Background BPDCN is an orphan and aggressive hematologic malignancy characterized by CD123 expression and frequent involvement of the skin, bone marrow, blood, lymph nodes, liver, and spleen. An objective of first-line (1L) therapy is to induce a rapid and durable complete response without extended myelosuppression, enabling timely transition to hematopoietic stem cell transplantation (HSCT) in eligible patients (pts). Tagraxofusp (TAG), a first-in-class CD123-targeted agent, is the only approved treatment for BPDCN in the US and EU, with approval based on a multicenter phase 2 trial (NCT02113982)—the largest prospective study in BPDCN using predefined multisystem response criteria. In both clinical and real-world settings, TAG has demonstrated high rates of rapid, durable responses that allow effective bridging to HSCT with associated long-term survival (Pemmaraju, JCO 2022; Herling,Ann Hematol In press). Although venetoclax (VEN) is not approved for BPDCN, real-world use has been reported in limited studies (Gangat, Am J Hematol 2022; Pemmaraju, Blood Neoplasia 2025). In light of this practice, we aimed to evaluate overall survival (OS) in BPDCN pts treated with a TAG- or VEN-based regimen in a US real-world setting.

Methods This retrospective, observational cohort study utilized US claims data from the Komodo Research Database. Eligible pts had ≥1 diagnosis of BPDCN between January 2016 and December 2023 and subsequently initiated treatment with a TAG- or VEN-based regimen. The index date was defined as the first inpatient administration of TAG or the start of VEN-based therapy. Lines of therapy (LOTs) were determined using a claims-based algorithm; monotherapy was defined as a single agent ± intrathecal (IT) chemotherapy. TAG and VEN pts were matched 1:1 based on index LOT. Baseline characteristics were evaluated during the 6-month pre-index period. OS, defined as the time from index date to death from any cause, was estimated using Kaplan-Meier methodology; pts without an event were censored at the last date of data availability. A sensitivity analysis was conducted censoring at the time of HSCT. Subgroup analyses included pts without post-index HSCT, those treated in the 1L setting, stratification by treatment regimen (monotherapy vs combination), and receipt of IT chemotherapy.

Results A total of 47 pts treated with TAG-based regimens and 47 with VEN-based regimens were included. The mean (SD) age was 60.9 (19.6) yrs for TAG and 67.3 (18.8) yrs for VEN. Mean (SD) Charlson Comorbidity Index (CCI) scores were 0.8 (1.3) for TAG and 1.1 (1.5) for VEN. Common CCI comorbidities in TAG and VEN pts, respectively, included diabetes (30% vs 40%), peripheral vascular disease (13% vs 26%), and chronic pulmonary disease (21% vs 15%). Most pts (89%) received TAG or VEN as 1L therapy. Monotherapy was used in 85% of TAG pts and 49% of VEN pts. In the 24 pts who received VEN combination therapy, 21 received with hypomethylating agents. IT chemotherapy was administered in 34% of TAG and 19% of VEN pts. Rates of subsequent HSCT were similar between groups (TAG: 26%; VEN: 28%). A next line of therapy was received in 47% of patients who received a TAG-based regimen and 11 % of patients who received a VEN-based regimen.

Median follow-up was 13.4 mo for TAG-based regimens and 7.4 mo for VEN-based regimens. Median OS was longer in TAG vs VEN pts (35.3 mo vs 10.5 mo), with 12-mo survival rates of 72.1% and 42.8%, respectively. Among 1L-treated pts, median OS remained longer for TAG vs VEN (35.3 mo vs 11.8 mo). When censoring at HSCT, median OS was 19.8 mo for TAG and 8.6 mo for VEN. Among pts not undergoing HSCT, OS was longer with TAG (18.7 mo) than with VEN (6.9 mo). In monotherapy recipients, median OS was 35.3 mo for TAG vs 10.5 mo for VEN. Among pts receiving combination therapy, median OS was not reached (NR) for TAG and was 9.6 mo for VEN.

Conclusions In this cohort study of pts with BPDCN, treatment with a TAG-based regimen was associated with a clinically meaningful longer median OS (35.3 vs 10.5 mo) compared to VEN-based regimens, regardless of receipt of a HSCT. The longer survival observed with TAG was consistent across pts receiving monotherapy, combination therapy, or HSCT. Importantly, more pts were able to receive a subsequent line of therapy after TAG-based regimens. These results support the use of TAG as first-line standard of care therapy for both transplant-eligible and transplant-ineligible pts with BPDCN.

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2025
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