Investigators Turn a Focused Eye to Targeting Weaknesses in BPDCN

Eunice Wang, MD

Because of the disease’s rarity relative to other hematologic malignancies and challenges arriving at an accurate diagnosis, patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) have historically encountered a dearth of effective treatment options. Although no consensus on treatment approach has been established, more therapeutic choices have emerged in recent years as interest in the disease has ramped up.¹

Historical estimates of BPDCN incidence show that it accounts for only 0.44% of all hematologic malignancies, 0.7% of all cutaneous leukemias/lymphomas, and 0.04 cases per 100,000 in the United States.1 Patients with the disease have experienced high early death rates during multi-agent chemotherapy treatment, with an approximate median overall survival (OS) ranging from 8 to 16 months. According to the North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium, a uniform diagnostic approach for BPDCN is an essential component of the treatment of the disease, irrespective of whether the patient is being treated in a community or academic setting. The consortium suggests a multidisciplinary approach that includes input from specialists in leukemia or hematology-oncology, dermatology, and pathology.¹

“[Patients with BPDCN] can often have skin involvement that can be very broad, from bruise-like lesions to tumor-like lesions,” Patrick M. Brunner, MD, associate professor of dermatology and director of the Cutaneous Lymphoma Clinic in The Kimberly and Eric J. Waldman Department of Dermatology at the Icahn School of Medicine at Mount Sinai in New York, New York, said in an interview with OncLive^®. “The role of the dermatologist is to make the diagnosis by taking a skin biopsy. Further treatment is usually done by [a hematology/oncology specialist] because this is an aggressive malignancy.”

“When we look at the skin, typically we are using diagnostic tools such as immunohistochemistry, which looks at the expression of specific proteins on the surface or on cells that are infiltrating the skin and would be part of the biopsy material,” Joseph D. Khoury, MD, professor in the Department of Hematopathology and executive director of the MD Anderson Cancer Network in the Division of Pathology/Lab Medicine at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with OncLive. “In that case, having CD123 immunohistochemistry becomes critical. It has to be used in conjunction with other markers to confirm that one is dealing with BPDCN and exclude the possibility that the CD123 expression might actually be a feature of acute myeloid leukemia [AML].”

CD123 has emerged as a therapeutic target of great interest in BPDCN as it is overexpressed in virtually all patients with the disease. The molecule is found on the surface of malignant cells and possesses a potentially favorable therapeutic gradient between normal hematopoietic stem cells and the malignant BPDCN stem cells. Thus, investigators have begun development of additional agents, such as antibody-drug conjugates (ADCs), targeting CD123.¹

However, the first and to date only agent approved by the FDA for the treatment of BPDCN is the first-in-class, CD123-directed immunotoxin tagraxofusp-erzs (Elzonris). On December 21, 2018, the agency granted regular approval to tagraxofusp for the treatment of patients with BPDCN who are 2 years and older.²

Tagraxofusp is fusion protein of recombinant human interleukin-3 fused with a diphtheria toxin.³ “[This agent takes] advantage of the knowledge that CD123 surface protein antigen is extremely highly expressed on malignant cells in BPDCN,” Eunice Wang, MD, chief the Leukemia Service in the Department of Medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York, said in an interview with OncLive. “This immunotoxin binds to CD123 specifically and engenders a perfect targeted therapy identify and eradicate [this malignancy]. This has to be balanced against some of the known adverse effects [AEs]. Giving an immunotoxin to elderly individuals can be [met] with a lot of complications.”

The FDA approval was supported by findings from the phase 1/2 STML-401-0114 trial (NCT02113982). The open-label, single-arm trial enrolled patients with previously newly diagnosed or relapsed/refractory hematologic malignancies. Patients received intravenous tagraxofusp at the recommended dose of 12 μg/kg over a 15-minute span daily on days 1 to 5 of a 21-day cycle.⁴

Results from the study showed that patients with treatment-naïve BPDCN treated with tagraxofusp (n = 13) had a complete response (CR)/clinical complete response (CRc) rate of 53.8% (95% CI, 25.1%-80.8%). Notably, the median duration of response (DOR) in this cohort was not reached (NR; range, 3.9-12.2). The median duration of follow-up was 11.5 months (range, 0.2-12.7).⁴

Regarding safety, patients who received tagraxofusp at the 12 μg/kg dose level (n = 94) discontinued treatment with the agent because of an AE at a rate of 11%. Fatal AEs were reported in 2 patients; both were instances of capillary leak syndrome. Common any-grade AEs included capillary leak syndrome (55%), nausea (49%), and fatigue (45%). AEs of grade 3 or greater included febrile neutropenia (18%), capillary leak syndrome (9%), and hypotension (9%).⁴

Updated long-term findings published in the Journal of Clinical Oncology in September 2022 showed that, at a median follow-up of 34.0 months, patients who received tagraxofusp were still experiencing durable responses and the safety profile of the agent continued to be manageable.⁵

