At the end of 2018, a new intravenous drug, tagraxofusp (Elzonris, Stemline Therapeutics), was approved by the US Food and Drug Administration for the treatment of the rare blood cancer blastic plasmacytoid dendritic-cell neoplasm (BPDCN).
It was the first treatment ever approved for BPDCN, an aggressive hematologic cancer that tends to have leukemic involvement, skin tumors, and poor outcomes.
Now, the efficacy and safety data that served as the basis for approval by the US Food and Drug Administration have been published online April 24 in the New England Journal of Medicine.
To date, the standard of care for the difficult to diagnose disease has been intensive chemotherapy regimens followed by bone marrow transplantation, explain the authors, led by Naveen Pemmaraju, MD, from the University of Texas MD Anderson Cancer Center, Houston.
But the team point out that the chemotherapy regimens are not well tolerated by the typical patient with BPDCN, who is a mean age of about 70 years at diagnosis. Furthermore, this approach is associated with high relapse rates and has not produced long-term survival benefits. Although allogeneic stem cell transplantation has seen good results, the procedure requires initial chemotherapy. In short, overall, treatment results for this cancer have been "disappointing," said the authors.
Tagraxofusp, which is a cytotoxin consisting of recombinant human interleukin-3 and a diphtheria toxin, now addresses this need, suggest the authors.
The open-label, multicohort study involved 47 patients, with 32 receiving tagraxofusp as first-line treatment and 15 receiving it later line after previous treatment. All patients were enrolled in 2014-2017.
Among the 29 previously untreated patients who received tagraxofusp at a dose of 12 μg/kg (the other three received a lower dose), the primary outcome was achieved in 21 (72%), and the overall response rate was 90%. Median time to response was 43 days. Of these 29 patients, 45% went on to undergo stem-cell transplantation.
The primary outcome was the combined rate of complete response and clinical complete response among patients who had not received previous treatment for BPDCN.
Survival rates at 18 and 24 months were 59% and 52%, respectively among 32 patients treated in the first line.
Among the 15 previously treated patients, the response rate was 67%, and median overall survival was 8.5 months
The median age of all patients was 70 years (range, 22 to 84).
The activity of tagraxofusp in the treatment of this "very difficult disease" is "excellent," said Mounzer Agha, MD, director, Mario Lemieux Center for Blood Cancers, University of Pittsburgh, Pennsylvania, who was not involved with the research.\
It also creates a new treatment paradigm, he said.
"For the first time, patients with this disease achieved complete remission without the use of cytotoxic chemotherapy. This represents a major advance in the treatment, as it spares patients the toxicity of the aggressive cytotoxic chemotherapy regimen that has been utilized thus far," Agha said in an email to Medscape Medical News.
Agha highlighted the fact that 45% of the study patients were successfully bridged to stem-cell transplantation following treatment with tagraxofusp and that the median duration of response of these patients has not yet been reached.
The Pittsburgh clinician also observed that another drug, venetoclax (Venclexta, AbbVie), has been shown in case reports, including one of his patients, to have activity in the relapsed-refractory as well as the upfront setting.
He would like to see a study of these two agents, which have different mechanisms of action, in combination in the upfront setting, as well as a study of maintenance venetoclax in patients who achieve complete remission.
Clinical Complete Response Is a Novel Outcome
In the new study, the most common adverse events with tagraxofusp were increased levels of alanine aminotransferase (64%) and aspartate aminotransferase (60%), hypoalbuminemia (55%), peripheral edema (51%), and thrombocytopenia (49%). Capillary leak syndrome occurred in 19% of the patients, with two deaths attributed to this toxicity. But the problem was "manageable" with close monitoring and early intervention, said the authors.
Overall, about half (49%) the study population had at least one serious adverse event.
The study authors place the results in a historical context. Once the World Health Organization established diagnostic criteria for the rare cancer, complete remission rates, in various series, have ranged from 41% to 55% with various chemotherapy regimens. But such remissions "typically had a short duration" and median long-term survival was consistently stuck at 8 to 14 months, the authors observe.
All study patients received an intravenous infusion of tagraxofusp at a dose of 7 or 12 μg/kg on days 1 to 5 of each 21-day cycle.
Among the 32 previously untreated patients, the median duration of tagraxofusp exposure was 96 days (range, 2 to 927). Patients in this group underwent a median of five treatment cycles (range, 1 to 43).
The authors point out that prior to this study there have been no consensus guidelines for measuring a response to therapy specifically developed for BPDCN. So, the team developed a set of response criteria that included evaluation of the most commonly involved "disease compartments": skin, bone marrow, peripheral blood, lymph nodes, and viscera.
A complete response was defined as the disappearance of disease in each site of initial disease.
The team also created a novel outcome — clinical complete response — to account for patients who had a complete response in all nonskin disease sites as well as clearance of all skin lesions, but had residual skin abnormalities (not indicative of active BPDCN).
The study was funded by Stemline Therapeutics and the Therapy Acceleration Program of the Leukemia & Lymphoma Society. Some study authors are employees of Stemline, and other authors have ties to industry, including Stemline. Agha is an equity holder in AbbVie.
N Engl J Med. 2019;380:1628-37. Abstract
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