First‐line tagraxofusp induces durable responses with prolonged survival in adults younger than 50 years with blastic plasmacytoid dendritic cell neoplasm: Post hoc analysis of a phase 2 trial

To the Editor, Blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive and orphan haematological malignancy that expresses CD123 and other markers, presents in the skin, bone marrow (BM), blood and viscera.1, 2 Although the median age of patients at diagnosis is 67 years old, BPDCN can occur at any age and has a bimodal incidence with peaks seen in both those younger than 20 years and those older than 60 years.3-5 Data are limited on the management of BPDCN in patients <50 years, including the adolescent and young adult population defined as 15–39 years old in oncology studies.6, 7 Tagraxofusp, a first-in-class CD123-targeted therapy, is the only drug with regulatory approval for adults and children ≥2 years with treatment-naive or relapsed/refractory BPDCN in the United States8 and for adults with treatment-naive BPDCN in Europe.9 These approvals were supported by results from a pivotal, multicentre phase 2 study (NCT02113982) prospectively designed with prespecified, multisystem response criteria.10, 11 The 65 patients with BPDCN treated with first-line tagraxofusp (12 μg/kg once daily on days 1–5 of a 21-day cycle) in the pivotal study had a 75% overall response rate (ORR) and a 57% complete response (CR)/clinical CR (CRc; CR with residual skin abnormalities not indicative of active BPDCN) rate, with rapid and durable responses (median time to response: 23 days; median time to CR/CRc: 39 days; median duration of CR/CRc: 24.9 months).11 Tagraxofusp has a well-characterized and manageable safety profile with adverse events (AEs) being transient, occurring mostly in cycle 1, no cumulative long-term toxicity and no myelosuppression.11 The majority of patients have restoration of normal haematopoiesis at the end of cycle 1 irrespective of baseline BM involvement.12 While not approved, multi-agent induction chemotherapy has been used in young adult patients with BPDCN, resulting in short- and long-term toxicity, including prolonged myelosuppression.13-15 Therapeutic options that are more effective and without these long-term toxicities are needed to help patients achieve responses and more safely bridge to a potentially curative haematopoietic stem cell transplantation (HSCT). To evaluate the safety and efficacy of tagraxofusp in younger people with BPDCN, we performed a post hoc subgroup analysis of the pivotal study.10, 11 The pivotal study design, patient selection criteria and methods have been previously reported.10, 11 For this post hoc analysis, we analysed outcomes in adults 18–49 years with BPDCN prospectively treated with first-line tagraxofusp. Analysed outcomes included best objective response, time to best response, duration of response (DOR), overall survival (OS), bridging to HSCT and treatment-related AEs (TRAEs), including capillary leak syndrome (CLS). Patient baseline demographic and clinical characteristics were summarized, and descriptive statistics, such as median (range) and number of patients (percentage), were used for post-treatment outcomes. Ten patients aged <50 years were identified from the pivotal study and included in the analysis. The median age was 32 years (range, 22–45; Table 1), and the population included six young adults (age range, 22–32 years). All patients had an Eastern Cooperative Oncology Group performance status of 0 (80%) or 1 (20%). The most common sites of disease were skin (100%) and lymph node (60%); 60% of patients had ≥2 sites of disease. One patient (a 40-year-old woman) had a prior haematological malignancy (Hodgkin lymphoma). Patients received a median of 4 (range, 2–7) cycles of tagraxofusp. During the first cycle, patients received a median of five doses (range, 3–5), in line with the prescribed dosing.8, 9 At a median follow-up of 34 (range, 10–53) months, two CRs, five CRcs and one partial response (PR) were observed for an ORR of 80% (Figure 1A). The median time to response was 21 (range, 14–44) days, and the median DOR was not reached (NR; range, 0.9–51.8 months). The median time to CR/CRc was 41 (range, 14–44) days, and the median duration of CR/CRc was NR (range, 8.4–51.8 months). All patients were bridged to HSCT (seven allogeneic, two autologous, one cord blood stem cell). Seven of these patients were bridged to transplant (five allogeneic, two autologous) immediately following a tagraxofusp-induced CR/CRc at a median of 38 (range, 23–42) days from the last dose. Of these seven patients, none experienced post-transplant veno-occlusive disease (VOD), and no other post-transplant TRAEs were reported. Five of the patients remain alive (ongoing at last follow-up), and two had progressive disease after allogeneic HSCT (Figure 1B). Three patients, one with a PR and two with stable disease (SD) during tagraxofusp treatment, were bridged to HSCT after subsequent multiagent chemotherapy. The patient with a PR had skin and lymph node involvement, <5% baseline BM involvement, normal cytogenetics and no splenomegaly. One patient with SD had skin and lymph node involvement, ≥5% baseline BM involvement and moderate splenomegaly; the other patient with SD had skin involvement and <5% baseline BM involvement. The patient who achieved a PR and received subsequent therapy with methotrexate and hyper-cyclophosphamide/vincristine/doxorubicin/dexamethasone (CVAD) was determined to have VOD 45 days after allogeneic HSCT. The