First-line tagraxofusp leads to durable responses and prolonged survival in adults with blastic plasmacytoid dendritic cell neoplasm regardless of fitness level

Blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive, orphan hematologic neoplasm that expresses CD123 and other markers, presents primarily in skin, bone marrow, and blood.¹ While BPDCN impacts all ages, the median age of adults with BPDCN is 67 years.² The goal of first-line induction therapy is to attain a durable remission with limited side effects. For eligible patients who successfully achieve a rapid and durable complete response (CR) without cumulative non-hematologic or hematologic toxicities, hematopoietic cell transplantation (HCT) offers a potentially curative option.¹

The first-in-class CD123-directed agent tagraxofusp is the only approved treatment for BPDCN,^3,4 with a well-characterized and manageable safety profile without cumulative myelosuppression. Regulatory approvals were based on results from a prospective, multicenter phase II study (clinicaltrials gov. Identifier: NCT02113982) that employed prespecified, multisystem response criteria and endpoints.^5,6 In this pivotal study,^5,6 the overall response rate (ORR) was 75% in 65 first-line patients (median age 68 years) treated with tagraxofusp (12 µg/kg once daily during the first 5 days of a 21-day cycle). Moreover, 57% achieved a complete response (CR) or clinical CR (CRc: CR with residual skin abnormalities not indicative of active disease) with a median duration of 24.9 months. Half (51%) of these patients were successfully bridged to HCT and reached a median overall survival (OS) of 38.4 months.⁶ Real-world data confirm these results.⁷

While not approved for BPDCN, intensive multi-agent chemotherapy (IC) prior to HCT has been used, despite shortand long-term toxicities, including myelosuppression, and short duration of response (DOR). Because of age and comorbidities, many patients with BPDCN are ineligible for IC prior to consideration for HCT, and use is restricted to young/fit patients.⁸ Overall, these patients from all age groups could benefit from a safe and effective targeted first-line treatment with tagraxofusp to achieve rapid and durable CR to increase HCT eligibility, without risk of longterm toxicities.

Given the heterogeneity in patient fitness, an important clinical question is whether baseline fitness affects tagraxofusp treatment outcomes and safety. The HCT-specific comorbidity index (HCT-CI), a risk-stratification model developed to predict overall and non-relapse mortality after allogeneic-HCT, has been well validated in various hematologic malignancies and is useful for assessing fitness/frailty level.^9-11 HCT-CI includes categories of comorbidities/organ dysfunction assigned a weight of 0 (low-risk), 1-2 (intermediate-risk), or ≥3 (high-risk) based on a patient’s past medical history or abnormal laboratory values immediately prior to conditioning treatment. We, therefore, utilized the HCT-CI¹² in a post hoc analysis of the pivotal trial to assess tagraxofusp safety and efficacy across different baseline fitness levels.

Study methods and results have been previously published.^5,6 The study was approved by the institutional review board at each participating center and conducted in accordance with the principles of the Declaration of Helsinki and applicable clinical practice guidelines. All study participants provided written informed consent. This post hoc analysis categorized 65 treatment-naïve patients based on available medical history, concomitant medications, and laboratory values into previously validated HCT-CI low-risk (HCT-CI 0), intermediate-risk (HCT-CI 1-2), or high-risk (HCT-CI ≥3) groups.^9-11 Efficacy and safety data for each HCT-CI risk group were analyzed by descriptive statistics only.

Of the 65 patients analyzed, 15 (23%) patients had a low-risk score, 22 (34%) an intermediate-risk score, and 28 (43%) a high-risk score (Table 1). Prevalence of the HCT-CI comorbidities is shown in Online Supplementary Table S1. The proportion of patients with a normal Eastern Cooperative Oncology Group performance status decreased with increasing HCT-CI risk score (67%, 50% and 36%, respectively).

The median duration of follow-up was 27.7 months (range, 2.6-51.7) for the low-risk group, 36.6 months (range, 0.2-58.1) for intermediate-risk, and 36.3 months (range, 3.9-54.0) for high-risk. The three groups had a similar median duration of exposure: 72 days (range, 37-545) for low-risk, 71 days (range, 2-159) for intermediate-risk, and 68 days (range, 1-1,622) for high-risk. Patients in all groups started a median of four cycles and, in cycle 1, received a median of four doses for low-risk, five doses for intermediate-risk, and four doses for high-risk. Reasons for study discontinuation are shown in Online Supplementary Table S2.

The ORR was high in all groups: 80% (low-risk), 68% (intermediate-risk), and 79% (high-risk)(Figure 1A). Median time to response was rapid and similar: 24 days (range, 20-49) for low-risk, 22 days (range, 14-53) for intermediate-risk, and 25 days (range, 14-97) for high-risk. Median time to CR was numerically longer in the low-risk (45 days; range, 20-131) and high-risk (43 days; range, 22-107) groups than in the intermediate-risk group (24 days; range, 14-53). The median DOR was numerically longer in the low- (24.9 months; range, 1.0-51.1) and intermediate-risk (not reached [NR]; range, 0.9-57.4 months) groups than in the high-risk group (3.9 months; range, 0.7-52.3).

