Cytogenetics/genomic alterations

Cytogenetic aberrations have been shown to be significant prognostic factors in B-ALL.

Other studies have also demonstrated that patients with ETV6::RUNX1 gene fusions have a more favorable prognosis after relapse.[15,32,33]

Changes in variant profiles from diagnosis to relapse have been identified by gene sequencing.[34,35] While oncogenic gene fusions (e.g., TCF3::PBX1, ETV6::RUNX1) are almost always observed between the time of initial diagnosis and relapse, single nucleotide variants and copy number variants may be present at diagnosis, but not at relapse, and vice versa.[34,36] For example, while RAS family variants are common at both diagnosis and relapse, the specific RAS family variants may change from diagnosis to relapse as specific leukemic subclones rise and fall during the course of treatment.[34] By contrast, relapse-specific variants in NT5C2 (a gene involved in nucleotide metabolism) have been noted in as many as 45% of ALL cases with early relapse.[34,37,38]

TP53 alterations (variants and/or copy number alterations) are observed in approximately 10% of patients with ALL at first relapse and have been associated with an increased likelihood of persistent leukemia after initial reinduction and poor event-free survival (EFS) rates.[21,39] In one study, approximately one-half of the TP53 alterations were present at initial diagnosis and half were newly observed at time of relapse.[39]

IKZF1 deletions have also been reported to be associated with a poor prognosis in patients with B-ALL in first bone marrow relapse.[32] However, in a BFM study of patients with B-ALL who experienced a late first marrow relapse, IKZF1 deletions were not prognostically significant.[21]

RAS pathway variants (KRAS, NRAS, FLT3, and PTPN11) are common at relapse in B-ALL patients, and they were found in approximately 40% of patients at first relapse in one study of 206 children.[34,40] As observed at diagnosis, the frequency of RAS pathway variants at relapse differs by cytogenetic subtype (e.g., high frequency in hyperdiploid cases and low frequency in ETV6::RUNX1 cases). The presence of RAS pathway variants at relapse was associated with early relapse. However, presence of RAS pathway variants at relapse was not an independent predictor of outcome.