touchOPINION – the novel targeted therapy, tagraxofusp (SL-401), shows promise for blastic plasmacytoid dendritic cell neoplasm that currently has no standard of care
Dana-Farber Cancer Institute, Boston, US
Naveen Pemmaraju, Department of Leukemia, MD Anderson Cancer Center, Texas, US
Dr. Andrew Lane and Dr. Naveen Pemmaraju discuss the unmet needs for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) and the potential impact of tagraxofusp (SL-401), a novel targeted therapy directed to the interleukin-3 receptor-α (CD123), for improving the clinical outcomes for this aggressive hematological tumor type.
ADDRESSING TODAY’S CLINICAL CHALLENGES FOR MANAGING PATIENTS WITH BPDCN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematologic malignancy with patients typically having poor outcomes (median overall survival ranges from 8–14 months).1-11 BPDCN is derived from the plasmacytoid dendritic cell and was re-classified as a distinct myeloid neoplasm by the World Health Organization in 2008.1 BPDCN can occur at any age and in any geographical location; however, most patients are older adults with a median age of 67 years and it is 2-3 times more common in men than women.6,10,12 Although the exact incidence of BPDCN is unknown, given the historical changes in its classification and the difficulties involved in diagnosis, it accounts for <1% of all hematological malignancies with approximately 1,000–1,400 new cases in the US and Europe.10,13-15
Patients with BPDCN primarily present with bone marrow and/or skin involvement. Other sites, such as lymph nodes and viscera, may also become involved as the disease progresses.6,10 Skin involvement with BPDCN can be disfiguring and is a source of significant morbidity. BPDCN in the bone marrow can result in decreased blood cell counts, which can then lead to serious infections, fatigue, bleeding, and death.6,10,13 The rarity of this disease makes it easy to be misdiagnosed and there can be a significant delay between the onset of lesions and the final diagnosis.1,2 The diagnosis of BPDCN is based on immunophenotypic criteria, either by flow cytometry or immunohistochemistry, through recognition of its signature diagnostic triad: CD123/CD4/CD56 (and other markers such as TCL-1).16 It is important that BPDCN is differentiated from other cutaneous infiltrating hematological malignancies, such as NK/T-cell leukemia/lymphoma, cutaneous T-cell lymphoma and myelomonocytic acute leukemias,1,10 further adding to the difficulties that physicians face when diagnosing this rare disease.
Currently there are no drugs approved for BPDCN and no accepted standard of care, meaning it represents a significant clinical challenge for haemato-oncologists who are managing patients with this form of cancer. The rarity of this disease explains the absence of extensive literature regarding its management.1 Prospective data are lacking and while there are retrospective reports in the literature of combination chemotherapy providing disease responses of varying durability, largely in patients who can tolerate full doses, overall prognosis remains generally very poor. A stem cell transplant (SCT) may then be an option in select patients for whom an initial remission can be induced and maintained.6,10,13 Therefore, there is a critical unmet medical need to develop new treatments for this aggressive cancer.
Advances in the understanding of the pathobiology of the disease, as well as the results of early clinical studies, have revealed novel targets and potentially effective agents for BPDCN.10 One such novel targeted therapy is tagraxofusp (SL-401), which is directed to the cell surface target interleukin-3 receptor-α (CD123) that is highly expressed on BPDCN cells. Tagraxofusp (SL-401) was granted breakthrough therapy designation for BPDCN by the FDA13 and represents an exciting, potential option on the horizon for patients with the disease.
KEY LEARNING POINTS
- BPDCN is a rare and highly aggressive hematologic malignancy that is associated with poor patient outcomes and is often misdiagnosed.
- It is important that BPDCN is differentiated from other cutaneous infiltrating hematological malignancies – diagnosis is based on immunophenotypic criteria, either by flow cytometry or immunohistochemistry, through recognition of its signature diagnostic triad: CD123/CD4/CD56.
- Currently there are no drugs approved for BPDCN and no accepted standard of care – the novel targeted therapy tagraxofusp (SL-401), which is directed against CD123 that is highly expressed on BPDCN cells, represents a potential future option for patients with this disease.
INTRODUCING tagraxofusp (SL-401) – A NOVEL TARGETED THERAPY FOR BPDCN
Detailed results from the pivotal Phase II trial of tagraxofusp (SL-401) in BPDCN were presented for the first time at the 2017 Annual Meeting of the American Society of Hematology (ASH) by Dr Naveen Pemmaraju of the MD Anderson Cancer Center in Texas. This study is the largest, multi-center, prospective trial ever conducted in BPDCN. The trial enrolled 45 patients (32 first-line; 13 relapsed/refractory) across 7 sites in the US and consisted of 3 stages. In Stage 1 (lead-in, dose escalation), first-line and relapsed/refractory patients received a daily intravenous infusion of tagraxofusp (SL-401) at 7, 9, or 12 mcg/kg/day on days 1–5 of a 21-day cycle. In Stage 2 (expansion), first-line and relapsed/refractory patients received the dose determined to be optimal in Stage 1 (12 mcg/kg/day). Finally, Stage 3 (pivotal, confirmatory) enrolled first-line patients only and was prospectively designed to provide the pivotal, confirmatory evidence for the efficacy of tagraxofusp (SL-401) in BPDCN. Enrolment in Stages 1–3 has been completed and to ensure ongoing patient access, an additional cohort is currently open for enrolment of both first-line and relapsed/refractory patients.17
The median age of the patients included in Stages 1–3 of the trial was 70 years (range 22–84 years) and 82% were male (37/45 patients). The trial met its primary endpoint with a complete response (CR) + clinical CR (CRc) rate of 54% observed in the 13 first-line BPDCN patients enrolled in Stage 3. The overall response rate (ORR) was 77% in Stage 3, with 46% of these patients going on to receive a SCT following remission on tagraxofusp (SL-401). Similar encouraging results were seen in patients across all stages, lines, and doses of tagraxofusp (SL-401), with CR and ORR rates of 60% and 82%, respectively. In Stages 1–3, among the 29 first-line patients who received tagraxofusp (SL-401) at 12 mcg/kg/day dosing, the rate of CR + CRc + CR with incomplete hematologic recovery (CRi) was 72% and the ORR was 90%, with 45% receiving a SCT following remission.17
Moving on to the safety profile of tagraxofusp (SL-401), the most common treatment-related adverse events seen with the drug in BPDCN and other clinical trials (acute myeloid leukemia, myeloproliferative neoplasms, and multiple myeloma; n=148 patients) were hypoalbuminemia (47%), aspartate aminotransferase increase (46%), alanine aminotransferase increase (45%), nausea (28%), and thrombocytopenia (28%). Capillary leak syndrome (CLS), a well-documented side effect of tagraxofusp (SL-401), occurred in 19% of patients, of which 2% were grade 5, as previously reported.17 As of June 2018, the rate of CLS was 0.7% (1/144) for all trials (12 mcg/kg/day) and 1.7% (3/179) for all trials (all doses).18
In summary, tagraxofusp (SL-401) has demonstrated efficacy with a meaningful clinical benefit in BPDCN while maintaining a manageable safety profile and represents a major advancement in the management of patients with BPDCN.
