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CD123 in AML
Targeting CD123 in AML

Released: June 28, 2016

Expiration: June 27, 2017

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Authors: Jonathan Webster, MD, and B. Douglas Smith, MD

Novel antibody-mediated therapies have revolutionized the treatment of hematologic malignancies in recent years, as we have seen with the proliferation of CD19-targeted therapies such as blinatumomab and CAR T-cell therapy in acute lymphoblastic leukemia (ALL). In myeloid malignancies, however, novel therapies have met with limited success, with induction regimens in acute myeloid leukemia (AML) remaining little changed for decades and a continued poor prognosis in refractory disease. The CD33-targeted drug–antibody conjugate gemtuzumab ozogamicin is the only antibody-mediated therapy that has been approved for use in myeloid malignancies, but due to toxicity concerns and the lack of CD33 expression on AML stem cells, it has subsequently been withdrawn from the market.

The lack of progress in developing antibody-mediated therapies for AML partially stems from the difficulty in choosing therapeutically actionable targets in myeloid malignancies. For example, CD34+/CD38- cells were previously identified as leukemia stem cells (LSCs), but normal hematopoietic stem cells (HSCs) share this phenotype, such that targeting CD34+/CD38- cells to eradicate AML is impractical because it would also ablate normal hematopoiesis.

Subsequently, Jordan and colleagues determined that the interleukin-3 receptor alpha subunit (CD123) is expressed on > 90% of CD34+/CD38- LSCs in nearly 90% of AML patient samples, whereas < 1% of CD34+/CD38- HSCs express CD123 in normal patient samples. This differential expression of CD123 on LSCs and normal HSCs suggests that it is a promising target for antibody-mediated approaches for the treatment of AML and related diseases.

The first attempt at targeting CD123 with monotherapy in patients with relapsed/refractory AML was with the monoclonal antibody CSL360, but this agent only induced responses in < 10% of patients in a phase I trial.

A subsequent phase I study at our institution and 3 other centers of CSL362, a second-generation CD123 monoclonal antibody, explored the utility of targeting CD123 in patients with AML in CR following chemotherapy at high risk for early relapse. Ten patients in this study had biomarkers of minimal residual disease (MRD) upon study entry and were evaluable at follow-up, and 4 of those patients (40%) converted to MRD negative status at the conclusion of treatment.

This suggests that there may be a role for CD123-targeted monoclonal antibodies in patients with MRD. CSL362 is now being tested in combination with decitabine for patients with AML ineligible for intensive induction chemotherapy to determine if it may augment traditional cytotoxic chemotherapy, and other CD123-directed antibodies are also being explored as monotherapy in relapsed/refractory AML and myelodysplastic syndrome.

In addition, CD123 antibody–drug conjugates have also shown promise in the treatment of AML and other myeloid malignancies. SL-401 is a CD123 antibody conjugated to diphtheria toxin that has led to stabilization of disease in some patients with AML and an impressive 78% response rate in blastic plasmacytoid dendritic cell neoplasm (BPDCN). Most adverse events in this study were mild, and all grade 3/4 toxicities were transient. In addition to the treatment of AML and BPDCN, in vitro studies suggest that SL-401 could also serve as a useful adjunct to tyrosine kinase inhibitor therapy in chronic myeloid leukemia, including cell lines harboring the T315I mutation. Another CD123 antibody–drug conjugate, SGN-CD123A, has demonstrated promising preclinical results in AML, and clinical trials are upcoming.

Finally, trials with both CAR T-cells and dual specificity molecules designed to increase interactions between CD3+ lymphocytes and CD123+ blasts are ongoing. CD123-directed CAR T-cells have previously proven effective both in vitro and in vivo in a xenogeneic model of disseminated AML. On the basis of these results, there are currently 2 active trials investigating CD123-directed CAR T-cells, one in AML alone, and another in multiple myeloid malignancies. Meanwhile, numerous different bichimeric T-cell engager antibody constructs (BiTEs) and dual affinity retargeting proteins (DARTs) have demonstrated the ability to enhance cytotoxic T-cell responses to CD123+ AML blasts in vitro. These types of molecules are also being evaluated in ongoing clinical trials.

Although many of these studies are in early stages, given the plethora of emerging CD123-targeted options for the treatment of AML, there are opportunities for clinical trials for your patients as well as great enthusiasm that at least one of these approaches will prove effective and dramatically alter the treatment landscape for AML.

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