Kempter Tamara, Richter-Pechańska Paulina, Michel Katarzyna, Rausch Tobias, Erarslan-Uysal Büşra, Eckert Cornelia, Zimmermann Martin, Stanulla Martin, Schrappe Martin, Cario Gunnar, Köhrer Stefan, Attarbaschi Andishe, Korbel Jan O, Kunz Joachim B, Kulozik Andreas E
Department of Pediatric Oncology, Hematology, and Immunology and Hopp Children's Cancer Center Heidelberg, University of Heidelberg, Heidelberg, Germany.
Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany.
Blood Adv. 2025 Mar 25;9(6):1267-1279. doi: 10.1182/bloodadvances.2024014209.
Variations in the TP53 and KRAS genes indicate a particularly adverse prognosis in relapsed pediatric T-cell acute lymphoblastic leukemia (T-ALL). We hypothesized that these variations might be subclonally present at disease onset and contribute to relapse risk. To test this, we examined 2 cohorts of children diagnosed with T-ALL: cohort 1 with 81 patients who relapsed and 79 who matched nonrelapsing controls, and cohort 2 with 226 consecutive patients, 30 of whom relapsed. In cohort 1, targeted sequencing revealed TP53 clonal and subclonal variants in 6 of 81 relapsing patients but none in the nonrelapsing group (P = .014). KRAS alterations were found in 9 of 81 relapsing patients compared with 2 of 79 nonrelapsing patients (P = .032). Survival analysis showed that none of the relapsed patients with TP53 and/or KRAS alterations survived, whereas 19 of 67 relapsed patients without such variants did, with a minimum follow-up time of 3 years (P = .023). In cohort 2, none of the relapsing patients but 10 of 196 nonrelapsing patients carried TP53 or KRAS variants, indicating that mutation status alone does not predict poor prognosis. All 10 nonrelapsing patients with mutations had a favorable early treatment response. Among the total cohort of 386 patients, 188 showed poor treatment response, of whom 69 relapsed. Of these poor responders, 9 harbored TP53 or KRAS variants. In conclusion, subclonal TP53 and KRAS alterations identified at the time of initial diagnosis, along with a poor treatment response, characterize a subset of children with T-ALL who face a dismal prognosis and who may benefit from alternative treatment approaches.
TP53和KRAS基因的变异表明复发的儿童T细胞急性淋巴细胞白血病（T-ALL）预后特别不良。我们推测这些变异可能在疾病发病时以亚克隆形式存在，并导致复发风险。为了验证这一点，我们检查了2组诊断为T-ALL的儿童：队列1有81例复发患者和79例匹配的未复发对照，队列2有226例连续患者，其中30例复发。在队列1中，靶向测序显示81例复发患者中有6例存在TP53克隆和亚克隆变异，而未复发组中无此情况（P = 0.014）。81例复发患者中有9例发现KRAS改变，而79例未复发患者中有2例（P = 0.032）。生存分析表明，TP53和/或KRAS改变的复发患者无一存活，而67例无此类变异的复发患者中有19例存活，最短随访时间为3年（P = 0.023）。在队列2中，复发患者中无一携带TP53或KRAS变异，但196例未复发患者中有10例携带，这表明仅突变状态不能预测不良预后。所有10例有突变的未复发患者早期治疗反应良好。在386例患者的总队列中，188例显示治疗反应不佳，其中69例复发。在这些治疗反应不佳的患者中，9例携带TP53或KRAS变异。总之，初始诊断时发现的亚克隆TP53和KRAS改变，以及治疗反应不佳，是一部分T-ALL患儿的特征，这些患儿预后不佳，可能从替代治疗方法中获益。
