CD123 expression is strongly correlated with disease-relevant cytogenetic and molecular alterations in childhood acute myeloid leukemia (AML), and higher CD123 expression resulted in inferior clinical outcomes compared with lower CD123 expression, according to a study presented at the 2019 ASH Annual Meeting.
The phase III Children’s Oncology Group study assessed the efficacy of bortezomib in combination with standard chemotherapy in a cohort of 1,400 pediatric patients. All diagnostic specimens were centrally and prospectively evaluated for the expression of CD123 by multidimensional flow cytometry, and patients were categorized into four quartiles of CD123 expression (n=260 each). Patients were stratified to a low-risk (LR) or high-risk (HR) arm of the therapy based on cytogenetic and molecular alterations and end-of-induction (EOI) minimal residual disease (MRD). LR patients received four cycles of chemotherapy, while HR patients received three courses of chemotherapy followed by best allogeneic hematopoietic cell transplantation (alloHCT).
Surface CD123 expression on AML cells was available for 1,040 patients, and expression level varied significantly, with a median CD123 molecules per cell of 1,300 (range 120-13,100 molecules per cell).
Researchers observed significant variations in cytogenetic/molecular characteristics: Those with the highest CD123 expression had a lower prevalence of t(8;21), inv(16), and CEBPA mutations (P<0.001 for all) and a higher prevalence of KMT2A rearrangements and FLT3-ITD mutations (P<0.001 for both).
CD123 expression quartile did not significantly impact morphologic complete remission (P=0.278) or MRD negativity (P=0.182) at EOI. Patients with lower CD123 expression (quartiles 1-3) had similar relapse risk (RR), event-free survival (EFS), and overall survival (OS), while those with the highest CD123 expression (quartile 4) had significantly higher RR (53% vs. 39%; P<0.001), lower EFS (49% vs. 69%; P<0.001), and lower OS (32% vs. 50%; P<0.001) compared with quartiles 1-3. Patients with highest CD123 surface expression were more likely to have HR genetic alterations and a paucity of LR features.
In a multivariable Cox regression analysis of all prognostic factors, including cytogenetic/molecular risk group, age, MRD status, and FLT3-ITD status, the researchers observed that high CD123 expression was independently associated with worse OS (hazard ratio, 1.54; 95% confidence interval, 1.21-1.96; P<0.001).
“In pediatric and young adult patients with the highest risk disease, the higher CD123 expression represents a valuable therapeutic target in the development of immunotherapies for childhood AML,” the researchers concluded.
Reference
Lamble AJ, Brodersen LE, Alonzo TA, et al. Correlation of CD123 expression level with disease characteristics and outcomes in pediatric acute myeloid leukemia: a report from the Children’s Oncology Group. Abstract 459. Presented at the 2019 ASH Annual Meeting, December 8, 2019; Orlando, Florida.
