FAT1 Mutations Influence Time to First Treatment in Untreated CLL

Abstract

Introduction:Despite mapping of the mutational landscape in patients (pts) with chronic lymphocytic leukemia (CLL), there remains limited information regarding the functional or clinical impact of less common, recurrently mutated genes. Over the past several years, the influence of high-risk mutations has been reported. With the advent of readily available next generation sequencing (NGS), physicians receive a large amount of genomic data, many times without information regarding the clinical impact of less validated, mutations. Using results from a commercially available NGS platform, we identified a relatively high prevalence of mutations in the gene, FAT1, in treatment naïve (TN) CLL pts.FAT1 encodes a protein in the cadherin superfamily, important in regulating WNT signaling, with a role in tumor suppression. Aberrant mutated FAT1 expression has been associated with acute lymphoblastic leukemias with an intermediate clinical course. Loss of protein, through chromosomal deletions has been implicated in many solid tumors and associated with tumor progression. The majority of mutations arise in the cadherin repeats, previously shown to diminish antagonism of β-catenin, allowing its nuclear localization (Morris Nat Genetics 2013). In CLL, FAT1 mutations have been demonstrated to enrich in fludarabine refractory pts (10.3%) but with a relatively low prevalence in untreated pts (1.1%) (Messina, Blood 2014). Given a high prevalence of FAT1 mutations in our database and evidence suggesting mutated FAT1 contributes to tumor evolution, we investigated the clinical impact of clonal FAT1 mutations in pts with CLL.Methods:Patients were identified for inclusion if mutational analysis was performed prior to, or within 12 months of treatment start date. Only pts treated initially with a signal transduction inhibitor (STI) were included. Treated pts were either on protocol or received their STI as standard of care. All pts underwent whole exome profiling with a lymphoid specific NGS panel, including 75 genes (Genoptix Inc.). Analysis was performed on peripheral blood or bone marrow aspirates. The primary outcome was time to first treatment (TTFT). The log-rank test was used to compare Kaplan-Meir curves. Double-sided P values <0.05 were considered significant. Fischer exact test was used to compare baseline characteristics. All calculations were performed using Prism V6.0.Results:In total we analyzed 172 pts, 118 (69%) remain on observation, 54 (31%), have been treated at data cutoff. Nineteen (11%) pts were found to be FAT1 mutated (mFAT1) and 153 (89%) were FAT1 wild type (wtFAT1). The median time from diagnosis to mutational profiling for the cohort was 35 months (range 0-301). We identified 21 total mutations, 17 unique (82% cadherin domain, 18% EGF like region). Recurrent mutations were identified, each occurring in 2 pts (p.A636T, p.P1614L, p.R1257Q, p.R2041H). One pt had an indel and 1 pt had an inframe deletion, the remaining were missense. We found no significant differences between groups in regards to age, IGVH mutation status or co-occurrence of high-risk mutations in NOTCH1, SF3B1, TP53 or ATM. Only 17p deletions occurred significantly more in mFAT1 pts (24%) vs. wtFAT1 (7%), p=0.04, other cytogenetic abnormalities were balanced. mFAT1 pts had significantly shorter TTFT, 50 versus 143 months respectively, p=0.02. We investigated if mFAT1 status could stratify IGVH mutated pts but found no differences in TTFT. Eleven mFAT1 pts have received treatment (82% ibrutinib, 18% acalabrutinib), 8 remain on observation. All mFAT1 pts have responded.Conclusions:Given the increasing use of rapidly available NGS testing, physicians receive genomic information with limited data regarding clinical impact. We identified a higher prevalence of FAT1 mutations in TN pts, than that previously reported. FAT1 mutations associated with deletion 17p but not other high-risk genetic mutations. Recurrent FAT1 mutations were identified and commonly found in the cadherin domain. mFAT1 pts have a significantly shorter TTFT than wtFAT1 pts. When treated with novel agents, there was no difference in response rates. These findings suggest FAT1 mutations in TN pts may be more common than previously reported and identify an intermediate risk for progression. Additional studies investigating the influence of recurrent FAT1 mutations and association with 17p deletions in TN pts are warranted. DisclosuresAllan:Pharmacyclics: Speakers Bureau.