Introduction BPDCN is an aggressive orphan malignancy characterized by CD123 expression and involvement of the skin, bone marrow (BM), blood, and visceral organs. TAG, a first-in-class CD123-targeted therapy, is the only agent approved for treatment of BPDCN. In a multicenter phase 2 study of 65 treatment-naïve (1L) pts, TAG demonstrated high rates of rapid (median 39 days) and durable responses (median duration of complete response [CR]/clinical CR [CRc] 24.9 months [mo]), with a 75% objective response rate (ORR) and 51% of pts achieving CR/CRc proceeding to hematopoietic cell transplantation (HCT; Pemmaraju, JCO 2022). TAG has a well-characterized and manageable safety profile, with adverse events (AEs) occurring mostly in cycle 1, no cumulative long-term toxicity or myelosuppression, and with the majority of pts experiencing early restoration of normal hematopoiesis allowing for successful bridge to HCT (Konopleva, ASH 2024). However, the impact of baseline skin disease burden, the most common site of disease in BPDCN, on clinical outcomes remains unclear. To address this, we evaluated outcomes in 1L pts treated with TAG, stratified by pretreatment skin involvement using the modified Severity-Weighted Assessment Tool (mSWAT).

Methods A subgroup, descriptive analysis of the pivotal phase 2 trial (NCT02113982) of TAG monotherapy was conducted to evaluate outcomes in 62 efficacy-evaluable, 1L BPDCN pts with available pretreatment mSWAT scores. Using the median mSWAT of 6.85 (range, 0–102), pts were stratified into high (≥median) and low (<median) mSWAT subgroups. All pts received TAG 12 µg/kg intravenously on days 1–5 of a 21-day cycle. The analysis included best overall response, CR/CRc (defined as clinical CR or CR with residual skin findings not indicative of active disease), progression-free survival (PFS), overall survival (OS), rate of bridging to HCT, treatment-related AEs (TRAEs), and incidence of capillary leak syndrome (CLS).

Results The high (n=31) and low (n=31) mSWAT groups had comparable median pt ages (68 and 69 years, respectively). The high mSWAT group presented with numerically higher rates of BM involvement (61% vs 32%) and ≥2 disease sites (87% vs 52%) vs the low mSWAT group. A prior or concomitant hematologic malignancy (PCHM) was observed in 2 pts in the high group and 5 in the low group. Median follow-up was 34.3 mo for the high group and 30.0 mo for the low group. The ORR was similar in the high mSWAT group (81%) vs the low group (71%), while both groups had CR/CRc rates of 58%. Median time to CR/CRc was 44 days in the high group and 23.5 days in the low group. Median duration of CR/CRc was not reached (NR) (high) and 24.9 mo (low). Median PFS was 7.3 mo (high) and 4.1 mo (low), while median OS was 25.8 mo and 12.0 mo, respectively, highlighting favorable outcomes even in the high mSWAT group. Excluding pts with PCHM, median OS was 27.7 mo in the high group and 18 mo in the low group. A similar number of pts in both groups successfully underwent HCT following TAG: 11 pts (high) and 10 pts (low). Among these pts, median PFS post-HCT was NR in the high group and 25.5 mo in the low group; median OS was NR and 38.4 mo, respectively, demonstrating durable benefit from HCT after TAG-induced remission irrespective of baseline skin involvement. More pts in the high group (n=18/31, 58%) underwent HCT at any time vs the low group (n=14/31, 45%). TRAEs were comparable across groups, with grade 3-4 events reported in 52% (high) and 65% (low). Incidence of any-grade CLS was similar (16% high, 19% low); no grade 3-4 CLS events occurred in the high group, while observed in 10% of pts in the low group.

Conclusions 1L TAG enabled pts with BPDCN to achieve CR/CRc and successfully bridge to HCT, independent of their baseline skin disease burden. Despite a higher overall disease burden, pts with high mSWAT scores achieved substantial clinical benefit, with a median OS of 25.8 mo. Across both mSWAT groups, pts who bridged to HCT following a TAG-induced remission demonstrated prolonged survival, underscoring the critical role of TAG in facilitating this potentially curative intervention. Furthermore, the comparable safety profile and, notably, the reduced incidence of grade 3-4 CLS in the high mSWAT group are important clinical observations. These results confirm TAG is an effective 1L therapy irrespective of disease burden or clinical presentation, and serves as the standard of care in all eligible pts with BPDCN.

This content is only available as a PDF.
2025
Sign in via your Institution