Comparison of immunoglobulin high-throughput sequencing MRD in bone marrow and peripheral blood in pediatric B-ALL: A report from the Children's Oncology Group AALL1731.
Authors: Rachel Rau, Sumit Gupta, John A Kairalla, Cindy Wang, Lik Wee Lee, Heidi Michelle Simmons, Karen R. Rabin, Anne Angiolillo, Mary Shago, Andrew J. Carroll, Brent L. Wood, Michael J. Borowitz, Yvonne Moyer, Alexis Cameron, Christian Deardorff, Tyler Jones, Allison Jacob, Ilan Richard Kirsch, Elizabeth A. Raetz, Mignon Loh
Journal: Journal of Clinical Oncology (2024)

10014 Background: Minimal (measurable) residual disease (MRD) at end of induction (EOI) therapy is a strong predictor of outcome in pediatric B-ALL. Currently, EOI MRD is assessed in bone marrow (BM). We hypothesized that the highly sensitive assay, high-throughput sequencing (HTS) of immunoglobulin loci, can effectively monitor MRD in peripheral blood (PB) and may provide a less invasive way to track therapy response. Methods: We conducted HTS MRD on paired EOI BM and PB samples from 808 NCI standard risk (SR) pediatric B-ALL patients enrolled on Children’s Oncology Group study AALL1731 (NCT03914625). We determined the correlation between BM and PB HTS MRD via Spearman’s rank correlations. We calculated the BM/PB MRD ratio and compared these by subgroup using Kruskal-Wallis tests. We defined subgroups by cytogenetics (cyto) ( ETV6::RUNX1, double trisomies of chromosome 4 and 10 (DT), Unfavorable (hypodiploidy, iAMP21, or KMT2A-rearranged), or Neutral (lacking ETV6::RUNX1, DT, or unfavorable)), and risk group (SR-average (AVG) and SR-High). Flow cytometry-defined EOI BM MRD was &lt; 0.01% for all SR-AVG patients (N = 623) and ≥0.01% for selected SR-High patients (N = 185). Results: There was strong correlation between PB and BM HTS MRD with an overall correlation coefficient of 0.75 (P &lt; 0.001). Correlation was similar by cytogenetics: ETV6::RUNX1, 0.69 (N = 63; P &lt; 0.001), DT, 0.75 (N = 147; P &lt; 0.001), Neutral, 0.74 (N = 580; P &lt; 0.001), and Unfavorable, 0.66(N = 18; P = 0.003). For risk groups, correlation for SR-AVG was 0.67 (p &lt; 0.001) and SR-High, 0.64 (p &lt; 0.001). Of the 591 SR-AVG patients with detectable BM HTS MRD, PB HTS MRD was detectable in 474 (80.2%), undetectable in 94 (15.9%) and indeterminate (no leukemic cell detected and &lt; 500,000 total cells in sample) in 23 (3.9%). Among 182 SR-High patients with detectable BM HTS MRD, 175 (96.2%) had detectable PB HTS MRD. Disease burden was higher in the BM than PB with a significantly higher BM/PB ratio in SR-High compared to SR-AVG patients (median 16.5 vs 2.6, P &lt; 0.001). The median BM/PB ratio also varied by cytogenetics with those with Unfavorable cyto having the highest ratio (15.3 vs 6.3 in DT, 3.8 in ETV6::RUNX1, 3.1 in Neutral; P = 0.013). Conclusions: This is the largest analysis of paired B-ALL BM/PB HTS MRD to date. We show strong correlation between PB and BM across risk and cytogenetic groups. The ratio of BM/PB MRD varied and was highest among patients with Unfavorable cyto suggesting BM tropism. Importantly, PB MRD was detectable in nearly all patients with flow EOI BM MRD ≥0.01%, a threshold warranting therapy intensification. However, most patients with EOI BM flow MRD &lt; 0.01% also had detectable PB HTS MRD. Thus, PB HTS MRD may provide a useful adjunct for screening and clinical management of B-ALL patients. Defining a PB HTS MRD threshold useful for risk stratification will require correlation with outcome.