The Hematologist

September-October 2018, Volume 15, Issue 5

Treating Blastic Plasmacytoid Dendritic Cell Neoplasm

Naveen Pemmaraju, MD Associate Professor, Department of Leukemia
MD Anderson Cancer Center, Houston, TX
Marina Konopleva, MD, PhD Professor, Department of Leukemia
MD Anderson Cancer Center, Houston, TX

Published on: August 28, 2018

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a historically rare, highly aggressive disease for which there are no approved or standard therapies, and median overall survival (OS) reported by most groups for adult patients is eight to 14 months, despite use of multiagent cytotoxic chemotherapy programs as used in acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or lymphomas.1,2 Originally classified as a member of the AML/related family of neoplasms by the World Health Organization (WHO) in 2008,3 greater understanding of BPDCN’s unique clinical presentation, clinical course, and disease biology has justified classification into its own category under myeloid neoplasms in the WHO 2016 reclassification.4 Clinically, BPDCN affects the skin most commonly, followed by the bone marrow or lymph nodes, with other extramedullary sites also commonly involved. While there is no dominant, recurring cytogenetic lesion defining BPDCN, the most commonly occurring molecular mutations include TET2, ASXL1, RAS, and TP53; not only are these mutations consistent with mutations occurring in the myeloid malignancies, but we and others also have observed that myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML) frequently co-occurs with BPDCN.5-9 In terms of diagnostics, there is now a defined immunophenotypic triad that helps to identify the disease: CD4+CD56+CD123+ (pneumonic: think “CD123456”) with other markers such as TCL-1, CD303, and TCF4 further adding specificity to the diagnosis and helping the clinicopathologic team to distinguish among other competing/mimicking diagnoses.5,6,10 The major conceptual breakthrough in the field has been the recognition of overexpression of IL3Rα (CD123) at the level of the leukemia stem cell in most patients with AML and in virtually 100 percent of patients with BPDCN.11-14 A small subset of younger/healthy patients with BPDCN seem to benefit from stem cell transplantation (SCT), especially if done in first complete remission (CR1); however, this doesn’t apply to the majority of patients in our field, as the median age reported by most groups is 70 years and older.15,16 Therefore, new therapeutic approaches based on these scientific breakthroughs are sorely needed.17

The Case:

A 22-year-old man with no significant prior medical history presented to his local clinic with a two-month history of maculopapular skin lesions. An initial lesion noted on the face adjacent to his nose was non-pruritic and had a purplish discoloration. Several other lesions appeared in subsequent weeks, and the patient was seen by his local primary care team. He had no fevers, night sweats, or weight loss. Results from both standard complete blood count and chemistry panel were within normal ranges (no circulating blasts, no liver/kidney abnormalities, adequate albumin level). He was given a working diagnosis of a nonspecific skin infection, was prescribed antibiotics, and was asked to return. Upon return three weeks later, the skin lesions had not resolved, with several more appearing in the trunk and lower extremities. The clinic performed a biopsy of one of the target lesions, with the differential diagnosis in this previously young, healthy patient including various common skin infections and common dermal/cutaneous tumors. To the surprise of the local team and the patient, the final diagnosis was BPDCN. With an ECOG performance status of zero, the patient inquired about frontline therapy options and was referred to our clinic for discussion of clinical trial approaches.

Patient Management

With its history of confusing nomenclature and diverse clinical manifestations, BPDCN has been a truly protean disease for pathologists and clinicians alike. While not the only hematologic malignancy to involve the skin, BPDCN is now recognized as one of the most common and most deadly blood-skin connecting cancers in this limited differential diagnosis space. Frequently, patients can present with skin-only disease, which can precedes blood/marrow involvement, but this is still associated with a poor prognosis and rapid evolution to an acute leukemia state in many patients, despite no marrow involvement at baseline.5 We stage all patients with BPDCN to reflect the three most common compartments of involvement — skin, bone marrow, lymph nodes. In fact, this patient had involvement of all three; bone marrow was ultimately positive for involvement (with flow and IHC demonstrating CD4+CD56+CD123+), and computed tomography imaging revealed lymph node enlargement.

