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Copy number alterations predict poor prognosis in adult ALL
Deletions of certain copy number alterations independently predicted poor prognosis for adolescent and adult patients with precursor B-cell acute lymphoblastic leukemia, according to study results.
These copy number alterations should be included in the initial risk assessment for ALL due to their significance, the researchers wrote.
“Chromosome aberrations are key drivers of leukemogenesis, but additional abnormalities are required for leukemia development,” Josep-Maria Ribera, MD, PhD, of the clinical hematology department at Catalan Institute of Oncology’s Jose Carreras Leukemia Research Institute, and colleagues wrote. “Sequence mutations, copy number alterations (CNAs), and losses of heterozygosity in genes involved in lymphoid development, cell cycle and tumor suppression have been studied in pediatric ALL. … However, controversial results have been reported. The prognostic implications of CNAs have been less studied in adult ALL.”
Ribera and colleagues evaluated 142 adolescent and adult patients (median age, 40 years; 54% male) with de novo precursor B-cell ALL from 642 patients already enrolled in PETHEMA group protocols. Eighty-seven percent (n = 124) of patients had high-risk ALL.
The researchers used multiplex ligation-dependent probe amplification to ascertain the frequency and prognostic impact of CNAs of 12 genetic regions.
Median follow-up was 3.7 years (range, 0.6-11.3).
Researchers reported a complete remission rate of 85% (n = 121). They calculated a 5-year cumulative incidence of relapse probability of 46% (range, 35-57), with an OS probability of 43% (range, 34-52).
The researchers observed the cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) as the most frequent CNA deletion, occurring in 42% (n = 59) of patients.
Other frequent CNA deletions included the Ikaros family zinc finger 1 (IKZF1; n = 42) — which exhibited prevalence in patients with Philadelphia chromosome (Ph)-positive ALL, older patients and patients with high white blood cell counts.
In multivariate analysis, older age corresponded with chemotherapy resistance in the entire population (HR = 0.94) and the subgroup of Ph-negative patients (HR = 0.13).
Further, deletions of the early B-cell factor 1 (EBF1) CNA predicted chemotherapy resistance in both groups (entire cohort, HR = 0.94; subgroup, HR = 0.11).
High white blood count (HR = 1) and focal IKZF1 deletions (HR = 1.86) correlated with disease recurrence. Older age influenced OS in the entire study population (HR = 1.03) and the Ph-negative subgroup (HR = 1.04), as did losses to the CDKN2A/B CNA (entire cohort, HR = 2.54; subgroup, HR = 2.1).
The researchers acknowledged limitations of their study, including the small numbers of standard-risk and Ph-positive patients. Further, the researchers lacked information on minimal residual disease for many patients.
“The results of the current study could help to refine the risk stratification of adolescent and adult ALL patients according to their genetic features,” Ribera and colleagues concluded. “Remarkably, EBF1 deletions had an impact on the complete remission rate, IKZF1 deletions were markers of the relapse propensity, and CDKN2A/B deletions were associated with a reduction in OS in both the whole series and the Ph-negative ALL series. … However, because of the controversial prognostic significance of some CNAs in ALL, more studies of uniformly treated patients should be performed to clarify the prognostic impact of these and other genetic alterations.” – by Cameron Kelsall
Disclosure: The researchers report no relevant financial disclosures.