Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Leukemia. 2022 Aug;36(8):2022-2031. doi: 10.1038/s41375-022-01622-0. Epub 2022 Jun 10.
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) and worse event-free survival (28.7% vs. 56.5% P = 4.08 * 10) 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.
吉妥珠单抗奥佐米星（GO）是一种抗 CD33 单克隆抗体，与 calicheamicin（一种 DNA 损伤剂）相连，是治疗急性髓细胞白血病（AML）的成熟疗法。在这项研究中，我们使用 LASSO 回归建模来开发一个 10 个基因的 DNA 损伤反应基因表达评分（CalDDR-GEx10），以预测接受包含 GO 的治疗方案治疗的儿科 AML 患者的临床结果，该方案来自 AAML03P1 和 AAML0531 试验（ADE+GO 臂，N=301）。当用 ADE+GO 治疗时，CalDDR-GEx10 评分高的患者完全缓解率较低（62.8% vs. 85.5%，P=1.7710），无事件生存率较差（28.7% vs. 56.5%，P=4.0810）与 CalDDR-GEx10 评分低的患者相比。然而，CalDDR-GEx10 评分与单独接受标准化疗的患者的临床结果无关（ADE，N=242），这表明 CalDDR-GEx10 评分对 calicheamicin 诱导的 DNA 损伤反应具有特异性。在调整风险组、FLT3 状态、白细胞计数和年龄的多变量模型中，CalDDR-GEx10 评分仍然是接受 ADE+GO 治疗的患者结局的重要预测指标。我们的研究结果提出了一种潜在的工具，可以通过评估诊断性白血病细胞基因表达来预先评估对 calicheamicin 诱导的 DNA 损伤的反应，并指导与使用 GO 相关的治疗决策。
