Bridging to SCT With Targeted Therapy in BPDCN

Peers & Perspectives in OncologyJanuary 2024
Volume 2
Issue 1
Pages: 26

Blastic plasmacytoid dendritic cell neoplasm is a rare disease with limited treatment options, making the use of targeted therapies crucial in this patient population.

Image credit: © [annamaria] -

BLASTIC PLASMACYTOID DENDRITIC cell neoplasm (BPDCN) is a rare and aggressive disease that has gone through several classification changes throughout the years. It was not until 2016 that BPDCN was considered by the World Health Organization (WHO) as a unique myeloid neoplasm, whereas before it was considered a subset of acute myeloid leukemia (AML) and not a distinct disease.1 In 2022, the WHO produced its fifth edition of the WHO classification of haematolymphoid tumors, where it reclassified BPDCN under dendritic cell and histiocytic neoplasms and plasmacytoid dendritic cell (pDC) proliferation associated with myeloid neoplasm, which is also looked at as its own unique disease.2 The arrival of next-generation sequencing (NGS) and stronger biopsy techniques has allowed for a better detection of this disease, but the prognosis and treatment still remains challenging, even as the landscape has evolved for the better.

It is estimated that the incidence of BPDCN cases ranges from 1000 to 4000 in a single year in the United States and Europe combined, with most cases occurring in patients who are 60 years of age or older.3 Overall survival (OS) estimates sit at approximately 1 year with the use of combination chemotherapies, but new targeted treatments and clinical trials are looking to increase that OS time. However, the main mode of treatment still remains to make sure patients can receive allogeneic stem cell transplant (SCT).

“It’s important to refer these patients. If you decide to treat them in the community, you should refer them for a consultation to get the donor application going and start transplant as early as possible,” Vinod A. Pullarkat, MD, said while moderating a live virtual Case-Based Roundtable event discussing the rare disease. “The lucky patients are the ones who get a complete response [to initial treatment] and are able to proceed in a timely manner to SCT.”


The clinical presentation of the disease is involved in the bone marrow, lymph nodes, and visceral organs, along with disease in the central nervous system (CNS), but the most common area of involvement is the bone marrow.4 The majority of patients will have violaceous skin lesions that present as bruise-like, nodules, patches, or plaques. According to Elizabeth Griffiths, MD, who moderated another Case-Based Roundtable event on the diagnosis and management of treatment for patients with BPDCN, if the disease is present on the skin, it should be considered a systemic disease and not isolated to the skin, as the patient will recur without an aggressive systemic approach. These skin lesions are asymptomatic and appear in approximately 90% of patients, but there are rare occurrences where patients with BPDCN will have no skin lesions and present with a leukemic phase of the disease.4

The pDCs reside in the blood and tissues and mediate between the innate and adaptive immune systems.4 The pDCs are continuously produced in the bone marrow and will then emerge as mature cells on the periphery, and the overexpression of these cells play a role in the development of the disease. According to an overview of BPDCN in the Journal of the National Comprehensive Cancer Network, these cells release cytokines and express the bromodomain and extraterminal domain BRD4 protein that regulates the TCF4, the E-box transcription factor, which in turn controls BPDCN cells. TCF4 controls the development of pDCs from common dendritic cells progenitors, and a decrease in TCF4 leads to a reduction in CD123 and CD56 expression on pDCs that in turn develops BPDCN.4

The disease itself presents with diffuse mono-morphous blasts with irregular nuclei in dermis and subcutaneous fat and will be positive for pDC markers CD4, CD56, CD123, TCL1, and CD303.4 NGS has also led to the identification of mutations common with BPDCN, including TET2, ASXL1, ZRSR2, SRSF2, U2AF1, NRAS, KRAS, and ATM.

Some rarer mutations that can be detected in BPDCN also include PC, BRAF, IDH1, IDH2, KIT, KRAS, MET, MLH1, RB1, RET, TP53, CDKN1B, CDKN2A, and VHL. IKZF1 abnormalities are also common in BPDCN but are notably absent in myeloid neoplasms, further distinguishing BPDCN as its own disease state.4 However, morphology of the disease in the blood has given clinicians a challenge in readily identifying whether the patient has BPDCN, according to Griffiths.

“The morphology in the blood can be quite variable,” she said. “Sometimes these look more like lymphoblasts, so they’re smaller and more organized. Other times, they’re very big and much more like lymphoma cells or AML cells in the peripheral blood. So the pathologist and the treating clinician need to have a conversation about what we’re looking at and get a feeling for what the clinical presentation is to get the diagnosis effectively.”


