Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients

Shuangtao Zhao, Rashmi Kanagal-Shamanna, Lucy Navsaria, Chi Young Ok, Shaojun Zhang, Krystle Nomie, Guangchun Han, Dapeng Hao, Holly A. Hill, Changying Jiang, Yixin Yao, Loretta Nastoupil, Jason Westin, Luis Fayad, Ranjit Nair, Raphel Steiner, Sairah Ahmed, Felipe Samaniego, Swaminathan P. Iyer, Onyeka OriabureWendy Chen, Xingzhi Song, Jianhua Zhang, Maria Badillo, Omar Moghrabi, Jorge Aranda, Guilin Tang, C. Cameron Yin, Keyur Patel, Leonard Jeffrey Medeiros, Shaoying Li, Francisco Vega, Selvi Thirumurthi, Guofan Xu, Sattva Neelapu, Christopher R. Flowers, Jorge Romaguera, Nathan Fowler, Linghua Wang, Michael L. Wang, Preetesh Jain

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)623-629
Number of pages7
JournalAmerican Journal of Hematology
Volume95
Issue number6
DOIs
StatePublished - Jun 1 2020

ASJC Scopus subject areas

  • Hematology

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    Zhao, S., Kanagal-Shamanna, R., Navsaria, L., Ok, C. Y., Zhang, S., Nomie, K., Han, G., Hao, D., Hill, H. A., Jiang, C., Yao, Y., Nastoupil, L., Westin, J., Fayad, L., Nair, R., Steiner, R., Ahmed, S., Samaniego, F., Iyer, S. P., ... Jain, P. (2020). Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients. American Journal of Hematology, 95(6), 623-629. https://doi.org/10.1002/ajh.25796