Prognostic relevance of CD123 expression in adult AML with normal karyotype

Acute myeloid leukaemia (AML) encompasses a large biologically and clinically heterogenous group of neoplasms with 40–50% of AML being identified to have a grossly normal karyotype (NK-AML) using classical cytogenetics. Increased understanding and characterization of this biological heterogeneity has triggered interest in molecular and immunophenotypic targeted approaches for personalized therapy. Interleukin-3 receptor α chain (CD123) is a type I cytokine receptor normally expressed on early haematopoietic cells. It transmits the signal of interleukin-3 upon forming a heterodimer with IL-3Rβ, activating the JAK/STAT pathway necessary for haematopoiesis. Recent evidence suggests that CD123 is frequently overexpressed in primitive leukaemic stem cells, and at a much lower level by normal myeloid progenitors (Jordan et al., 2000). Thus, CD123 has become an attractive therapeutic target, with the potential to both debulk and lower residual disease burden for long-term therapeutic responses. However, the frequency of CD123 expression and its prognostic implication have not been systematically studied in patients with NK-AML. We retrospectively analyzed 231 patients diagnosed with de novo adult NK-AML who did not undergo allogeneic haematopoietic stem cell transplantation between August 2012 and January 2018 at our institution. Patients with blastic plasmacytoid dendritic cell neoplasm were excluded. Most patients were treated with an induction regimen consisting of seven-day continuous infusion of cytarabine 200 mg/m2 per day (reduced to 100 mg/m2 per day for patients ≥60 years) and daunorubicin 60 mg/m2 for three days, while some older patients received supportive therapy. Our cohort had a median age of 68·3 years (range, 19·3–88·8 years) at diagnosis. The median follow-up time was 9·08 months (range, 0·1–64·9 months); 134 (58%) patients had died at the time of last follow-up. The median morphologic aspirate blast count was 67% (range, 20–98%). Ninety-one (39%) patients were positive for CD123 (CD123+), defined by at least 20% expression on the blast cells using multiparameter flow cytometry whereas residual normal lymphocytes in each sample were used as negative control. The median CD123 expression in CD123+ patients was 72% of the blasts (range, 21–99%). Thus, we determined 72% to be a suitable threshold to classify patients into high expression (CD123high). CD123+ AML was positively correlated with high white blood cell (WBC) count (≥30 × 109/l) at diagnosis (P < 0·0001) and increased marrow blast percentage at diagnosis (r = 0·236, P < 0·001). CD123 positivity per se did not significantly correlate with sex, age, remission rate, or relapse rate. However, patients with CD123high had a lower remission rate (54·3% vs. 74·0%; P = 0·041). Furthermore, CD123 positivity correlated with the expression of CD11b, CD11c and CD36, but not of other immunophenotypic markers tested including CD4, CD7, CD13, CD33, CD34, CD38, CD56, CD64, CD65, CD71 and CD117. Targeted analysis of FLT3-ITD and NPM1 hotspot truncating variants was performed in 196/231 (85%) patients from our cohort. CD123 positivity was associated with both FLT3-ITD and NPM1 mutations (P < 0·0001 and P = 0·0017, respectively). Recent studies have shown that higher FLT3-ITD burdens are associated to poor outcome of disease (Cucchi et al., 2018). We investigated the correlation of CD123 positivity with FLT3-ITD levels; 13/196 (7%) of patients analyzed harboured a high burden of FLT3-ITD (FLT3-ITDhigh determined by the ratio ≥0·5 of FLT3-ITD over total FLT3 levels observed). Of these patients, 12 (92%) were also CD123+; we found that CD123 positivity was correlated with FLT3-ITDhigh (P < 0·0001). Upon univariate analysis using the log-rank test for event-free survival (EFS) and overall survival (OS), CD123 positivity showed no correlation with either EFS or OS (P = 0·078 and P = 0·094, respectively). However, patients with CD123high had a decreased median EFS (6·2 months vs. 10·5 months; P = 0·012) and median OS (7·9 months vs. 18·0 months; P = 0·017). The Kaplan–Meier curves for CD123 expression at 20% and 72% threshold are presented in Fig 1. Multivariable analysis using a backward stepwise Cox proportional hazards regression was performed with CD123high, age ≥60 years, FLT3-ITDhigh and NPM1 mutations as covariates. WBC count (≥30 × 109/l) was excluded from the multivariable analysis as it was univariately insignificant and correlated with CD123 expression. Age ≥60 years and FLT3-ITDhigh retained significance for decreased EFS (P = 0·003 and P > 0·0001, respectively) and OS (P = 0·004 and P > 0·0001, respectively). NPM1 mutation was an independent predictor for longer EFS (P = 0·023), but not OS (P = 0·092). CD123high did not retain significance for either EFS or OS (P = 0·141 and P = 0·165, respectively). Results from multivariable analysis are summarized in Table 1. The correlation of CD123 positivity to FLT3-ITD and NPM1 mutations is in accordance with immunohistochemical and flow cytometry studies performed by other groups (Rollins-Raval et al., 2013; Safaei et al., 2018). Testa et al. (2002) previously found high CD123 to be associated with high blast counts, lower complete remission rates, higher relapse rates, and lower OS. Their results help to confirm our findings; however, we did not find an association between high CD123 expression and higher relapse rates (P = 0·267). Furthermore, Nomdedeu et al. (2010) also suggested that CD123 expression at a higher threshold (≥52%) had significant prognostic implications in NPM1-mutated de novo AML patients. No previous study conducted multivariable analysis on high CD123 expression alone. We did not find CD123high to be an independent prognostic factor, likely due to its correlation with a high allele burden of FLT3-ITD. We also investigated the prognostic relevance of CD123 in the absence or low allele burden of FLT3-ITD and did not find that CD123high had a significant impact on EFS or OS (P = 0·96 and P = 0·86, respectively). Similarly, Angelova et al. (2019) did not find CD123 positivity to retain significance in multivariable analysis for decreased relapse-free survival in T-cell acute lymphoblastic leukaemia patients. Although CD123 positivity may not confer prognostic implications alone, its differential expression in normal haematopoietic stem cells and leukaemic stem cells has generated interest in its potential as a target for tailored therapies. Furthermore, Vergez et al. (2011) showed that a high CD34+CD38low/− CD123+ population is associated with poor response to therapy and decreased disease-free and overall survivals. Various bispecific and monoclonal anti-CD123 antibodies have been synthesized for preclinical and clinical studies (Testa et al., 2014). Of note, SL-401, a fusion protein formed by recombinant IL-3 fused to diphtheria toxin, is in ongoing phase I and II studies (Lane et al., 2016). In conclusion, our study confirms CD123 is frequently overexpressed in adult de novo NK-AML, and thus a suitable immunotherapeutic target. High CD123 expression appears associated with worse clinical outcome but it does not confer independent prognosis, likely due to its correlation with FLT3-ITD. GJ performed the research, analyzed data, and drafted the letter. EA and JMG analyzed data. MD provided clinical data and critical revision; HC designed the study, supervised the research, and analyzed data. All authors contributed to revisions, read, and approved the final version of this manuscript. We thank the staff of the Department of Medical Hematology and Oncology at the University Health Network for the outstanding care of the patients in this study, and the support of the UHN cancer registry program. The authors have no conflict of interest to disclose.

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