Kamel Azza M, Elsharkawy Nahla M, Kandeel Eman Z, Hanafi Marwa, Samra Mohammed, Osman Randa A
Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt.
Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt.
Front Oncol. 2022 Apr 8;12:867684. doi: 10.3389/fonc.2022.867684. eCollection 2022.
Acute myeloid leukemia (AML) is a heterogenous disease in which the initiation and maintenance of the malignant clone is blamed on a rare population of leukemia stem cells (LSCs). The persistence of such a malignant population is referred to as measurable/minimal residual disease (MRD). Evaluation of MRD is the gold standard for follow-up of therapy and constitutes an independent prognostic parameter. As LSCs are the main contributor to the persistence of MRD, then MRD should correlate with the bulk of LSCs at the individual case level. MRD is measured at defined time points during therapy. However, LSCs can be evaluated at diagnosis, which ensures the advantage of early prediction of high-risk patients and allows for early therapeutic decisions. Using two simple four-color monoclonal antibody combinations (CD38/CD123/CD34/CD45 and CD90/CD133/CD45/CD33) and the prism function of the Coulter Navios flow cytometer, the frequency of LSC subsets was evaluated in 84 newly diagnosed adult AML patients. For each panel, 16 possible combinations were detected. Our results showed that there was extreme variability in the percentage of the LSC fraction between different cases, as well as at the individual case level. For each LSC subset, the median value was used to divide cases into low and high expressors. LSC subsets that showed an impact on overall survival (OS) and disease-free survival (DFS) included CD123+, CD 123+/CD34-, CD34-/CD38+/CD123+, CD34+/CD38-/CD123+, CD133+, and CD133+/CD33-. On multivariate analysis, only CD123 (p ≤ 0.001, SE = 0.266, HR = 2.8, 95% CI = 1.74.7) and CD133+/CD33- (p = 0.017, SE = 0.263, HR = 1.9, 95% CI = 1.1-3.1) retained their significance for OS. Likewise, only CD34+/CD38-/CD123+ (p ≤ 0.001, HR 2.3, SE: 0.499, 95% CI: 2.4-17.4) and CD133 (p = 0.015, HR 2.3, SE 0.34, 95% CI: 1.2-4.4) retained their statistical significance for DFS. The LSC frequency at diagnosis showed a moderate to strong correlation with MRD status at day 14 and day 28. In conclusion, the level of LSCs at diagnosis correlated with MRD status at day 14 and day 28 in AML patients and had a deleterious impact on OS and DFS. It may be used as an early marker for high-risk patients allowing for early therapeutic decisions.
急性髓系白血病（AML）是一种异质性疾病，其中恶性克隆的起始和维持归因于罕见的白血病干细胞（LSC）群体。这种恶性群体的持续存在被称为可测量/最小残留病（MRD）。MRD评估是治疗随访的金标准，并且是一个独立的预后参数。由于LSC是MRD持续存在的主要因素，因此在个体病例水平上，MRD应与LSC的数量相关。MRD在治疗期间的特定时间点进行测量。然而，可以在诊断时评估LSC，这确保了早期预测高危患者的优势，并允许做出早期治疗决策。使用两种简单的四色单克隆抗体组合（CD38/CD123/CD34/CD45和CD90/CD133/CD45/CD33）以及库尔特Navios流式细胞仪的棱镜功能，在84例新诊断的成年AML患者中评估了LSC亚群的频率。对于每个组合，检测到16种可能的组合。我们的结果表明，不同病例之间以及个体病例水平上，LSC分数的百分比存在极大差异。对于每个LSC亚群，使用中位数将病例分为低表达者和高表达者。对总生存期（OS）和无病生存期（DFS）有影响的LSC亚群包括CD123 +、CD123 + /CD34 -、CD34 - /CD38 + /CD123 +、CD34 + /CD38 - /CD123 +、CD133 +和CD133 + /CD33 -。多变量分析显示，仅CD123（p≤0.001，SE = 0.266，HR = 2.8，95%CI = 1.7 - 4.7）和CD133 + /CD33 -（p = 0.017，SE = 0.263，HR = 1.9，95%CI = 1.1 - 3.1）对OS仍具有显著意义。同样，仅CD34 + /CD38 - /CD123 +（p≤0.001，HR 2.3，SE：0.499，95%CI：2.4 - 17.4）和CD133（p = 0.015，HR 2.3，SE 0.34，95%CI：1.2 - 4.4）对DFS仍具有统计学意义。诊断时的LSC频率与第14天和第28天的MRD状态呈中度至高度相关。总之，AML患者诊断时的LSC水平与第14天和第28天的MRD状态相关，并对OS和DFS有有害影响。它可作为高危患者的早期标志物，以便做出早期治疗决策。