patient was alive at last follow-up 813 days post-transplant; one patient with SD remained alive at last follow-up, while the other had an OS of 653 days. The median OS was 38.4 (range, 10.2–53.1) months for all patients and 38.4 (range, 17.8–53.1) months for the seven patients who bridged to HSCT immediately after tagraxofusp treatment (Figure 1C). Most TRAEs were grade 1–2, and no grade 5 events occurred. The most common grade 3–4 TRAEs were alanine aminotransferase increased (20%), aspartate aminotransferase increased (20%) and thrombocytopenia (20%). TRAEs primarily occurred during cycle 1 (Figure 1D; Figure S1), and the majority resolved within the same cycle (Table S1). There were no dose reductions or discontinuations due to TRAEs. Although some patients required dose interruption due to weight gain (50%) or hypoalbuminaemia (10%), none had investigator-assessed CLS. Transfusions were uncommon and limited to cycle 1. Two patients had red blood cell transfusion, one patient had a platelet transfusion and one patient had granulocyte colony-stimulating factor. After cycle 1, none of the patients required transfusion or growth factor support. Results from this post hoc subgroup analysis show that first-line tagraxofusp, a chemotherapy-free option, induced a high rate of CR/CRc, durable response and prolonged survival in adults with BPDCN who ranged in age from 22 to 45 years, including six young adults. All patients <50 years who achieved CR/CRc during tagraxofusp treatment were bridged to HSCT immediately after tagraxofusp (70%) or following subsequent therapy. This younger population of patients tolerated tagraxofusp well, with no cumulative haematological or non-haematological TRAEs, and no CLS. The absence of investigator-assessed CLS may reflect the positive impact of early recognition of signs and symptoms (i.e. weight gain and hypoalbuminaemia) and their effective management. Historically, while not approved for BPDCN treatment, intensive chemotherapy regimens adopted from other haematological malignancies were used to treat younger patients with BPDCN. However, these regimens have not been formally tested in a prospective trial with prespecified response criteria, and relapses remain common.3, 14 Multi-agent chemotherapy regimens are also associated with short- and long-term toxicities, which may hinder a patient's ability to proceed to stem cell transplantation once a remission is achieved.2, 3 Findings of this subgroup analysis suggest that tagraxofusp is a safe and highly effective treatment in younger adults with BPDCN, supporting tagraxofusp as the standard of care for all eligible patients with BPDCN. Response to treatment coupled with avoidance of short- and long-term toxicities associated with chemotherapy allows patients to bridge to HSCT and experience long-term survival. The three patients who did not achieve a CR/CRc were able to receive salvage chemotherapy and ultimately proceeded to HSCT. Prospective studies, including combinations with tagraxofusp, and real-world observations are needed to further optimize and understand curative approaches to BPDCN. In conclusion, these results confirm the safety and effectiveness of first-line tagraxofusp therapy in younger adults with BPDCN. ASS and JK contributed to the conception and design of this post hoc analysis; all authors acquired the data; all authors analysed the data; and all authors contributed to data interpretation; manuscript writing, editing and content review; and approved the final draft of the manuscript. Medical writing and editing assistance was provided by Monica Nicosia, PhD, CMPP, of Phillips Group Oncology Communications, Inc., and funded by the Menarini Group. ASS: Honoraria from Amgen, Syndex Bio, Debio Pharma; Consultant for Debio Pharma, Syndex Bio. AAL: Institutional research funding from AbbVie, Stemline Therapeutics; Consulting or advisory role for Cimeio Therapeutics, IDRx, Jnana Therapeutics, ProteinQure, Qiagen, Stelexis BioSciences; Steering Committee for Stemline Therapeutics; Stock or stock options with Medzown, Stelexis BioSciences. KLS: Institutional research funding from Incyte, Jazz; Advisory/consultant role for JazzBri, Nkarta, Novartis; Honoraria from Bristol Myers Squibb; Expert testimony with Nelson Mullins; Travel accommodations/expenses from Bristol Myers Squibb, Jazz; Participation on a DSMC or advisory board for Karyopharm; Stock or stock options with BeiGene. SV: Institutional research funding from Sanofi; Participation on a DSMB or advisory board for Alexion. AT: Employment with Menarini Group. JK: Employment with Menarini Group and previous employment, stock or stock options with AbbVie. MK: Institutional research funding from Abbvie, Janssen, Klondike Biopharma; Consulting/advisory role for AbbVie, Adaptive, AmMax, Curis, Janssen, Kyowa Kirin, Menarini/Stemline Therapeutics, Novartis, Sanofi Aventis, Servier, Vincerx; Participation on a DSMB or advisory board for Abbvie, Auxenion GmbH, Dark Blue Therapeutics, Legend, MEI Pharma, Menarini/Stemline Therapeutics, Norvartis, Syndax. NP: Institutional research grant from NIH/NCI, US Dept of Defense; Consultant/scientific advisory board/speaking for AbbVie, Aplastic Anemia and MDS International Foundation, Aptitude Health, Astellas Pharma US, Blueprint Medicines, Bristol Myers Squibb, 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, PharmaEssentia, 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. This study was funded by the Menarini Group. 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