Clinical characteristics of patients with central nervous system relapse in BCR-ABL1-positive acute lymphoblastic leukemia: the importance of characterizing ABL1 mutations in cerebrospinal fluid

Ricardo Sanchez, Rosa Ayala, Rafael Alberto Alonso, María Pilar Martínez, Jordi Ribera, Olga García, José Sanchez-Pina, Santiago Mercadal, Pau Montesinos, Rodrigo Martino, Pere Barba, José González-Campos, Manuel Barrios, Esperanza Lavilla, Cristina Gil, Teresa Bernal, Lourdes Escoda, Eugenia Abella, Ma Luz Amigo, Ma José Moreno, Pilar Bravo, Ramón Guàrdia, Jesús-María Hernández-Rivas, Antoni García-Guiñón, Sonia Piernas, José-María Ribera, Joaquín Martínez-López

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.