Treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN): focus on the use of tagraxofusp and clinical considerations

Abstract

BPDCN is an aggressive myeloid malignancy with a poor prognosis. It derives from the precursors of plasmacytoid dendritic cells and is characterized by CD123 overexpression, which is seen in all patients with BPDCN. The CD123-directed therapy tagraxofusp is the only approved treatment for BPDCN; it was approved in the US as monotherapy for the treatment of patients aged ≥2 years with treatment-naive or relapsed/refractory BPDCN. Herein, we review the available data supporting the utility of tagraxofusp in treating patients with BPDCN. In addition, we present best practices and real-world insights from clinicians in academic and community settings in the US on how they use tagraxofusp to treat BPDCN. Several case studies illustrate the efficacy of tagraxofusp and discuss its safety profile, as well as the prevention, mitigation, and management of anticipated adverse events.

Keywords:

• Blastic plasmacytoid dendritic cell neoplasm
• tagraxofusp
• SL-401
• Elzonris
• CD-123 directed therapy

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Introduction

BPDCN is an aggressive myeloid malignancy that is associated with a poor prognosis. BPDCN arises from the precursors of plasmacytoid dendritic cells, and is characterized by CD123+, CD4+, and CD56+ ­expression, with CD123 overexpressed in all cases of BPDCN. Clinical presentation typically involves the skin, bone marrow, lymph nodes, and viscera; central nervous ­system (CNS) and other extramedullary sites may also be affected [1, 2].

Tagraxofusp (TAG), the first-in-class CD123-directed agent, is the only drug approved for the treatment of patients with BPDCN. Prior to this, BPDCN was treated with diverse treatment modalities, including surgery or radiation therapy for localized cutaneous disease. While initial responses have been seen to either ­treatment, these tend to be short-lived, and patients frequently experience relapse; moreover, there is no standardized dose for radiation [3–6]. Multiagent ­cytotoxic chemotherapy regimens that are typically used to treat aggressive hematologic malignancies have also been used to treat patients with BPDCN. These include: acute myeloid leukemia (AML) regimens, which generally comprise cytarabine plus an ­anthracycline; acute lymphoblastic leukemia regimens, such as high doses of methotrexate and cytarabine or cyclophosphamide, vincristine, doxorubicin, and ­dexamethasone (hyper-CVAD); and cytotoxics used to treat aggressive lymphomas, for example the CHOP (cyclophosphamide, doxorubicin, vincristine) or CHOP-like regimens used for non-Hodgkin lymphoma [1, 3, 7, 8]. Generally, suboptimal responses have been observed following treatment using these multiagent protocols, with complete response (CR) rates of ∼40%–60% reported in larger series [1, 9, 10]. Moreover, none of these regimens have been prospectively evaluated in patients with BPDCN. Rather, the data have been collected retrospectively with no predefined or specific BPDCN criteria used for determining efficacy. This ­further underscores the need for novel therapies whose safety and efficacy profiles have been thoroughly investigated in patients with BPDCN.

Irrespective of the treatment modality used, stem cell transplantation (SCT) should follow when possible. When SCT is performed in the first complete disease remission, it has been shown to improve overall survival (OS) [11] and represents a potential curative treatment option for patients with BPDCN [12]. However, induction chemotherapy regimens have proven inadequate in bridging many patients to SCT, primarily due to the high rates of early treatment-related mortality [1], the short-lived responses, and the high rates of relapse [1, 7, 9, 11, 13, 14]. Moreover, the regimens are associated with high levels of organ ­toxicity, including bone marrow toxicity, which can limit their utilization as a therapy overall, and as a means to bridge to SCT. The utility of these regimens may be further limited in certain patient populations, such as the elderly, who tend to be less tolerant to high-dose induction regimens [9, 11, 15]. This is especially problematic given that, while BPDCN can affect patients of all ages, the median age at presentation is 60–67 years [16, 17].

TAG was approved by the US Food and Drug Administration (FDA) in 2018 as monotherapy for patients with treatment-naive and relapsed/refractory (R/R) BPDCN aged ≥2 years, and by the European Medicines Agency (EMA) in January 2021 for treatment-naive adult patients with BPDCN. Since the validation of CD123 as an actionable therapeutic target in BPDCN and subsequent approval of TAG, a number of follow-on CD123-targeted therapies have been developed and are currently under evaluation. Pivekimab sunirine (PVEK, IMGN632) is an investigational antibody-drug conjugate comprising an anti-CD123 antibody coupled to a DNA-alkylating cytotoxic payload of the indolinobenzodiazepine pseudo-dimer class of compounds [18]. It is currently being evaluated in a phase 1b/2 study (NCT03386513) in patients with treatment-naive and R/R BPDCN or with AML. In addition, several CD123 chimeric antigen receptor (CAR) T-cell therapies are being evaluated in patients with BPDCN, including MB-102 (NCT02159495) and UniCAR02-T (NCT04230265), and the CD123-targeting dual-affinity retargeting antibody (DART) flotetuzumab is also in phase 1 development (NCT04681105). The safety and efficacy of these agents has yet to be fully determined.

