Tagraxofusp Achieves Anti-Tumor Activity with Rapid Restoration of Normal Hematopoiesis in Treatment-Naïve Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): Subanalysis of a Pivotal Trial
Authors: Konopleva Marina , Pemmaraju Naveen , Sweet Kendra L. , Stein Anthony S. , Rizzieri David A. , Wang Eunice S. , Vasu Sumithira , Rosenblat Todd , Zuurman Michael , Gupta Ira , Lane Andrew A. 
Published: December 2024

Introduction
BPDCN, an aggressive hematologic malignancy, derives from plasmacytoid dendritic cells that express CD123 and other markers. Tagraxofusp (TAG) is a first-in-class CD123-targeted therapy and the only drug approved in the US and EU to treat BPDCN. Results from the pivotal phase 2 trial of TAG in BPDCN demonstrated a high overall response rate [ORR] (75%) with rapid and durable responses (23 days median time to response; 24.9 mo median duration of CR + CRc) in 65 treatment-naïve patients (Pemmaraju et al, JCO 2022). TAG's safety profile is well-characterized and manageable, with transient adverse events (AEs) mostly in cycle 1 and no cumulative hematologic toxicity or myelosuppression. We assessed changes in specific hematologic laboratory parameters to determine hematopoietic and bone marrow effects of TAG treatment in adult patients with BPDCN over time.
Methods
We analyzed a phase 1/2 trial (NCT02113982) of TAG monotherapy to assess hematologic laboratory values in 66 treatment-naïve patients with BPDCN included in the safety population. All patients received TAG 12 mcg/kg intravenously on days 1-5 of a 21-day cycle. Neutrophils, platelets, hemoglobin (Hb), and peripheral leukemic blasts were assessed at time points through the first 4 TAG cycles as the median number of cycles administered was 4 (range 1-76) and reported as mean values ± standard deviations. Transfusions over time and hematologic treatment-related adverse events (TRAEs) were also measured.
Results
Baseline demographics included median age of 68.5 years (range 22-84), 80% male, 96% ECOG PS 0-1, 92% BPDCN skin involvement, 50% lymph node involvement, and 49% bone marrow involvement. Overall, we found that hematologic parameters stabilized over time with each subsequent TAG treatment cycle. Neutrophils remained in normal range (2.6-8 x 109/L) during TAG treatment; from a mean of 2.8 ± 2.6 at baseline, up to 3.5 ± 2.5 at day 1 of cycle 4, while colony-stimulating factor was administered to 6.1%, 1.8%, and 2.1% of patients in cycles 1-3, respectively, with no use beyond cycle 3. Platelet counts (109/L), which were below normal range (150-300) at baseline (131.7 ± 78.3), returned to normal after one cycle of TAG treatment (212 ± 115.4, day 1 of cycle 2), and remained normal in subsequent cycles. Accordingly, the percentage of patients who required platelet transfusions declined over time from 17% in cycle 1, to less than 3% in cycles 2-4. TAG was not associated with decreases in Hb. Cycle day 1 Hb levels remained consistent with baseline Hb (11.6 g/dL ± 2.4) over subsequent cycles. Within cycles, Hb values increased post dosing over time (mean [g/dL] day 8 of cycles 2-4: 12.2 ± 1.7, 12.7 ± 1.3, 12.9 ± 1.7, respectively). This was also reflected in the percentage of patients who received red blood cell transfusions, which decreased from 21% in cycle 1 to 5% in cycle 2 and remained less than 10% in subsequent cycles, consistent with improved Hb over treatment time. Clearance of peripheral blasts was observed in all patients by cycle 2 of TAG treatment. Hematologic TRAEs occurred primarily in cycle 1 without cumulative toxicity and resolved quickly. Hematologic TRAEs in ≥5% of patients included thrombocytopenia (31.8%), anemia (13.6%), neutropenia (10.6%), and leukopenia (7.6%), with no Grade 5 hematologic TRAEs. Resolution and median time to resolution (days) was 81% (8) for thrombocytopenia, 89% (12.5) for anemia, 100% (9.0) for neutropenia, and 100% (7.0) for leukopenia. For the patients with bone marrow involvement (n=32), the stabilization of hematologic parameters, colony-stimulating factor use, platelet transfusions, red blood cell transfusions, and observed hematologic TRAEs is consistent with the above analysis. Notably 28% of patients with bone marrow involvement had platelet transfusions in cycle 1, which decreased to less than 6% in subsequent cycles.
Conclusions
As demonstrated previously, TAG offers rapid and durable responses in front-line treated BPDCN patients. The observed safety profile, lack of cumulative myelosuppression, and restoration of normal hematopoiesiswith TAG treatment support the efficacy and tolerability of TAG as monotherapy for BPDCN and makes TAG a safe and promising combination partner for treatment of other CD123+ hematologic malignancies.