Impact of gene mutations and chromosomal aberrations on progression-free survival in chronic lymphocytic leukemia patients treated with front-line chemoimmunotherapy: Clinical practice experience

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Title in English Impact of gene mutations and chromosomal aberrations on progression-free survival in chronic lymphocytic leukemia patients treated with front-line chemoimmunotherapy: clinical practice experience
Authors

ŠPUNAROVÁ Michaela TOM Nikola PAVLOVÁ Šárka MRÁZ Marek BRYCHTOVÁ Yvona DOUBEK Michael PANOVSKÁ Anna SKUHROVÁ FRANCOVÁ Hana BRZOBOHATÁ Anna POSPÍŠILOVÁ Šárka MAYER Jiří TRBUŠEK Martin

Year of publication 2019
Type Article in Periodical
Magazine / Source Leukemia Research
MU Faculty or unit

Faculty of Medicine

Citation
Web http://dx.doi.org/10.1016/j.leukres.2019.04.015
Doi http://dx.doi.org/10.1016/j.leukres.2019.04.015
Keywords CLL; chemoimmunotherapy; deletion 11q22; IGHV; BIRC3; ATM
Description The impact of genetic aberrations on rituximab-based therapeutic regimens has been intensely studied in chronic lymphocytic leukemia (CLL). According to the current consensus chemoimmunotherapy consisting of rituximab and DNA-damaging drugs is not suitable for patients with TP53 defects. In our study, we focused on CLL patients with an intact TP53 gene and investigated four recurrently mutated genes in CLL, genomic aberrations by FISH, and IGHV status with the aim of analyzing their impact on progression-free survival (PFS) after front-line therapy with FCR (fludarabine, cyclophosphamide, rituximab) or BR (bendamustine, rituximab) regimens. Using next-generation sequencing, we analyzed 120 patients treated with FCR and 57 patients treated with BR at a university hospital. We used a 10% cut-off for variant allele frequency and recorded the following mutation frequencies in the pre-therapy samples: ATM 23%, SF3B1 20%, NOTCH1 19% and BIRC3 11%. The data on cytogenetic aberrations (11q22, 13q14, trisomy 12) and IGHV mutation status were also considered in PFS analyses. In univariate analyses, we observed a negative impact of BIRC3 mutations and 11q22 deletion in both regimens, while the unmutated IGHV status was associated with a significantly shorter PFS only in the FCR-treated cohort. In a multivariate analysis, only deletion 11q22 in both regimens, and the unmutated IGHV in the FCR cohort maintained an independent association with the reduced PFS. Notably, sole 11q22 deletion, without an ATM mutation on the other allele, manifested the shortest PFS of all analyzed markers. Deletion 11q22 and IGHV status predict PFS in previously untreated CLL patients.
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