Analyzing Transcriptional Changes in Patients With CLL Starting Venetoclax Therapy

Venetoclax induces a distinct and prominent transcriptional response in patients with chronic lymphocytic leukemia (CLL) and appears to have a broad impact on tumor biology, according to a study presented at the 65th ASH Annual Meeting & Exposition, which is taking place December 9-12 in San Diego, California.

“Venetoclax is a selective BCL-2 inhibitor that was recently approved for CLL treatment. [The therapy] inhibits the pro-survival protein BCL-2 and induces deep and durable responses in a significant proportion of CLL patients,” the investigators wrote. They “aimed to study gene expression changes in leukemic cells from CLL patients during the ramp-up period of venetoclax treatment and to assess the transcriptional effect of escalating doses of BCL-2 inhibition on tumor biology.”

Layla M. Saleh and colleagues performed RNA sequencing on the CD19+ selected tumor cells of 29 patients. They administered a ramped-up regimen of venetoclax, with weekly increments ranging from 20 mg to 400 mg. They also collected 4 samples per patient at baseline and after completing 1 week on venetoclax 50 mg, 100 mg, and 400 mg.

To assess the impact of venetoclax on the CLL transcriptome, researchers performed a gene set enrichment analysis using the Hallmark and C3 gene sets from the molecular signature database. They noted that gene sets were identified using a false discovery rate of <0.05 and a normalized enrichment score of ≥|1.8|. In the off-Bruton’s tyrosine kinase inhibitor (BTKi) patient group, 27 gene sets were identified as statistically significantly enriched at 100-mg and 400-mg doses, while in the “other” patient group, 15 gene sets were found to be significantly enriched at the same doses.

The study also identified upregulation of the NRF2, NFE2, TCF11, and BACH motif gene sets. “The apparent more pronounced transcriptional response to venetoclax in the off-BTKi group prompted us to look more closely at changes in genes,” the researchers wrote of the results. At baseline, they observed that expression of BCL2L2 and NOXA was appreciably lower in the off-BTKi patients versus the “other” patients. Surprisingly, at the 50-mg dose, expression of both the pro-apoptotic and anti-apoptotic BCL-2 family members was notably increased in the off-BTKi patient group compared with the “other” patient group; at the 100-mg dose, only pro-apoptotic genes remained significantly overexpressed in the off-BTKi patient group.

“Venetoclax induced a distinct and prominent transcriptional response in CLL patients, indicating broad impact on tumor biology, even at doses below 400 mg,” the researchers concluded. It will be “interesting to correlate the identified transcriptional changes with the depth and durability of the venetoclax response,” they added.

Reference

Saleh LM, Mhibik M, Chen J, Sun C, Pleyer C, Wiestner A. Transcriptional changes in patients with CLL starting venetoclax therapy identifies inflammatory and adaptive stress responses. Abstract #4196. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.