Comparison of Current and Enhanced Risk Stratification of 21,199 Children, Adolescents, and Young Adults with Acute Lymphoblastic Leukemia Using Objective Risk Categorization Criteria: A Children's Oncology Group Report

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.2382-2382
• Main Authors: Delrocco, Natalie, Loh, Mignon L., Borowitz, Michael, Rabin, Karen R, Zweidler-McKay, Patrick A, Maloney, Kelly W, Mattano, Leonard A., Larsen, Eric C, Angiolillo, Anne L, Schore, Reuven J, Burke, Michael J., Salzer, Wanda L, Wood, Brent L., Carroll, Andrew J, Heerema, Nyla A., Reshmi, Shalini C, Gastier-Foster, Julie M, Harvey, Richard C, Chen, I-Ming L, Roberts, Kathryn G, Mullighan, Charles G., Willman, Cheryl L, Winick, Naomi J, Carroll, William L., Hunger, Stephen P., Raetz, Elizabeth A., Devidas, Meenakshi, Kairalla, John
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-148593

Contemporary risk stratification algorithms commonly use threshold-defined categories of clinically relevant risk factors. The Children's Oncology Group (COG) uses National Cancer Institute (NCI) risk group (RG), cytogenetics, and early response to therapy measured by minimal residual disease (MRD) using flow cytometry on day 8 peripheral blood (D8 PB) and day 29 bone marrow (D29 BM). However, it is unclear whether assigning different weights to individual risk factors, as well as using numerical values as continuous, rather than categorical, would more accurately predict relapse risk. Previous work (Loh, ASH 2020) described validation of a continuous prognostic index (PI) for risk of relapse published by UK investigators incorporating favorable and unfavorable genetics, white blood cell count (WBC), and D29 BM as continuous variables (O'Connor, JCO 2018; Enshaei, Blood 2020), and assessed the added value of D8 PB. We now extend this work by comparing patient outcomes with current COG risk classification to PI-derived risk classifications on the previously described population (Loh, ASH 2020). We first retrospectively classified patients (pts) (N=21,199 from prior COG trials AALL0331/0232 or AALL0932/1131 enrolled 2004-2019) in our analysis population using the COG risk stratification algorithm employed in the current generation of COG trials. Pts with Down syndrome or BCR/ABL1 were excluded. We classified our analysis population as SR-Favorable [SR-Fav, 24.5% (5-year relapse free survival (RFS) probability 0.97)], SR-Favorable/Average (not distinguishable because of missing D8 PB) [SR-Fav/Avg, 5.3% (.96)], SR-Avg [20.5% (0.93)], SR-High [12.5% (0.83)], HR-Fav [3.0% (0.96)], HR [29.6% (0.82)], and Very HR [VHR, 1.1% (0.54)] according to NCI RG, CNS status, cytogenetics, D8 PB where relevant, D29 BM, and EOC MRD. Ninety-seven percent of pts had sufficient data to be retrospectively classified and thus 20,176 pts were considered for subsequent analyses. We next developed a multivariable model for RFS using log transformed MRD (τ(MRD)). Temporal external validation was first employed by developing models considering AALL0932/1131 data (n=12,453) and then validating them with AALL0331/0232 data (n=7,723). Of the full cohort of 20,176 pts, 24.4% could not be classified by COG PI, primarily due to missing D8 PB MRD which was not assessed routinely in earlier studies; thus the model was developed on 11,151 pts and validated on 4,103 pts. The COG PI (PI COG) was c