Université de Paris, Institut Necker-Enfants Malades, Institut National de Recherche Médicale U1151, Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.
Université de Paris, EA-3518, Institut de Recherche Saint-Louis, Hematology Adolescent and Young Adult Unit, Assistance Publique-Hôpitaux de Paris, Saint-Louis Hospital, Paris, France.
Leukemia. 2020 Jul;34(7):1730-1740. doi: 10.1038/s41375-019-0685-4. Epub 2020 Jan 28.
The prognostic value of IL7-receptor pathway (IL7Rp) mutations in T-cell acute lymphoblastic leukemia (T-ALL) remains unclear. We performed a comprehensive study of 200 adult patients with T-ALL included in the GRAALL2003/2005 protocols to address the clinical significance of IL7Rp mutations. Next-generation sequencing of the IL7Rp (IL7R/JAK1/JAK3/STAT5B) revealed that IL7Rp mutations were frequent in adult T-ALL (28%) particularly in immature/early T-cell progenitor (ETP)-ALL. They were associated with mutations of NOTCH-pathway, PHF6, and PRC2 components but not with K/NRAS. IL7Rp mutated (IL7Rp) T-ALL were slow-responders, with a high rate of M2/M3 day-8 marrow compared with IL7Rp non-mutated (IL7Rp) T-ALL (p = 0.002) and minimal residual disease positivity at 6-weeks (MRD1) (p = 0.008) but no difference in MRD2 positivity at 12-weeks. Despite this, no adverse prognosis was evidenced when censored for allogeneic hematopoietic stem cell transplantation (HSCT). In time-dependent analysis, HSCT did not benefit IL7Rp patients whereas it was of marked benefit to IL7Rp cases. IL7Rp-mutations identify a subgroup of slow-responder T-ALLs which benefit from post-induction chemotherapy regimens but not from HSCT. Our data suggest that prior knowledge of the mutation status of IL7Rp may influence HSCT decision and help to guide therapy reduction.
IL7 受体通路（IL7Rp）突变在 T 细胞急性淋巴细胞白血病（T-ALL）中的预后价值尚不清楚。我们对包括在 GRAALL2003/2005 方案中的 200 例成人 T-ALL 患者进行了全面研究，以解决 IL7Rp 突变的临床意义。IL7Rp（IL7R/JAK1/JAK3/STAT5B）的下一代测序显示，IL7Rp 突变在成人 T-ALL 中较为常见（28%），尤其是在不成熟/早期 T 细胞祖细胞（ETP）-ALL 中。它们与 NOTCH 通路、PHF6 和 PRC2 成分的突变有关，但与 K/NRAS 无关。与 IL7Rp 非突变（IL7Rp）T-ALL 相比，IL7Rp 突变（IL7Rp）T-ALL 是慢反应者，第 8 天骨髓 M2/M3 比例较高（p=0.002），6 周时微小残留病阳性（MRD1）（p=0.008），但 12 周时 MRD2 阳性无差异。尽管如此，在异基因造血干细胞移植（HSCT）的情况下，并未证明存在不良预后。在时间依赖性分析中，HSCT 对 IL7Rp 患者没有获益，而对 IL7Rp 患者则有显著获益。IL7Rp 突变鉴定出一组缓慢反应性 T-ALL，这些患者从诱导后化疗方案中获益，但不能从 HSCT 中获益。我们的数据表明，IL7Rp 突变状态的先验知识可能会影响 HSCT 的决策，并有助于指导治疗减少。
