Tagraxofusp-erzs is an effective therapy for blastic plasmacytoid dendritic-cell neoplasm, according to recently published results from a multistage trial that led to the drug's 2018 approval. In the trial, the drug elicited high overall response rates, and many patients went on to receive a stem-cell transplant. However, it also caused some serious side effects.

Tagraxofusp-erzs (Elzonris; Stemline Therapeutics) is an effective therapy for blastic plasmacytoid dendritic-cell neoplasm (BPDCN), according to recently published results that supported the drug's 2018 approval. In a multistage trial, patients had high overall response rates (ORR), and many subsequently received a stem-cell transplant. However, the therapy caused some serious side effects, including capillary leak syndrome.

BPDCN is a rare but aggressive blood cancer that arises when plasmacytoid dendritic cells become malignant. Until now, the disease—which was only formally named in 2008—has been treated like acute myeloid leukemia (AML) or acute lymphoblastic leukemia: typically, intensive chemotherapy followed by stem-cell transplant. “Before this trial, there was no approved drug for the disease, and really not a standard of care,” says Andrew Lane, MD, PhD, of Dana-Farber/Harvard Cancer Center in Boston, MA, who co-led the trial with Naveen Pemmaraju, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Because BPDCN universally exhibits high CD123 expression, researchers developed tagraxofusp-erzs. The drug consists of recombinant human interleukin-3—the ligand for CD123—fused to a truncated diphtheria toxin. Once bound to CD123, the drug moves inside, where the diphtheria toxin inhibits protein synthesis, killing the cell.

Lane, Pemmaraju, and colleagues tested the drug in a multicenter, open-label trial of newly diagnosed and previously treated patients with BPDCN. In 29 newly diagnosed patients, the drug elicited an ORR of 90%, a complete response rate of 72%, and estimated survival rates of 59% and 52% at 18 and 24 months, respectively; median overall survival (OS) was not reached. In total, 45% of these patients went on to stem-cell transplant. Fifteen previously treated patients had an ORR of 67% and a median OS of 8.5 months.

Overall, 81% of patients experienced adverse events of grade 3 or higher—most commonly increased alanine aminotransferase and aspartate aminotransferase levels and thrombocytopenia. Notably, capillary leak syndrome—characterized by a dangerous drop in blood pressure—occurred in 19% of patients and caused two deaths. To mitigate the risk, the trial was amended to include only patients with normal cardiac function and albumin levels, and patients were closely monitored.

The drug is likely to change clinical practice, Lane says, and it may be particularly useful as a bridge to transplant for patients who can't tolerate intensive chemotherapy. He is now interested in the longer-term follow-up results, including how patients who didn't have transplants fared.

“For the first time we have a glimpse into what the future of BPCDN therapy would look like—tagraxofusp-erzs really represents a major innovation,” says Joseph Khoury, MD, also of MD Anderson, who was not directly involved in the trial. However, “much work remains to be done; we need to understand mechanisms of resistance and why they arise, and we need to identify other vulnerabilities in BPDCN that could be targeted, most likely by other drugs used in conjunction with tagraxofusp-erzs,” he says.

“I think anybody who gets this disease is going to get this drug somewhere along the line,” adds Stephen Forman, MD, of City of Hope Comprehensive Cancer Center in Duarte, CA, who was also not connected to the trial. For him, the next question is when tagraxofusp-erzs should be used in relation to chemotherapy and stem-cell transplant.

Ongoing studies are investigating tagraxofusp-erzs in other CD123-expressing blood cancers such as AML, myelodysplastic syndromes, and multiple myeloma; researchers are also developing other CD123-targeted therapies. “In addition to being the first approved therapy for BPDCN, it is actually the first ever approved CD123-directed therapy,” Pemmaraju says. “I think this could be the start of a greater effort to develop this new field of therapeutics.” –Catherine Caruso