Durable Outcomes with Manageable Safety Leading to Prolonged Survival with Tagraxofusp for Treatment-Naive Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm: Updated Results from a European Named Patient Program

Introduction:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive orphan hematologic malignancy that mostly presents in skin, bone marrow, and blood. BPDCN is characterized by clonal expansion of plasmacytoid dendritic tumor cells that express specific markers, including CD123. Historically, median overall survival (OS) has been ~8-14 months (mos) following chemotherapy, and the only potential cures can be conferred by hematopoietic stem cell transplantation (HSCT) following successful induction. Tagraxofusp (TAG) is a first-in-class CD123-directed therapy and the only drug approved in the US and EU to treat BPDCN. In August 2019, a global Named Patient Program (NPP) was initiated in Europe to increase patient (pt) access to TAG. We present updated results, including over two years of follow-up, in treatment-naïve pts with BPDCN from the NPP to assess TAG safety and efficacy in the real-world setting.

Methods:A European multi-center, non-interventional, retrospective study was conducted in adult BPDCN pts that had access to TAG via the NPP. The main inclusion criterion was a diagnosis of BPDCN. Intravenous TAG as first-line therapy was given at 12 mcg/kg once daily on days 1-5 (up to day 10 allowed) of a 21-day cycle. Hospitalization was required for the first cycle only; subsequent cycles could be administered in an outpatient setting. Training of physicians, nurses, and pharmacists on clinical management guidelines was mandatory before initiation of treatment.The main endpoints were complete response (CR) rates and incidence and grade (G) of capillary leak syndrome (CLS). Secondary outcomes included the number of pts bridged to HSCT, OS, and safety.

Results: Twenty-two treatment-naïve adult pts were enrolled in the European NPP from 08/2019 to 12/2021. Median age was 68 yrs (21 - 82), and 86% were male. Sites of disease involvement at diagnosis included skin 77%, bone marrow 59%, lymph nodes 55% (9% single; 46% multiple), and spleen 36%; 10% had CNS involvement at baseline. Median time from diagnosis to initiating TAG was 1.5 mos (range, 0.4 - 9), and the median number of TAG cycles was 3 (1 - 8). At a median follow-up of 10 mos (0.2 - 25), 18 pts had at least 1 tumor assessment. The overall response rate (ORR) was 89% (95% CI, 65 - 99), including a CR rate of 67% (95% CI, 41 - 87) and a partial response (PR) rate of 22%. Median time to ORR was 21 days (11 - 74), and median time to CR was 29 days (11 - 58). Allogeneic HSCT was undertaken in 11/22 (50%) pts; of these 7 (64%) pts were in CR prior to HSCT, and 4 (36%) pts were in PR. Of the 2 pts with CNS involvement at baseline, both had CNS clearance by intrathecal chemotherapy (IC), achieved a CR in response to TAG, and were transplanted. Median OS for all pts was 20 mos (95% CI, 10 - not reached [NR]), Figure. Median OS was NR in transplanted pts (n = 11) and was 11 mos in non-transplanted pts (n=11; 95% CI, 0.2 - NR). Median duration of response (ie, time from CR/CRi to progression or death) was 8.9 mos (95% CI, 2.2 - NR). The majority of G3/4 adverse events (AEs) or serious AEs, regardless of their relationship to TAG therapy, occurred during cycle 1. Thrombocytopenia was the most frequent hematological G3/4 AE occurring in 7 pts (32%), followed by neutropenia (18%). Overall, CLS events were observed in 10 pts (ie, edema [n=9], weight gain [n=8], hypotension [n=5], and/or hypoalbuminemia [n=1]). Nine events occurred in cycle 1, and 3 pts experienced a second CLS event. The majority of CLS events were mild to moderate (69% G≤2; 31% G3). There were no G4/5 events. Most CLS events were managed with albumin supplementation (92%) and temporary changes in TAG scheduling (69%). Median duration of CLS was 8 days, and all events resolved. No patient with CNS involvement had a CLS event. As of the data cut-off, 2 pts (9%) remain on treatment with TAG.

Conclusion: Pts with treatment-naïve BPDCN who received TAG achieved durable outcomes with prolonged survival, including those with known CNS involvement. With over 2 yrs of follow-up, median OS was 20 mos with TAG, which compares favorably to chemotherapy's shorter median OS of ~8-14 mos. No new safety signals were observed. CLS was manageable; the majority of events occurred in cycle 1 and were mild/moderate, with no G4/5 events. These real-world results from a European NPP are consistent with the long-term safety and efficacy results demonstrated in the pivotal TAG monotherapy study (Pemmaraju JCO 2022) and further support TAG treatment for pts with BPDCN.