FDA-approved treatment puts rare cancer with skin manifestations on the map

July 31, 2020
Lisette Hilton

Lisette Hilton is president of Words Come Alive, based in Boca Raton, Florida.

Those who study blastic plasmacytoid dendritic cell neoplasm (BPDCN) struggle to make dermatologists and others aware that the rare hematologic malignancy that often first presents with skin manifestations exists.

A small group of scientists and clinicians are trying to build awareness of this cancer, and how to diagnose and treat it. While this rare and aggressive hematologic malignancy hasn’t had a standardized therapeutic approach in the past, that is also changing. The FDA approved tagraxofusp (Elzonris, Stemline) in 2019 as the first medication indicated to treat BPDCN, according to a drug review published June 24, 2020 in the journal Expert Review of Anticancer Therapy.1

Progress aside, there’s still a long way to go in creating awareness among dermatologists, primary care physicians, emergency department providers and pediatricians – all of whom are most likely to encounter people with possible BPDCN, says Naveen Pemmaraju, M.D., associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center. Dr. Pemmaraju is senior author on the recent Expert Review of Anticancer Therapy paper, and he led the pivotal study published in April 2019 in the New England Journal of Medicine that led to the FDA’s approval of tagraxofusp for the treatment of BPDCN.2

“Having the clinical trial is great, but now that the drug is commercially available there was a call for what are the practical considerations for Tagraxofusp in BPDCN?” Dr. Pemmaraju says. “That’s why we wrote this paper.”

Dermatologists, take note
Dr. Pemmaraju points to three stand-out practical considerations for providers.

“One is that most people in medicine have yet to even hear about the disease,” he says. “When people on the frontlines see skin lesions, the only way they’re going to know whether it’s BPDCN is with a biopsy. ‘Tissue is the issue,’ as they say. If something looks irregular, abnormal and if it’s clinically indicated to do a biopsy, do a biopsy. A lot of these patients get mistaken for other diseases, infections, other cancers. So, I think the biopsy is important.”

The need for expert review goes along with the first practical consideration.

CD123 (interleukin-3 receptor alpha unit) is overexpressed in 100% of BPDCN patients. But that’s not the only way to differentiate this cancer on biopsy. CD123, CD4, CD56 as the golden triad of BPDCN, according to Dr. Pemmaraju.

“Now we know there are other markers, TCL1, TCF 4, CD303 and others. When you put together these three to six markers, it helps you distinguish BPDCN, which is extraordinarily rare compared to the more common cancers like acute myeloid leukemia (AML), cutis, cutaneous t-cell lymphoma…. Obviously, this differentiates completely from skin infections and all these other noncancer entities,” Dr. Pemmaraju says.

The second practical consideration is that, although rare diseases commonly have limited-to-no treatment options, a therapy for BPDCN exists and more are being investigated. Studies suggest that BPDCN incidence is as low as 0.44% of all hematologic cancers and 0.7% of cutaneous lymphomas, according to the paper. Despite the low numbers, BPDCN treatment is available with tagraxofusp. Researchers are also conducting multiple clinical trials for BPDCN drugs in development, including the B-cell lymphoma-2 (BCL-2) inhibitor, venetoclax, and a chimeric antigen receptor (CAR) T-cell therapy.

The third consideration: The significance of dermatologists’ and dermatopathologists’ roles in BPDCN diagnosis.

“As we educate our fellow hematologists/oncologists, we must continue to educate dermatologists, many of whom are going to see this disease for the very first time in the clinic before anybody else. I believe BPDCN will soon appear on dermatology and derm-path board exams,” Dr. Pemmaraju says.

BPDCN skin lesions usually present as dark and purplish and can be maculopapular.

“I would say clinically there is a somewhat distinct look, although I would add the caveat that these lesions act heterogeneously,” he says.

Focusing on Tagraxofusp
Researchers reported that tagraxofusp, a CD123-directed cytotox, demonstrated efficacy in BPDCN patients along with an overall manageable safety profile, according to the NEJM study.

A historically deadly disease, BPDCN’s median overall survival after chemotherapy had been 8 to 14 months, according to Dr. Pemmaraju. Hematopoietic stem cell transplant might prolong survival in patients healthy enough to have the stem cell transplant.

“Among the 29 previously untreated patients, the survival rates of 59% at 18 months and 52% at 24 months — rates that were influenced by the number of patients who went into remission after tagraxofusp therapy and could thus undergo hematopoietic stem-cell transplantation — represent an improvement over rates in historically published data. We also observed a 67% overall response rate among previously treated patients. Notably, we report a meaningful survival with tagraxofusp among patients with relapsed or refractory disease (median overall survival, 8.5 months),” Dr. Pemmaraju and colleagues report in the NEJM.

Interestingly, patients’ skin lesions went away rapidly in the vast majority of people treated with tagraxofusp, according to Dr. Pemmaraju.

Capillary leak syndrome emerged as the most drug-associated serious adverse, manifested by edema, tachycardia, hypoalbuminemia and hypotension.

There also is the issue of drug resistance. Researchers have found, in vivo, that resistance to tagraxofusp in cell lines is associated with decreased DPH1 expression and azacitadine might reverse tagraxofusp resistance.

More research is needed to study how combining tagraxofusp with other targeted therapies may improve outcomes. Research also is needed to study tagraxofusp use in pediatric patients. The FDA’s approval is for tagraxofusp is as first-line therapy for BPDCN for adults and children ages 2 years and older. But only a small number of pediatric patients have been treated so far, the authors report.

Disclosure
MD Anderson funded the study. Dr. Pemmaraju has received research funding/clinical trials support from Affymetrix, SagerStrong Foundation, Novaris, Stemline, Samus, AbbVie, Cellectis, Daiichi Sankyo, and Plexxikon.

References

1. Lee SS, Mccue D, Pemmaraju N. Tagraxofusp as treatment for patients with blastic plasmacytoid dendritic cell neoplasm. Expert Rev Anticancer Ther. 2020;:1-8.

2. Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm. N Engl J Med. 2019;380(17):1628-1637.

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