Prognostic significance of copy number alterations in adolescent and adult patients with precursor B acute lymphoblastic leukemia enrolled in PETHEMA protocols

Abstract

; for the Spanish PETHEMA Group and the Spanish Society of Hematology BACKGROUND: Some copy number alterations (CNAs) have independent prognostic significance for adults with acute lymphoblastic leukemia (ALL). METHODS: This study analyzed via multiplex ligation-dependent probe amplification the frequency and prognostic impact of CNAs of 12 genetic regions in 142 adolescents and adults with de novo precursor B-cell ALL. RESULTS: The cyclindependent kinase inhibitor 2A/B (CDKN2A/B) deletion (59 of 142 or 42%) was the most frequent CNA, and it was followed by Ikaros family zinc finger 1 (IKZF1) losses (49 of 142 or 35%). IKZF1 deletions were more prevalent in Philadelphia chromosome (Ph)-positive ALL and were associated with advanced age and high white blood cell (WBC) counts. The multivariate analysis showed that advanced age and early B-cell factor 1 (EBF1) deletions were associated with chemotherapy resistance in both the whole series (hazard ratios, 0.949 and 0.135, respectively) and the Ph-negative subgroup (hazard ratios, 0.946 and 0.118, respectively). High WBC counts and focal IKZF1 deletions correlated with disease recurrence (hazard ratios, 1.005 and 1.869, respectively), whereas advanced age and CDKN2A/B losses influenced overall survival in both the whole series (hazard ratios, 1.038 and 2.545, respectively) and the Ph-negative subgroup (hazard ratios, 1.044 and 2.105, respectively). CONCLUSIONS: Deletions of EBF1, IKZF1, and CDKN2A/B have an independent adverse prognosis for adolescents and adults with B-precursor ALL, and this suggests that these CNAs should be included in the initial risk assessment of ALL. Cancer 2015;121:3809-17.

Prognostic significance of copy number alterations detected by multi‑link probe amplification of multiple genes in adult acute lymphoblastic leukemia

“…In the present study, IKZF1 gene deletions were predominant, followed by CDKN2A/2B deletions. Ribera et al (15) reported that German adolescents and adult patients with ALL exhibited prevalent deletions of CDKN2A/2B.…”

“…The proportion of patients with a better prognosis was 1, 5, and 0%, respectively. Ribera et al (15) reported that the 5-year cumulative incidence rate (CIR) was higher and that the OS was poorer in patients with IKZF1 deletion than in those without the deletion. Additionally, CDKN2A/2B deficiency in patients with B-ALL was associated with a poor OS.…”

The Genomic Landscape of <b><i>PAX5</i></b>, <b><i>IKZF1</i></b>, and <b><i>CDKN2A/B </i></b>Alterations in B-Cell Precursor Acute Lymphoblastic Leukemia

“…Biallelic deletions of CDKN2A/B were observed in 9 of 12 cases, more com-monly among adolescent and adult BCR-ABL1 -negative patients. Nevertheless, deletions of CDKN2A/B are associated with poor outcome [Moorman et al, 2014;Ribera et al, 2015], and aCGH analysis provides more accurate results, since it has the ability to identify deletions <190 kb in size, which therefore are undetectable by a commercially available p16 (CDKN2A) FISH probe.…”

Molecular profiling refines minimal residual disease‐based prognostic assessment in adults with Philadelphia chromosome‐negative B‐cell precursor acute lymphoblastic leukemia

“…5 PETHEMA high-risk (HR) BCP ALL was defined as those patients older than 30 years, with hyperleukocytosis over 30 × 10 9 /L or patients with MLL/KMT2A rearrangements at presentation. 5 PETHEMA high-risk (HR) BCP ALL was defined as those patients older than 30 years, with hyperleukocytosis over 30 × 10 9 /L or patients with MLL/KMT2A rearrangements at presentation.…”