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Several CD123-targeted therapies have been in development following the FDA’s 2018 approval of tagraxofusp for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN), but important questions remain when it comes to targeting CD123 in myeloid malignancies.
CD123, the alpha chain of the interleukin (IL)-3 receptor, has emerged as an attractive cell surface target in leukemia therapy. Several CD123-targeted therapies have been in development following the FDA’s 2018 approval of the first-in-class CD123 targeting agent tagraxofusp (Tagraxofusp-erzs, Elzonris, Stemline Therapeutic) for treatment of the rare hematologic malignancy BPDCN.
But important questions remain when it comes to targeting CD123 in myeloid malignancies, Andrew A. Lane, M.D., Ph.D., associate professor of medical oncology at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School, wrote in his paper “Targeting CD123 in AML,” published Sept. 1, 2020 in Clinical Lymphoma, Myeloma and Leukemia.
About BPDCN and why dermatologists often see these patients first
BPDCN was previously known as natural killer cell leukemia/lymphoma, but the World Health Organization (WHO) later named it blastic plasmacytoid dendritic cell neoplasm and, in 2016, listed BPDCN in its own category.
BPDCN often presents with features of both lymphoma and leukemia. Average age of diagnosis is between 60 and 70 years and patients are predominately male. But it does occur in children, according to the Leukemia and Lymphoma Society.
Dermatologists often encounter people with BPDCN who have yet to be diagnosed. That is because while BPDCN is a hematologic cancer, 90% of patients have skin involvement and 50% have disease detectable only in the skin at presentation. Those skin lesions can remain despite complete responses at other sites, including bone marrow.
“Nearly all patients with BPDCN have prominent skin involvement, with cutaneous infiltration occupying the dermis and subcutis,” Dr. Lane and coauthors wrote in a metagenomic analysis of microbial associations with BPDCN published earlier this year in Blood Advances.
About CD123, tagraxofusp
CD123 heterodimerizes with CD131 to form the active IL3 receptor complex. It expresses uniformly and highly on all BPDCNs and a pathognomonic marker of the disease. CD123 expresses in about 80% of acute myeloid leukemias and in some other myeloid neoplasms, Dr. Lane wrote in Clinical Lymphoma, Myeloma and Leukemia.
Given by intravenous infusion, tagraxofusp is a recombinant fusion protein comprised of IL-3 linked to a truncated diphtheria toxin payload.
It targets and binds to the CD123 protein on the surface of BPDCN cells, is internalized and escapes endosomes into the cytoplasm, according to Dr. Lane.
“There, the [diphtheria] toxin subunit binds to eukaryotic elongation factor 2 (eEF2) and inhibits protein synthesis, resulting in cell death,” he wrote.
FDA based its approval of the drug on a phase 1/2 study of 47 BPDCN treatment-naïve or relapsed/refractory disease patients. Tagraxofusp induced a complete response or clinical complete response in 72% of treatment naïve patients and 45% of those went on to receive stem cell transplantation.
“About half of patients in the previously untreated group (52%) were still alive 2 years after the start of the trial,” according to Cancer.gov.“Among patients who had received previous treatment for BPDCN, 67% responded to tagraxofusp. The median length of response was 3 months. One patient in this group went on to receive a stem cell transplant.”
Among the common adverse events were an increase in liver enzymes, low albumin, swelling in the legs or other extremities and low platelets. About half of patients experienced serious adverse events, including 19% of participants who experienced capillary leak syndrome.
Interestingly, Dr. Lane wrote, resistance to tagraxofusp does not seem to be from CD123 downregulation, loss or modification.
Tagraxofusp-resistant cells have decreased sensitivity not to CD123 loss but rather to cell death induced by diphtheria toxin, specifically decreased DPH1 expression, he wrote.
“In the same [tagraxofusp]-resistant cells, treatment with DNA hypomethylating agents, such as azacytidine, reverses the hypermethylation of DPH1, increases DPH1 expression, and restores sensitivity to [tagraxofusp],” according to Dr. Lane.
Many CD123-targeted therapies are in the pipeline. Some are being studied as monotherapy; some in combination trials.
Among the important questions that remain about CD123-targeting agents, according to Dr. Lane, are: “What determines sensitivity to CD123 targeted agents?
Is the significant single-agent activity of TAG in BPDCN simply related to high target expression or are there other biomarkers such as genetics, lineage or maturation state, or baseline diphthamide pathway activity that also contribute to sensitivity?
Do we need a more standardized method for quantitating CD123 surface expression, as this is currently done differently across centers?
The half-life of [tagraxofusp] is short — will more sustained pressure on CD123 with longer-acting agents result in more significant myelosuppression and/or more likelihood of CD123-negative escape?
Will immune-based CD123-targeted therapies such as bispecific T cell engagers or CAR-T cells have different mechanisms of resistance?”
Disclosures: Dr. Lane has received research support from AbbVie and Stemline Therapeutics and consulting fees from N-of-One/Qiagen.
Lane AA. Targeting CD123 in AML. Clin Lymphoma Myeloma Leuk. 2020 Sep;20 Suppl 1:S67-S68. doi: 10.1016/S2152-2650(20)30466-3. PMID: 32862874.