Pediatric acute lymphoblastic leukemia

Abstract

The last decade has witnessed great advances in our understanding of the genetic and biological basis of childhood acute lymphoblastic leukemia (ALL), the development of experimental models to probe mechanisms and evaluate new therapies, and the development of more efficacious treatment stratification. Genomic analyses have revolutionized our understanding of the molecular taxonomy of ALL, and these advances have led the push to implement genome and transcriptome characterization in the clinical management of ALL to facilitate more accurate risk-stratification and, in some cases, targeted therapy. Although mutation- or pathway-directed targeted therapy (e.g., using tyrosine kinase inhibitors to treat Philadelphia chromosome [Ph]-positive and Phlike B-cell-ALL) is currently available for only a minority of children with ALL, many of the newly identified molecular alterations have led to the exploration of approaches targeting deregulated cell pathways. The efficacy of cellular or humoral immunotherapy has been demonstrated with the success of chimeric antigen receptor T-cell therapy and the bispecific engager blinatumomab in treating advanced disease. This review describes key advances in our understanding of the biology of ALL and optimal approaches to risk-stratification and therapy, and it suggests key areas for basic and clinical research.

Figure 1.

Change in overall survival of pediatric patients treated on the historical St. Jude Total Therapy studies.

Figure 2.

Distribution of B-cell acute lymphoblastic leukemia (B-ALL) subtypes within each age group. SR: standard risk; HR: high risk; WBC: white blood cell count; AYA: adolescent and young adult.

Figure 3.

Kinase pathways deregulated in Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL). The diverse signaling alterations observed in Ph-like ALL are grouped into JAK-STAT activating lesions (most commonly CRLF2 rearrangement, but also JAK mutation and rearrangement, IL7R mutation, truncating rearrangements of EPOR, and SH2B3 deletion/mutation), rearrangements involving ABL-class tyrosine kinases; rearrangements of genes encoding other kinases (FGFR1, NTRK3, FLT3), and Ras pathway mutations. Ras pathway mutations are not restricted to Ph-like ALL and are observed in other subtypes of leukemia (e.g., hyperdiploid ALL, PAX5 P80R ALL). They are also observed as co-mutations in a proportion of cases with CRLF2 rearrangements. These alterations typically activate the logical downstream signaling pathway, as well as other pathways that serve as additional avenues for therapeutic intervention (e.g., PI3K, BCL2).

Figure 4.

Immunotherapy in acute lymphoblastic leukemia. CAR T cells: chimeric antigen receptor T cells; ALL: acute lymphoblastic leukemia; TSLPR: thymic stromal lymphopoietin receptor.

Graphical Abstract