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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

Leukemia volume 36, pages 2022–2031 (2022)Cite this article

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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.

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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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Authors and Affiliations

  1. Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA

    Mohammed O. Gbadamosi, Vivek M. Shastri, Abdelrahman H. Elsayed, Oluwaseyi Olabige, Nam H. K. Nguyen, Angelica De Jesus & Jatinder K. Lamba

  2. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Rhonda Ries & Soheil Meshinchi

  3. COG Statistics and Data Center, Monrovia, CA, USA

    Yi-Cheng Wang, Alice Dang & Todd A. Alonzo

  4. University of Minnesota, Minneapolis, MN, USA

    Betsy A. Hirsch

  5. Biostatistics Division, University of Southern California, Los Angeles, CA, USA

    Todd A. Alonzo

  6. Department of Hematology-Oncology, Children’s Mercy Hospitals and Clinics, Kansas City, MO, USA

    Alan Gamis

  7. Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, FL, USA

    Jatinder K. Lamba

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Contributions

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 36, 2022–2031 (2022). https://doi.org/10.1038/s41375-022-01622-0

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