Sanchez Ricardo, Ayala Rosa, Alonso Rafael Alberto, Martínez María Pilar, Ribera Jordi, García Olga, Sanchez-Pina José, Mercadal Santiago, Montesinos Pau, Martino Rodrigo, Barba Pere, González-Campos José, Barrios Manuel, Lavilla Esperanza, Gil Cristina, Bernal Teresa, Escoda Lourdes, Abella Eugenia, Amigo Ma Luz, Moreno Ma José, Bravo Pilar, Guàrdia Ramón, Hernández-Rivas Jesús-María, García-Guiñón Antoni, Piernas Sonia, Ribera José-María, Martínez-López Joaquín
Instituto de Investigación Hospital 12 de Octubre (i+12), Servicio de Hematología, Hematología Traslacional, Hospital Universitario 12 de Octubre, Avda de Andalucía s/n, 28041, Madrid, Spain.
Institut de Recerca contra la Leucèmia Josep Carreras, ICO-Hospital Germans Trias i Pujol, Badalona, Spain.
Ann Hematol. 2017 Jul;96(7):1069-1075. doi: 10.1007/s00277-017-3002-1. Epub 2017 Apr 27.
We investigated the frequency, predictors, and evolution of acute lymphoblastic leukemia (ALL) in patients with CNS relapse and introduced a novel method for studying BCR-ABL1 protein variants in cDNA from bone marrow (BM) and cerebrospinal fluid (CSF) blast cells. A total of 128 patients were analyzed in two PETHEMA clinical trials. All achieved complete remission after imatinib treatment. Of these, 30 (23%) experienced a relapse after achieving complete remission, and 13 (10%) had an isolated CNS relapse or combined CNS and BM relapses. We compared the characteristics of patients with and without CNS relapse and further analyzed CSF and BM samples from two of the 13 patients with CNS relapse. In both patients, classical sequencing analysis of the kinase domain of BCR-ABL1 from the cDNA of CSF blasts revealed the pathogenic variant p.L387M. We also performed ultra-deep next-generation sequencing (NGS) in three samples from one of the relapsed patients. We did not find the mutation in the BM sample, but we did find it in CSF blasts with 45% of reads at the time of relapse. These data demonstrate the feasibility of detecting BCR-ABL1 mutations in CSF blasts by NGS and highlight the importance of monitoring clonal evolution over time.
我们研究了中枢神经系统（CNS）复发的急性淋巴细胞白血病（ALL）患者的发生率、预测因素及病情演变，并引入了一种新方法来研究骨髓（BM）和脑脊液（CSF）原始细胞cDNA中的BCR-ABL1蛋白变体。在两项PETHEMA临床试验中，共分析了128例患者。所有患者在伊马替尼治疗后均达到完全缓解。其中，30例（23%）在达到完全缓解后复发，13例（10%）出现孤立性CNS复发或CNS与BM联合复发。我们比较了有和没有CNS复发患者的特征，并进一步分析了13例CNS复发患者中2例患者的CSF和BM样本。在这两名患者中，对CSF原始细胞cDNA中BCR-ABL1激酶结构域进行经典测序分析，均发现了致病性变体p.L387M。我们还对其中一名复发患者的三个样本进行了超深度二代测序（NGS）。我们在BM样本中未发现该突变，但在复发时CSF原始细胞中发现了该突变，其reads占比为45%。这些数据证明了通过NGS检测CSF原始细胞中BCR-ABL1突变的可行性，并突出了随时间监测克隆演变的重要性。
