Genetics and prognosis of ALL in children vs adults

Abstract

Acute lymphoblastic leukemia (ALL) is characterized by genetic alterations that block differentiation, promote proliferation of lymphoid precursor cells, and are important for risk stratification. Although ALL is less common in adolescents and young adults (AYAs) and adults than children, survival rates are inferior, and long-term prognosis for adults is poor. Thus, ALL remains a challenging disease to treat in the AYA and adult populations. A major contributing factor that influences prognosis in this population is the reduced prevalence of genetic subtypes associated with favorable outcome and a concomitant increase in subtypes associated with poor outcome. Recent advances in genomic profiling across the age spectrum continue to enhance our knowledge of the differences in disease biology between children and adults and are providing important insights into novel therapeutic targets. Philadelphia chromosome-like (Ph-like) ALL is one such subtype characterized by alterations that deregulate cytokine receptor or tyrosine kinase signaling and are amenable to inhibition with approved tyrosine kinase inhibitors. One of the greatest challenges now remaining is determining how to implement this breadth of genomic information into rapid and accurate diagnostic testing to facilitate the development of novel clinical trials that improve the outcome of AYAs and adults with ALL.

Figure 1.

Distribution of B-ALL subtypes within each age group. Subtypes are grouped as aneuploid/copy number gain, transcription factor (TF) rearrangement, other TF driven, kinase driven, and all others.

Figure 2.

Distribution of kinase subtypes in Ph-like ALL within each age group.^,,, Combined prevalence of Ph-like ALL subtypes in childhood NCI standard risk (SR; age 1-9.99 years and white blood cells <50 000/μL), NCI high risk (HR; age 10-15 years or white blood cells ≥50 000/μL), AYAs (16-39 years), and adults (older than or equal to 40 years). Genomic subtypes include IGH-CRLF2, P2RY8-CRLF2, ABL-class fusions (ABL1, ABL2, CSF1R, LYN, PDGFRA, and PDGFRB), JAK2 and EPOR rearrangements, other mutations in JAK-STAT signaling (JAK1/3, IL7R, SH2B3, TYK2, and IL2RB), other kinase alterations (FLT3, FGFR1, and NTRK3,), Ras mutations (KRAS, NRAS, NF1, PTPN11, BRAF, and CBL), and unknown alterations.

Figure 3.

Alterations identified in PAX5alt and PAX5 P80R subtypes. PAX5alt: genetic alterations including gene rearrangements (PAX5r), sequence mutations (PAX5mut), and focal intragenic amplifications (PAX5amp) are shown in the heat map. PAX5 P80R: protein domain plot of PAX5 showing the 57 mutations detected in 44 patients in the PAX5 P80R subtype. CNA, copy number alteration; CN-LOH, copy-neutral loss of heterozygosity; hetero, heterozygous mutation; homo, homozygous mutation; NA, not available; NLS, nuclear localization signal; WT, wild type.