Blastic Plasmacytoid Dendritic Cell Neoplasm

Alison Carulli, PharmD BCOP
Clinical Pharmacy Specialist, Hematology/Oncology
Hospital of the University of Pennsylvania
Philadelphia, PA

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy.¹ The exact incidence is unknown, but BPDCN is believed to account for 0.5% of all hematologic malignancies, with approximately 1,000 new cases diagnosed per year in the United States. Although it has been described in children, it is more commonly reported in adults; the median age at diagnosis is 65 years. The incidence is three times more common in men.² The majority of patients present with skin manifestations; however, bone marrow, lymph node, and splenic involvement are also commonly reported.¹

Because of the rarity of BPDCN, no prospective clinical trials have been conducted for its treatment, and no standard of care has been established.³ Commonly, lymphoma- or leukemia-based chemotherapy regimens have been used to treat BPDCN, with 50%–90% of patients achieving complete remission after initial treatment. However, virtually all patients relapse, and survival outcomes are poor, with a median survival of 12–14 months after diagnosis.¹ Tagraxofusp is the first medication that has been prospectively studied and approved for treating BPDCN.⁴

Tagraxofusp
Tagraxofusp is the only approved CD123-directed cytotoxin that is composed of recombinant human interleukin-3 (IL-3) fused to truncated diphtheria toxin. Tagraxofusp binds to IL-3 receptors, which are overexpressed in almost all cases of BPDCN, allowing it to be internalized and the diphtheria toxin to be released. This results in the ADP-ribosylation of elongation factor 2, inhibition of protein synthesis, and apoptosis.^4-6

Tagraxofusp is the first therapy to be approved by the U.S. Food and Drug Administration (FDA) for treating BPDCN in adults and pediatric patients 2 years and older.⁴ After receiving orphan-drug status for treating both acute myeloid leukemia (AML) and BPDCN in 2011 and 2013, respectively, tagraxofusp was granted breakthrough-therapy designation for BPDCN in August 2016 and approved by the FDA in December 2018.⁷

Clinical Trials
The first prospective study for BPDCN was a phase 1/2 study of SL-401 (tagraxofusp) in 11 patients who had either recurrent or refractory BPDCN or were ineligible for standard chemotherapy treatments.⁶ Participants received 12.5 mcg/kg intravenously (IV) once daily for five doses. Treatment could be delayed if a patient experienced toxicities, but all doses had to be administered within 10 days. Nine patients were evaluated for response, with 5 having a complete response and 2 having a partial response. The median duration of response was 5 months (range, 1–20 months). The majority of adverse events reported were grade 1 or 2, with the most common being chills, fever, hypoalbuminemia, transaminitis, and myelosuppression. Grade 3 or 4 adverse events included thrombocytopenia (5 patients), elevated liver transaminases (5 patients), neutropenia (1 patient) and hyponatremia (1 patient).⁶

The approval for tagraxofusp was based on a nonrandomized open-label trial that consisted of three stages.³ Stage 1 was a dose-escalation design that determined 12 mcg/kg on days 1 through 5 every 21 days to be the recommended dosage. Stage 2 evaluated efficacy and safety. Stage 3 further confirmed efficacy. Forty-seven patients with BPDCN were treated: 32 were treatment naive, and 15 had received previous treatment. Of the 29 treatment-naive patients who were evaluated, 72% had a complete response, and the overall response rate was 90%. The response rate was 67% in the 15 patients who had received previous therapy. The most common adverse events reported were elevated hepatic transaminases (60%), hypoalbuminemia (55%), peripheral edema (51%), and thrombocytopenia (49%).³

Preparation and Administration
Preparation of tagraxofusp consists of several complex steps.⁴ Step 1 includes diluting 1 mL of tagraxofusp in 9 mL of 0.9% sodium chloride to obtain a final concentration of 100 mcg/mL of tagraxofusp. Step 2 involves preparing the infusion set for tagraxofusp. The required dose of tagraxofusp should be drawn up into a syringe. A separate syringe should also be drawn up to flush the infusion set. The manufacturer recommends a minimum volume of 3 mL of 0.9% sodium chloride in the flush syringe to ensure that all the tagraxofusp has been flushed out of the tubing set. Each syringe should be attached to one arm of the mini-bifuse Y-connector, and the Y-connector should be attached to microbore tubing. The entire infusion set, including the filter, should be primed with tagraxofusp. After the infusion set is ready for administration, the entire dose should be administered via syringe pump over 15 minutes.⁴

