For the Treatment of BPDCN, the Future Is Now

Specialists are exploring a variety of new ways to target blastic plasmacytoid dendritic cell neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy that presents with skin nodules and tumors, lymph node and splenic enlargement, central nervous system involvement, circulating leukemia, and/or bone marrow infiltration.¹

In 2016, the World Health Organization listed BPDCN as its own category in its classification of myeloid neoplasms and acute leukemia.² Before that, the disease was sometimes lumped in with other lymphomas or leukemias and had many prior names, according to Naveen Pemmaraju, MD, Associate Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center. These names included CD4+CD56+ hematodermic neoplasm, blastic natural killer cell lymphoma, and agranular CD4-positive natural killer cell leukemia.

“These name changes have occurred about once a decade,” Dr. Pemmaraju said. “The main reason for the name changes is that in each era, something new [about the disease] is understood, but it also causes confusion.”

The rarity of the disease and the evolution of its name make it difficult to define the exact incidence, but it is estimated to occur in about 500 to 1,000 patients per year in the United States.

“We used to see two or three cases a year at Dana-Farber, but now we see one or two cases a month,” said Andrew A. Lane, MD, PhD, Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm Center at Dana-Farber Cancer Institute. “A general oncologist in a community setting may never see a case.”

Even if a patient presenting to a general oncologist does have BPDCN, it may be misdiagnosed. About 20% of BPDCN cases will coexist with myelodysplastic syndromes or chronic myelomonocytic leukemia or convert to acute myeloid leukemia (AML). In fact, many initial therapeutic approaches to treat BPDCN included regimens borrowed from acute leukemia or lymphoma.

As more is learned about BPDCN, researchers have worked to identify novel approaches to its management and treatment. Blood Cancers Today recently spoke with some clinicians who specialize in BPDCN to find out more about the disease and these novel therapeutic approaches.

Traditional Treatment

BPDCN is a very aggressive disease. In the past, the main treatment approaches for BPDCN included chemotherapy and allogeneic hematopoietic stem cell transplantation (AHSCT). Historically, initial response to cytotoxic chemotherapy was high, but patients regularly relapse. Median overall survival (OS) was about 1 to 1.5 years.³

Patients who could tolerate high-dose acute leukemia-based chemotherapy and undergo AHSCT had the best outcomes. A single-center analysis of 17 patients with BPDCN who underwent AHSCT at MD Anderson Cancer Center showed a two-year survival rate of 65% and a five-year survival rate of 40%. For patients who were in first complete remission at transplant, the five-year progression-free survival and OS rates were 80%.⁴

Similarly, a multicenter study of 45 patients from eight centers in the United States and Canada showed a three-year OS rate of 74% for patients with BPDCN in first complete remission who underwent allogeneic transplant.⁵

AHSCT still plays a critical role for patients with BPDCN, according to Dr. Pemmaraju, but additional and more effective therapies are still needed, as the majority of patients presenting to the clinic with BPDCN are older and unfit for intensive approaches or have significant comorbidities preventing consideration of AHSCT.

A Breakthrough

One of the biggest breakthroughs in BPDCN research was the discovery that the interleukin-3 receptor α, or CD123, is nearly universally and highly expressed on BPDCN tumors.

“It is a pathognomonic marker that pathologists must see for it to be called BPDCN,” Dr. Lane said. “CD123 is of interest to scientists and pharma because it is also expressed on many other blood cancers.”

An initial prospective study of SL-401, a CD123-directed cytotoxin, was conducted in 11 patients with BPDCN with a response rate of 78%. The median duration of response was five months (range, 1-20+ months).⁶

These positive results led to a larger study of SL-401—now known as tagraxofusp-erzs (ELZONRIS^®, Stemline Therapeutics, Inc). Drs. Pemmaraju and Lane, as well as Marina Y. Konopleva, MD, of the University of Texas MD Anderson Cancer Center, and colleagues treated 47 patients with untreated or relapsed BPDCN with tagraxofusp until disease progression or unacceptable toxicity. In the group of patients with no prior treatment, the overall response rate was 90%, and 45% of patients who responded were able to undergo subsequent stem cell transplantation. Among previously treated patients, the response rate was 67%.⁷

These results led to the U.S. Food and Drug Administration (FDA) approval of tagraxofusp-erzs for BPDCN in adult and pediatric patients aged two years or older.⁸

“This was the first-ever approved drug against CD123, and it was a major breakthrough for our field,” Dr. Pemmaraju said.

