In childhood B-ALL, among the recently described subtypes were DUX4 and PAX5 altered (PAX5alt). Using whole transcriptome RNA sequencing (RNA-Seq) in 377 B-ALL children from MaSpore ALL 2003/2010 (MS2003/MS2010) studies, we found that, after hyperdiploid and ETV6-RUNX1, the third and fourth most common subtypes were DUX4 (n= 51; 14%) and PAX5alt (n= 36; 10%). DUX4 also formed the largest genetic subtype among patients with poor Day 33 MRD (n=12/44). But despite the poor MRD, outcome of DUX4 B-ALL was excellent (5-year cumulative risk of relapse (CIR) 8.9% [95% CI, 2.8% to 19.5%], 5-year OS 97.8% [95% CI, 85.3% to 99.7%]). In MS2003, 21% DUX4 B-ALL had poor peripheral blood (PB) response to prednisolone at day 8, higher than other subtypes (8%; P=0.03). In MS2010, with vincristine at day 1, no day 8 poor PB response was observed in DUX4 subtype (P=0.03). PAX5alt group had an intermediate risk of relapse (5-year CIR 18.1%) but when IKZF1 was not deleted, outcome was excellent with no relapse among 23 patients. Compared to MS2003, outcome of PAX5alt B-ALL with IKZF1 co-deletion was improved by treatment intensification in MS2010 (5-year CIR 80.0% vs 0%; P=0.05). In conclusion, despite its poor initial response, DUX4 B-ALL had a favorable overall outcome, and the prognosis of PAX5alt was strongly dependent on IKZF1 co-deletion.

Acute lymphoblastic leukemia (ALL) is the most common cancer among children. This aggressive cancer comprises multiple molecular subtypes, each harboring a distinct constellation of somatic, and to a lesser extent, inherited genetic alterations. With recent advances in genomic analyses such as next-generation sequencing techniques, we can now clearly identify >20 different genetic subtypes in ALL. Clinically, identifying these genetic subtypes will better refine risk stratification and determine the optimal intensity of therapy for each patient. Underpinning each genetic subtype are unique clinical and therapeutic characteristics, such as age and presenting white blood cell (WBC) count. More importantly, within each genetic subtype, there is much less variability in treatment response and survival outcomes compared with current risk factors such as National Cancer Institute (NCI) criteria. We review how this new taxonomy of genetic subtypes in childhood ALL interacts with clinical risk factors used widely, i.e., age, presenting WBC, IKZF1del, treatment response, and outcomes.