Safety
Although the drug is generally well tolerated, capillary leak syndrome (CLS) has been reported in 55% (9% ≥ grade 3) of patients.^3,4 All but one of the CLS events occurred during the first cycle of treatment.3 Although the mechanism of action has not been fully elucidated, the authors hypothesized that the CLS is due to the uptake of diphtheroid toxin by vascular endothelium, resulting in endothelial cell apoptosis and vessel wall leakage.⁶ Symptoms include hypoalbuminemia, edema, hypotension, elevated creatinine, fatigue, and weight gain. The most reliable predictor of CLS was hypoalbuminemia during the earliest days of the first cycle.³ To mitigate this effect, it is recommended that the first cycle of tagraxofusp be administered while the patient is hospitalized and that the first dose of tagraxofusp be withheld until the patient's serum albumin level is 3.2 g/dL or higher.⁴ The median time to onset of CLS was 5 days (range, 4–51 days), and the median duration was 4 days (range, 3–19 days).³ Management of CLS is described in the package insert and includes administering albumin as frequently as necessary, administering corticosteroids, and giving additional supportive care management (Table 1—see PDF). Administration of tagraxofusp can be resumed after symptoms resolve. Permanent discontinuation is recommended if patients show signs of hemodynamic instability that require intervention.⁴

Hypersensitivity reactions have occurred with tagraxofusp (46%, any grade; 10%, grade ≥3).^3,4 The mechanism is unknown, but the reactions are hypothesized to be caused by the release of cytokines from damaged BPDCN blasts.⁶ The majority of the reactions were reported within the first few hours, although several infusion reactions occurred 4–8 hours after administration. Premedication with an H1 antagonist, a corticosteroid, and acetaminophen is recommended 60 minutes prior to tagraxofusp to mitigate hypersensitivity reactions.⁴

Other side effects reported in clinical trials included elevated liver enzymes (88%, any grade; 40%, grade ≥3) that resolved several weeks after therapy, thrombocytopenia (49%), nausea (45%), hyperglycemia (36%), and anemia (23%).^3,4

Future Directions
Tagraxofusp use is being studied in a variety of other diseases, including AML, chronic myelomonocytic leukemia, myelofibrosis, and multiple myeloma.^7-9 In addition, trials evaluating tagraxofusp in combination with other therapeutic agents, such as hypomethylators, are in active development.¹⁰

Conclusion
Tagraxofusp is the first CD123-directed cytotoxin approved by the FDA and the first agent approved for the treatment of BPDCN in both adults and children 2 years of age or older.⁴ Although the drug is generally well tolerated, hepatotoxicity, infusion reactions, and CLS have been reported. CLS commonly occurs within 5 days of cycle 1 and requires close inpatient monitoring for the first cycle. The patient’s serum albumin levels should be checked frequently, and therapy should be withheld if signs of hypoalbuminemia are present.^3,4 Despite these careful monitoring requirements, tagraxofusp represents one of the first therapeutic advances for BPDCN, and further studies are required to determine its place in therapy for other malignancies.

References

1. Sullivan J, Rizzieri D. Treatment of blastic plasmacytoid dendritic cell neoplasm. Hematology. 2016;16-22.
2. Aoki T, Suzuki R, Kuwatsuka Y, et al. Long-term survival following autologous and allogeneic stem cell transplantation for blastic plasmacytoid dendritic cell neoplasm. Blood. 2015;125(23):3659-3664.
3. Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N Engl J Med. 2019;380(17):1628-1637.
4. Elzonris (tagraxofusp) [package insert]. New York, NY. Stemline Therapeutics, Inc.; 2018.
5. Frankel A, Liu JS, Rizzieri D, Hogge D. Phase I clinical study of diphtheria toxin-interleukin 3 fusion protein in patients with acute myeloid leukemia and myelodysplasia. Leuk Lymphoma. 2008;49(3):543-553.
6. Frankel AE, Woo JH, Ahn C, et al. Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients. Blood. 2014;124(3):385-392.
7. Syed YY. Tagraxofusp: first global approval. Drugs. 2019;79(5):579-583.
8. Pemmaraju N. Novel pathways and potential therapeutic strategies for blastic plasmacytoid dendritic cell neoplasm (BPDCN): CD123 and beyond. Curr Hematol Malig Rep. 2017;12(6):510-512.
9. Ray A, Das DS, Song Y, et al. A novel agent SL-401 induces anti-myeloma activity by targeting plasmacytoid dendritic cells, osteoclastogenesis, and cancer stem-like cells. Leukemia. 2017;31(12):2652-2660.
10. Krishnan A, Li B, Pagane M. Evaluation of combination tagraxofusp (SL-401) and hypomethylating agent (HMA) therapy for the treatment of chronic myelomonocytic leukemia (CMML). Blood. 2018;132:1809.