As TAG is the only therapy approved for BPDCN, we believe a review of TAG is beneficial. We also present insights into the authors’ clinical experiences using TAG for patients with treatment-naive and R/R BPDCN in academic and community settings in the US. Viewpoints related to safety (in particular the prevention, mitigation, and management of anticipated adverse events [AEs]) and efficacy are discussed. For illustration, several real-world case studies are also presented.

Tagraxofusp

Following the seminal observation over 20 years ago that CD123, the α-subunit of the interleukin-3 (IL-3) receptor, was overexpressed in the leukemia stem cell compartment in patients with AML [19], diverse myeloid and lymphoid malignancies were also found to be associated with CD123+ expression. Thereafter, significant progress has been made in the clinical development of CD123-targeting therapy, especially in myeloid malignancies. Since all BPDCN cells ­overexpress CD123, agents targeting this protein represent an attractive strategy for the treatment of patients with BPDCN. TAG is a CD123-directed therapy comprising a recombinant human IL-3 fused to a truncated diphtheria toxin (DT) payload. Preclinical studies have demonstrated that the IL-3 receptor binds with high affinity to the TAG IL-3 domain [20–22] and following internalization of this complex the DT domain is released into the cytosol, resulting in apoptotic cell death [23, 24] (Figure 1) [21].

Figure 1. Structure and mechanism of action of tagraxofusp. ADP, adenosine diphosphate; IL-3, interleukin-3; IL-3R, IL-3 receptor. Reproduced under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) from Alkharabsheh O, Frankel AE. Clinical Activity and Tolerability of SL-401 (Tagraxofusp): Recombinant Diphtheria Toxin and Interleukin-3 in Hematologic Malignancies. Biomedicines. 2019;7:6. [21] Minor changes (e.g. color) were made.

The safety and efficacy of TAG have been evaluated in a multistage, multicenter, single-arm trial in adults with treatment-naive and R/R BPDCN [25–27]. This ­pivotal study consisted of four stages: (1) dose finding, (2) dose expansion, (3) pivotal/confirmatory, and (4) continued access. This represents the largest trial, and first prospectively designed study with prespecified multisystem endpoints, conducted to date in patients with BPDCN. The trial developed the first formal response criteria for BDPCN based on evaluating ­disease in the most commonly involved disease ­compartments (skin, bone marrow, lymph nodes, peripheral blood, and viscera). A CR was thus defined as the ­disappearance of disease in each site of initial disease, while the new category of ‘clinical complete response’ (CR [clinical] with minimal skin abnormality [CRc]) was identified for those patients who had a CR in all nonskin disease sites and marked clearance of all skin lesions from baseline but had residual skin abnormalities that were not indicative of active BPDCN; this CRc was validated as a measure of clinical benefit [26].

The initial results of the pivotal trial [26], reporting data from 47 patients, demonstrated that TAG ­monotherapy was tolerable and resulted in high and durable response rates, which led to the approval of TAG by the FDA. More recently, longer-term data following a median follow-up time of 34 months of the 89 patients who received 12 µg/kg/day TAG, including those enrolled in the Stage 4 continued-access phase, have been reported [27]. In treatment-naive patients (n = 65) with a median age of 68 years (range 22–84 years), the overall response rate (ORR) was 75%, with 57% achieving complete response (CR)/CR with residual skin abnormality not indicative of active ­disease (CRc). The time to CR/CRc was rapid and durable (median time to response = 39 days; median duration of CR/CRc = 24.9 months). Of those patients who achieved remission, 51% were bridged to SCT; these patients had a median OS of 38.4 months and 72% remained in remission for ≥12 months post-SCT.

In patients with R/R disease (n = 19) with a median age of 72 years (range 44–87 years), the ORR was 58%, which was notable given that little to no meaningful efficacy of other treatment regimens has been ­previously reported in R/R disease [4, 13, 28, 29]. Response to TAG was also rapid in these patients with R/R disease, occurring after 1–2 cycles.

The pivotal trial also demonstrated that TAG had a predictable and manageable safety profile with no cumulative toxicity over multiple cycles. The most ­frequent AEs were elevated liver enzymes (alanine aminotransferase [ALT], 64%; aspartate aminotransferase [AST], 60%) and hypoalbuminemia (51%), which were mostly limited to the first cycle of treatment. The most serious AE, capillary leak syndrome (CLS), occurred in 21% of patients and predominantly in the first cycle. Most events were nonsevere (grade 2, n = 12 [14%]) and resolved; in addition, three (3%) patients had a grade 3 event, two (2%) had a grade 4 event, and three (3%) had a grade 5 event [27].

