CD3-CD123 Bispecific Antibody Promising in High-Risk Myeloid Neoplasms

A phase 2 study highlighted the potential of CD3-CD123 bispecific T-cell engaging antibody, vibecotamab, for treatment of high-risk myeloid neoplasms, including myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). The study demonstrated encouraging response rates in these challenging-to-treat populations.

CD123 is highly expressed on leukemic stem cells compared with normal hematopoietic stem cells, making it a promising therapeutic target in myeloid neoplasms. Daniel Nguyen, MD, PhD, University of Texas MD Anderson Cancer Center, Houston, shared the results of the phase 2 trial (NCT05285813), which enrolled 37 adults: 19 with MDS or CMML after failure of hypomethylating agents (HMAs) and 18 with measurable residual disease (MRD)–positive AML in morphologic remission.¹

Participants were required to have CD123 expression of greater than 20% on myeloid blasts. Vibecotamab was administered in a dose-escalation schedule over the first 8 days, followed by weekly doses for up to four 28-day cycles. Primary endpoints included the overall response rate in the MDS/CMML group and the achievement of MRD negativity in the AML group.

In the MDS/CMML cohort, 68% of participants responded to treatment, with 63% achieving complete marrow remission and 5% showing hematologic improvement. Responses were observed across risk groups, including 50% of those with TP53 mutations. Most responses occurred after the first cycle, with a median duration of 5.2 months. Despite the high initial response rate, relapses were common, particularly after protocol therapy completion. Median overall survival was 10.3 months, and ongoing responses were noted in two participants at follow-up.

In the AML MRD cohort, 28% of participants achieved MRD negativity, with responses typically seen after the first cycle. Response durability varied, with three participants maintaining MRD-negative status for more than 2 years. The baseline MRD burden was significantly lower in responders, but the level of CD123 expression did not predict outcomes. As in the MDS/CMML group, most relapses occurred after completion of protocol therapy.

Vibecotamab was well tolerated, with no discontinuations due to adverse events. Infusion-related reactions were the most frequent side effects in 68% of participants, primarily at lower grades. Minimal myelosuppression was observed, which was consistent with previous studies.

These results demonstrate the clinical activity of vibecotamab in low-blast, high-risk myeloid neoplasms. Further research is warranted to understand how to optimize its use and expand the therapeutic options for these challenging conditions.

Reference

1. Nguyen D, Ravandi F, Wang SA, et al. Updated results from a phase II study of vibecotamab, a CD3-CD123 bispecific T-cell engaging antibody, for MDS or CMML after hypomethylating failure and in MRD-positive AML. Abstract #1007. Presented at the American Society of Hematology Annual Meeting; December 7-10, 2024; San Diego, California.