Integrated drug resistance and leukemic stemness gene-expression scores predict outcomes in large cohort of over 3500 AML patients from 10 trials - PubMed (original) (raw)

doi: 10.1038/s41698-024-00643-5.

Xueyuan Cao # 2, Richard J Marrero 1, Nam H K Nguyen 1, Huiyun Wu 3, Yonhui Ni 3, Raul C Ribeiro 4, Herold Tobias 5, Peter J Valk 6, François Béliveau 7, Guillaume Richard-Carpentier 8 9, Josée Hébert 7 10 11, C Michel Zwaan 12 13, Alan Gamis 14, Edward Anders Kolb 15, Richard Aplenc 16, Todd A Alonzo 17 18, Soheil Meshinchi 19, Jeffrey Rubnitz 4, Stanley Pounds 3, Jatinder K Lamba 20 21

Affiliations

Integrated drug resistance and leukemic stemness gene-expression scores predict outcomes in large cohort of over 3500 AML patients from 10 trials

Abdelrahman H Elsayed et al. NPJ Precis Oncol. 2024.

Abstract

In this study, we leveraged machine-learning tools by evaluating expression of genes of pharmacological relevance to standard-AML chemotherapy (ara-C/daunorubicin/etoposide) in a discovery-cohort of pediatric AML patients (N = 163; NCT00136084 ) and defined a 5-gene-drug resistance score (ADE-RS5) that was predictive of outcome (high MRD1 positivity p = 0.013; lower EFS p < 0.0001 and OS p < 0.0001). ADE-RS5 was integrated with a previously defined leukemic-stemness signature (pLSC6) to classify patients into four groups. ADE-RS5, pLSC6 and integrated-score was evaluated for association with outcome in one of the largest assembly of ~3600 AML patients from 10 independent cohorts (1861 pediatric and 1773 adult AML). Patients with high ADE-RS5 had poor outcome in validation cohorts and the previously reported pLSC6 maintained strong significant association in all validation cohorts. For pLSC6/ADE-RS5-integrated-score analysis, using Group-1 (low-scores for ADE-RS5 and pLSC6) as reference, Group-4 (high-scores for ADE-RS5 and pLSC6) showed worst outcome (EFS: p < 0.0001 and OS: p < 0.0001). Groups-2/3 (one high and one low-score) showed intermediate outcome (p < 0.001). Integrated score groups remained an independent predictor of outcome in multivariable-analysis after adjusting for established prognostic factors (EFS: Group 2 vs. 1, HR = 4.68, p < 0.001, Group 3 vs. 1, HR = 3.22, p = 0.01, and Group 4 vs. 1, HR = 7.26, p < 0.001). These results highlight the significant prognostic value of transcriptomics-based scores capturing disease aggressiveness through pLSC6 and drug resistance via ADE-RS5. The pLSC6 stemness score is a significant predictor of outcome and associates with high-risk group features, the ADE-RS5 drug resistance score adds further value, reflecting the clinical utility of simultaneous testing of both for optimizing treatment strategies.

© 2024. The Author(s).

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1

Fig. 1

Overall study design.

Fig. 2

Fig. 2. ADE-resistance score predicts AML outcome in discovery cohort.

High ADE-resistance score (ADE-RS5) significantly predicts MRD1 positivity (A), lower EFS and OS (B) probability in AML02 discovery cohort (n = 163). Association of the four groups classification based on integration of pLSC6 and ADE-RS5 scores (LSC6/RS5) with MRD1 (C), EFS and OS (D) probability in AML02 cohort. Forest plot showing results of multivariable cox regression analysis of association of ADE-RS, and the integrated pLSC6/ADE-RS5 score groups with EFS (E and G) and OS (F and H) after adjusting for risk group assignment, diagnostic WBC count, FLT3 status and age. For integrated LSC6RS5 scores: Group 1 = both LSC6 and ADE-RS5 scores are low; Group 2 = Low LSC6 score and High ADE-RS5 score; Group 3 = High LSC6 score and low ADE-RS5 score; Group 4= both LSC6 and ADE-RS5 scores are high.

Fig. 3

Fig. 3. ADE-RS5, pLSC6 and integrated score groups predict EFS and OS in large pediatric and adult AML validation cohorts.

Association of ADE-RS5 (A), pLSC6 (B), and the integrated LSC6/ADE-RS5 four score groups (C) with EFS and OS in the combined pediatric AML validation cohorts from multiple multi-site clinical trials (N = 1861, 4 trials). Association of ADE-RS5 (D), pLSC6 (E), and the integrated LSC6/ADE-RS5 four score groups (F) with OS in the combined adult AML validation cohorts from multiple multi-site clinical trials (N = 1669 patients, 5 cohorts).

Fig. 4

Fig. 4. ADE-RS5, pLSC6 and integrated score groups predict MRD after induction 1 in large pediatric AML validation cohorts.

Association of ADE-RS5 (A), pLSC6 (C), and the integrated LSC6/ADE-RS5 four score groups (E) with MRD1 in 1507 pediatric AML patients (COG-cohort1, COG-cohort2, and AML08 datasets). Forest plots showing results of multivariable cox regression analysis of association of ADE-RS5 (B), pLSC6 (D), and the integrated score groups (F) and MRD1 after adjusting for risk group assignment, diagnostic WBC count, FLT3 status and age. * MRD1 data was not available from the pediatric GSE17855 dataset.

Fig. 5

Fig. 5. Metanalysis forest plots for ADE-RS5, pLSC6 and integrated score groups in 10 AML cohorts.

Meta-analysis of EFS in 8 pediatric and adult AML datasets and OS in 10 pediatric and adult AML datasets by pLSC6 (A, B), ADE-RS5 (C, D), and integrated LSC6/ADERS scores group 1 vs. 2 (E, F), group 1 vs. group 3(G, H), group 1 vs. group 4 (I, J).

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