Prognostic Significance of CD123 Expression in Acute Myeloid Leukemia Treated with Venetoclax and Hypomethylating Agents
Authors: Tiu Bruce C , Su Christina J , St. Martin Emma C , Oak Jean S , Zhang Tian Y , Mannis Gabriel N 
Published: December 2024

Introduction
Acute myeloid leukemia (AML) with overexpression of CD123 is hyperproliferative, resistant to cell death, and has worse prognosis and survival in patients treated with intensive chemotherapy [Testa et al. 2002, Blood]. Multiple therapeutics that target CD123 are in development, with several planned studies exploring these agents in combination with venetoclax and hypomethylating agents (HMA) for the treatment of patients with newly diagnosed AML who are ineligible for intensive chemotherapy (IC). To date, no study has evaluated the prognostic significance of CD123 status for IC-ineligible patients with AML treated with venetoclax and an HMA.
Methods
We performed a retrospective cohort study of adult patients with AML or blast-phase myeloid neoplasms initiated on first-line therapy with venetoclax and an HMA (decitabine or azacitidine) at Stanford Health Care between November 2019 and December 2023. Patients were excluded if they did not survive at least 2 months after starting therapy, and were censored at 1 month after stem cell transplant or treatment failure, or at the end of the study period in June 2024. CD123 median fluorescence intensity (CD123-MFI) was measured on blasts identified by flow cytometry immunophenotyping from each patient's bone marrow at the time of diagnosis. Measurable residual disease (MRD) was also assessed by flow cytometry. The optimal discriminatory MFI for survival was selected by the method of maximally selected rank statistics. Distributions were compared using Mann-Whitney U or Fisher's exact tests. Cumulative incidence functions were estimated for complete remission (CR) accounting for the competing risk of death and compared with Gray's test.
Results
176 of the 322 patients with AML treated with venetoclax-based regimens in this period received first-line treatment with venetoclax and an HMA without antecedent therapy. 64 of these patients had bone marrow specimens analyzed for CD123 and met inclusion criteria. The median age at therapy initiation was 73 years [IQR 69-81]. The median CD123-MFI of the blast populations was 720 [IQR 402-1046]. An MFI of 340 (19th percentile) was used to create two cohorts (CD123lo, n=12; and CD123hi; n=52) based on the maximized log-rank statistic. The median survival was 10 months [95% CI 4.8-not reached] for CD123lo and 17 months [95% CI 14-36] for CD123hi (p=0.047). Patients with CD123lo received a median number of 2.5 cycles [IQR 2.0-5.5], compared to patients in CD123hi who received 5 cycles [IQR 3-12] (p=0.17).
No difference was observed between achievement of CR (95% CI) at 6 months between CD123lo (58±17%) and CD123hi(64±3.3%) (p=0.82); similarly, no difference was seen in achievement of a MRD negative CR (p=0.41). Fewer patients with CD123hi who responded to venetoclax/HMA underwent stem cell transplant compared to those with CD123lo (15%, 6/41; vs 22%, 2/9; p=0.03).
Across the cohort, there were no differences in CD123-MFI distributions between types of AML (de novo, therapy-related, or secondary AML), ELN risk categories, or the presence of a monosomal karyotype. The distributions of CD123-MFI did vary with mutational subgroups: CD123-MFIs were higher in patients with gene mutations in FLT3-ITD (p=0.0005) and RUNX1 (p=0.0009), and approached significance in IDH2-mutated AML (p=0.13). By comparison, CD123-MFIs were lower in ASXL1-mutated AML (p=0.04) and trended lower in TP53-mutated AML (p=0.23) compared to wild-type. When comparing CD123lo and CD123hi, FLT3-ITD (27%, 14/52), NPM1 (19%, 10/52), and IDH2 mutated-AML (10%, 5/52) were only observed in CD123hi, with none in CD123lo (0/12 for each). More patients with CD123lo (42%, 5/12) than CD123hi (23%, 12/52) had TP53 mutations.
Conclusions
Although high CD123 expression predicts poor outcomes in AML treated with IC, in our cohort, high CD123 expression was associated with improved survival in patients treated with venetoclax plus HMA. FLT3-ITD, NPM1, and IDH2 also associated with increased CD123 expression, which may represent a shared feature of susceptibility to venetoclax-based regimens. However, the relative resistance of FLT3-ITD AML suggests that additional mechanisms likely contribute [Bataller et al. 2024, Blood Adv]. Future studies should explore mechanistic explanations and further correlate CD123 expression and mutational status with responsiveness to CD123-directed therapies in combination with venetoclax plus HMA.