Various drugs commonly used for the treatment of patients with cancer have been seen to induce CLS. Examples include chemotherapy [30], bacterial toxin-based targeted therapies [31–34], and immune checkpoint ­inhibitors [35, 36], although recent evidence suggests that the agents most likely to cause drug-induced CLS are gemcitabine, monoclonal antibodies, and therapeutic growth factors or cytokines [37, 38]. The etiology of anticancer drug-induced CLS is not fully understood, although a toxic effect of the agent on the vascular endothelium likely plays a role [39]. Consequently, the characteristics of drug-induced CLS may differ according to the toxicity of the anticancer drug that is administered. In contrast with other anticancer agents, such as gemcitabine, nivolumab, and ipilimumab, TAG-associated CLS tends to occur early in treatment, generally resolves quickly without the need for permanent drug discontinuation, and usually does not recur in subsequent cycles. It also presents differently, with hypoalbuminemia and presence of edema, weight gain, and hypotension/hemodynamic instability as the primary symptoms [26, 27].

While CLS is often a serious AE and can be fatal, the condition can be resolved with proper treatment and management [33, 40]. Strategies for managing TAG-associated CLS were developed during the course of the pivotal trial and include delaying and/or ­withholding doses, administering intravenous (IV) albumin and glucocorticoids, and managing the intravascular volume (see Table 1). To reduce the risk of developing CLS, clinicians should ensure that a patient’s serum albumin is ≥3.2 g/dL prior to administering the first dose of TAG. Data from the pivotal trial demonstrated that adherence to these guidelines, together with ­vigilant monitoring, could mitigate the risk of CLS and result in timely resolution of such events [26, 27].

Table 1. Recommendations for recognizing and managing CLS.

Category	Recommendation
General	For management of CLS specifically, it is critical that patients and the interdisciplinary team receive extensive education for early recognition Of note, there is no absolute definition or definite treatment for CLS, and presentation can vary from patient to patient Closely follow the package label – pay special attention to baseline albumin, creatinine, liver function tests, and daily weights Early treatment is crucial, as CLS can rapidly become fatal, and requires aggressive, team-based interventions
Labs	Laboratory assessments should occur at least daily during treatment, including albumin, ALT, AST, and creatinine Extensive cardiopulmonary assessment should be performed prior to TAG administration (volume status, EF, history of cardiac or pulmonary issues)
TAG dosing	Lead physician approves each dose Dose should be administered midday, when all staff are on duty Therapy should begin on a Monday, if possible
Weight	Weight should be measured daily The same scale should be used daily for an individual patient
Albumin	Early adoption of albumin infusion and measuring drop in albumin to identify CLS is recommended Albumin should be administered once or twice a day when CLS occurs Securing doses of IV albumin before initiating TAG is necessary, as TAG should not be administered if albumin is not available at the center

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CLS, capillary leak syndrome; EF, ejection fraction; IV, intravenous; TAG, tagraxofusp.

As mentioned above, TAG treatment has been associated with elevations in ALT and AST. These generally occur in the first cycle of treatment and are reversible following dose interruption. As per the prescribing information [41], patients receiving TAG should have ALT and AST monitored prior to each TAG infusion. If transaminases rise to greater than five times the upper limit of normal (ULN), TAG should be withheld, and treatment resumed upon resolution or normalization.

Thrombocytopenia may occur, although this is ­generally within cycle 1, with no evidence of cumulative toxicity. Patients’ platelet counts should be monitored regularly while on TAG.

A European named patient program (NPP) was ­initiated in August 2019 to enable patient access to TAG. A noninterventional, retrospective, multicenter, single-arm study evaluated TAG in adult patients with BPDCN from the NPP in a real-world setting [42]. In total, 40 adult patients were enrolled; 22 (55%) patients were treatment-naive and 18 (45%) had R/R disease. The majority were male ­(treatment-naive, 86%; R/R, 89%) and had skin involvement at initial skin diagnosis (treatment-naive, 77%; R/R, 67%) [42, 43]. In the treatment-naive setting, the median follow-up time was 10 months (range 0.2–25). An ORR of 89% (95% CI, 65–99) was reported, with a CR rate of 67% and a partial response (PR) rate of 22%. The median time to ORR was 21 days (range 11–74), and the median time to CR was 29 days (range 11–58). TAG enabled 50% (11/22) of patients to be bridged to allogeneic SCT. Median OS was 20 months (95% CI, 10–not reached) [43]. In the R/R setting, the ORR was 57% (95% CI, 18.4–90.1), including 14% of patients with CR and 43% of patients with PR; allogeneic SCT was undertaken in 29% of patients. With a median follow-up of 9.5 months (range 1.0–25.0), the median OS was 4.3 months in patients with R/R disease [42]. In this real-world setting, TAG was also seen to have a manageable safety profile and the majority of grade 3/4 AEs or serious AEs occurred in cycle 1. In total, 10 (45%) treatment-naive patients and 11 (61%) patients with R/R disease experienced CLS. The majority of events were grade 1/2, with one grade 4 event reported in the R/R setting; importantly, no grade 5 events occurred. CLS was managed by TAG dose interruption and IV albumin supplementation, and all events resolved [42, 43]. The absence of any grade 5 CLS events attests to the effectiveness of adherence to CLS monitoring and management guidelines in the real-world setting.

