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

Ann Hematol. 2017 Jul;96(7):1069-1075. doi: 10.1007/s00277-017-3002-1. Epub 2017 Apr 27.

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.

Keywords: Acute lymphoblastic leukemia relapse; BCR-ABL1; Central nervous system; Mutation analysis; Neoplasia.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Central Nervous System / pathology*
  • Feasibility Studies
  • Female
  • Fusion Proteins, bcr-abl / blood
  • Fusion Proteins, bcr-abl / cerebrospinal fluid
  • Fusion Proteins, bcr-abl / genetics*
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Models, Molecular
  • Mutation*
  • Outcome Assessment, Health Care
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / therapy
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-abl / cerebrospinal fluid
  • Proto-Oncogene Proteins c-abl / chemistry
  • Proto-Oncogene Proteins c-abl / genetics*
  • Recurrence

Substances

  • BCR-ABL1 fusion protein, human
  • Fusion Proteins, bcr-abl
  • Proto-Oncogene Proteins c-abl