Early Diagnostic Precision Matters: Navigating Therapeutic Uncertainty in Pediatric BPDCN Illustrated by Misdiagnosis Sequelae and Fleeting CAR-T Response

Xiao-Yan ChenJiaYi WangWenge HaoQu YuhuaXiaojing WangHua JiangWeina Zhang^*

• Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy in children. Distinct from other myeloid neoplasms phenotypically, BPDCN arises from the aberrant transformation of plasmacytoid dendritic cells, typically involves the skin, bone marrow, lymph nodes, and central nervous system , and associates with poor prognosis. This disease predominantly affects elderly individuals, with a low incidence in children. Immunophenotypic analysis using multicolor flow cytometry is essential for diagnosis, demonstrating pDC-associated markers on BPDCN cells such as CD123, BDCA2, and TCF4, aiding in the differential diagnosis from conditions like acute myeloid leukemia (AML) with cutaneous involvement. Characteristic molecular features include rearrangements involving the MYC or MYB genes, which are generally mutually exclusive. MYB rearrangements are more common in children and young adults. MYB plays a role in cell cycle regulation, and its rearrangement can impact the activity of the MYB transcription factor. Due to the rarity of BPDCN and challenges in its pathological definition and diagnosis, standardized prognostic factors for routine clinical practice have not been established. The optimal timing for allogeneic hematopoietic stem cell transplantation remains to be defined. Studies have reported improved outcomes with high-risk acute lymphoblastic leukemia (ALL)-like chemotherapy regimens, and allo-HSCT was utilized in children with multi-organ involvement, positive minimal residual disease and/or persistent disease. Promising results have emerged from clinical trials evaluating novel targeted therapies based on the characteristic overexpression of BCL-2 and CD123, including venetoclax and agents such as tagraxofusp. The use of CD123-directed chimeric antigen receptor T-cell (CAR-T) immunotherapy to eradicate tumor cells has also been reported.The diagnosis and management of this rare disease continue to pose significant challenges. Herein, we summarize the clinical courses of two BPDCN pediatric patients treated with different therapeutic regimens, who achieved differential treatment outcomes. This report represents the first documentation of BPDCN's variable sensitivity to multiple pharmacological agents. Notably, we identified one novel MYB gene rearrangement (MYB::TBC1D5), expanding the molecular spectrum of pediatric BPDCNAdditionally, we describe a novel MYB gene rearrangement and we report the potential utility of AML-type chemotherapy regimens and CLL1-targeted CAR-T therapy in managing this disease.