Determining patient eligibility for TAG

Several guidelines recommend TAG as a preferred option for first-line therapy for all patients with newly diagnosed BPDCN [44, 45]. TAG has proven successful in treating patients across all age groups [26], including middle-aged patients, young, fit patients, and those older patients who are considered unfit to receive intensive cytotoxic chemotherapy regimens. In a subgroup analysis from the pivotal study, similar rates of CR/CRc were seen in patients aged <65 years and in those aged 65 and above (58% and 56%, respectively) [27].

Subgroup analyses demonstrated that TAG was also efficacious in those patients who may be ­considered higher risk, with promising rates of CR/CRc seen in patients with cardiac history (59%), patients who had bone marrow (BM) blasts ≥5% (53%), and in those who had two or more sites of disease (51%). TAG also enabled patients in each of these subgroups to be bridged to SCT; of those patients who achieved a CR/CRc following TAG treatment, 41% of patients aged ≥65 years, 40% of those who had a cardiac history, 41% of those with BM blasts ≥5%, and 48% of those who had two or more disease sites were bridged to SCT. Importantly, of the patients who achieved CR/CRc and were not transplanted, four patients had prolonged responses (>6 months), including two patients with response of 27 and 52 months, respectively [27].

A recent patient case series has also shown that TAG can be used successfully in patients with CNS involvement. Five adult patients with BPDCN who were enrolled in the TAG NPP were assessed for CNS ­involvement. Three patients with confirmed CNS involvement received intrathecal (IT) chemotherapy (cytarabine and dexamethasone with or without methotrexate) with each TAG cycle (median number of cycles: three); two patients without CNS involvement received IT chemotherapy as prophylaxis. All patients achieved a response, irrespective of baseline CNS involvement, and no unexpected safety events occurred when TAG was administered concomitantly with CNS prophylaxis or treatment [46].

TAG is FDA approved for the treatment of adult and pediatric (≥2 years of age) patients. Initial data from three pediatric patients with BPDCN treated with TAG under compassionate use demonstrated a safety profile similar to that seen in adults. Significant and rapid clinical improvement was observed in two of the three pediatric patients after treatment with TAG, although these responses were transient [47]. A recent case series of eight pediatric/young adults with treatment-naive and R/R BPDCN also demonstrated the efficacy of TAG. Three of eight (38%) patients achieved a CR and five of eight (63%) were bridged to SCT, including two of three (67%) patients who had R/R disease. TAG demonstrated a manageable and predictable safety profile [48].

TAG as an induction therapy and bridge to SCT

Based on current clinical experience, and in line with the recently published position statement from the North America BPDCN Consortium (NABC) [49], the treatment goal for all patients with BPDCN should be SCT in CR1 unless otherwise contraindicated. SCT ­represents a potential curative option [12] and various studies have demonstrated that patients who ­underwent SCT had much better OS than those who did not [4, 7, 11, 12, 17]. An allogeneic SCT is the preferred option, and currently a donor for allogeneic transplant can be found for the majority of patients. For those patients who achieved CR following radiotherapy or on chemotherapy regimens but are ineligible for SCT, outcomes are poor with high rates of relapse and shorter OS [17].

TAG first-line has been shown to induce high rates of durable response and enable many patients to be bridged to SCT. In clinical practice, many patients have been seen to have an early response to TAG, with little to no myelosuppression. This is in line with the results of the pivotal trial, where 57% of patients achieved a CR/CRc in cycle 1 after five doses, 47% had a CR/CRc after only receiving up to three doses, and the median time to first CR was 39 days (range 14–131) [27]. Hence, response should be assessed mid- to end of cycle 1, although some patients may require two to four cycles to achieve their best response. Response assessments comprise skin exams, biopsies (including bone marrow biopsies and aspirates), imaging, and laboratory results, with lumbar punctures highly recommended to rule out the possibility of CNS disease, as per the recommendations of the NABC [49]. Positron emission tomography (PET) scans are also recommended in patients where extramedullary disease and/or lymphadenopathy is suspected [42].

TAG as long-term treatment

Some patients, despite achieving a durable response with TAG, may not be able to be bridged to SCT (e.g. failure to find a donor). In this instance, the patient may receive TAG as a long-term treatment, or in sequence with other therapies. The long-term analysis of the pivotal trial of TAG in patients with BPDCN, with a median follow-up time of 34 months and up to 76 cycles administered, demonstrated the drug’s safety and efficacy [27]. Long-term administration of TAG is feasible and has been achieved with no evidence of bone marrow or other cumulative toxicities over multiple cycles; of note, CLS occurs almost exclusively during the first cycle of treatment, so is not an AE of concern over long-term therapy. The possibility of long-term treatment with TAG offers a potential alternative treatment path for patients who decline or are unsuitable for SCT due to issues such as comorbid conditions, lack of a donor match, older age, or lack of adequate support that is necessary for transplantation.

