RAS and TP53 can predict survival in adults with T‐cell lymphoblastic leukemia treated with hyper‐CVAD

Abstract

Adult T‐cell acute lymphoblastic leukemia (T‐ALL) is a heterogeneous group of acute leukemias that account for about one third of all cases of Philadelphia chromosome (Ph)‐negative ALL. Recently, a molecular classifier using the mutational status of NOTCH1, FBXW7, RAS, and PTEN (NFRP) has been shown to distinguish low‐ vs high‐risk groups in adult T‐ALL patients treated using the Berlin‐Frankfurt‐Münster ALL protocol. However, it is unknown if this molecular classifier can stratify adult T‐ALL patients treated with hyper‐CVAD ± nelarabine. We identified a relatively small cohort of 27 adults with T‐ALL who were uniformly treated with hyper‐CVAD ± nelarabine with available mutational analysis at time of diagnosis. The most commonly mutated genes in this group were NOTCH1 (52%), NRAS (22%), DNMT3A (19%), KRAS (15%), and TP53 (7%). The NFRP molecular classifier failed to stratify overall survival (OS; P = .84) and relapse‐free survival (RFS; P = .18) in this cohort. We developed a new stratification model combining K/NRAS and TP53 mutations as high‐risk factors and showed that mutations in these genes predicted poorer OS (P = .03) and RFS (P = .04). While the current study is limited by cohort size, these data suggest that the NFRP molecular classifier might not be applicable to adult T‐ALL patients treated with hyper‐CVAD ± nelarabine. RAS/TP53 mutation status, however, was useful in risk stratification in adults with T‐ALL.

CDKN2A deletions are associated with poor outcomes in 101 adults with T‐cell acute lymphoblastic leukemia

“…Recently, NOTCH1/FBXW7/RAS/PTEN ‐based oncogenetic risk classification has been reported to predict outcome in adult patients with T‐ALL treated with the BFM protocol 3 . However, this molecular classifier failed to stratify patients with T‐ALL treated with non‐BFM protocols 4 . Similarly, this model did not show risk stratification in our cohort of adult T‐ALL.…”

“…3 However, this molecular classifier failed to stratify patients with T-ALL treated with non-BFM protocols. 4 Similarly, this model did not show risk stratification in our cohort of adult T-ALL. This result might be due to the relatively short duration of follow-up, as we started testing NGS in January 2018.…”

“…Recently, a molecular classifier using the mutational status of NOTCH1 , FBXW7 , RAS , and PTEN (NFRP) was used to distinguish low‐risk and high‐risk groups in adult patients with T‐ALL treated with the Berlin‐Frankfurt‐Münster (BFM) ALL protocol 3 . In addition, the MD Anderson Center (MDACC) found that RAS/TP53 mutation was useful for risk stratification of adult patients with T‐ALL treated with hyper‐CVAD 4 . However, these risk stratification methods cannot be widely adopted in clinical practice due to their complexity.…”

“…3 In addition, the MD Anderson Center (MDACC) found that RAS/TP53 mutation was useful for risk stratification of adult patients with T-ALL treated with hyper-CVAD. 4 However, these risk stratification methods cannot be widely adopted in clinical practice due to their complexity. Therefore, we attempted to develop a simple, feasible and practical approach to identify high-risk subgroups of patients.…”

TNFAIP3 mutation is an independent poor overall survival factor for patients with T‐cell acute lymphoblastic leukemia

“… 9 , 10 , 11 , 12 Moreover, genetic alterations exert an important role in prognostic stratification in precision therapy. 13 , 14 , 15 , 16 , 17 Although multiple studies have been conducted to explore the role of genetic alterations combined with minimal residual disease (MRD) in risk stratification for T‐ALL, high heterogeneity has led to difficulty in accurately stratifying all patients. 14 , 18 Therefore, further exploration of novel biomarkers to improve risk stratification for T‐ALL patients is needed.…”