Insights into the treatment and management of BPDCN: CD123-targeted agents & combination therapy

An overview of the biology of BPDCN

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematological malignancy associated with poor clinical outcomes. BPDCN is challenging to diagnose and manage due to its varied clinical presentation and complex genetic profile. Appropriate management has been further hindered by frequent changes to the nomenclature.¹

BPDCN arises from clonal proliferation of precursor plasmacytoid dendritic cells with a specific immunophenotypic profile including CD123, CD4, CD56, CD303, TCF4, and TCL-1, with primary involvement of the skin, bone marrow, and lymph nodes. Central nervous system involvement can also occur, posing further challenges in the treatment of this malignancy.^1,2 Several genetic mutations have been identified in BPDCN, including inactivating tumor suppressor genes (TP53, CDKN2A), activating oncogenes (NRAS, KRAS), mutated RNA spliceosomes, and epigenetic dysregulators (IDH1, IDH2, TET2).¹

There is currently no standard of care for patients with BPDCN; treatment approaches have historically involved chemotherapy-based regimens adapted from acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), in addition to allogeneic stem cell transplantation (alloSCT).³ However, intensive chemotherapy and alloSCT may be unsuitable for older patients, highlighting a major unmet need in this patient population.

We recently spoke with Andrew Lane, MD, PhD, Dana-Farber Cancer Institute, Boston, MA, who highlighted the rarity of BPDCN and the challenges associated with treating this disease.

Tagraxofusp

Despite the difficulties associated with treating BPDCN, the introduction of CD123-targeting agents has been a breakthrough in the field. As CD123 is overexpressed in all cases of BPDCN, it makes for a valuable therapeutic target.⁴

Tagraxofusp, a first-in-class CD123-directed agent, was the first agent to be approved for the treatment of BPDCN. It was approved by the US Food and Drug Administration (FDA) in 2018, followed by approval in Europe in 2021, offering a promising, novel therapeutic modality for patients.^5,6 Tagraxofusp works by high-affinity binding to IL-3, leading to receptor-mediated endocytosis, downstream inactivation of EF2, and subsequent apoptosis.^5,7

The FDA approval of tagraxofusp was based on results from the multicenter, multicohort, single-arm Phase I/II STML-401-0114 trial (NCT02113982), in which patients received 12 μg/kg of tagraxofusp. Of the 47 patients enrolled, 32 received this agent as first-line treatment, and 15 had been previously treated. Tagraxofusp treatment resulted in an overall response rate (ORR) of 90% in previously untreated patients, and an ORR of 67% in those who had received previous treatment.

The most common adverse events (AEs) included increased levels of alanine aminotransferase (64%) and aspartate aminotransferase (60%), hypoalbuminemia (55%), peripheral edema (51%), and thrombocytopenia (49%). In 19% of patients, capillary leak syndrome (CLS) was reported and was associated with one death in each of the dose subgroups.⁸

We caught up with Naveen Pemmaraju, MD, The University of Texas MD Anderson Cancer Center, Houston, TX, who discussed best practices for community physicians when using tagraxofusp to treat patients with BPDCN.

Pivekimab sunirine and CAR T-Cells

Based on the promising outcomes observed with the use of tagraxofusp, there has been an increased interest in exploring other CD123-targeting agents in this space. One agent which is being investigated is pivekimab sunirine, a CD123-directed antibody-drug conjugate (ADC) comprised of a high-affinity CD123 antibody, a cleavable linker, and an indolinobenzodiazepine pseudodimer payload.^9,10

Pivekimab sunirine is currently being explored in clinical trials for patients with CD123-positive hematological malignancies, including BPDCN and AML. One clinical trial of interest evaluating the safety and efficacy of this agent is the ongoing, first-in-human, Phase I/II CADENZA trial (NCT03386513).

At the 2023 EHA annual meeting, an interim analysis of this study was presented. In this trial, adult patients with frontline or relapsed/refractory (R/R) BPDCN received 0.045 mg/kg of pivekimab sunirine on Day one of a 21-day cycle. Of the 58 patients for which safety data are available, an ORR of 81% was observed in frontline patients (n=16), with a composite complete remission (CCR) of 75%.

In patients with R/R disease (n=42), the ORR was 31%, with a CCR of 19%, including patients who failed intensive chemotherapy and transplantation.¹¹The most common treatment-emergent adverse events (TEAEs; all grades) reported in >20% of all patients were peripheral edema (53%), thrombocytopenia (31%), infusion-related reactions (26%), constipation (24%), fatigue (22%), nausea (22%), and neutropenia (22%). No CLS or cytokine release syndrome were reported.

Along with antibodies and ADCs, CAR T-cell therapy has demonstrated promising outcomes in hematological malignancies. There are ongoing studies exploring the potential role of CD123-targeting CAR T-cells for BPDCN. Some of these agents include UCART123, MB-102, and UniCAR02-T.⁶

Combination approaches with venetoclax

In addition to CD123, BCL2 is another target of interest. BCL2 is a protein that regulates apoptosis and is overexpressed in BPDCN cells. The BCL2 inhibitor venetoclax is currently being explored in this disease setting and has demonstrated clinical activity in R/R BPDCN. Venetoclax is undergoing further clinical investigation as a monotherapy (NCT03485547) and in combination with other agents including azacitidine and tagraxofusp (NCT03113643). These combinations may offer a benefit to patients who are refractory to tagraxofusp or those who are unable to tolerate CD123-based therapy.¹²

In a recent interview, Andrew Lane, MD, PhD, Dana-Farber Cancer Institute, Boston, MA, discussed a study exploring the combination of tagraxofusp, azacitidine, and venetoclax in patients with BPDCN and AML.

Despite the challenging landscape in BPDCN, there have been promising advances made in the field, namely with the introduction of CD123-directed agents. Ongoing research will continue to explore how to treat this difficult and rare malignancy, with the goal of providing more hope to patients.