Administration of TAG

As per the US prescribing information [41] and the EU summary of product characteristics [50], TAG is infused IV at a recommended dose of 12 µg/kg/day over 15 minutes once daily on days 1–5 of a 21-day cycle. Repeated cycles of TAG treatment are recommended until patients have evidence of progressive disease or ­experience unacceptable toxicity. Dosing within a TAG cycle may be modified, to accommodate dose delays up to day 10 (i.e. a 10-day dosing window), in response to a number of clinical or laboratory value changes, including serum albumin, daily weight, ALT or AST ­levels, serum creatinine, blood pressure, heart rate, or hypersensitivity, as detailed in Table 2 [41]. If a patient receives fewer than all five doses during the first treatment cycle, they may, per physician discretion, resume the recommended five doses in subsequent cycles.

Table 2. Recommended TAG dosage modifications [41].

Parameter	Severity Criteria	Dosage Modification
Body weight	≥1.5 kg over pretreatment body weight on prior treatment day	Interrupt TAG dosing until the relevant CLS sign/symptom has resolved
Body temperature	≥38 °C	Withhold TAG until body temperature is <38 °C
Serum creatinine	>1.8 mg/dL (159 micromol/L) or creatinine clearance <60 mL/minute	Withhold TAG until serum creatinine resolves to ≤1.8 mg/dL (159 micromol/L) or creatinine clearance ≥60 mL/minute
Serum albumin	<3.5 g/dL or reduced ≥0.5 g/dL from value measured before initiation of the current cycle	Interrupt TAG dosing until the relevant CLS sign/symptom has resolved
AST or ALT	Increased >5 times the upper limit of normal	Withhold TAG until transaminase elevations are ≤2.5 times the upper limit of normal
Systolic blood pressure	≥160 mmHg or ≤80 mmHg	Withhold TAG until systolic blood pressure is <160 mmHg or >80 mmHg
Heart rate	≥130 bpm or ≤40 bpm	Withhold TAG until heart rate is <130bpm or >40bpm
Hypersensitivity reactions	Mild or moderate	Withhold TAG until resolution of any mild or moderate hypersensitivity reaction. Resume TAG at the same infusion rate
	Severe or life-threatening	Discontinue TAG permanently

ALT, alanine aminotransferase; AST, aspartate aminotransferase; bpm, beats per minute; CLS, capillary leak syndrome; TAG, tagraxofusp.

The initial cycle of TAG should be administered in a hospital setting, although subsequent cycles of TAG are generally administered in outpatient infusion centers. The principal reason for initial hospitalization of patients receiving TAG is to optimize the management of AEs, should they occur. Patients should be observed for at least 24 hours following the last infusion of the first cycle in the inpatient setting to monitor for the potential onset of any event, and CLS in particular. For subsequent cycles administered in an outpatient setting, patients may be monitored for the onset of AEs for at least 4 hours. Table 1 outlines some general guidelines for managing and recognizing CLS, as its presentation often varies between patients; below, a three-pronged approach is described that we recommend practitioners adopt [51]:

1. All healthcare professionals who are involved in the administration of TAG should receive education on the early recognition/identification of CLS, and prior to TAG administration, clinicians must establish that a patient has adequate cardiac function.

2. The package insert should be closely followed regarding baseline and follow-up values of albumin, creatinine, liver function tests, and daily weights. Special attention should be given to baseline albumin and when or how to replace with IV albumin. If baseline albumin is <3.2 g/dL, TAG should not be initiated, as patients with lower baseline albumin who then have a rapid drop in albumin levels during therapy are at highest risk for CLS. The ­common signs and symptoms of CLS (decreased albumin, weight gain, edema, and decreased blood pressure) should be assessed before each dose. If any signs or symptoms of CLS are present, then the TAG dose should be withheld (Supplementary Table 1).

3. When CLS occurs, early and aggressive team-based interventions are necessary, as it can rapidly worsen. CLS can be treated via administration of IV albumin replacement, ­corticosteroids, fluid diuresis (or fluid replacement), and early administration of vasopressors to maintain mean arterial pressure. TAG ­administration may be resumed once albumin levels, weight gain, and hypotension resolve, and ­provided the patient did not require treatment for hemodynamic instability [41].

There have been rare instances when a hypersensitivity reaction occurred with TAG treatment. Such reactions can manifest in a variety of presentations, including rash, pruritus, stomatitis, swelling of the face, and wheezing. If a reaction occurs, then institutional ­hypersensitivity protocols should be followed. In the rare occurrence of a severe and life-threatening ­reaction, TAG should be discontinued permanently.

Some patients may also experience elevations in ALT or AST to more than five times the upper limit of normal. In this instance, TAG administration should be put on temporary hold and possibly discontinued for the remainder of the cycle. Treatment can resume once the ALT/AST ­levels have improved, or in the following cycle.