A biologics license application submission to the FDA for tagraxofusp (SL-401) was completed in June 2018. If granted approval, tagraxofusp (SL-401) would be the first drug ever approved for BPDCN and could potentially transform the treatment paradigm in this disease.
KEY LEARNING POINTS
- The Phase II trial of tagraxofusp (SL-401) is the largest, multi-center, prospective trial ever conducted in BPDCN (45 patients; first-line and relapsed/refractory) and consists of three stages: (1) lead-in, dose escalation; (2) expansion; and (3) pivotal, confirmatory.
- Tagraxofusp (SL-401) demonstrated efficacy with a meaningful clinical benefit in patients with BPDCN while maintaining a manageable safety profile.
- A biologics license application for tagraxofusp (SL-401) was submitted to the FDA in June 2018 – if approval is granted, tagraxofusp (SL-401) would be the first drug ever approved for BPDCN and could potentially transform the treatment paradigm in this disease.
This educational initiative is supported by an unrestricted independent educational grant from Stemline.
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- Julia F, Petrella T, Beylot-Barry M, et al., Blastic plasmacytoid dendritic cell neoplasm: clinical features in 90 patients, Br. J. Dermatol, 2013;169:579–586.
- Feuillard J, Jacob M, Valensi F, et al., Clinical and biologic features of CD4(+) CD56(+) malignancies. Blood, 2002;99:1556–1563.
- Herling M and Jones D., CD4+/CD56+ hematodermic tumor: the features of an evolving entity and its relationship to dendritic cells. Am. J. Clin. Pathol. 2007;127:687–700.
- Jacob M, Chaperot L, Mossuz P, et al., CD4+ CD56+ lineage negative malignancies: a new entity developed from malignant early plasmacytoid dendritic cells, Haematologica, 2003;88:941–955.
- Pagano L, Valentini C, Pulsoni A, et al., Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study, Haematologica, 2013;98:239–246.
- Dalle S, Beylot-Barry M, Bagot M, et al., Blastic plasmacytoid dendritic cell neoplasm: is transplantation the treatment of choice, Br. J. Dermatol, 2010;162:74–79.
- Petrella T, Bagot M, Willemze R, et al., Blastic NK-cell lymphomas (agranular CD4 + CD56 + hematodermic neoplasms): a review, Am. J. Clin. Pathol, 2005;123:662–675.
- Rauh M, Rahman F, Good D, et al., Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation, lacking cutaneous involvement: case series and literature review, Leuk Res, 2012;36:81–86.
- Riaz W, Zhang L, Horna P, et al., Blastic Plasmacytoid Dendritic Cell Neoplasm: Update on Molecular Biology, Diagnosis, and Therapy, Cancer Control, 2014;21:279–289.
- Pemmaraju N. Novel Pathways and Potential Therapeutic Strategies for Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): CD123 and Beyond, Curr Hematol Malig Rep, 2017;12:510–512.
- Julia F, Dalle S, Duru G, et al., Blastic plasmacytoid dendritic cell neoplasms: clinico-immunohistochemical correlations in a series of 91 patients, Am J Surg Pathol, 2014;38:673–680.
- Pemmaraju N., Blastic Plasmacytoid Dendritic Cell Neoplasm, Clin Adv Hematol Oncol, 2016;14:220–222.
- Wang H, Cao J, Hong X., Blastic Plasmacytoid Dendritic Cell Neoplasm without Cutaneous Lesion at Presentation: Case Report and Literature Review, Acta Haematol, 2012;127:124–127.
- Bueno C, Almeida J, Lucio P, et al., Incidence and characteristics of CD4+/HLA DRhi dendritic cell malignancies, Haematologica, 2004;89:58–69.
- Pagano L, Valentini C, Grammatico S et al., Blastic plasmacytoid dendritic cell neoplasm: diagnostic criteria and therapeutical approaches, Br J Haematol, 2016;174:188–202.
- Pemmaraju N, Sweet K, Lane A, et al., Results of Pivotal Phase 2 Trial of SL-401 in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN). Presented at the 2017 Annual Meeting and Exposition of the American Society of Hematology. Abstract 1298.
- Pemmaraju N, Lane A, Sweet K, et al., Results of Pivotal Phase 2 Trial of SL-401 in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN). Presented at the 2018 European Hematology Association Congress. Abstract S116.