Philadelphia Chromosome–Negative B-Cell Acute Lymphoblastic Leukemia in Adolescents and Young Adults

Amy Y. Wang, MD, MPH; Lori S. Muffly, MD, MS; Wendy Stock, MD


J Oncol Pract. 2020;16(5):231-238. 

In This Article

Update on Biologic Insights

The search for genetic aberrations that may drive outcomes in B-cell ALL has uncovered a biologic continuum across the age span[5–11] (Table 1). Unfortunately, ALL subtypes commonly associated with a favorable prognosis, such as hyperdiploidy and ETV6-RUNX1, decrease in prevalence beyond childhood. In contrast, many high-risk aberrations increase in prevalence with age beyond young adulthood, such as the Ph-positive BCR-ABL1 fusion and the KMT2A (MLL) rearrangements.[5,6]

Several alterations are more common in the AYA age group. Amplification of the long arm of chromosome 21 occurs in approximately 12% of AYAs between age 17 and 45 years and is associated with a poor prognosis, although this can be improved with intensive treatment.[5,10] Immunoglobulin heavy chain locus (IGH) rearrangements are relatively frequent in AYAs, peaking in incidence to 11% in the 20- to 24-year age group.[9] A more recently described high-risk subtype is Ph-like ALL, a biologically diverse entity that shares similar gene expression profiles to Ph-positive ALL but lacks the BCR-ABL1 fusion. The prevalence of Ph-like ALL peaks in the AYA population, accounting for approximately 28% of AYA ALL as compared with approximately 10% of pediatric ALL and 20% of older adult ALL.[5] Ph-like ALL is typically associated with more aggressive disease, lower rates of minimal residual disease (MRD)–negative responses, and inferior survival.[7] Several newly described gene fusions are also more prevalent among AYAs: double homeobox 4 (DUX4) gene, zinc finger protein 384 (ZNF384), and myocyte enhancer factor 2D (MEF2D) rearrangements.[8] Previously, the remainder of patients who lacked a known abnormality would fall into the other subtype. However, using whole-transcriptome sequencing, the Mullighan group recently described several additional subtypes of significance: IGH rearrangements to BCL2, MYC, and/or BCL6; NUTM1 rearrangements; and PAX5-driven subtypes.[11]