Childhood ALL: Small Patients, Yet Everbigger Genetic Complexity

Acute lymphoblastic leukemia (ALL) is the most common cancer occurring in children. Survival now exceeds 90 percent with multidrug frontline chemotherapy regimens tested and refined via cooperative group clinical trials during the past 40 years.^1,2  Modern risk stratification and therapeutic selection for pediatric patients with ALL depends on leukemia immunophenotype, age, and white blood cell count at diagnosis; central nervous system and other extramedullary sites of leukemia involvement; cytomolecular characteristics; and response to initial chemotherapy via minimal/measurable residual disease (MRD) assessment.^3,4  Patients with specific high-risk genetic alterations require postinduction chemotherapy intensification and, in some cases, additional drugs (e.g., tyrosine kinase inhibitors for Ph+ ALL) or immunotherapy/hematopoietic stem cell transplantation to maximize cure.^5-7  Conversely, children with “low risk” ALL who have particularly favorable features (National Cancer Institute standard risk by age and white blood cell count, no central nervous system involvement [CNS1], ETV6::RUNX1 fusion or high hyperdiploidy with trisomies 4 and 10, and negative early- and end-induction MRD) have event-free and overall survival rates exceeding 95 percent and benefit from chemotherapy reduction that preserves these outstanding cure rates while reducing therapy-associated toxicity.^8-10 

A recent landmark collaborative study, led by first authors Drs. Samuel Brady and Kathryn Roberts and senior authors Drs. Stephen Hunger, Jinghui Zhang, and Charles Mullighan, performed comprehensive paired tumor/normal whole-exome sequencing, whole-genome sequencing, single nucleotide polymorphism array, and/or tumor-only whole transcriptome RNA sequencing on 2,288 and 466 cases of newly diagnosed B-cell ALL (B-ALL) and T-cell ALL (T-ALL), respectively, occurring in children and adolescents/young adults treated on Children’s Oncology Group or St. Jude Children’s Research Hospital clinical trials. Results from this study validated the prognostic significance of more than 30 known genetic subtypes of pediatric ALL.¹¹  The results also refined or newly defined the spectrum of clonality, co-occurrence, and acquisition timing of germline and somatic leukemia-associated primary and secondary genetic alterations. The investigators reported a median of four somatic oncogenic driver mutations per case and noted that nearly 3 percent of cases harbored pathogenic, or likely-pathogenic, germline variants associated with cancer predisposition. New findings from this study also shed further light on the probable sequence of fusion and mutation acquisition in specific childhood ALL subtypes and discovery of potential ultraviolet light–induced ALL-associated mutations that occur at different frequencies among patients of specific race/ethnicity/ancestry backgrounds. Importantly, the authors highlighted differences in timing acquisition of kinase-signaling gene mutations in between B-ALL and T-ALL cases, cautioning that clinical targeting with tyrosine kinase inhibitor–based therapies may have differential activity (i.e., lesser in B-ALL with later-gained mutations and greater in T-ALL with earlier-gained mutations).

Lastly, the investigators report detailed overall survival data for children with 22 B-ALL and 11 T-ALL genetic subtypes, as well as for “B-other” and “T-other” cases lacking known canonical genetic rearrangements or expression signatures. These clinical outcomes data increase our robustness of knowledge regarding newly identified B-ALL subtypes, such as those involving DUX4, MEF2D, ZNF384, and NUTM1 rearrangements. In total, the investigators identified 376 putative ALL-associated driver genes involved in perturbation of lymphoid maturation, transcriptional dysregulation, cell cycle regulation, chromatin modification, and kinase signaling, which further highlights the genetic complexity and heterogeneity of childhood ALL that often confers prognostic and/or therapeutic significance.