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Investigational agents to treat hematologic malignancy in pipeline

Dermatology TimesDermatology Times, October 2020 (Vol. 41, No. 10)
Volume 41
Issue 10

Blastic plasmacytoid dendritic neoplasm (BPDCN) is a rare but aggressive hematologic malignancy that often manifests with asymptomatic skin lesions that often appear as bruise-like lesions, plaques or nodules. With one approved drug available, researchers are studying additional investigational agents.

Researchers are learning more about how to diagnose and better treat blastic plasmacytoid dendritic cell neoplasm, a rare cancer that often presents with skin manifestations, according to a review published March 2020 in Current Opinion in Hematology.1

Blastic plasmacytoid dendritic neoplasm patients have suffered historically poor outcomes. Years ago, doctors were limited to treating these patients primarily with intensive chemotherapy regimens used to treat acute myeloid leukemia or acute lymphoblastic leukemia patients. 

But in 2018, the U.S. Food and Drug Administration (FDA) approved tagraxofusp-erzs (Elzonris, Stemline).

Tagraxofusp-erz is the first approved drug indicated specifically for blastic plasmacytoid dendritic neoplasm, and its use is recommended in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. 
Newer targeted agents to treat the hematologic malignancy are in the pipeline. 

Notable changes in recent years

The World Health Organization (WHO) named blastic plasmacytoid dendritic cell neoplasm (BPDCN) and classified it under acute myeloid leukemia and related precursor neoplasms in 2008. Some eight years later, WHO established BPDCN as a distinct entity. 

Just how many people have BPDCN isn’t clear. But it is thought that there are about 0.04 cases of the cancer per 100,000 people. And about three in four patients are older men. 

Derived from plasmacytoid dendritic cells, BPDCN generally is an aggressive disease. It presents clinically on the skin in about nine out of every 10 cases. Skin lesions tend to be asymptomatic, often appearing as bruise-like lesions, plaques or nodules, according to the paper. 

While a small percentage of patients will present with skin disease only, most show signs of BPDCN in the bone marrow, lymph nodes or visceral organs. Rarely, patients will have no cutaneous evidence and instead present with the leukemic phase of the cancer. About 30% of patients also have central nervous system involvement. 

“Flow cytometry to determine the immunophenotype is an essential component of diagnosing [blastic plasmacytoid dendritic cell neoplasm],” the author wrote. 

CD123, an interleukin-3 receptor alpha, is over expressed in nearly all BPDCN cases. These cancer cells also may be positive for CD4, CD56, CD303 or TCL1, according to the paper. 

Some authors have found a recurrent MYC gene rearrangement in these patients. That particular genetic aberration is associated with an older age at diagnosis and worse prognosis. 

Treatment is evolving

Unfortunately, doctors have to rely largely on retrospective studies looking at BPDCN treatment options. 
Those studies suggest that BPDCN, generally, responds better to acute lymphoblastic leukemia regimens compared to acute myeloid leukemia treatment options. However, most responses to these regimens are transient, the author reported. 

Retrospective studies suggest allogeneic stem cell transplant for eligible patients in their first remission offer the highest overall survival rates, including 3- and 4-year overall survival rates ranging from 74% to 82%. 
Tagraxofusp-erzs targets CD123. It consists of recombinant human interleukin-3 fused to a truncated diphtheria toxin, according to the paper. 

“Binding the drug to CD123 on the cell surface leads to cellular internalization of the diphtheria toxin, which ultimately leads to inhibition of protein synthesis and cell death,” the author wrote. 

In a phase I/II clinical trial of 44 untreated or relapsed/refractory BPDCN patients, 21 of 29 previously untreated patients achieved complete remission and 13 of those went on to have a stem cell transplant. Overall response rate of the 15 patients with relapsed/refractory BPDCN was 67% with tagraxofusp-erzs, with an average overall survival of 8.5 months. 

Eighteen of the 44 patients studied developed the most critical treatment-related adverse event, capillary leak syndrome. Two patients died from capillary leak syndrome during the study.
Researchers are studying investigational agents aimed at treating BPDCN. These include IMGN632, a humanized antibody-drug conjugate with an anti-CD123 monoclonal antibody conjugated to a DNA-alkylating payload, the author wrote. 

Researchers are evaluating the safety and efficacy of treating CD123-positive malignancies including BPDCN with the monoclonal antibody targeting CD123 and CD3 XmAb14045.

Venetoclax, a BCL-2 inhibitor, is yet another agent in the pipeline for BPDCN patients. 

“… as knowledge is gained on the molecular changes that occur in [blastic plasmacytoid dendritic cell neoplasm], this will ideally lead to more targeted and effective therapies in the years to come,” the author wrote.


Kendra Sweet, MD, has received honoraria from Stemline Therapeutics.


1 Sweet K. Blastic plasmacytoid dendritic cell neoplasm: diagnosis, manifestations, and treatment. Curr Opin Hematol. 2020;27(2):103-107.

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