Prognostic Impact of Mutations in CLL Can Depend on IGHV Status

By Cecilia Brown - April 8, 2023

The prognostic impact of mutations in patients with chronic lymphocytic leukemia (CLL) can vary based on IGHV gene somatic hypermutation status, according to a recent study.

Larry Mansouri, PhD; Birna Thorvaldsdottir, PhD; and Lesley-Ann Sutton, PhD, of the Karolinska Institutet in Stockholm, Sweden, and colleagues conducted the research and published its results in Leukemia.

They conducted the study because “recent evidence suggests that the prognostic impact of gene mutations” in patients with CLL “may differ” depending on the IGHV gene somatic hypermutation status.

The researchers assessed the impact of mutations in BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1 in pretreatment samples from 4,580 patients with CLL. The study’s primary endpoint was the time to first treatment in relation to the IGHV gene somatic hypermutation status.

More than one-third (34.7%) of patients had at least one mutation in one of the nine genes analyzed. Mutations in NOTCH1 were the most common, detected in 9.8% of patients, while mutations in EGR2 were the least common, observed in 2.3% of patients. SF3B1 mutations occurred in 9.3% of patients, TP53 mutations occurred in 7%, XPO1 mutations occurred in 3.8%, NFKBIE mutations in occurred in 3.3%, POT1 mutations occurred in 3.1%, BIRC3 mutations occurred in 2.7%, and MYD88 mutations occurred in 2.5%.

With the exception of MYD88, mutations in all genes were associated with a significantly shorter time to first treatment in both univariate and multivariate analyses.

In patients who had Binet stage A, a multivariate analysis performed separate for patients with mutated IGHV and nonmutated IGHV showed a “different spectrum of gene alterations independently predicted short [time to first treatment] within the two subgroups,” the researchers wrote.

SF3B1 and XPO1 mutations were independent prognostic variables of short time to first treatment in patients with and without IGHV mutations.

These results “reinforce SF3B1 mutations as a key biomarker with a very strong negative impact” on time to first treatment in patients with or without mutations in IGHV and “highlight XPO1 as an additional highly relevant gene in both subgroups,” the study’s authors wrote.

BIRC3 and EGR2 aberrations were significant predictors of short time to first treatment only in patients without IGHV mutations, while mutations in NOTCH1 and NFKBIE were significant predictors only in patients with IGHV mutations.

“Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among [patients with CLL who have IGHV mutations], with potential implications for stratified management,” the study’s authors concluded.


Mansouri L, Thorvaldsdottir B, Sutton LA, et al. Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY. Leukemia. 2023;37(2):339-347. doi:10.1038/s41375-022-01802-y

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