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Target therapies under study to treat BPDCN


Researchers are looking at treating blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematolymphoid malignancy, with investigational agents equipped with different mechanisms of action, including XmAb14045 and IMGN632.

Researchers are looking at treating blastic plasmacytoid dendritic cell neoplasm (BPDCN) with investigational agents with different mechanisms of action, including XmAb14045 and IMGN632.

IMGN632, a CD123-targeting antibody-drug conjugate, consists of a humanized anti-CD123 antibody linked to an DNA mono-alkylating cytotoxic payload, according to the paper. IMGN632 is being studied as a monotherapy in relapsed/refractory BPDCN, as is XmAb14045, a tumor-targeted antibody that contains a CD123 binding domain and a cytotoxic T-cell binding domain, CD3, according to the paper CD123 as a Biomarker in Hematolymphoid Malignancies: Principles of Detection and Targeted Therapies1 (nih.gov), published in the November issue of Cancers.

BPDCN is an aggressive, deadly hematolymphoid malignancy. Dermatologists often encounter these patients because more than 80% of people with BPDCN present with skin lesions.

In recent decades scientists have identified new biomarkers for BPDCN and other hematolymphoid cancers that have significant diagnostic, prognostic and therapeutic implications. Among the most notable biomarkers is cluster of differentiation (CD)123.

The α chain of the interleukin (IL)-3 receptor, CD123, over-expresses in many hematolymphoid neoplasms, including BPDCN, acute myeloid leukemia, acute lymphoblastic leukemia, hairy cell leukemia and systemic mastocytosis, according to the paper.

CD123 has emerged as a novel therapy target. Its expression is upregulated in leukemic stem cells relative to non-neoplastic malignancies, according to the authors, who included researchers at the University of Texas MD Anderson Cancer Center, Houston. CD123 detection is vital to diagnosing BPDCN, the authors wrote And, researchers have found the biomarker is a viable drug target. The U.S. Food and Drug Administration (FDA) approved the CD123-targeted treatment tagraxofusp-erzs injection (ELZONRIS, Stemline Therapeutics) in late 2018, making it the first approved therapy indicated for BPDCN.

About CD123 and BPDCN detection

CD123 is a member of a family of membrane receptors that regulate hematopoietic cell growth, proliferation, survival, differentiation, immunity and inflammatory response, according to the paper.

BPDCN over-expresses not only CD123 but also T-cell factor (TCF)4. Absent are lineage-specific markers including CD3, CD19, CD64 and myeloperoxidase, the authors explained.

“Most BPDCN cases are positive for CD4, CD56, and TCL1. Proliferations of mature [plasmacytoid dendritic cells] have also been described, particularly in association with chronic myelomonocytic leukemia…,” they wrote.

To use newer and investigational CD123-targeted therapies, including tagraxofusp, providers first must determine the patient’s CD123 status at baseline and later during treatment, the authors wrote.

Clinical practice providers assess CD123 expression using flow cytometry or immunohistochemistry.

Many assess hematolymphoid cancer patients’ eligibility for CD123-targeted therapies with flow cytometry immunophenotyping. It can detect different cellular characteristics, from cell size to protein expression levels. In flow cytometry, the number of CD123 molecules expressed is indirectly reflected in the intensity of fluorescence detected, according to the authors.

“Furthermore, by employing carefully selected lineage and maturation-associated markers, CD123 expression on neoplastic cells can be clearly distinguished from that on other cell populations within a given sample. While this might not be critical in samples with a heavy disease burden, it is particularly important in the context of minimal/measurable residual disease evaluation,” they wrote.

But flow cytometry has limitations. Flow cytometry labs need fresh samples, which might not be an issue if the lab is near to the location where the samples are collected. Providers who need to transport samples might face challenges with flow cytometry. Flow cytometry also is technical and interpretive. Inexperienced labs might lack the proficiency needed to accurately assess CD123 expression.

Immunohistochemistry, a tissue sampling immunophenotyping technique, allows for antigen assessment in most formalin-fixed paraffin-embedded sample types, including percutaneous core biopsies and surgical samples. Immunohistochemistry has evolved into a more sensitive, specific and reproducible option than in the past, according to the paper.

CD123 is expressed in a restricted way in tissue, notably by endothelial cells and alongside TCF4 and plasmacytoid dendritic cells, making CD123 immunohistochemistry indispensable for detecting BPDCN with skin biopsy samples, the authors wrote.

Like flow cytometry, immunohistochemistry has limitations for use, mostly because it is less sensitive to low-level CD123 expression than flow cytometry.

Targeting CD123 to treat BPDCN

“Promising CD123 targeted therapies have been developed and continue to be examined, ensuring the continued need to evaluate CD123 expression as an integral biomarker whose presence represents a targetable vulnerability,” the authors wrote.

The FDA based its approval of tagraxofusp-erzs, an anti-CD123 antibody conjugated to a diphtheria toxin, for BPDCN based on a phase 3 trial of 47 patients with untreated and relapsed BPDCN, published in April 2019 in the New England Journal of Medicine.2 In the study, the response rate for relapsed patients was 67%, with a median overall survival of 8.5 months. More than 70% of the untreated patients had a complete response. While the most common adverse events in the NEJM study were increased levels of alanine aminotransferase, aspartate aminotransferase, hypoalbuminemia, peripheral edema and thrombocytopenia, researchers also reported a concerning 19% of patients had capillary leak syndrome.

Disclosures: The study’s senior author Joseph D. Khoury, MD, received honoraria and research funding from Stemline, Inc. The other authors declared no conflicts of interest, according to the paper.


1. El Achi H, Dupont E, Paul S, Khoury JD. CD123 as a Biomarker in Hematolymphoid Malignancies: Principles of Detection and Targeted Therapies. Cancers (Basel). 2020;12(11):3087. Published 2020 Oct 23. doi:10.3390/cancers12113087

2. Pemmaraju N, Lane A, Sweet K Et Al. Tagraxofusp In Blastic Plasmacytoid Dendritic-Cell Neoplasm. N Engl J Med 2019; 380:1628-1637 Published 2019 April 25. doi: 10.1056/nejmoa1815105

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