The best survival outcomes are in patients who undergo transplant after tagraxofusp.

“The historical prognosis for this disease before we knew much about it was about eight to 12 months,” Dr. Lane said. “In the age of [tagraxofusp], we are seeing survival a little bit higher, in the range of 18 to 24 months.”

Tagraxofusp treatment is not without side effects though, the most notable of which is capillary leak syndrome, which occurs commonly at different grades.⁹ The labeling for tagraxofusp contains a Boxed Warning to alert health care professionals and patients about the increased risk of capillary leak syndrome, which may be life-threatening or fatal to patients in treatment.

Despite having a newly approved drug for BPDCN, response durations can be short in some patients, and more approaches are still needed, Dr. Pemmaraju said.

Multipronged Attack

Another approach being explored to treat BPDCN is the use of a CD123-targeting antibody-drug conjugate. Dr. Pemmaraju presented early data at the 2020 American Society of Hematology Annual Meeting and Exposition on IMGN632 in 23 patients with relapsed or refractory BPDCN, about half of whom had previous treatment with anti-CD123 targeted therapy (tagraxofusp). The objective response rate was 29%, and there was a 31% response rate among patients who had received tagraxofusp.¹⁰ IMGN632—now known as pivekimab sunirine (ImmunoGen, Inc.)—was later granted Breakthrough Therapy Designation by the FDA for this patient population.¹¹ Studies are enrolling patients to explore the utility of IMGN632 in the frontline setting as well.

There is also interest in combining therapies, Dr. Lane said, particularly looking at inhibiting BCL-2. Based on encouraging data in the AML setting, there are trials looking at decitabine with the BCL-2 inhibitor venetoclax in frontline and relapsed/refractory BPDCN, a trial looking at venetoclax with azacitidine in the relapsed/refractory setting, and a trial looking at combining tagraxofusp with azacitidine and venetoclax in relapsed/refractory BPDCN (NCT03113643).

Dr. Pemmaraju and colleagues also recently published retrospective data on outcomes of patients with BPDCN who had been treated with the cytotoxic chemotherapy backbone regimen called hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone (hyper-CVAD).¹²

Prior to the development of tagraxofusp, patients with BPDCN were often treated with chemotherapy regimens used in other leukemias and lymphomas. Specifically, patients with BPDCN often experience systemic or central nervous system relapses; chemo­therapy administered via lumbar punctures have been used for patients with BPDCN.¹³

The retrospective study looked at 100 patients who had received frontline hyper-CVAD-based therapy (n=35), tagraxofusp (n=37), or other regimens (n=28). No significant difference in OS or remission duration probability was seen among treatment groups, and similar rates of AHSCT occurred among patients treated with hyper-CVAD and tagraxofusp, suggesting “a continued important role for hyper-CVAD-based chemotherapy in BPDCN, even in the modern targeted-therapy era.”¹²

“We believe that this cytotoxic chemotherapy approach, which also includes intrathecal chemotherapy, may actually cross the blood-brain barrier,” Dr. Pemmaraju explained. “Chemotherapy should be part of a total therapy plan for BPDCN.”

There is currently a phase II trial (NCT04216524) for frontline patients with BPDCN that combines tagraxofusp with hyper-CVAD and venetoclax as a comprehensive treatment strategy called triple/total therapy, according to Dr. Pemmaraju.

Cellular Therapy

CD123 is also being explored as a target for chimeric antigen receptor (CAR) T-cell therapy.

When a target is being explored for potential CAR T-cell therapy, two factors play a role, explained Dr. Konopleva. The first factor is that the target—CD123—is universally and highly expressed on the tumor. That is the case with BPDCN.

“If you look at AML, CD123 is also expressed, but in BPDCN, it is about 10-fold higher,” Dr. Konopleva said.

The second factor is that one must look at whether the target is expressed in other tissue in the body outside of the tumor.

