New Series by Nico Gagelmann: Rarity in Hematology – BPDCN

Nico Gagelmann, Hematologist at University Hospital Hamburg-Eppendorf, Young National Society Ambassador at European Hematology Association (EHA), and Chair of the CAR-T for plasma cell disorder committee at The EBMT, shared a post on X:

“Welcome to a new series.

Rarity in hematology.

Starting with BPCDN.

Share hematological conditions you never really understood or heard of, but would like to know more about.

I guarantee I will cover all suggestions in future threads!

Rarity in hematology.

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Rare but aggressive blood cancer with a name as complex as its behavior.

Let’s break it down in an educational.

Definition:

• a rare hematologic malignancy arising from precursors of plasmacytoid dendritic cells (pDCs)
• can involve skin, bone marrow, blood, lymph nodes, central nervous system
• more common in adults (60-70 years) and males (~3:1)

First signs? often purple skin lesions.

Diagnosis hinges on immunophenotyping:

• Remember the signature: ‘123, 4, 56’
• CD123+, CD4+, CD56+
• additional pDC markers: TCF4, TCL1, CD303, CD304
• negative for CD3, CD14, CD34, MPO

Classic clinical presentation:

• deep violaceous plaques or nodules (esp. on scalp, face, chest)
• often misdiagnosed as bruises or benign skin lesions
• 80-90% have skin involvement at diagnosis

BE AWARE

CNS and systemic disease:

• CNS involvement common, often asymptomatic
• ‘systemic-only’ disease less common but under-recognized
• always evaluate CSF + perform CNS prophylaxis

Pathophysiology:

• BPDCN harbors mutations commonly found in myeloid malignancies
• -TET2 (most frequent)
• -ASXL1, TP53, ZRSR2 (X-linked, linked to male predominance)
• -MYC or MYB fusions (esp. in children)

ALSO, think of associated conditions

• Up to 30-50% of adult BPDCN cases have concurrent or preceding CMML, MDS, or AML
• This dual pathology can influence treatment decisions

Prognosis:

• median overall survival: 18–24 months
• 3 key variables for worse outcomes:
• -age ≥ 50
• -bone marrow involvement of ≥5%
• -activating signaling mutations (e.g., NRAS, KRAS)
• stratifies patients into favorable, intermediate and adverse risk

Treatment options in a nutshell (1st line):

• hyper-CVAD (ALL-based chemo) for young, fit patients
• Tagraxofusp (CD123-targeted therapy), FDA-approved
• hypomethylating agents + venetoclax for older or less fit patients

Tagraxofusp (SL-401):

• IL-3 + diphtheria toxin fusion
• targets CD123
• response rate ~72%
• risk: Capillary Leak Syndrome (CLS)
• only agent FDA and EMA-approved specifically for BPDCN

CLS, the Achilles’ heel of Tagraxofusp:

• life-threatening capillary leak risk
• careful patient selection, premedication and inpatient monitoring in Cycle 1 is essential
• CLS is mostly a Cycle 1 toxicity

Venetoclax-based regimens:

• effective in older adults
• often combined with azacitidine (HMA)
• responses often seen but typically short-lived
• useful when intensive chemo or tagraxofusp is contraindicated

CNS prophylaxis is a must

• 60% of patients may have occult CNS involvement at diagnosis
• all patients should receive intrathecal chemo
• pediatric ALL regimens naturally cover CNS

Novel therapies in the pipeline:

• Tagraxofusp-azacitidine-venectoclax triplet
• IMGN632 (anti-CD123 ADC)
• CD123 CAR-T and CAR-NK cells
• bispecifics (e.g., flotetuzumab)

Trials are expanding rapidly.

Drug spotlight: IMGN632 (pivekimab sunirine)

• CD123-targeted antibody-drug conjugate in trials for both newly diagnosed and relapsed/refractory BPDCN
• doesn’t cause CLS, although though peripheral edema has been reported
• active even in some patients who failed tagraxofusp

Pediatric BPDCN is different:

• more favorable biology (e.g., MYB rearrangements)
• better response to pediatric ALL protocols
• transplant may not always be necessary

Post-remission consolidation:

• allogeneic hematopoietic stem cell transplantation is standard for eligible adults in first complete remission
• 5-year OS ~50%
• potential for tagraxofusp maintenance after transplant
• consider auto-HSCT only in select low-risk cases

Relapse management:

• repeat profiling
• switch treatment class
• clinical trial enrollment strongly encouraged
• second transplants, donor lymphocyte infusion or newer targeted therapies

Take-home message:

• BPDCN is rare but deadly
• Increased awareness, early diagnosis, and evolving therapies like tagraxofusp, venetoclax and transplant are changing the game
• Still, relapse is common

Follow and read Naveen Pemmaraju, Shai Shimony, and others to learn more.

References and resources on BPDCN.”

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): 2025 Update on Diagnosis, Pathophysiology, Risk Assessment, and Management

Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia

A Study of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate, for Patients with Frontline and Relapsed/Refractory Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Allogeneic hematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: a CIBMTR analysis

Targeting CD123 in blastic plasmacytoid dendritic cell neoplasm using allogeneic anti-CD123 CAR T cells

Tagraxofusp maintenance post-hematopoietic stem cell transplantation provides long-term survival and manageable safety for a patient with blastic plasmacytoid dendritic cell neoplasm

BPDCN: state of the art

Flow Cytometry Profiling of Plasmacytoid Dendritic Cell Neoplasms

Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm

Central nervous system involvement in blastic plasmacytoid dendritic cell neoplasm

Blastic Plasmacytoid Dendritic Cell Neoplasm 1

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