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

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.

MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

“…Early clinical data as well as preclinical data indicate that also in mantle cell lymphoma, which is largely characterized by high expression of BCL-2 and showed a more promising clinical response to venetoclax than other subtypes of B-cell lymphoma [ 102 ], MCL-1 may be a valuable therapeutic target. This may be particularly the case in the context of acquired resistance to venetoclax, which has been described to be associated with a shift toward MCL-1-dependency [ 111 ]. Therefore, inhibition of MCL-1 may be a particularly promising strategy in patients that relapse after venetoclax treatment.…”

Combination strategies to overcome resistance to the BCL2 inhibitor venetoclax in hematologic malignancies

“…Amplification of BCL2, MCL1, and BCL-XL in CLL when venetoclax therapy failed, and the overexpression of these genes in CLL cell line increased the IC50 of venetoclax [ 39 ]. In MCL, clonal evolution also drove drug resistance [ 42 ]. In patients resistant to ibrutinib, a combination of ibrutinib with venetoclax showed a synergistic effect; however, drug resistance was inevitable.…”

“…Whole-exome sequencing showed SMARCA4 and KMT2C/D mutations as new genome alterations at progression. Harboring these two gene mutations might initiate de novo clone formation and venetoclax resistance [ 42 ].…”

BH3 Mimetics for the Treatment of B-Cell Malignancies—Insights and Lessons from the Clinic

“…However, to date, none of these mechanisms have been seen in patients with MCL treated with venetoclax. Recently, whole-exome sequencing of biopsy samples from seven patients with multiply relapsed MCL who received venetoclax-based therapies has revealed that unlike in CLL, BCL2 mutations are infrequent in venetoclax-resistant MCL, occurring in only one patient at progression; instead, the acquisition of non-BCL2 mutations, including alterations in TP53 , SMARC4 , CELSR3 , CCND1 and KMT2D , may play a role in disease progression [ 113 ]. In FL, venetoclax resistance has been studied in t(14;18) positive cell lines and increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and decreased levels of BIM were seen in cell populations that survived venetoclax treatment [ 97 ].…”