Ninety percent of patients with previously untreated blastic plasmacytoid dendritic cell neoplasm (BPDCN) responded to treatment with tagraxofusp, a CD123-targeted agent previously known as SL-401, according to results published in the New England Journal of Medicine. Response rates also were high in patients with relapsed disease, at 67%.
Based in part on these findings, the U.S. Food and Drug Administration approved tagraxofusp for the treatment of adults and children (≥2 years of age) with BPDCN, marking the first approval for this rare disease.
“This agent is now the only targeted agent approved in BPDCN, and it is the first-ever CD123-directed therapy approved,” lead study author Naveen Pemmaraju, MD, of the MD Anderson Cancer Center, told ASH Clinical News.
This nonrandomized, multistage, open-label, multicenter trial evaluated single-agent tagraxofusp in 47 patients (median age = 70 years; range = 22-84 years): 32 had treatment-naïve disease and 15 had previously treated BPDCN.
The study was conducted in four stages:
- stage 1: dose-escalation phase (n=9)
- stage 2: expansion phase (n=23)
- stage 3: pivotal phase, including a cohort of 13 patients with treatment-naïve BPDCN
- stage 4: continued-access phase, including 2 patients with previously treated BPDCN
Tagraxofusp was administered on days 1 through 5 of each 21-day cycle, at either 7 μg/kg or 12 μg/kg. Patients continued treatment with tagraxofusp until disease progression or unacceptable toxicity.
The study’s primary endpoint was the combined rate of complete response (CR) and clinical CR in patients who received tagraxofusp as frontline treatment. Response duration served as a secondary endpoint.
After a median follow-up of 19 months (range = 1-42 months), 29 previously untreated patients received tagraxofusp at a dose of 12 μg/kg. Twenty-one patients (72%) experienced a CR, and the overall response rate was 90%. Notably, 13 patients (45%) in this group were subsequently bridged to hematopoietic cell transplantation.
After a median follow-up of 25 months (range not reported), the median overall survival (OS) had not been reached. This translated to:
- 12-month OS: 62%
- 18-month OS: 59%
- 24-month OS: 52%
“The majority of patients experienced a major response … in only the first cycle of therapy, rapidly and early on in the treatment course.”
—Naveen Pemmaraju, MD
In the group of 15 patients with previously treated disease, two-thirds of patients responded to treatment. The median duration of OS in this treatment arm was 8.5 months (range not reported).
“One of the remarkable findings is that the majority of patients experienced a major response, often a complete response, in only the first cycle of therapy, rapidly and early on in the treatment course,” Dr. Pemmaraju said. In the previously treated group, the median time to response was 24 days (range = 17 to 48 days), with a median duration of response of 2.8 months (range = 0.7-14.0 months).
The authors also reported that treatment with tagraxofusp induced dermatologic responses in the 44 participants who had skin manifestations of BPDCN. “Another interesting finding, outside of the robust skin responses, was the encouraging bone marrow responses, despite some patients having a high number of bone marrow blasts at baseline,” Dr. Pemmaraju added. These results suggest that “the drug works in all of the various disease compartments, not only in the skin.”
Across both patient groups, the most common adverse events included abnormalities in liver function tests, hypoalbuminemia, peripheral edema, and thrombocytopenia (TABLE). Most toxicities were observed during the first treatment cycle.
Systemic capillary leak syndrome (SCLS) was observed in eight patients (18%) who received tagraxofusp 12 μg/kg, including six grade 2 events, one grade 4 event, and one grade 5 event. Another patient in the tagraxofusp 7 μg/kg died after developing SCLS, prompting investigators to amend the study protocol to include mitigation strategies such as thresholds for early signs of SCLS within a treatment cycle. After the implementation of this amendment, when 34 patients in the study had been enrolled, one death occurred in a patient who was receiving tagraxofusp 12 μg/kg, the researchers noted.
“Capillary leak syndrome can be a life-threatening condition, and so recognition and awareness of this is important,” stressed Dr. Pemmaraju. “Notably, there were rigorous measures that we implemented during the conduct of the study, including following and intervening on dosing with regards to daily weights/fluid retention status, albumin, creatinine, and liver function tests.”
Limitations of the study included the lack of a randomized control, the small sample size, and the open-label design.
The authors report relationships with Stemline Therapeutics, which sponsored the trial.
Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N Engl J Med. 2019;380:1628-37.