Multidisciplinary care teams and patient engagement

Formal, structured interprofessional care and ­communication is necessary for the optimal treatment of patients with TAG [49, 52–55]. As best practice, the multidisciplinary team, which should include medical oncologists, dermatologists, pharmacy staff, nursing, inpatient teams, and outpatient teams, should be alerted and convened prior to initiating treatment with TAG in order to discuss the patient, review the ­treatment plan and management/mitigation of any potential AEs, and solicit feedback to optimize efficient care [52–55]. The bone marrow transplant team should also be engaged early in the process.

Adopting a patient-centered approach and having personalized management plans are very important to ensuring effective treatment, as additional services, support programs, and resources, such as financial planning, nutrition counseling, support groups, and integrative therapies (including massage and acupuncture), may be required. Central to the patient-centric approach is managing patients’ expectations. Furthermore, patients should receive an in-depth overview of TAG dosing and administration that includes dispensing differences in the in- vs outpatient setting, a review of potential side effects, and direction that they must notify the care team if new or different symptoms emerge. Education for patients should include measuring weight on the same scale daily and monitoring (including photographs) disease-related skin lesions and rashes. Other considerations to review with patients include whom to contact at different points of care and different cycles in their treatment regimen, and ensuring they know the key members of their multidisciplinary healthcare team. Finally, patients should be made aware of the external BPDCN educational resources available to them (Supplementary Materials).

Case studies

To illustrate the real-world management of patients with BPDCN receiving TAG, we present two case ­studies: one of a patient with CNS involvement, and one of a patient who was successfully bridged to SCT following TAG treatment.

Patient with CNS involvement

An 80-year-old male presented with asymptomatic ­erythematous to violaceous nodules on his forehead, arms, chest, abdomen, and back. He was evaluated by a dermatologist and a skin biopsy confirmed a diagnosis of BPDCN. He underwent initial imaging for staging purposes, which included a computed tomography (CT) scan of the neck/chest/abdomen/pelvis, and demonstrated involvement in the right lingual tonsil, lymphadenopathy in multiple areas (pericardiophrenic, gastrohepatic/periportal, and retroperitoneal), and splenomegaly (∼18 cm). A bone marrow biopsy showed 10% BPDCN involvement in a hypercellular marrow (80% cellularity), although no increases in blasts were observed. Flow cytometry/immunohistochemistry ­analysis showed positivity for CD123, CD4, CD56, and TCL1. Next-generation sequencing, which the NABC has recently advocated as an essential part of BPDCN ­diagnostic workup [50], was also performed and revealed multiple genomic abnormalities including TET2, NRAS, ASXL1, SRSF2, and ZRSR2 mutations. The patient underwent a diagnostic lumbar puncture to complete staging evaluation. The cerebrospinal fluid flow cytometry analysis was positive for CD56+ atypical cells, which was consistent with BPDCN involvement.

The patient was admitted for the first cycle of ­treatment with TAG in combination with IT chemotherapy. Following the first dose, the patient had fever, ­hypotension, tachycardia, a drop in urinary output, peripheral edema, and an albumin drop from 4.0 to 2.0 g/dL. Grade 3 CLS was diagnosed, and the patient was treated with IV albumin and furosemide, IV ­methylprednisone, and withholding/delaying of the second TAG dose. He was treated with the second dose on day +5 with recurrent CLS (managed with further IV albumin, furosemide, and methylprednisone), and received dose 3 on day 8 and dose 4 on day 9. CLS symptoms resolved after the completion of cycle 1 and there was no recurrence of CLS with subsequent treatment cycles. The patient was able to complete a total of four out of five doses in the first cycle.

After completion of the second treatment cycle, the patient had a PR, with all lymph nodes showing an ∼33% reduction; the spleen remained unchanged, but the bone marrow and CNS were clear of any ­disease. Cycles were planned every 28 days due to thrombocytopenia, and the patient continued on ­treatment with monthly IT methotrexate. The patient went on to achieve a CR, and BPDCN in the CNS ­compartment remained in full remission. In total, 14 cycles of TAG with alternating IT methotrexate and IT cytarabine were administered. After over 13 months on therapy with TAG, the patient experienced disease relapse presenting as a single skin nodule. He then enrolled in a clinical trial, where he received five cycles of PVEK. Following an initial response, the patient’s disease relapsed again and was treated with three cycles of venetoclax and azacitidine, after which the disease went into remission and the patient then opted to receive home hospice care. The patient died 32.5 months following his initial diagnosis.

