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ACUTE MYELOID LEUKEMIA

A ten-gene DNA-damage response pathway gene expression signature predicts gemtuzumab ozogamicin response in pediatric AML patients treated on COGAAML0531 and AAML03P1 trials

Abstract

Gemtuzumab ozogamicin (GO) is an anti-CD33 monoclonal antibody linked to calicheamicin, a DNA damaging agent, and is a well-established therapeutic for treating acute myeloid leukemia (AML). In this study, we used LASSO regression modeling to develop a 10-gene DNA damage response gene expression score (CalDDR-GEx10) predictive of clinical outcome in pediatric AML patients treated with treatment regimen containing GO from the AAML03P1 and AAML0531 trials (ADE + GO arm, N = 301). When treated with ADE + GO, patients with a high CalDDR-GEx10 score had lower complete remission rates (62.8% vs. 85.5%, P = 1.7 7 * 10−5) and worse event-free survival (28.7% vs. 56.5% P = 4.08 * 10−8) compared to those with a low CalDDR-GEx10 score. However, the CalDDR-GEx10 score was not associated with clinical outcome in patients treated with standard chemotherapy alone (ADE, N = 242), implying the specificity of the CalDDR-GEx10 score to calicheamicin-induced DNA damage response. In multivariable models adjusted for risk group, FLT3-status, white blood cell count, and age, the CalDDR-GEx10 score remained a significant predictor of outcome in patients treated with ADE + GO. Our findings present a potential tool that can specifically assess response to calicheamicin-induced DNA damage preemptively via assessing diagnostic leukemic cell gene expression and guide clinical decisions related to treatment using GO.

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Fig. 1
Fig. 2: CalDDR-GEx10 score group is associated with complete remission (CR), event-free survival (EFS), and overall survival (OS) in patients treated with ADE + GO but not in patients treated with ADE alone.
Fig. 3: The CalDDR-GEx10 Score is an independent predictor of event-free survival (EFS) in patients treated with ADE + GO.
Fig. 4: The CalDDR-GEx10 shows predictive power in patients of different risk groups treated with ADE + GO.
Fig. 5: Patients in the low CalDDR-GEx10 score perform better when treated with ADE + GO vs ADE alone.

Data availability

The transcriptomic and clinical data used in this study were obtained from the TARGET database (https://target-data.nci.nih.gov/Public/AML/mRNA-seq), however, data are only publicly available for N = 128 treated with ADE + GO and N = 175 patients treated with ADE alone. Other controlled data used in this study were obtained and used with permission from the Children’s Oncology Group.

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Acknowledgements

This work was supported by the NIH (R21CA155524), The Leukemia Lymphoma Society (6610-20), The St Baldrick’s Foundation, University of Florida Health Cancer Center, and College of Pharmacy, University of Florida. NIH awards U10CA180899, U10CA180886, U10CA98413, and U10CA098543 supported the clinical trial.

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Study concept and design: JKL and MOG; Acquisition of clinical data: RR, TAD, AG, SM, and BAH; Data generation, analysis, and interpretations: MOG, VS, RR, AHE, OO, NN, ADJ, YW, AD, TAD, SM, and JKL; Manuscript writing and preparation: MOG and JKL; Revision and review of manuscript: All authors.

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Correspondence to Jatinder K. Lamba.

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Gbadamosi, M.O., Shastri, V.M., Elsayed, A.H. et al. A ten-gene DNA-damage response pathway gene expression signature predicts gemtuzumab ozogamicin response in pediatric AML patients treated on COGAAML0531 and AAML03P1 trials. Leukemia (2022). https://doi.org/10.1038/s41375-022-01622-0

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