Genetic mutation predicts poor outcomes in CLL
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Patients with chronic lymphocytic leukemia who carried the IGLV3-21R110 mutation appeared to have poor outcomes, according to study results presented at the virtual ASH Annual Meeting and Exposition.
These findings suggest that this population of patients could benefit from novel targeted therapies, Ferran Nadeu, postdoctoral researcher at Institut d’Investigacions Biomèdiques August Pi I Sunyer in Spain, said during a presentation.
“Previous research has shown that IGLV3-21 expression is associated with aggressive disease and poor outcomes and that IGLV3-21 expression could be enriched in specific epigenetic subtypes of CLL. More recently, it was reported that its poor prognosis was associated with the presence of a specific mutation, R110, that triggers autonomous B-cell receptor signaling,” Nadeu said. “A unifying study linking all previous findings in large, population-based cohorts and aiming to clarify the prognostic utility of IGLV3-21R110 in the clinical practice setting was missing.”
Investigators sought to characterize the clinical value of IGLV3-21R110 considering IGHV mutation status, epigenetic subtypes, and genomic and transcriptomic landscapes of these tumor types among 584 patients with CLL. Researchers used RNA sequencing data from 369 patients for gene-expression analyses and verified expression levels of WNT5A and WNT5B through quantitative polymerase chain reaction with reverse transcriptase.
Time to first treatment and OS from time of diagnosis served as primary endpoints.
Results showed 6.5% of patients harbored the IGLV3-21R110 mutation, with similar distribution among patients with mutated (6.5%) and unmutated (6.6%) IGHV. IGLV3-21R110 was more common in intermediate CLL (38%) than memory-like CLL (1.7%) and naive-like CLL (0.5%).
All patients in stereotype subset No. 2, a previously defined subset that included those with aggressive disease and poor clinical outcome independent of their IGHV mutational status, carried IGLV3-21R110. However, 62% of IGLV3-21R110 mutations were not stereotyped.
Patients with intermediate CLL with IGLV3-21R110 had a higher median IGHV mutational status than those who did not have IGLV3-21R110 (97.7% vs. 96.2%; P = .005). Moreover, those with intermediate CLL and IGLV3-21R110 had a significantly higher frequency of SF3B1 and ATM mutations.
“Nonetheless, three cases with the R110 mutation harbored deletion 13q and one case did not have any of the previously described driver alterations in this disease,” Nadeu said.
Intermediate CLL with the IGLV3-21R110 mutation resembled unmutated IGHV CLL, with 64 genes having overexpression of WNT5A and WNT5B. Although researchers observed no differences in the expression profile of subset No. 2 and non-subset No. 2 IGLV3-21R110 tumors among patients with intermediate CLL, they did find that those who lacked the IGLV3-21R110 mutation were phenotypically similar to mutated IGHV cases. Further, intermediate CLL with IGLV3-21R110 appeared to have prognostic value independent of IGHV status and subset No. 2.
Researchers then divided intermediate patients with CLL into two subsets based upon the presence or absence of IGLV3-21R110 and found that the mutation refined the prognostic value of CLL epigenetic subtypes. However, intermediate CLL lost its prognostic value for both time to first treatment and OS, according to Nadeu.
“We have confirmed that IGLV3-21R110 has prognostic value independently of the IGHV mutational status of tumors and furthermore refines the prognostic value of the proposed epigenetic classification of CLL, which has been reported to be superior to the IGHV mutational status in different studies,” Nadeu said. “Our results emphasize that CLL with the IGLV3-21R110 is a specific clinical and biological subtype of the disease that needs to be recognized in clinical practice to properly stratify patients in different risk groups. Clinical trial cohorts could be used to assess how these patients respond to novel inhibitors. Our study also highlights the relevance to characterize the light-chain gene rearrangement of the immunoglobulin. In the future, we might find additional light-chain genes and mutations that are biologically and clinically relevant.”
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Nadeu F, et al. Abstract 350. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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