“We know there is some expression on normal stem cells, although it is not nearly as high as with BPDCN,” Dr. Konopleva said. “There is the question of whether this therapy will cause healthy bone marrow damage and patients will require a stem cell transplant for hematopoietic system rescue.”

Another concern from preclinical studies is findings that showed CD123 is expressed on some endothelial cells. There was concern that using CAR T-cell therapy targeting CD123 may lead to vessel damage and capillary leak syndrome.

“Because of the approval of tagraxofusp where some of these toxicities were manageable, it was felt that CAR-T therapy should be feasible and potentially highly effective,” Dr. Konopleva said.

Dr. Konopleva and colleagues recently published results of preclinical experiments testing UCART123, an investigation allogeneic CAR T-cell targeting CD123.¹⁴

“This preclinical work has shown that UCART123 cells are highly effective in tissue culture and can cure mice that carry human BPDCN,” Dr. Konopleva said.

UCART123 is a genetically modified product that eliminates the potential for graft-versus-host reactions. Using preclinical models of BPDCN, the work showed that UCART123 had selective antitumor activity against CD123-positive primary BPDCN samples, largely sparing normal hematopoietic progenitor cells. The product eradicated BPDCN and resulted in long-term disease-free survival in a subset of the patient-derived BPDCN xenograft mouse models.

In their experiments, Dr. Konopleva and colleagues came across one patient-derived xenograft model where mice progressed after an initial response.

“In this human-derived model, we found there was a loss of the CD123 as a target,” Dr. Konopleva said. “This has been described in other tumors as a common mechanism of resistance to CAR T-cell therapy but was unexpected to see in our short-term study.”

Tumor progression and death were associated with the emergence of CD123-negative BPDCN clones. The finding, she said, will add to knowledge regarding mechanisms of potential relapse after this therapy. Once CAR-T advances to clinic, tumor staging for potential relapses should be monitored carefully, with mechanisms of escape to be studied.

Other Considerations

Despite all the recent progress, there is still a lot to be learned about BPDCN, what drives the disease, and how best to manage it.

For example, BPDCN also sets itself apart from other types of leukemia by occurring at least three times more frequently in men than in women.

“There is an extreme male bias that we don’t fully understand,” Dr. Lane said.

Dr. Lane and colleagues are working to explore genes on the X chromosome that may contribute to that bias. They have found that loss-of-function mutations in ZRSR2, an X chromosome gene encoding a splicing factor, are enriched in BPDCN, and nearly all mutations occur in males. This mutation impairs plasmacytoid dendritic cell activation and apoptosis after inflammatory stimuli, which is associated with an inability to upregulate the transcription factor IRF7.¹⁵

More research is also needed to explore the use of maintenance therapy after AHSCT, Dr. Lane said.

There is currently a phase II study looking at tagraxofusp therapy in patients with BPDCN post-autologous or post-allogeneic hematopoietic transplantation (NCT04317781).

“These studies looking at [tagraxofusp] and other agents as maintenance are important because the longer we can keep the disease in remission, the better,” Dr. Lane said.

Looking to the future, Dr. Lane also expects that more work will be done to improve minimal residual disease (MRD) monitoring in patients responding to treatment of BPDCN. Detection of MRD requires distinction between BPDCN cells and non-neoplastic plasmacytoid dendritic cells, which complicates detection.

A study attempting to characterize the immunophenotype of BPDCN showed that, although most BPDCN cells had CD56 expression (97%), there was also a subset of CD56-positive healthy plasmacytoid dendritic cells. However, the CD56-positive plasmacytoid dendritic cells were also positive for CD38, CD2, and CD303, and negative for CD7, distinguishing them from BPDCN. Based on this and other markers, researchers developed a 10-color flow cytometry assay for BPDCN and tested it in 19 bone marrow samples from seven patients with BPDCN. The assay effectively distinguished BPDCN cells in all cases.¹⁶

“Currently there is no standard way to look at MRD in BPDCN,” Dr. Lane said. “We adapt a lot of techniques used in AML, but I think it will become more standardized and integrated into clinical trials.”

Finally, it is also important to continue to increase awareness of BPDCN and increase confidence in its diagnosis and management.