Historically, chemotherapies meant for the treatment of other hematologic diseases like AML were used in this setting because the rarity of this disease has not led to a standardized chemotherapy regimen.5 According to the National Comprehensive Cancer Network (NCCN) guidelines, if a patient with BPDCN is a candidate for intensive remission induction therapy, the chemotherapies they may be given include cytarabine with idarubicin or daunorubicin, a hyper-CVAD (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride [Adriamycin], methotrexate, cytarabine, and dexamethasone) regimen, or a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen. Additionally, if patients have CNS involvement at diagnosis, methotrexate and cytarabine can be used.5

Although initial responses to most of these regimens trend higher, the rates of early relapse are also high, even for patients who achieve a complete response (CR). For example, in a retrospective study of 41 patients with BPDCN, 26 patients were given AML-type induction regimens and 15 were given acute lymphoblastic leukemia (ALL)/lymphoma-type regimens.6

Researchers saw an overall CR rate of 41%, with more patients achieving a CR in the AML-type induction group compared with the ALL-type induction group at 10 vs 7 patients, respectively. A median OS of 8.7 months (range, 0.2-32.9) was observed, with a longer median OS of 12.3 months with ALL-type chemotherapies vs 7.1 months with AML-type chemotherapies (P = .02). Further, patients who were then able to receive transplant had a significantly longer OS than patients without transplant, at 22.7 months vs 7.1 months (P = .03), respectively.

Age was also an important OS prognostic factor, as patients older than 65 years had a median OS of 7.1 months vs 12.6 months in patients younger than 65 years, respectively (P = .04). However, 35% of patients in the study had a relapse of their disease at a median of 9.1 months.6 According to both Griffiths and Pullarkat, there is a high number of toxicities experienced with these chemotherapies, making the use of targeted treatment with tagraxofusp-erzs (Elzonris) appealing, but not without its challenges.

Still, in their respective events, both physicians highlighted that the importance of making sure the patient had a CR to induction therapy as soon as possible so they could receive subsequent SCT was one of the most important aspects of care. According to Pullarkat, who is a professor in the Division of Leukemia and associate professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope in Duarte, California, physicians should pursue transplant as soon as possible because the only long-term survivors of BPDCN are patients who have had SCT. Therefore, clinical trials or multitherapy approaches are also considered for these patients’ induction therapy.

Recent data have shown that a role for chemotherapy may continue, even with tagraxofusp leading the way. In a retrospective study of 100 patients with BPDCN, 35 patients were treated with frontline hyper-CVAD–based chemotherapy, 37 received tagraxofusp, and 28 were given other therapies.7 An 80% CR rate was seen for patients who received hyper-CVAD–based chemotherapies compared with 59% who received tagraxofusp and 43% who received other treatments (P = .01). No significant difference between median OS was seen in the hyper-CVAD, tagraxofusp, and other regimens groups, at 28.3 months vs 13.7 months vs 22.8 months, respectively, nor in remission duration. Yet, when looking at how many patients were bridged to hematopoietic cell transplantation (HCT) in these 3 groups, more patients in the hyper-CVAD group went on to receive HCT compared with those who received tagraxofusp or other therapies at 51% vs 49% vs 38%, respectively, but these differences were not significant.7

“The bottom line is: If you can get a CR and take the patient to transplant, that’s probably your best outcome,” said Griffiths, who is an associate professor of medicine in the leukemia section at Roswell Park Comprehensive Cancer Center and also also an associate professor with the State University of New York at Buffalo. “I think there are some people who would consider giving a hyper-CVAD–based regimen to start, then transition to tagraxofusp on cycle 2. I think the best approach would probably be a multiagent approach that included chemotherapy and tagraxofusp, but I think that’s only available to use in the context of a clinical trial. So, most of us would say [to get the patient on a] clinical trial with a multiagent therapy [approach] that may include a targeted agent.”


CD123 (also known as IL3Rα) overexpression is present in essentially all cases of BPDCN, and tagraxofusp is a “recombinant fusion protein made up of the catalytic and translocation domains of diphtheria toxin fused to IL-3 targeting CD123 and has shown activity against BPDCN,” according to the NCCN.8 This CD123-targeted agent gained approval by the FDA to treat patients with BPDCN based on the results of the STML-401-0114 trial (NCT02113982).9 The phase 1/2 multicenter, multicohort, open-label, single-arm clinical trial observed patients who had untreated or relapsed/refractory BPDCN and were given 12 mg/kg of tagraxofusp intravenously for 15 minutes once a day on days 1 through 5 of a 21-day cycle.9