Twenty-one patients were bridged to HCT (5 low-risk, 10 intermediate-risk, 6 high-risk). The three groups of bridged patients had received a median of four cycles from start of tagraxofusp to HCT, and had a similar median time from diagnosis to HCT and a similar median time from the first dose of tagraxofusp to HCT (Online Supplementary Table S3). Pre-transplant CR/CRc rates were high in all three risk groups (100% low-risk, 90% intermediate-risk, 83% high-risk; Figure 1B). Transplanted patients in the low- and intermediate-risk groups had numerically shorter median times to overall response (21 days, range, 20-49; and 23 days, range, 14-53, respectively) than patients in the high-risk group (41 days, range, 23-57). The median DOR for transplanted patients was NR in any group.

The median OS in the overall population was 38.4 months (95% confidence interval [CI]: 8.6-not estimable [NE]) in the low-risk group, 15.8 months (95% CI: 9.0-NE) in the intermediate-risk group, and 11.8 months (95% CI: 6.2-18.9) in the high-risk group (Figure 1C). Notably, in the transplanted population, median OS was 38.4 months (95% CI: 27.7-NE) in the low-risk group and NR (95% CI: 3.4-NE and 95% CI: 4.1-NE) in both intermediate- and high-risk groups (Figure 1D).

The safety profile of tagraxofusp was consistent across HCT-CI risk groups and with the overall trial population. Table 2 summarizes treatment-emergent adverse events (AE) leading to dose reduction, dose interruption, and the most common hematologic and non-hematologic any-grade treatment-related AE (TRAE). Most hematologic and non-hematologic TRAE occurred during cycle 1 and were transient. Grade 3-4 TRAE occurred in 60% (low-risk), 46% (intermediate-risk), and 64% (high-risk) of patients. Common grade 3-4 TRAE included increased alanine/aspartase aminotransferase (40%, 14%, and 29%, respectively) and, to a lesser extent, thrombocytopenia (33%, 14%, and 14%, respectively) and neutropenia (7%, 5%, and 11%, respectively). Capillary leak syndrome (CLS) was observed in 7% (low-risk), 23% (intermediate-risk), and 21% (high-risk) of patients. CLS events were predominantly grade 1-2, occurred in cycle 1, and resolved at a median of 4-6 days across all risk groups (Online Supplementary Table S4). Deaths due to TRAE were two (9%) patients with CLS and one (5%) patient with myocardial infarction in the intermediate-risk group. There were no deaths due to TRAE in the low-risk or high-risk groups.

Table 1.Baseline characteristics by hematopoietic cell transplantation-comorbidity index risk groups of all patients treated with first-line tagraxofusp.

This analysis represents the first reported use of a pre-treatment HCT-CI score to evaluate treatment outcomes in patients with BPDCN, demonstrating how tagraxofusp performs across varying levels of comorbidities and (chemotherapy) fitness. Tagraxofusp demonstrated uniformly high response rates irrespective of HCT-CI fitness risk level, with an 80% ORR for low-risk, 68% for intermediate-risk, and 79% for high-risk groups. Responses were durable, and importantly, patients across all fitness groups successfully bridged to transplant. Overall, OS was prolonged in the transplanted population, with median OS NR in intermediate- and high-risk patients bridged to HCT. Tagraxofusp’s safety profile remained consistent across all HCT-CI risk groups, mirroring previously reported data for the overall population.^5,6

Figure 1.Efficacy outcomes by hematopoietic cell transplantation-comorbidity index risk groups. (A) Objective responses in all patients.^a (B) Objective responses in patients bridged to transplant. (C) Kaplan-Meier overall survival (OS) curves in all patients. (D) Kaplan-Meier OS curves in patients bridged to transplant. BPDCN: blastic plasmacytoid dendritic cell neoplasm; CI: comorbidity index; CR: complete response; CRc: CR with residual skin abnormalities not indicative of active BPDCN; HCT: hematopoietic cell transplantation; NE: not estimable; NR: not reached; ORR: objective response rate; PR: partial response. ^aFour patients in the intermediate-risk group were not evaluable; mo: months;

Table 2.Adverse events in four or more patients in any hematopoietic cell transplantation-comorbidity index risk group treated with first-line tagraxofusp.

The HCT-CI, specifically developed and validated for patients undergoing HCT for hematologic malignancies, offers superior sensitivity and predictive accuracy over more general comorbidity indices (e.g., Charlson Comorbidity Index), by incorporating transplant-relevant comorbidities.¹² Unlike with IC where high-risk HCT-CI subgroups in acute myeloid leukemia have shown significant early mortality (29% within 28 days),¹³ thus limiting treatment options, the current analysis establishes tagraxofusp as a safe and efficacious treatment for BPDCN across all HCT-CI subgroups. While acknowledging the post hoc nature of this analysis, the patient population’s distribution across low-, intermediate-, and high-risk HCT-CI categories (23%, 34%, and 43% respectively) closely aligns with a large BPDCN cohort from the Center for International Blood and Marrow Transplant registry (26%, 31%, and 42% respectively).¹⁴ This robust comparability strengthens the validity of our stratification methodology. Notably, the high-risk group included older patients who had more BPDCN organ involvement, which aligns with previous reports showing number of comorbidities and BPDCN disease sites are associated with older age.¹⁵ Similarly, the distribution of patients with ≥5% bone marrow blasts at baseline was highest in the high-risk group. In conclusion, results from this post hoc analysis show that tagraxofusp induced durable responses without the prolonged myelosuppression and cumulative toxicities associated with IC. Critically, tagraxofusp also enabled bridging to HCT for eligible patients across the entire spectrum of fitness, including those high-risk individuals potentially deemed ineligible for intensive cytotoxic upfront regimens. These results affirm tagraxofusp as the standard of care first-line treatment for all eligible patients with BPDCN irrespective of baseline fitness level.

