Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): Long-Term Outcomes and Novel Observations from a Large BPDCN Cohort

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN), is an ultra-rare, clinically aggressive, CD123-overexpressing hematologic malignancy now reclassified in the 5^th edition WHO under dendritic cell and histiocytic neoplasms (Khoury J Leukemia 2022). BPDCN is characterized by involvement of 4 major compartments: skin, bone marrow, lymph nodes, and central nervous system (CNS). BPDCN has been historically associated with a lack of treatment options, dismal outcomes (median OS 8-16 months). Now, in the modern treatment era, with CD123-based and combination therapies, emerging data and a number of significant clinical/translational breakthroughs have led to progress in this rare disease field (Pemmaraju N JCO 2022; Pemmaraju N Blood Adv 2022). In this analysis, we aim to describe long-term patient characteristics and outcomes in one of the largest ongoing, single-institution, prospectively followed group of patients (pts) with BPDCN in the world.

Patient Characteristics: All pts ages ≥ 18 years with a confirmed pathological diagnosis of BPDCN and treated at our institution were included in this analysis. During Oct 1998-July 2022, 118 pts with BPDCN were identified. Median age was 66 years [range 19-86 years]. 81% were male. At presentation to our institution: n=78 untreated; n=40 had prior therapy (median # prior therapies = 1 [1-5]). Bone marrow (BM) was involved in 75 (64%), skin-only in 41 (35%), lymph node-only in 2 (2%). In addition to CD4+ and CD56+ tumor immunophenotype demonstrated: TCL-1+ (77/77 tested) and CD123+ in 100%. Cytogenetics among 106 pts available: diploid (74%), complex (22%), del (12p) in 2%, miscellaneous (2%). Median BM blast count was 8% [0-95]. Historically, as there has been no standard of care therapeutic approach, a variety of frontline chemotherapy regimens were administered over time (including in this cohort: CD123-based; ALL-based; AML-based; CHOP/lymphoma-based; HMA+VEN based; other regimens).

Results, overall cohort (n=118): The median follow-up time was 23 months [4.1 - 91 mo]. Median # of chemotherapy regimens was 1 [1-6]. Median overall survival (OS) was 23 mo [0.9 -158.0 mo]. 78 (66%) pts died, with the most common cause of death being multi-organ failure. Skin-only pts with BPDCN: Remarkably, in this long-term f/u, there was no statistically significant difference between skin (n=41) vs BM involved BPDCN (n=75) in terms of either OS (20 mo vs 23 mo) or CR1 (21 vs 38 mo). SCT: 40 pts (33%) received stem cell transplant (SCT) during CR1. The median OS for pts receiving SCT was statistically significantly superior at 66 mo [5.3-90.8 mo] vs a median OS for non-SCT group in CR1 (n=31) of 23 mo [4.1-158.0], p =0.003. CNS involvement BPDCN: Notably, in this longer f/u of our series, we found that a high rate, 33%, of our pts had CSF+ at any time during the course of their BPDCN, with the vast majority of cases detected on routine/asymptomatic lumbar punctures. Prior or concomitant hematologic malignancies (PCHM): The occurrence of PCHM remains quite common in BPDCN, making up 24% of our total BPDCN population, with MDS/CMML representing the most common PCHM.

Next-generation Sequencing (NGS): A molecular gene panel via NGS on BM specimens was done in n=80; 60 (75%) had TET2 abnormality (standard mutation=36, standard+variant=2, variants=22), which was the most common molecular abnormality among our BPDCN cohort. There was no statistically significant difference in terms of OS or CR1 in pts with known TET2 mutations/variants vs all others/not done. The second most common mutation was ASXL1 in 38%, followed by RAS mutations in 19%.

Conclusions: This longer-term analysis (med f/u ~ 2 years) of a large, ongoing cohort of pts with BPDCN reveals several important findings including continued overall similar long-term outcomes in skin-only vs BM-involved BPDCN; significant OS improvement in CR1 for younger/fit pts who are able to proceed to SCT when available; a strikingly high incidence of CSF+ in BPDCN which is a higher incidence than previously recognized, and has led to our practice-changing approach of standard incorporation of routine LP with IT chemo for all pts with BPDCN; and a notably common occurrence of PCHM in BPDCN to be aware of in both diagnostic and treatment paradigms. With median OS still only ~2 years, BPDCN remains a highly aggressive hematologic malignancy still in need of active clinical/translational research and novel therapeutic approaches.

Pemmaraju:stemline: Consultancy; abbvie: Consultancy; immunogen: Consultancy; mustangbio: Research Funding; incyte: Consultancy; novartis: Research Funding; pacylex: Consultancy, Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; cellectis: Research Funding; cellularity: Research Funding. Kantarjian:Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; Novartis: Honoraria, Research Funding; ImmunoGen: Research Funding; NOVA Research: Honoraria; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Takeda: Honoraria. Jain:Cellectis: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; Incyte Corporation: Research Funding; Cellectis: Honoraria, Research Funding; Servier Pharmaceuticals LLC: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pharmacyclics, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novalgen: Research Funding; Loxo Oncology: Research Funding; Medisix: Research Funding; Genentech, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support; Pfizer: Research Funding; Dialectic Therapeutics: Research Funding; Newave: Research Funding; TransThera Sciences: Research Funding; Beigene: Honoraria; TG Therapeutics: Honoraria; MEI Pharma: Honoraria; Ipsen: Honoraria; CareDx: Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; ADC Therapeutics: Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support, Research Funding; Takeda: Research Funding; Mingsight: Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding. Loghavi:QualWorld: Consultancy; PeerView: Honoraria; Amgen: Research Funding; Astellas: Research Funding; GLG: Consultancy; Abbvie: Consultancy, Current equity holder in publicly-traded company. Garcia-Manero:Genentech: Honoraria, Research Funding; Acceleron Pharma: Consultancy; Gilead Sciences: Research Funding; Curis: Honoraria, Research Funding; Astex: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Aprea: Honoraria. Jabbour:AbbVie: Other: Advisory Role, Research Funding; Amgen: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Genentech: Other: Advisory Role, Research Funding; Pfizer: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; Takeda: Other: Advisory Role, Research Funding; Spectrum: Research Funding. Daver:Amgen: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Servier: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Celgene: Consultancy; Novimmune: Research Funding; Jazz: Consultancy; Novartis: Consultancy; Arog: Consultancy; Glycometrics: Research Funding; Hanmi: Consultancy, Research Funding; Trovagene: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Syndax: Consultancy; Shattuck: Consultancy; Agios: Consultancy. Borthakur:Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees.

BPDCN has only one FDA approved agent. all others are by definition off label.