Outcomes in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): Longer-Term Follow-up Demonstrates Poor Outcomes in Patients with Skin-Only Presentation
Authors: Pemmaraju Naveen , Kantarjian Hagop M. , Khoury Joseph David , O'Brien Susan M. , Cortes Jorge E. , Garcia-Manero Guillermo , Jabbour Elias J. , Jain Nitin , Aung Phyu , Yin C. Cameron , Konoplev Sergej Naumovich , Patel Keyur , Pierce Sherry A. , Zhou Lingsha , Konopleva Marina Y. 
Published: October 2019

Abstract
Background: Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is a rare, distinct myeloid malignancy with historically poor survival, a high transformation rate to acute myeloid leukemia (AML), and no standard of care therapeutic approach. It is characterized by the overexpression of CD123+/IL3Rα, BCL-2 overexpression, and splicing factor abnormalities. BPDCN most commonly affects: skin, bone marrow (BM), and lymph node (LN). We sought to determine the outcomes of pts with BPDCN with focus on compartment of disease [(skin vs BM) at presentation.
Patient Characteristics: We included in this analysis all pts age ≥ 18 years with a confirmed diagnosis of BPDCN treated at our institution. During October 1998-July 2018, a total of 70 pts were identified. At presentation to our institution: n=46 untreated; n=24 had prior therapy (median number therapies = 1 [1-6]. 61 (87%) were male, in line with historical expectation for BPDCN. Median age was 64 years [range 20-86 years]. BM was involved in 46 (66%), skin-only in 23 (33%), LN-only 1(1%). In addition to CD4+ and CD56+, tumor immune-phenotype demonstrated: TCL-1+ (44/44) and CD123+ (42/42). Conventional cytogenetics among 57 pts with available data showed: diploid in 40 (57%), complex in 13 (19%), deletion (12p13) in 2 (3%), miscellaneous in 2 (3%). Median BM blast count was 14% [0-95]. Historically, as there has been no standard of care, a variety of frontline chemotherapy regimens have been administered over time: HCVAD (n=24); clinical trial/targeted therapy (n=23); other/miscellaneous regimens (n=10); CHOP (n=7); hypomethylator (n=2); bortezomib-based (n=2); AML-based induction (n=2).
Results, overall cohort (n=70): The median follow-up time in our series has now exceeded the one-year mark: 16.8 months [0.6 - 53.8 mo]. First complete remission (CR1) (by standard AML criteria) was achieved in 43 pts (61%); median CR1 duration: 6.7 mo [1.5-54.3 mo]. Median overall survival (OS) was 21.7 mo [0.6-158.0 mo]. 45 (64%) pts died, with the most common cause of death being multi-organ failure.
Skin-only pts with BPDCN: Among 24 (34%) pts without BM involvement at diagnosis, 23 had skin-only involvement (1 pt with LN-only involvement at presentation). Comparison of pts with BM involvement versus those with skin-only demonstrated no statistically significant differences in outcomes: for pts with BM disease, the median OS, and median CR1 duration were 22.8 mo [0.6-65.8 mo], 6.0 mo [1.8-54.3 mo], respectively. For pts with skin-only disease, the median OS and median CR1 duration were 13.4 mo [2.4-158.0+ mo], 7.6 mo [1.5-21.4 mo], respectively, p =0.7 (OS), p =0.7 (CR1) [Figure]
Next-generation Sequencing: A molecular gene panel has been performed prospectively in the BM specimens as part of standard of care in n=34; 29 (85%) have expressed some form of TET2 abnormality (standard mutation=14, variants=11, standard + variant=4). There was no statistically significant difference in terms of response rates in pts with known TET2 mutations/variants vs all others/not done. The second most common mutation was ASXL1 (n=17), followed by RAS mutations (n=9) (no statistically significant differences in OS or CRD for pts with ASXL1 or RAS vs others). Unexpectedly, there were pts with BPDCN with skin-only involvement who were noted to have occurrence of molecular mutations in the BM on their baseline gene panel; among these skin-only pts with material available for mutational analysis, the most common molecular abnormality was TET2 abnormality in the vast majority: 10/11 (91%).
Conclusions: Even with longer-term follow-up, and despite various on- and off-protocol approaches implemented over the years for pts with BPDCN, it is notable that in this large series of pts treated at our institution, that the overall poor outcomes in this rare disease persist even in pts with skin-only disease (no marrow involvement at baseline), and that many of these skin-only pts harbor a genetic mutation, most commonly TET2 abnormality, even in the absence of marrow disease. These findings highlight the stem cell/clonal disease origins of BPDCN, and emphasize the aggressive nature of this hematologic malignancy even in the absence of overt marrow disease at diagnosis, highlighting the continued need for the development of novel targeted therapy approaches for pts with BPDCN including agents directed at CD123, BCL-2, and splicing pathways.
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Disclosures
Pemmaraju: Affymetrix: Research Funding; stemline: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; novartis: Research Funding; SagerStrong Foundation: Research Funding; abbvie: Research Funding; plexxikon: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; daiichi sankyo: Research Funding. Khoury:Stemline Therapeutics: Research Funding. O'Brien:Vaniam Group LLC: Consultancy; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding; Aptose Biosciences Inc.: Consultancy; GlaxoSmithKline: Consultancy; Pharmacyclics: Consultancy, Research Funding; Abbvie: Consultancy; Astellas: Consultancy; Pfizer: Consultancy, Research Funding; Amgen: Consultancy; Janssen: Consultancy; Gilead: Consultancy, Research Funding; Alexion: Consultancy; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; Kite Pharma: Research Funding; Acerta: Research Funding. Cortes:novartis: Research Funding. Jabbour:novartis: Research Funding. Jain:Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Pfizer: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; BMS: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Cellectis: Research Funding; BMS: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Servier: Research Funding; Verastem: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Verastem: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Incyte: Research Funding; Infinity: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Celgene: Research Funding; Astra Zeneca: Research Funding; ADC Therapeutics: Research Funding; Pfizer: Research Funding; Servier: Research Funding; ADC Therapeutics: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Genentech: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Aung:Stemline Therapeutics: Research Funding. Konopleva:Immunogen: Research Funding; abbvie: Research Funding; Stemline Therapeutics: Research Funding; cellectis: Research Funding.