未能对诱导化疗作出反应预示儿童急性淋巴细胞白血病（ALL）的结果不佳，而T细胞ALL（T-ALL）比B细胞ALL更为频繁。我们的目标是在T-ALL诱导失败（IF）患者队列中探讨影响结果的临床和基因因素的认识的限制。我们研究了英国两个连续的多中心随机试验UKALL2003和UKALL2011中所有T-ALL IF病例，以定义危险因素、治疗和结果。我们进行多组学分析以表征基因组景观。IF发生在10.3％的病例中，并与年龄增长显著相关，在16岁及以上的患者中发生率为20％。IF患者5年总生存率（OS）为52.1％，对响应患者为90.2％（P <.001）。尽管使用了己烯革霉素为基础的化疗联合造血干细胞移植在UKALL2011中增加，但结局并未改善。在巩固治疗末期持续的分子残留病会导致明显更差的结果（5年OS，14.3％VS 68.5％；HR，4.10；95％CI，1.35至12.45；P=.0071）。基因组分析揭示不同发病病变的25种不同类型并聚集在10个亚型定义的基因上，呈现出异质性的图片。TAL1非编码病变数量惊人，与糟糕的结果（5年OS，12.5％）相关。将TAL1病变与MYC和RAS途径的突变结合起来，可以产生一个基因分层器，可以识别出高度可能失败传统治疗的患者（5年OS，23.1％VS 86.4％；HR，6.84；95％CI，2.78至16.78；P＜.0001），因此应考虑使用实验性药物治疗。T-ALL中的IF结果仍然不佳，现有治疗方法需采取替代方法，特别是使用免疫疗法，亟需开展研究。

Failure to respond to induction chemotherapy portends a poor outcome in childhood acute lymphoblastic leukemia (ALL) and is more frequent in T-cell ALL (T-ALL) than B-cell ALL. We aimed to address the limited understanding of clinical and genetic factors that influence outcome in a cohort of patients with T-ALL induction failure (IF).We studied all cases of T-ALL IF on two consecutive multinational randomized trials, UKALL2003 and UKALL2011, to define risk factors, treatment, and outcomes. We performed multiomic profiling to characterize the genomic landscape.IF occurred in 10.3% of cases and was significantly associated with increasing age, occurring in 20% of patients age 16 years and older. Five-year overall survival (OS) rates were 52.1% in IF and 90.2% in responsive patients (P < .001). Despite increased use of nelarabine-based chemotherapy consolidated by hematopoietic stem-cell transplant in UKALL2011, there was no improvement in outcome. Persistent end-of-consolidation molecular residual disease resulted in a significantly worse outcome (5-year OS, 14.3% v 68.5%; HR, 4.10; 95% CI, 1.35 to 12.45; P = .0071). Genomic profiling revealed a heterogeneous picture with 25 different initiating lesions converging on 10 subtype-defining genes. There was a remarkable abundance of TAL1 noncoding lesions, associated with a dismal outcome (5-year OS, 12.5%). Combining TAL1 lesions with mutations in the MYC and RAS pathways produces a genetic stratifier that identifies patients highly likely to fail conventional therapy (5-year OS, 23.1% v 86.4%; HR, 6.84; 95% CI, 2.78 to 16.78; P < .0001) and who should therefore be considered for experimental agents.The outcome of IF in T-ALL remains poor with current therapy. The lack of a unifying genetic driver suggests alternative approaches, particularly using immunotherapy, are urgently needed.