Groups worldwide have borrowed from the experience of acute leukemia and lymphoma for delivery of therapeutic regimens to patients with BPDCN.18,19 In our own experience with the ALL-based regimen (HCVAD alternating with methotrexate and ARA-C), we observed a greater than 80 percent overall response rate (ORR) in the frontline setting; however, relapses occur at a high rate, and the median OS still remains at two years or less, and the most common causes of death remain relapse and multiorgan failure.5 On the basis of the finding of almost universal positivity for CD123, we performed a small pilot study for patients with BPDCN with a CD123-targeting agent known as diphtheria toxin–interleukin-3(DT-IL3), later known as SL-401 (tagraxofusp; Stemline Inc). In this study, seven of nine evaluable patients achieved a major response with one cycle of available drug, five of which were CRs.13 On this basis, we set out to conduct a larger multicenter clinical trial with multiple cycles of SL-401.20 As updated recently at the 2018 European Hematology Association Annual Congress, 45 patients treated in stages 1-3 (median age 70 years, range 22-84) achieved an ORR of 90 percent in the frontline setting at the target dose identified (12 μg/kg/day IV, days 1-5 on a 21-day cycle [n=29]), with 45 percent of patients in the frontline setting being bridged to SCT and a 69 percent ORR in the relapsed/refractory setting. Among 114 patients treated across all clinical trials with SL-401 as a single agent at 12 μg/kg/day dosing, the most notable safety signal was the occurrence of capillary leak syndrome (CLS), which constituted 20 percent of all adverse events at all grades. CLS has been found to be expected and generally manageable with safety parameters in place; these consist of assessment of baseline heart and organ function and careful daily assessments of clinical parameters prior to each dose, including albumin levels, patient weight, renal function, and liver function. Now, with median follow-up of 13.8 months (range 0.2-37.4 months+), the median OS has not yet been reached among frontline treated patients at 12 μg/kg/day dosing.21

Patient Disposition and Long-Term Follow-Up

Historically, we have treated younger patients with ALL-based chemotherapy such as hyper-CVAD. We reviewed cytotoxic chemotherapy options versus clinical trial options. After discussion about the natural history of BPDCN and limited therapy options, the patient opted for clinical trial with frontline SL-401. He received a total of five cycles, achieved a CR, maintained fit performance status throughout, and saw resolution of his skin lesions, normalization of marrow studies, and resolution of enlarged lymph nodes. He had no major complications during therapy and was able to proceed to an allogeneic SCT in CR1. Post-SCT, he was monitored closely and experienced no graft-versus-host disease. At the one-year mark, the patient was noted to remain in CR1 and thriving. Indeed, based on an ORR of 90 percent and a 45 percent rate of proceeding to SCT in the frontline setting, if/when available, the SL-401 clinical trial has now become our de facto frontline standard of care for patients with BPDCN.

Future Directions and Therapy Strategies

In terms of targeting CD123, an emerging area of research is yielding novel therapeutic approaches with monoclonal antibodies, bi-specific antibodies, immunotherapy, and CAR-T therapies.17 Moving beyond single-agent CD123, therapies other than CD123 or combinations with CD123 will represent the next era of research in BPDCN. Other therapy approaches based on newer gene signature studies or novel biological rationale include bortezomib,22 BCL-2 inhibitors,23 hypomethylator therapies,24 and bromodomain inhibitors.10,25 For those patients who are able to, SCT still seems to be the best overall curative option as part of any therapy program (cytotoxic chemotherapy, hypomethylator, or targeted therapy) given the poor durability in many patients treated with cytotoxic chemotherapy alone and still unknown long-term durability of targeted agents in BPDCN. Approaches in the SCT field besides allogeneic SCT in CR1 will include further investigation of timing, intensity, and types of allogeneic SCT, particularly in older patients, investigation of maintenance therapies post-SCT, as well as more focus on autologous SCT for some patients (perhaps skin-only, or older patients unfit for allogeneic SCT), as some studies have suggested long-term benefit in select patients.26


