Correlation of CD123 Expression Level with Disease Characteristics and Outcomes in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group

Introduction: Despite maximally intensified chemotherapy, cure rates remain suboptimal for children and young adults with acute myeloid leukemia (AML). As CD123 (IL3RA) is expressed on the majority of AML cells, it is a promising immunotherapeutic target. Increased CD123 expression has been linked to high-risk disease characteristics in adult AML, but clinical implications for childhood AML are less well-defined.

Methods: The Children's Oncology Group AAML1031 phase 3 trial (NCT01371981) tested the efficacy of the addition of bortezomib to standard chemotherapy in a randomized fashion. A total of 1400 children and young adults were enrolled on study. All diagnostic specimens were centrally and prospectively evaluated for the expression of CD123 by multi-dimensional flow cytometry (MDF) at Hematologics, Inc. Patients were stratified to either 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) measured by MDF. LR patients received four cycles of chemotherapy, while HR patients received 3 courses of chemotherapy followed by best allogeneic hematopoietic stem cell transplantation (HSCT). Patients with high allelic ratio FLT3-ITD enrolled on arm C received sorafenib in combination with standard chemotherapy followed by HSCT. Here we provide data on expression of CD123 across all patients and correlate this expression with disease characteristics and clinical outcomes.

Results: Surface CD123 expression on AML cells was available for 1040 patients, and expression level varied significantly across the study population with a median CD123 molecules per cell of 1300 (range 120-13,100 molecules per cell). For analysis, the study population was divided into quartiles (n=260 each) based on CD123 expression levels. Significant variation in cytogenetic/molecular characteristics was observed across the four quartiles, where those with highest CD123 expression had a lower prevalence of t(8;21), inv(16), and CEBPA mutations (p<0.001 for all) and higher prevalence of KMT2A rearrangements and FLT3-ITD mutations (p<0.001 for both) (Figure 1A). CD123 expression quartile was not significantly different among those in morphological complete remission (CR) (p=0.278) or MRD negative (bone marrow < 0.1%) (p=0.182) at EOI. Evaluation of outcome parameters across the four quartiles demonstrated that those in lower CD123 expression quartiles 1, 2 and 3 (Q1-3) had similar relapse risk (RR), event-free and overall survival (EFS and OS). However, those with the highest CD123 expression (Q4) had a 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) (Figure 1B) in comparison to Q1-3. These differences were maintained within the protocol-defined LR cohort, as those with LR disease but high CD123 expression (Q4) had worse RR, EFS, and OS versus those in Q1-3 (p<0.001 for all) (Figure 1C). Given the observed association of CD123 expression with known risk groups, we performed a multivariable Cox regression analysis of all prognostic factors, including cytogenetic/molecular risk group, age, MRD status, and FLT3-ITD status, which demonstrated that high CD123 expression was independently associated with worse OS (HR 1.54, 95% CI 1.21-1.96, p<0.001) (Figure 1D).

Conclusions: CD123 expression is strongly associated with disease-relevant cytogenetic and molecular alterations in childhood AML. Patients with highest CD123 surface expression are more likely to have HR genetic alterations and a paucity of LR features. Further, despite similar induction remission rates, those with high CD123 expression had inferior clinical outcomes compared to patients with lower CD123 expression. However, despite an association with HR features, expression of CD123 appears to be independently associated with therapeutic response given that outcome differences were maintained in multivariate regression analysis. This suggests that CD123 expression may provide additional prognostic information, as highlighted by the inferior outcomes in LR patients that had high CD123 expression. 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.

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