Treatment-naïve patients (n = 65) achieved an overall response rate (ORR) of 75%, including a 57% (95% CI, 44.0%-69.2%) CR/CRc rate. The median time to CR/CRc was 39 days (range, 14-131) and the median duration of CR/CRc was 24.9 months (95% CI, 3.8-NR). The median OS was 15.8 months (95% CI, 9.7-25.8).⁵

Among efficacy-evaluable patients with relapsed/refractory disease (n = 19), the ORR was 58% (95% CI, 33.5%-79.7%), with 1 patient achieving a CR and 2 others experiencing a CRc. At a median follow-up of 33.5 months, the median time to response was 29 days (range, 21-82) and the median OS was 8.2 months (95% CI, 4.1-11.9).⁵

Safety findings from the update were mostly consistent with the results that supported tagraxofusp’s approval; 7% of patients in the safety population (n = 89) discontinued treatment because of an AE. Most patients (69%) experienced an AE leading to dose interruption. Common any-grade AEs included increased alanine aminotransferase (64%), increased aspartate aminotransferase (60%), and hypoalbuminemia (51%).⁵

Additionally, at the 64th American Society of Hematology Annual Meeting and Exposition, Pemmaraju et al presented findings from a subgroup analysis of the pivotal trial. Investigators stratified first-line patients by prior or concomitant hematologic malignancies (n = 8) and those without prior or concomitant hematologic malignancies (n = 57). The median age was 69 years (range, 40-84) and 68 years (range, 22-84), respectively. Most patients in both subgroups were men (75% vs 81%) and were White (100% vs 86%).⁶

Findings from the analysis showed that first-line patients with prior or concomitant hematologic malignancies experienced a slight benefit in ORR compared with those without prior or concomitant hematologic malignancies at 88% vs 74%, respectively (P = .6675). However, the CR/CRc rate was not increased for these patients; these rates were 50% vs 58%, respectively. The median duration of CR/CRc was 3.0 months (95% CI, 1.0-NR) vs NR (95% CI, 4.4-NR), respectively (P = .0088).⁶

Notably, patients without prior or concomitant hematologic malignancies experienced a survival benefit vs those with prior or concomitant hematologic malignancies. The median OS was 18.9 months (95% CI, 11.5-38.4) vs 6.3 months (95% CI, 5.2-12.1), respectively (P = .0021). The 12-month survival probability was 59% vs 25%, respectively, and the 18-month probability was 55% vs 13%, respectively.⁶

Investigators concluded that, despite the relatively low patient numbers, their findings provided evidence that treatment with tagraxofusp is effective in first-line patients with BPDCN who had prior or concomitant hematologic malignancies. Their data also highlighted the importance of making an accurate diagnosis of BPDCN to enable treatment with disease-directed therapy, they wrote.⁶

ADCs, T-cell Therapies Aim to Expand Effective Treatment Options

In the ongoing phase 1/2 CADENZA trial (NCT03386513), investigators are evaluating the CD123-directed ADC pivekimab sunirine (formerly IMGN632) among adult patients with treatment-naïve or relapsed/refractory BPDCN.⁷

“[Pivekimab sunirine] links CD123 to a different DNA-damaging agent,” Wang said. The ADC comprises a CD123 antibody with high affinity, a cleavable linker, and an indolinobenzodiazepine pseudodimer payload. “This agent in and of itself can induce direct cell death and doesn’t potentially have the same AEs, [such as] capillary leak syndrome. In early studies [of] patients with relapsed/refractory BPDCN, we have seen responses even in patients who failed frontline therapy and we are currently exploring it in the upfront setting to see if we can more safely deliver a CD123 agent and get equivalent or even greater efficacy with a different toxicity profile.”

Intravenous pivekimab sunirine will be administered on the first day of each 21-day cycle. The primary end point of the study is CR/CRc rate. Secondary end points include duration of CR/CRc, treatment-related AEs, DOR, and OS.^7,8

Frontline findings from the phase 2 portion of the study released August 31, 2022, showed that patients with de novo BPDCN who received the agent (n = 4) achieved a CR/CRc rate of 50%. Moreover, among 6 patients with a prior or concomitant hematologic malignancy, 4 experienced a CR/CRc/CR with partial hematological recovery (CRh). Two patients with de novo BPDCN and 1 with a prior or concomitant hematologic malignancy who were enrolled prior to the opening of the pivotal cohort also achieved CR/CRc.⁷

The FDA granted breakthrough therapy designation to pivekimab sunirine for the treatment of patients with relapsed/refractory BPDCN in October 2020. The manufacturer of pivekimab sunirine noted in a news release that top-line data regarding the primary and key secondary end points will be announced in 2024.⁷