Twenty-nine of the 47 patients on the initial study achieved the primary end point of reaching the combined rate of CR and clinical CR (cCR) and had an overall response rate (ORR) of 90%.10 Forty-five percent of those patients went on to undergo SCT, and the survival rates for these patients at 18 months was 59% vs 52% at 24 months. For the patients who were previously treated and relapsed, the ORR was 67% and the median OS was 8.5 months. The most common adverse events (AEs) seen on the initial study were increased levels of alanine aminotransferase (ALT; 64%) and aspartate aminotransferase (AST; 60%), hypoalbuminemia (55%), peripheral edema (51%), and thrombocytopenia (49%). Further, capillary leak syndrome (CLS) was seen in 19% of patients and was associated with 2 deaths on the trial.10

“[Most] of the time, patients who receive tagraxofusp have AEs that are characterized by [CLS, which] is why it is very important to maintain an albumin greater than 3.5 in these patients,” Griffiths said. “When you first treat with this [drug], you’re essentially giving people [diphtheria toxin], so you can get impressive edema, swelling, and reactions. Generally…to provide supportive care, you replace the albumin and then you can dose again.”

At a median of 34.0 months of follow-up for 89 patients on STML-401-0114, the ORR for treatment-naive patients was 75%, with 57% of patients having a CR combined with a cCR.11 The median duration of the CR plus cCR was 24.9 months (95% CI, 3.8-not reached), and 19 of these patients were bridged to SCT where they had a median duration of CR plus cCR of 22.2 months (range, 1.5-57.4). The median time to remission in these patients was 39 days (range, 14-131). Overall, 21 patients were bridged to SCT before achieving a CR plus cCR and their OS probability at 12, 18, and 24 months was 55%, 50%, and 40%, respectively.11

Of the patients who had relapsed/refractory disease, the ORR was 58% (95% CI, 33.5%-79.7%) with 1 CR and 2 cCRs.11 Their median time to response was 29 days (range, 21-82) and their median OS was 8.2 months (95% CI, 4.1- 11.9), but only 1 patient had disease remission and could be bridged to allogeneic SCT.11

With tagraxofusp, treatment-emergent AEs (TEAEs) that led to discontinuation occurred in 6 patients, and 61 patients had an AE that led to a dose interruption.11 These included an increase in weight (27%), AST levels (19%), and ALT levels (17%), as well as hypoalbuminemia (16%). Further, the most common TEAEs that occurred in at least 20% of patients included an increase in ALT (64%) and AST levels (60%), as well as hypoalbuminemia (51%). Twenty-one percent of patients reported CLS, but most of these cases were grade 2, occurred in the first cycle of treatment, and were resolved. According to Pullarkat, CLS is a leakage of protein-rich fluids into the tissue that leads to hypoglycemia, and to stay on top of this TEAE with tagraxofusp, it’s important to monitor the patient’s weight while they are receiving treatment. He added that holding the dose to let the CLS subside is the best method to treat while replacing albumin and/or providing concurrent steroids to patients.


1. 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. doi:10.1182/blood-2016-03-643544

2. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/ dendritic neoplasms. Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375- 022-01613-1

3. Sullivan JM, Rizzieri DA. Treatment of blastic plasmacytoid dendritic cell neoplasm. Hematology Am Soc Hematol Educ Program. 2016;2016(1):16-23. doi:10.1182/asheducation-2016.1.16

4. Jain A, Sweet K. Blastic plasmacytoid dendritic cell neoplasm. J Natl Compr Canc Netw. 2023;21(5):515-521. doi:10.6004/jnccn.2023.7026

5. NCCN. Clinical Practice Guidelines in Oncology. Acute myeloid leukemia, version 6.2023. Accessed December 14, 2023.

6. Pagano L, Valentini CG, Pulsoni A; Gruppo Italiano Malattie EMatologiche dell’Adulto, Acute Leukemia Working Party. Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study. Haematologica. 2013;98(2):239-246. doi:10.3324/haematol.2012.072645

7. 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. doi:10.1182/ bloodadvances.2021006645

8. Pollyea DA, Altman JK, Assi R, et al. Acute myeloid leukemia, version 3.2023, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2023;21(5):503-513. doi:10.6004/jnccn.2023.0025

9. FDA approves tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm. FDA. December 26, 2018. Accessed December 14, 2023. http://tinyurl. com/2c7rhz2y

10. Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N Engl J Med. 2019;380(17):1628-1637. doi:10.1056/NEJMoa1815105

11. Pemmaraju N, Sweet KL, Stein AS, et al. Long-term benefits of tagraxofusp for patients with blastic plasmacytoid dendritic cell neoplasm. J Clin Oncol. 2022;40(26):3032-3036. doi:10.1200/JCO.22.00034

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