Footnotes

• Received October 10, 2025
• Accepted December 31, 2025

Correspondence

N. PEMMARAJU - npemmaraju@mdanderson.org

Disclosures

NP discloses institutional research grant from NIH/NCI, US Department of Defense; consultant/scientific advisor board/ speaking for AbbVie, Aplastic Anemia & MDS International Foundation, Aptitude Health, Astellas Pharma US, Blueprint Medicines, Bristol Myers Squibb Pharmaceuticals, CancerNet, CareDx, Celgene, Cimeio Therapeutics AG, ClearView Healthcare Partners, CTI BioPharma, Curio Science, Dava Oncology, EUSA Pharma, Harborside Press, Imedex, Immunogen, Intellisphere, Karyopharm, Magdalen Medical Publishing, Medscape, Menarini Group, Morphosys, Neopharm, Novartis Pharmaceuticals, OncLive, Pacylex, Patient Power, PeerView Institute for Medical Education, Pharma Essentia, and Physician Education Resource (PER); board of directors/management for Dan’s House of Hope; leadership with ASH committee on communications, ASCO Cancer.Net editorial board; licenses with Karger Publishers; editorial board (unpaid) for HemOnc Times/Oncology Times. MH discloses research funding from BeiGene and JanPix; consulting or advisory role for BeiGene, Janssen, Stemline Menarini and Takeda; honoraria from BeiGene, Janssen, Roche, Stemline Menarini and Takeda; expert testimony for Stemline Menarini; travel accommodations/expenses from BeiGene and Janssen. KLS discloses institutional research funding from Incyte and Jazz; advisory/consultant role for JazzBri, Nkarta and Novartis; honoraria from Bristol Myers Squibb; expert testimony with Nelson Mullins; travel accommodations/expenses from Bristol Myers Squibb and Jazz; participation on a DSMB or advisory board for Karyopharm; stock or stock options with BeiGene. ASS discloses honoraria from Amgen, Syndex Bio and Debio Pharma; consultant for Debio Pharma and Syndex Bio. SV discloses institutional research funding from Sanofi; participation on a data safety monitoring board or advisory board for Alexion. TLR has no conflicts of interest to disclose. DAR discloses data safety monitoring board or advisory board for Cellectis. CP discloses consulting/advisory role and participation on a data safety monitoring board or advisory board for AbbVie, Astellas, Blueprint, Delbert Laboratories, GSK, ImCheck, Istituto Gentili, Janssen, Jazz Pharmaceuticals and Pfizer; honoraria from AbbVie, Amgen, Astellas, Bristol Myers Squibb, Incyte, Janssen, Menarini/Stemline, Novartis, Pfizer and Servier. ESW discloses advisory/consulting for AbbVie, Blueprint, Daiichi Sankyo, Immunogen, Kite, Kura, Novartis, Qiagen, Rigel, Ryvu, Schrodinger, Servier, Stemline, Syndax and Takeda; speaking for Pfizer, Astellas and Dava; data safety monitoring board for Gilead and AbbVie; section editor for UpToDate. MK discloses institutional research funding from AbbVie, Janssen and Klondike Biopharma; consulting/ advisory role for AbbVie, Adaptive, AmMax, Curis, Janssen, Kyowa Kirin, Menarini/Stemline Therapeutics, Novartis, Sanofi Aventis, Servier and Vincerx; participation on a data safety monitoring board or advisory board for AbbVie, Auxenion GmbH, Dark Blue Therapeutics, Legend, MEI Pharma, Menarini/Stemline Therapeutics, Novartis and Syndax. MZ and AT disclose employment with Menarini Group. MQ discloses research funding from Angiocrine, Janssen and Sanofi; consulting/advisory role for Sanofi; participation on a data safety monitoring board or advisory board for Autolus. AAL discloses institutional research funding from AbbVie and Stemline Therapeutics; consulting or advisory role for Cimeio Therapeutics, IDRx, Jnana Therapeutics, ProteinQure, Qiagen and Stelexis BioSciences; steering committee for Stemline Therapeutics; stock or stock options with Medzown and Stelexis BioSciences.

Contributions

ad hoc

Funding

This study was funded by the Menarini Group.

Acknowledgments

We thank the patients and their families, and the investigators, co-investigators, and their participating institutions. Medical writing and editing assistance was provided by Monica Nicosia and Claire Gilmore of Phillips Group Oncology Communications, Inc., and funded by the Menarini Group.