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

doi:10.1007/s00277-017-3002-1

Abstract

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.

Highlights

About 25% of adults and about 5% of children with acute lymphoblastic leukemia (ALL) have the Philadelphia chromosome or the BCR-ABL1 rearrangement
A secondary aim was to evaluate the use of a novel method for studying the pathogenic mechanisms and variants of uncertain significance (VUS) in the BCR-ABL1 kinase domain using cDNA from samples of bone marrow (BM) and cerebrospinal fluid (CSF) blasts with the idea of selecting optimal tyrosine kinase inhibitor (TKI) treatment based on clonal evolution from BM to CSF cells
We reviewed the CNS relapse data of patients who were included in two consecutive clinical trials, LAL-OPH-2007 [8] and LAL-PH-2008 [9], which were performed by the PETHEMA Group for patients with Philadelphia chromosome-positive ALL who were older or younger than 55 years, respectively

Summary

Introduction

About 25% of adults and about 5% of children with acute lymphoblastic leukemia (ALL) have the Philadelphia chromosome or the BCR-ABL1 rearrangement. A secondary aim was to evaluate the use of a novel method for studying the pathogenic mechanisms and variants of uncertain significance (VUS) in the BCR-ABL1 kinase domain using cDNA from samples of bone marrow (BM) and CSF blasts with the idea of selecting optimal TKI treatment based on clonal evolution from BM to CSF cells. Of the 57 LAL-OPH07 patients, 57 (100%) achieved complete remission (CR), 39 (68%) of who had not relapsed at the time of the analysis.

Results

Conclusion