The combination of subclonal and clonal TP53 and KRAS alterations and poor response to first line therapy identifies ultra-high-risk patients with pediatric T-lymphoblastic leukemia (T-ALL)

It has been the hypothesis of this study that clonal or subclonal variants of TP53 and KRAS that signify ultra-high risk in relapsed pediatric T-ALL indicate a poor prognosis at initial disease. We analyzed two cohorts of 160 and 226 BFM-patients, one consisting of 81 patients who later relapsed and 79 matched non-relapsing controls. Cohort-2 consisted of consecutive patients of whom 30 relapsed. In cohort-1 targeted sequencing revealed TP53 clonal and subclonal variants in 6/81 relapsing but in none of the non-relapsing patients (p=0.014). KRAS alterations occurred in 9/81 relapsing and 2/79 non-relapsing patients (p=0.032). No relapsing patient with TP53 and/or KRAS alterations survived, whereas 19/67 relapsing patients without such variants did (p=0.023). In cohort-2, 196 patients without relapse included 10 with TP53 or KRAS variants, all of whom were non-high risk based on treatment response. However, in the entire group of 386 patients the 188 patients with poor treatment response included 9 with such a variant of whom 8 relapsed and died. Of these, 5 had not undergone stem-cell-transplantation. In conclusion, these data show that subclonal and clonal TP53 and KRAS alterations at initial diagnosis indicate a dismal prognosis in children with T-ALL and poor treatment response.