Molecular Genetics and Prognosis in Younger Patients with Chronic Lymphocytic Leukemia (CLL)

Background: While CLL is commonly diagnosed in older patients, there are ~15% of patients diagnosed at ages younger than 50. Several past studies have investigated differences in clinical parameters and treatment outcomes in younger patients with CLL, including a shorter time to first treatment (TTFT) among younger patients (Parikh et al. 2014). However, few studies have reported on the genetic mutational differences between younger and older cohorts. To bridge this gap, we investigated the mutational landscape between younger and older patients and evaluated the clinical outcome TTFT, hypothesizing that our younger cohort of patients would associate with higher risk lesions and behave more aggressively.

Methods: We conducted a single center retrospective database review of 557 patients diagnosed with CLL from 1980 to 2019 who underwent whole exome profiling between 2015 to 2019 with a lymphoid specific 75-gene next generation sequencing (NGS) panel (Genoptix Inc). A Pearson's chi-square test was used to compare categorical variables between groups and a Wilcoxon rank sum test was used to compare medians. The TTFT was estimated using Kaplan-Meier methods, and the difference between groups was compared using the log-rank test. Multivariate regression using a Cox proportional hazards model was used to compare TTFT between groups independent of well-accepted clinical risk factors for treatment initiation.

Results: Of the 557 patients who underwent NGS testing, 92 (16.5%) were younger than 50 years old with a median age of 44.9 years old compared to a median age of 62.7 years old in the 465 (83.5%) patients older than 50 years old. There was no difference between the two groups with regards to previous treatment prior to NGS testing with 29.2% in the older patients and 26.1% in the younger patients having previously been treated (p=0.63). The median time from CLL diagnosis to initial NGS testing was 5.2 years in the younger cohort vs. 3.2 years in the older cohort (p=0.04). There were no differences in baseline prognostic factors between younger and older patients, including Rai stage, IGVH status, CD38 positivity, ZAP70 expression, and cytogenetic abnormalities. We found a lower frequency of TP53 mutations in younger compared to older patients (6.5% vs 15.7%, p=0.03) but otherwise found no differences in any other genetic mutations between the two groups, including NOTCH1, FAT1, ATM, and SF3B1 (Table 1). There was a longer TTFT in younger patients with a median TTFT of 7.61 years compared to 4.42 years in older patients (p=<0.001) (Figure 1). The difference in TTFT was independent of TP53 mutation status in a multivariate analysis.

Conclusions: We found no enrichment of specific genetic mutations in younger versus older patients except a lower prevalence of TP53 mutations in our younger patient population. We found younger patients have a longer TTFT, which is contrary to previous studies that have identified younger age as a negative prognostic marker. Future research is needed to determine why younger patients in our cohort appear to have a more indolent disease course in terms of TTFT despite similar baseline prognostic factors and molecular genetics to older patients.

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