Comprehensive Childhood ALL Genotyping May Optimize Risk Stratification

“Accurately predicting outcome in children diagnosed with SR B-ALL or HR cases with favorable genetics is critical for tailoring treatment intensity to maximize cure and minimize toxicity,” wrote Ti-Cheng Chang, PhD.

To maximize efficacy and minimize toxicity, comprehensive genotyping of newly diagnosed pediatric patients with standard risk B-progenitor acute lymphoblastic leukemia (SR B-ALL) may optimize risk stratification, according to results of a case-control study published in the Journal of Clinical Oncology.

Results revealed that genomic subtype was associated with relapse, with occurrences in close to 50% of PAX5-altered ALL cases (OR, 3.31; 95% CI, 2.17-5.03; P = 3.18 x 10^-8). Additionally, ETV6::RUNX1-like (OR, 4.01; 95% CI, 2.02-8.00; P = 9.08 x 10^-5), TCF3/4::HLF (compared with EVT6::RUNX1 ALL, OR, 23.20; 95% CI, 2.42-3,091.00; P = 3.86 x 10^-3), BCR::ABL1-like (OR, 2.15; 95% CI, 1.05-4.29; P = 3.72 x 10^-2), and PAX5-altered ALL (OR, 3.31; 95% CI, 2.17-5.03; P = 3.18 x 10^-8) were all associated with the highest risks of relapse. Those with Down syndrome B-ALL were also at an increased risk of relapse (OR, 7.10l 95% CI, 2.80-19.91).

By contrast, lower relapse rates were observed with 62.0% of hyperdiploid cases with DT of chromosomes 4 and 10 than ETV6::RUNX1 ALL (OR, 0.65; 95% CI, 0.45-0.93; P = .017).

“Accurately predicting outcome in children diagnosed with SR B-ALL or HR cases with favorable genetics is critical for tailoring treatment intensity to maximize cure and minimize toxicity,” wrote Ti-Cheng Chang, PhD, genomics group lead of Applied Bioinformatics at St. Jude Children’s Research Hospital in Memphis, Tennessee, with coinvestigators in the publication. “However, because of the lack of large studies of uniformly treated ALL analyzed with comprehensive genomic approaches, recent studies refining the genetic taxonomy of B-ALL have not adequately addressed this question. To address this gap, we conducted integrated genomic analysis on a large group of patients using a design that specifically enriched for relapsed cases.”

The study group initially consisted of 1381 patients enrolled on National Cancer Institute-led SR B-ALL trials, comprising those with favorable (n = 776) or neutral (n = 605) cytogenetic features. A 1:2 case-control design was used for the study to select cases where patients experienced relapse (n = 439, 29.3%) up to the cutoff date of March 31, 2021. The relapse population consisted of 405 and 35 standard- and high-risk patients, respectively, including 115 with high-risk B-ALL who had favorable cytogenetic features.

Primary leukemia samples were obtained prior to start of treatment and were paired with health blood or bone marrow tissue at the end of induction (EOI). Three samples had whole-transcriptome sequencing (WTS), 31 had whole-genome sequencing (WGS), and 1462 had both.

ETV6::RUNX1 (n = 557, 37.2%) and hyperdiploidy with gain of 5 or more chromosomes (n = 514, 34.4%) were identified as the most common genomic subtypes. Additionally, the relapse frequency was higher in favorable-risk subtypes than in previous studies not enriched for patients experiencing relapse (ETV6::RUNX1, 23.2%; hyperdiploidy, 23.5%).

No associations between clinical features and relapse or minimal residual disease (MRD) were observed, except for age at diagnosis of 3 to 5 years and EOI MRD (OR, 0.68; 95% CI, 0.50-0.93; P = .016). Additionally, time to relapse was shortest for TCF3::PBX1 (median time to relapse, 19.2 months; 95% CI, 15.8-21.0) and PAX5-altered cases (29.0 months; 95% CI, 23.8-37.6) vs ETV6::RUNX1 (42.7 months; 95% CI, 40.1-45.7).

“[W]e report a large, comprehensively analyzed predominantly NCI SR group enriched for relapse and have identified additional mutational events or patterns of aneuploidy that refine current risk predictors […] it is essential to comprehensively genotype newly diagnosed patients with SR ALL to accurately tailor the intensity of therapy to minimize the toxicity without increasing the risk of relapse,” concluded Chang and study coinvestigators.

Reference

Chang TC, Chen W, Qu C, et al. Genomic determinants of outcome in acute lymphoblastic leukemia. J Clin Oncol. Published online August 9, 2024. doi:10.1200/JCO.23.02238