  1. Pemmaraju N. Blastic plasmacytoid dendritic cell neoplasm. Clin Adv Hematol Oncol. 2016;14:220-222.
  2. Pagano L, Valentini CG, Pulsoni A, et al. Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study. Haematologica. 2013;98:239-246.
  3. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937-951.
  4. 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;127:2391-2405.
  5. Pemmaraju N, Kantarjian HM, Khoury JD, et al. Long-term outcomes in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). Blood. 2017;130:3855.
  6. Alayed K, Patel KP, Konopley S, et al. TET2 mutations, myelodysplastic features, and a distinct immunoprofile characterize blastic plasmacytoid dendritic cell neoplasm in the bone marrow. Am J Hematol. 2013;88:1055-1061.
  7. Sapienza MR, Fuligni F, Agostinelli C, et al. Molecular profiling of blastic plasmacytoid dendritic cell neoplasm reveals a unique pattern and suggests selective sensitivity to NF-κB pathway inhibition. Leukemia. 2014;28:1606-1666.
  8. Jardin F, Ruminy P, Parmentier F, et al. TET2 and TP53 mutations are frequently observed in blastic plasmacytoid dendritic cell neoplasm. Br J Haematol. 2011;153:413-416.
  9. Stenzinger A, Endris V, Pfarr N, et al. Targeted ultra-deep sequencing reveals recurrent and mutually exclusive mutations of cancer genes in blastic plasmacytoid dendritic cell neoplasm. Oncotarget. 2014;5:6404-6413.
  10. Ceribelli M, Hou ZE, Kelly PN, et al. A druggable TCF4- and BRD4-dependent transcriptional network sustains malignancy in blastic plasmacytoid dendritic cell neoplasm. Cancer Cell. 2016;30:764-778.
  11. Testa U, Pelosi E, Frankel A. CD 123 is a membrane biomarker and a therapeutic target in hematologic malignancies. Biomark Res. 2014;2:4.
  12. Jordan CT, Upchurch D, Szilvassy SJ, et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia. 2000;14:1777-1784.
  13. 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;124:385-392.
  14. Han L, Qiu P, Zeng Z, et al. Single-cell mass cytometry reveals intracellular survival/proliferative signaling in FLT3-ITD-mutated AML stem/progenitor cells. Cytometry A. 2015;87:346-356.
  15. Roos-Weil D, Dietrich S, Boumendil A, et al. Stem cell transplantation can provide durable disease control in blastic plasmacytoid dendritic cell neoplasm: a retrospective study from the European Group for Blood and Marrow Transplantation. Blood. 2013;121:440-446.
  16. Kharfan-Dabaja MA, Lazarus HM, Nishihori T, et al. Diagnostic and therapeutic advances in blastic plasmacytoid dendritic cell neoplasm: a focus on hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013;19:1006-1012.
  17. Pemmaraju N. Novel pathways and potential therapeutic strategies for blastic plasmacytoid dendritic cell neoplasm (BPDCN): CD123 and beyond. Curr Hematol Malig Rep. 2017;12:510-512.
  18. Garnache-Ottou F, Feuillard J, Saas P. Plasmacytoid dendritic cell leukaemia/lymphoma: towards a well defined entity?. Br J Haematol. 2007;136:539-548.
  19. Pagano L, Valentini CG, Grammatico S, et al. Blastic plasmacytoid dendritic cell neoplasm: diagnostic criteria and therapeutical approaches. Br J Haematol. 2016;174:188-202.
  20. Pemmaraju N, Lane AA, Sweet KL, et al. Results from Phase 2 trial ongoing expansion stage of SL-401 in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). Blood. 2016;128:342.
  21. Pemmaraju N, Sweet K, Lane A, et al. Results of pivotal phase 2 trial of SL-401 in patients with blastic plasmacytoid dendritic cell neoplasm. EHA Learn Cent. 2018;214438.
  22. Philippe L, Ceroi A, Bôle-Richard E, et al. Bortezomib as a new therapeutic approach for blastic plasmacytoid dendritic cell neoplasm. Haematologica. 2017;102:1861-1868.
  23. Montero J, Stephansky J, Cai T, et al. Blastic plasmacytoid dendritic cell neoplasm is dependent on BCL2 and sensitive to venetoclax. Cancer Discov. 2017;7:156-164.
  24. Laribi K, Denizon N, Besançon A, et al. Blastic plasmacytoid dendritic cell neoplasm: from origin of the cell to targeted therapies. Biol Blood Marrow Transplant. 2016;22:1357-1367.
  25. Emadali A, Hoghoughi N, Duley S, et al. Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms. Blood. 2016;127:3040-3053.
  26. 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;125:3559-3562.

Conflict of Interests

Dr. Pemmaraju and Dr. Konopleva indicated that they have received research funding from, and/or consulted with, Stemline, Cellectis, Abbvie, ImmunoGen, Daiichi Sankyo, Plexxikon, and Novartis. back to top