Patient bridging to SCT

A 65-year-old male with no other past medical history presented with a right-sided scalp lesion. The patient was treated with antibiotics with no effect. Several months later, the patient underwent a biopsy of the scalp lesion, which showed a CD123, CD4, CD56, BCL2-positive phenotype, consistent with BPDCN. The following month, a bone marrow biopsy confirmed the presence of BPDCN, with ∼20% of cells positive for CD123, CD4, and CD56, but negative for CD34, CD3, and terminal deoxynucleotidyl transferase. A CT chest/abdomen/pelvis examination revealed no pathologic nodes by size criteria or other findings, but the patient had larger retropharyngeal, periportal, and inguinal bilateral nodes, but none exceeding 1.5 cm. The left inguinal nodal area was palpable on clinical exam. In July 2019, the patient had a transthoracic echocardiogram ejection fraction of 62%, and repeat bone marrow evaluation showed 50% BPDCN involvement with the karyotype 46,XY. A targeted sequencing panel revealed: ASXL1 NM_015338 c.2077C > T p.R693* in 40.6% of 246 reads; TET2 NM_001127208 c.2381C > A p.S794* in 48.3% of 588 reads; TET2 NM_001127208 c.2626C > T p.Q876* in 46.7% of 3193 reads; and ZRSR2 NM_005089 c.376C > T p.R126* in 61.1% of 144 reads.

TAG treatment was initiated, and the patient received all five doses in the first cycle. After the final dose, the patient experienced an infusion-related reaction, but this resolved following treatment with meperidine. No CLS was observed. The patient had a dramatic response to TAG treatment with resolution of all skin lesions, including the bulky areas on the scalp, chest, and back, as well as complete regression of the left inguinal node after one cycle. Cycle 2 of TAG was administered with daily 100 mg methylprednisolone sodium succinate ­premedication (increased from 50 mg), and with this there were no further infusion-related reactions. Following cycle 3 of TAG, the disease was in complete remission with no evidence of BPDCN in the bone ­marrow, a negative PET-CT, and clinically negative skin examination. The patient was bridged to reduced-intensity conditioning allogeneic SCT. On day 100, PET-CT, bone marrow evaluation (including flow cytometric analysis), and skin examination revealed the patient was in full remission. Ten months post-SCT, the patient had a recurrence in the skin and enrolled in a clinical trial (NCT04024761), where he received an infusion of donor memory-like natural killer cells. The patient achieved a CR for 6 months. However, 17 months after transplantation, the patient experienced widespread relapse, including disease in the CNS. Salvage treatment with venetoclax and azacitidine was initiated followed by donor lymphocyte infusion, which resulted in a CR. The patient died 2 years post-SCT as a result of severe graft-vs-host disease and infection with no indication of active BPDCN.

TAG in combination with other agents

A number of studies are ongoing to explore the safety and efficacy of regimens featuring TAG as the backbone therapy combined with other agents, in order to further explore the utility of TAG and provide additional treatment options for patients with BPDCN. For example, TAG is being combined with BCL2 inhibitors such as venetoclax, on the basis of the observation that primary BPDCN cells can express and are dependent on BCL2 [56, 57]. Azacitidine is another potential combinatorial agent, as it can reverse the downregulation of the ­diphthamide synthesis pathway and loss of the intracellular target for diphtheria toxin, a process associated with TAG resistance [58]. A phase 1 trial is currently investigating the combination of TAG with azacitidine and venetoclax in patients with treatment-naive and R/R BPDCN, AML, or myelodysplastic syndrome [59]. Initial results demonstrate that of the three patients with R/R BPDCN who received TAG, azacitidine, and venetoclax, one achieved a CRc and one patient achieved a CR with incomplete hematologic recovery (CRi), and both were successfully bridged to allogeneic SCT. Of the nine treatment-naive patients with AML, eight achieved a best response of CR or CRi, and four of the eight patients were bridged to SCT; three remained on therapy. No unexpected safety signals have been reported to date for this trial [60]. TAG is also being investigated as part of a regimen containing venetoclax and hyper-CVAD [61] in patients with BPDCN, as well as a posttransplant maintenance treatment as monotherapy in patients who have CD123+ AML, myelofibrosis, or chronic myelomonocytic leukemia [62].

Conclusions

Herein, we present best practices and real-world insights on treating patients with BPDCN using the CD123-directed agent TAG as monotherapy. Treatment with TAG has been approved for frontline and subsequent-line therapy for all patients aged ≥2 years diagnosed with BPDCN in the US and approved by the EMA for treatment-naive adult patients with BPDCN. Additionally, data illustrate that TAG with IT chemotherapy in patients with BPDCN was associated with promising efficacy, without significant safety effects. These data are of interest, given that several guidelines advocate administering CNS-directed IT ­chemotherapy when patients with BPDCN have CNS ­disease involvement [44, 45].

The most serious AE is CLS, although it is noteworthy that data in a real-world setting showed few severe cases [42, 43]; the majority of CLS events are mild to moderate in nature and can be effectively controlled by following monitoring and management guidelines. Overall, the safety profile of TAG is predictable and manageable, with a lower overall risk of treatment-related mortality vs chemotherapy and no association with prolonged bone marrow suppression.

TAG induces complete remissions in many patients and can be successfully used to bridge patients to SCT; in those patients who do not wish to be ­transplanted or are not eligible, TAG may also be used for long-term outpatient treatment.

