A ten-gene DNA-damage response pathway gene expression signature predicts gemtuzumab ozogamicin response in pediatric AML patients treated on COGAAML0531 and AAML03P1 trials.
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.
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Gbadamosi MO, Shastri VM, Elsayed AH, 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;36(8):2022-2031. doi:10.1038/s41375-022-01622-0