In 2021, Dr. Pemmaraju and colleagues presented data on the use of an online education tool to improve knowledge of the interdisciplinary physician team members about BPDCN. Dermatologists, pathologists, and hematologist/oncologists participated in a series of live continuing medical education activities. About half of the participating physicians in all three specialties had a measurable increase in confidence about BPDCN, resulting in 30% of dermatologists, 31% of pathologists, and 36% of hematologist/oncologists who were mostly or very confident in diagnosing the disease.¹⁷

Dr. Pemmaraju’s outlook on advances in treating BPDCN was positive: “We are starting to see the future in front of our eyes.”

Leah Lawrence is a freelance health writer and editor based in Delaware.

References

1. Montero J, Stephansky J, Cai T, et al. Blastic plasmacytoid dendritic cell neoplasm is dependent on BCL-2 and sensitive to venetoclax. Cancer Discov. 2017;7(2):156-164.
2. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405.
3. Leukemia & Lymphoma Society. Facts about blastic plasmacytoid dendritic cell neoplasm (BPDCN). Revised July 2019. Accessed May 20, 2022. www.lls.org/sites/default/files/2021-05/FSHP2_BPDCN_FINAL_2019.pdf
4. Bashir Q, Milton DR, Popat UR, et al. Allogeneic hematopoietic cell transplantation for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). Bone Marrow Transplant. 2022;57(1):51-56.
5. Kharfan-Dabaja MA, Al Malko MM, Deotare U, et al. Haematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: a North American multicentre collaborative study. Br J Haematol. 2017;179(5):781-789.
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. Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N Engl J Med. 2019;380(17):1628-1637.
8. S. Food & Drug Administration. FDA approves tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm. December 26, 2018. Accessed May 17, 2022. www.fda.gov/drugs/fda-approves-tagraxofusp-erzs-blastic-plasmacytoid-dendritic-cell-neoplasm
9. Pemmaraju N, Konopleva M. Approval of tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm. Blood Adv. 2020;4(16):4020-4027.
10. Pemmaraju N, Martinelli G, Todisco E, et al. Clinical profile of UMGN632, a novel CD123-targeting antibody-drug conjugate (ADC) in patients with relapsed/refractory (R/R) blastic plasmacytoid dendritic cell neoplasm (BPDCN). Presented at the 62nd ASH Annual Meeting and Exposition. Abstract 167.
11. ImmunoGen announces FDA Breakthrough Therapy Designation for IMGN632 in relapsed or refractory blastic plasmacytoid dendritic cell neoplasm. October 5, 2020. Accessed May 18, 2022. https://investor.immunogen.com/news-releases/news-release-details/immunogen-announces-fda-breakthrough-therapy-designation-imgn632
12. Pemmaraju N, Wilson NR, Garcia-Manero G, et al. Characteristics and outcomes of patients with blastic plasmacytoid dendritic cell neoplasm treated with frontline HCVAD. Blood Adv. 2022;6(10):3027-3035.
13. Pemmaraju N, Wilson NR, Khoury JD, et al. Central nervous system involvement in blastic plasmacytoid dendritic cell neoplasm. Blood. 2021;138(15):1373-1377.
14. Cai T, Gouble A, Black KL, et al. Targeting CD123 in blastic plasmacytoid dendritic cell neoplasm using allogeneic anti-CD123 CAR T cells. Nat Commun. 2022;13(1):2228.
15. Togami K, Chung SS, Madan V, et al. Sex-biased ZRSR2 mutations in myeloid malignancies impair plasmacytoid dendritic cell activation and apoptosis. Cancer Discov. 2022;12(2):522-541.
16. Wang W, Khoury JD, Miranda RN, et al. Immunophenotypic characterization of reactive and neoplastic plasmacytoid dendritic cells permits establishment of a 10-color flow cytometric panel for initial workup and residual disease evaluation of blastic plasmacytoid dendritic cell neoplasm. Haematologica. 2021;106(4):1047-1055.
17. Willis L, Stein AS, Sweet K, et al. Education on blastic plasmacytoid dendritic cell neoplasms significantly impacts the interdisciplinary physician team. Blood. 2021;138(Suppl 1):3021.