Oncogenic mutations combined with MRD improve outcome prediction in pediatric T-cell ALL
Risk stratification for pediatric T-ALL is based primarily on clinical findings and MRD. This study aimed to identify new genetic prognostic factors to improve the detection of patients at risk of relapse. Mutations in the Notch1 and Ras pathway were selected based on their recognition as oncogenic pathways in T-ALL and the reports in adult literature demonstrating their prognostic value.
220 patients treated prospectively on the FRALLE 2000T study (France) from 2000 to 2010 who had DNA material available were retrospectively analyzed for mutations in Notch1 (N), FBXW7 (F), K-RAS/N-RAS (R) and PTEN (P), both somatic and germline. The low-risk group was defined as having N/F mutations in the absence of R/P mutations. High-risk group was defined as having both N/F and R/P somatic mutations or either N/F germline or R/P germline mutations. Multi-variable regression analyses were performed to assess whether this classification of patients into low (n=111) and high-risk (n=109) groups was prognostic. Of note, on the FRALLE 2000T study, risk stratification was based on MRD.
Classification into low-risk and high-risk genetic groups was an independent prognostic risk factor. 5-year cumulative incidences of relapse were 11% and 36% for low-risk and high-risk groups respectively. When combined with WBC count and MRD, genetic risk groups helped further identify patients at low and high risk of relapse: Patients with a WBC > 200,000/µL, high-risk genetics and MRD > 1x10e4 had a cumulative incidence of relapse of 46% as compared to only 2% for patients with a WBC 200,000/µL, low-risk genetics and MRD 1x10e4.
Retrospective analysis of a prospective cohort. Similar study based on UK2003 study did not demonstrate significance of K/N-ras and PTEN mutations.