Lamble Adam J, Eidenschink Brodersen Lisa, Alonzo Todd A, Wang Jim, Pardo Laura, Sung Lillian, Cooper Todd M, Kolb E Anders, Aplenc Richard, Tasian Sarah K, Loken Michael R, Meshinchi Soheil
Division of Hematology/Oncology, Seattle Children's Hospital, University of Washington, Seattle, WA.
Hematologics Inc, Seattle, WA.
J Clin Oncol. 2022 Jan 20;40(3):252-261. doi: 10.1200/JCO.21.01595. Epub 2021 Dec 2.
Increased CD123 surface expression has been associated with high-risk disease characteristics in adult acute myeloid leukemia (AML), but has not been well-characterized in childhood AML. In this study, we defined CD123 expression and associated clinical characteristics in a uniformly treated cohort of pediatric patients with newly diagnosed AML enrolled on the Children's Oncology Group AAML1031 phase III trial (NCT01371981).
AML blasts within diagnostic bone marrow specimens (n = 1,040) were prospectively analyzed for CD123 protein expression by multidimensional flow cytometry immunophenotyping at a central clinical laboratory. Patients were stratified as low-risk or high-risk on the basis of (1) leukemia-associated cytogenetic and molecular alterations and (2) end-of-induction measurable residual disease levels.
The study population was divided into CD123 expression-based quartiles (n = 260 each) for analysis. Those with highest CD123 expression (quartile 4 [Q4]) had higher prevalence of high-risk rearrangements and -ITD mutations ( < .001 for both) and lower prevalence of low-risk t(8;21), inv(16), and mutations ( < .001 for all). Patients in lower CD123 expression quartiles (Q1-3) had similar relapse risk, event-free survival, and overall survival. Conversely, Q4 patients had a significantly higher relapse risk (53% 39%, < .001), lower event-free survival (49% 69%, < .001), and lower overall survival (32% 50%, < .001) in comparison with Q1-3 patients. CD123 maintained independent significance for outcomes when all known contemporary high-risk cytogenetic and molecular markers were incorporated into multivariable Cox regression analysis.
CD123 is strongly associated with disease-relevant cytogenetic and molecular alterations in childhood AML. CD123 is a critical biomarker and promising immunotherapeutic target for children with relapsed or refractory AML, given its prevalent expression and enrichment in patients with high-risk genetic alterations and inferior clinical outcomes with conventional therapy.
CD123表面表达增加与成人急性髓系白血病（AML）的高危疾病特征相关，但在儿童AML中尚未得到充分表征。在本研究中，我们在儿童肿瘤学组AAML1031 III期试验（NCT01371981）登记的新诊断AML儿科患者的统一治疗队列中定义了CD123表达及相关临床特征。
在中央临床实验室通过多维流式细胞术免疫表型分析对诊断性骨髓标本（n = 1,040）中的AML原始细胞进行前瞻性CD123蛋白表达分析。根据（1）白血病相关的细胞遗传学和分子改变以及（2）诱导结束时可测量的残留疾病水平，将患者分为低危或高危。
将研究人群分为基于CD123表达的四分位数（每组n = 260）进行分析。CD123表达最高者（四分位数4 [Q4]）具有更高的高危重排和内部串联重复（ITD）突变患病率（两者均P <.001），以及更低的低危t(8;21)、inv(16)和 突变患病率（所有均P <.001）。CD123表达较低四分位数（Q1 - 3）的患者具有相似的复发风险、无事件生存期和总生存期。相反，与Q1 - 3患者相比，Q4患者具有显著更高的复发风险（53% 对39%，P <.001）、更低的无事件生存期（49% 对69%，P <.001）和更低的总生存期（32% 对50%，P <.001）。当将所有已知的当代高危细胞遗传学和分子标志物纳入多变量Cox回归分析时，CD123对结局仍具有独立的显著性。
CD123与儿童AML中与疾病相关的细胞遗传学和分子改变密切相关。鉴于其在高危基因改变患者中的普遍表达和富集以及传统治疗较差的临床结局，CD123是复发或难治性AML儿童的关键生物标志物和有前景的免疫治疗靶点。
