Mutation Impact of Targeted Genes in Diffuse Large B-Cell Lymphoma Patients Treated with Ibrutinib

• Published in: Blood 2015-12, Vol.126 (23), p.2642-2642
• Main Authors: Cheung, Leo WK, Schweighofer, Karl J., Wu, Shiquan, Kuo, Hsu-Ping, Eckert, Karl, Balasubramanian, Sriram, Ricci, Deborah, Liang, Yu, Beaupre, Darrin, Chang, Betty Y.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V126.23.2642.2642

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma, accounting for approximately 30% of newly diagnosed cases in the United States. DLBCL can progress quickly and advanced cases are inconsistently cured with current therapies. Ibrutinib, a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, is approved in the US and EU for patients with previously-treated mantle cell lymphoma and chronic lymphocytic leukemia (CLL) who have had one prior treatment, CLL with 17p deletion, and Waldenström macroglobulinemia. The activated B-cell (ABC) subtype of DLBCL is considered especially high risk and is characterized by chronic active B-cell receptor signaling, which is blocked by ibrutinib. Recent phase 2 trial results of ibrutinib as a single agent in DLBCL patients show an overall response rate of 41% in the ABC subtype (Wilson et al. ASH 2012; Wilson et al. Nat Med, 2015). Through targeted deep sequencing, we investigated the impact of baseline mutations of 317 targeted genes on clinical response of 51 DLBCL patients treated with ibrutinib. Based on our mutation impact analysis, we identified potential biomarkers for predicting DLBCL patient response to ibrutinib. In particular, we found sets of gene mutation patterns indicating poor (or good) clinical response across all subtypes (ABC, germinal-center B-cell-like [GCB], non-GCB) of DLBCL as well as uniquely within a subtype. Methods: H&E-stained slides from DLBCL patients enrolled in either PCYC-04753 (NCT00849654) or PCYC-1106 (NCT01325701) were reviewed to ensure sufficient nucleated cellularity and tumor content. DNA and RNA were extracted from unstained sections of FFPE DLBCL tumor biopsies. Sequencing was performed using the FoundationOne™ Heme panel following the validated NGS-based protocol to interrogate complete DNA coding sequences of 405 genes, as well as selected introns of 31 genes involved in rearrangements. RNA sequences of 265 commonly rearranged genes were analyzed to identify gene fusions. A subgroup of samples were analyzed on earlier versions of the FoundationOne™ panels where only DNA was extracted and sequenced. Sequence data was processed and analyzed for base substitutions, insertions, deletions, copy-number alterations, and selected gene fusions. Mutation impact indices (MII) of 317 genes were calculated and plotted for overall gene mutation pattern recognition. Chi-square association tests were performed on cases where sufficient sa