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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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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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.
The authors declare no competing interests.
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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 36, 2022–2031 (2022). https://doi.org/10.1038/s41375-022-01622-0