Rob Dillard

DocwireNews

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 <a href="https://ash.confex.com/ash/2023/webprogram/Paper190376.html" target="_blank" rel="noopener">presented</a> at the 65th ASH Annual Meeting &amp; Exposition, which is taking place December 9-12 in San Diego, California.&ldquo;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,&rdquo; the investigators wrote. They &ldquo;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.&rdquo;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 &lt;0.05 and a normalized enrichment score of &ge;|1.8|. In the off-Bruton&rsquo;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 &ldquo;other&rdquo; 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. &ldquo;The apparent more pronounced transcriptional response to venetoclax in the off-BTKi group prompted us to look more closely at changes in genes,&rdquo; 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 &ldquo;other&rdquo; 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 &ldquo;other&rdquo; patient group; at the 100-mg dose, only pro-apoptotic genes remained significantly overexpressed in the off-BTKi patient group.&ldquo;Venetoclax induced a distinct and prominent transcriptional response in CLL patients, indicating broad impact on tumor biology, even at doses below 400 mg,&rdquo; the researchers concluded. It will be &ldquo;interesting to correlate the identified transcriptional changes with the depth and durability of the venetoclax response,&rdquo; they added.ReferenceSaleh 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 &amp; Exposition; December 9-12, 2023; San Diego, California.

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Analyzing Transcriptional Changes in Patients With CLL Starting Venetoclax Therapy

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Venetoclax induces a distinct and prominent transcriptional response in patients with chronic lymphocytic leukemia.

Analyzing Transcriptional Changes in Patients With CLL Starting Venetoclax Therapy 

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