Acknowledgments

Editorial and medical writing assistance was provided by Joanne Franklin, PhD, CMPP, from Aptitude Health, The Hague, the Netherlands, and funding of this was supported by Stemline Therapeutics Inc., NY, USA. The authors are fully responsible for all content and editorial decisions for this manuscript.

Disclosure statement

Naveen Pemmaraju: Consultancy fees: Pacylex Pharmaceuticals, Astellas Pharma US, ImmunoGen, Inc, Bristol-Myers Squibb Co., Cimeio Therapeutics AG, EUSA Pharma, Menarini Group, Blueprint Medicines, CTI BioPharma, ClearView Healthcare Partners, Novartis Pharmaceutical, Neopharm, Celgene Corporation, AbbVie Pharmaceuticals, Pharma Essentia, Curio Science, DAVA Oncology, Imedex, Intellisphere, CancerNet, Harborside Press, Aptitude Health, Medscape, Magdalen Medical Publishing, OncLive, CareDx, Patient Power, Physcican Education Resource (PER). Participation on Data Safety Monitoring Board or Advisory Board: Pacylex Pharmaceuticals, Astellas Pharma US, ImmunoGen, Inc, Bristol-Myers Squibb Co., Cimeio Therapeutics AG, EUSA Pharma, Menarini Group, Blueprint Medicines, CTI BioPharma, ClearView Healthcare Partners, Novartis Pharmaceutical, Neopharm, Celgene Corporation, AbbVie Pharmaceuticals, Pharma Essentia, Curio Science, DAVA Oncology, Imedex, Intellisphere, CancerNet, Harborside Press, Aptitude Health, Medscape, Magdalen Medical Publishing, OncLive, CareDx,, Patient Power, Physician Education Resource (PER). Leadership role: ASH Committee on Communications, ASCO Cancer. Net Editorial Board, Dan’s House of Hope, Karger Publishers. Yazan F. Madanat: Consultancy fees: Blueprint Medicinces, GERON, OncLive. Honoraria: Blueprint Medicinces, GERON, OncLive, Sierra Oncology, Stemline Therapeutics, Morphosys, Taiho Oncology, Novartis, Rigel Pharmaceuticals. Support for meetings/travel: Blueprint Medicines, Morphosys. David Rizzieri: Consultancy fees: Amgen, Celltrion, Kite, Arog Pharmaceuticals, Pharmacyclics, Pfizer, Novartis, Sanofi-Aventis, Jazz, AbbVie, Seattle Genetics, Incyte, Gilead. Honoraria: Celgene, Teva, Amgen, Celltrion/Teva, Kite, Arog Pharmaceuticals, Pharmacyclics, Pfizer, Novartis, Sanofi-Aventis, Jazz, AbbVie, Seattle Genetics, Incyte, Gilead. Salman Fazal: Honoraria: Amgen, Incyte Corporation, Jazz Pharmaceuticals, Gilead, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, Sanofi Genzyme, Taiho Pharmaceuticals, Servier Pharmaceuticals, Janssen Pharmaceuticals, CTI Biopharm, Pharmaessentia, Blueprint pharmaceuticals, Takeda Pharmaceuticals, Karyopharm. Raajit Rampal: Consultancy fees: Constellation, Incyte, Celgene, Promedior, CTI, Jazz Pharmaceuticals, Blueprint, Stemline, Galecto, Pharmessentia, Abbvie. Research funding: Incyte, Stemline, and Constellation. Gabriel Mannis: Consultancy fees: AbbVie, Agios, Astellas, BMS/Celgene, Genentech, Macrogenics, Servier, Stemline. Research funding: Astex, Celgene/BMS, Forty Seven/Gilead, Glycomimetics, ImmuneOnc, Immunogen, Jazz, Syndax. Eunice S. Wang: Consultancy fees: AbbVie, Astellas, BMS, Daiichi Sankyo, Genentech, Gilead, GlaxoSmithKline, Janssen, Jazz, Kite Pharmaceuticals, Kura Oncology, Novartis, Pfizer, Stemline Therapeutics, Takeda. Honoraria: Stemline Therapeutics, Kura, Pfizer, DAVA Oncology. Data Safety or Advisory Board participation: AbbVie, Gilead. James Foran: Consultancy fees: Revolution Medicine. Honoraria: Novartis, Servier and Pfizer. Research funding: AbbVie, Boehringer Ingelheim, Actinium Pharmaceuticals, Aprea Therapeutics, Aptose Biosciences, H3 Biomedicine, Kura Oncology, Tolero Pharmaceuticals, Trillium Therapeutics, Xencor and Takeda/Millennium. Andrew A. Lane: Consultancy fees: Cimeio Therapeutics, IDRx, Jnana Therapeutics, N-of-One, ProteinQure, Qiagen. Research funding: AbbVie, Stemline Therapeutics.

Correction Statement

This article was originally published with errors, which have now been corrected in the online version. Please see Correction (http://dx.doi.org/10.1080/10428194.2024.2327797)

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