In another ongoing phase 1 trial (NCT03113643), tagraxofusp is again being evaluated, this time in combination with venetoclax (Venclexta) and azacitidine (Onureg) for the treatment of patients with AML, high-risk myelodysplastic syndrome (MDS), or BPCDN. Investigators will enroll approximately 72 patients. Once on trial, patients with MDS will receive tagraxofusp plus the standard dose of azacitidine and patients with AML or BPDCN will receive tagraxofusp plus azacitidine and venetoclax.⁹

The primary outcome is determining the maximum tolerated dose of the combination. Secondary outcome measures include CR rate, time to response, and DOR. The trial is recruiting patients and no findings have been published to date.⁹

“We’ve found that BPDCN cells also express high levels of BCL2, which is blocked by venetoclax,” Wang said. “Combining some of these ADCs with that backbone venetoclax and azacitidine, which we already know is tolerated in elderly patients with aggressive malignancy, is highly promising. I’m also excited about some immunotherapeutic approaches looking at using chimeric antigen receptor [CAR] T cells. We know that dendritic cells are part of the immune system. Potentially using another arm of the immune system to direct host immune therapies toward that malignancy might be particularly useful.”

To Wang’s point, the safety and efficacy of CAR T-cell therapy for patients with BPCDN are being examined in the first-in-human clinical trial of a CD123-directed CAR. Prior to infusion with the CAR T-cell agent, patients undergo lymphodepletion, consisting of fludarabine 25 to 30 mg/m2 daily for 3 days and cyclophosphamide 300 mg/m2 daily for 3 days. Patients then receive a single dose of CD123 CAR T cells with an option for a second infusion if they continue to meet safety and eligibility criteria and their disease remains CD123 positive. The primary objective of the phase 1 trial (NCT02159495) is to test the safety and activity of the agent in patients with relapsed/refractory AML or BPDCN.^10,11

Data from the study published in Blood in 2017 showed that the lone patient with BPDCN treated with the agent to that point, who received a single dose of approximately 100 million autologous CD123 CAR T cells, remained in CR 60 days after infusion. Moreover, skin biopsies at the tumor site on days 14 and 28 showed no evidence of disease and, at day 28, additional clinical testing showed disease-free bone marrow, no new masses by CT scan, normalized blood counts, and complete resolution of clinical symptoms.¹⁰

The trial remains active, although it is not recruiting. Updated findings have yet to be presented.^10,11

References

1. Pemmaraju N, Kantarjian H, Sweet K, et al. North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: position on standards of care and areas of need. Blood. 2023;141(6):567-578. doi:10.1182/blood.2022017865
2. FDA approves tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm. FDA. December 26, 2018. Accessed March 21, 2023. bit.ly/402OMxr
3. Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N Engl J Med. 2019;380(17):1628-1637. doi:10.1056/NEJMoa1815105
4. Elzonris. Prescribing information. Stemline Therapeutics; 2018. Accessed March 21, 2023. bit.ly/3JTJVsW
5. Pemmaraju N, Sweet KL, Stein AS, et al. Long-term benefits of tagraxofusp for patients with blastic plasmacytoid dendritic cell neoplasm. J Clin Oncol. 2022;40(26):3032-3036. doi:10.1200/JCO.22.00034
6. Pemmaraju N, Konopleva M, Sweet K, et al. Tagraxofusp, an anti-CD123 therapy, in patients with blastic plasmacytoid dendritic cell neoplasm and prior or concomitant hematologic malignancies: subgroup analysis of a pivotal trial. Blood. 2022;140(suppl 1):6155-6157. doi:10.1182/blood-2022-159970
7. ImmunoGen provides update on pivotal CADENZA study of pivekimab sunirine in frontline blastic plasmacytoid dendritic cell neoplasm. News release. ImmunoGen. August 31, 2022. Accessed March 21, 2023. bit.ly/3Z9Gx1o
8. Study of IMGN632 in patients with untreated BPDCN and relapsed/refractory BPDCN. ClinicalTrials.gov. Updated March 15, 2023. Accessed March 21, 2023. https://clinicaltrials.gov/ct2/show/NCT03386513
9. SL-401 in combination with azacitidine or azacitidine/venetoclax in acute myeloid leukemia (AML), high-risk myelodysplastic syndrome (MDS) or blastic plasmacytoid dendritic cell neoplasm (BPDCN). ClinicalTrials.gov. Updated June 14, 2022. Accessed March 27, 2023. https://clinicaltrials.gov/ct2/show/NCT03113643
10. Budde L, Song JY, Kim Y, et al. Remissions of acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm following treatment with CD123-specific CAR T cells: a first-in-human clinical trial. Blood. 2017;130(suppl 1):811. doi:10.1182/blood.V130.Suppl_1.811.811
11. Genetically modified T-cell immunotherapy in treating patients with relapsed/refractory acute myeloid leukemia and persistent/recurrent blastic plasmacytoid dendritic cell neoplasm. Updated January 5, 2023. Accessed March 23, 2023. https://clinicaltrials.gov/ct2/show/NCT02159495