies are ongoing in MCL patients to evaluate the efficacy of venetoclax in combination with other agents and understand the biology of venetoclax resistance in MCL.
AB - Venetoclax is effective in relapsed patients with mantle cell lymphoma (MCL). Mechanisms of resistance to venetoclax in MCL are poorly understood. We describe the clinical outcomes and genomic characteristics of 24 multiply relapsed patients (median of five prior lines of therapy) who received venetoclax-based therapies; 67% had progressed on BTK inhibitors (BTKi) and 54% had blastoid or pleomorphic histology. Median follow up after venetoclax treatment was 17 months. The overall response rate was 50% and complete response (CR) rate was 21%, 16 patients had progressed and 15 died. The median progression free, overall and post venetoclax survival were 8, 13.5 and 7.3 months respectively. Whole-exome sequencing (WES) was performed on samples collected from seven patients (including five pairs; before starting venetoclax and after progression on venetoclax). The SMARCA4 and BCL2 alterations were noted only after progression, while TP53, CDKN2A, KMT2D, CELSR3, CCND1, NOTCH2 and ATM were altered 2-4-fold more frequently after progression. In two patients with serial samples, we demonstrated clonal evolution of novel SMARCA4 and KMT2C/D mutations at progression. Mutation dynamics in venetoclax resistant MCL is demonstrated. Our data indicates that venetoclax resistance in MCL is predominantly associated with non-BCL2 gene mutations. Further studies are ongoing in MCL patients to evaluate the efficacy of venetoclax in combination with other agents and understand the biology of venetoclax resistance in MCL.
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U2 - 10.1002/ajh.25796
DO - 10.1002/ajh.25796
M3 - Article
C2 - 32239765
AN - SCOPUS:85083556795
SN - 0361-8609
VL - 95
SP - 623
EP - 629
JO - American journal of hematology
JF - American journal of hematology
IS - 6
ER -