Higher mutational burden may predict shorter time to first treatment for CLL
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Key takeaways:
- Higher mutational burden linked with shorter time to first treatment in patients with CLL.
- Researchers did not observe co-occurrence of specific mutations in this CLL cohort.
Higher mutational burden was linked to shorter time to first treatment in untreated patients with chronic lymphocytic leukemia independently of other genomic events, according to an abstract presented at ASH Annual Meeting and Exposition.
In this study, Mariia Mikhaleva, MD, from the department of medical oncology at Dana-Farber Cancer Institute, and colleagues identified patterns of co-occurrence and mutual exclusivity among mutations in CLL and their impact on time to first treatment, defined as time from diagnosis to initial treatment.
The cohort included 795 treatment-naive patients with CLL, with a median follow-up of 3.91 years and median time from diagnosis to mutational analysis of 6.6 months.
Researchers performed mutational screening by a clinical targeted next-generation sequencing panel and analyzed IGHV gene mutational status, chromosomal aberrations (by FISH with probes for 11q, 13q, 17p, and trisomy 12), and stimulated karyotype (defining complex karyotype as three or more abnormalities). They examined co-occurrence and mutual exclusivity patterns in patients with a higher mutational burden — determined as two or more distinct mutated genes — and performed the Benjamini, Krieger and Yekutieli method to control for false discovery rate.
Mikhaleva and colleagues detected 1,798 mutations in 719 patients and no mutations in 76 patients. They identified a single mutated gene in 216 patients (27.2%), two mutated genes in 206 patients (25.9%), three mutations in 153 patients (19.2%) and four or more mutated genes in 144 patients (18.1%). The results showed that the most mutated genes were ATM (18.1%), NOTCH1 (17.7%), TP53 (13.2%), SF3B1 (12.3%), TET2 (10.2%) and DNMT3A (10.1%) in the cohort.
The investigators found that increased mutational burden in two or more distinct mutated genes predicted a shorter time to first therapy than zero or one mutated gene (HR = 2.16; 95% CI, 1.57–2.97). Mutated TP53 without del(17p) and wild-type TP53 with del(17p) did not significantly predict time to first therapy; however, the following factors were independently linked with shorter time to first therapy:
- Rai stages 1-4 (HR = 2.63; 95% CI, 1.88–3.7);
- UM-IGHV (HR = 2.4; 95% CI, 1.74–3);
- complex karyotype (HR = 1.47; 95% CI, 1.07–2);
- mutational burden in two or more genes (HR = 1.57; 95% CI, 1.14–2.2); and
- del(17p)/TP53mut (HR = 1.79; 95% CI, 1.15–2.8).
Greater mutational burden was linked to clinical Rai stages 1-4, elevated levels of baseline beta-2 microglobulin and established high-risk genomic features — such as del(17p), del(11q), complex karyotype, unfavorable ZAP70 and unmutated IGHV) — but cases with no or one mutation were more likely to have del(13q), according to the abstract. In addition, lack of any mutations was tied to absence of del(17p), lower rates of baseline beta-2 microglobulin, less frequent unmutated-IGHV, lower ratio of complex karyotype and age younger than 65 years at diagnosis.
The researchers also reported that no genes showed significant mutational co-occurrence after controlling for multiple comparisons. Other notable findings included:
- unmutated-IGHV cases were enriched in mutated ATM, NOTCH1, SF3B1 and XPO1;
- mutated NOTCH1 and KRAS occurred along with tri12;
- unmutated-IGHV did not co-occur with mutations in MYD88;
- del(13q) did not co-occur with mutated BRAF or BCOR; and
- mutated TP53 and SF3B1 were absent in tri12-positive cases.
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