Continuing Education Activity

Blastic plasmacytoid dendritic cell neoplasm is an uncommon myeloid cancer. Blastic plasmacytoid dendritic cell neoplasm typically manifests as cutaneous lesions with or without the involvement of extramedullary organs and leukemic spread. Given the clinical obscurity of blastic plasmacytoid dendritic cell neoplasm, it might be challenging to distinguish it from benign skin lesions or other neoplastic conditions with cutaneous involvement, such as T-cell lymphoma. Tagraxofusp is a Food and Drug Administration (FDA)-approved first-line treatment for blastic plasmacytoid dendritic cell neoplasm in adults and children older than two years. If tagraxofusp is unavailable or in children under two, chemotherapy regimens for acute myeloid leukemia, acute lymphoid leukemia, and myelodysplastic syndrome are appropriate alternatives. Unfortunately, relapse is common, and overall survival rates are dismal. In adults, allogeneic stem cell transplantation improves overall survival during initial remission.

Objectives:

• Outline the etiology and epidemiology of blastic plasmacytoid dendritic cell neoplasm.
• Identify the clinical presentation and diagnostic evaluation of blastic plasmacytoid dendritic cell neoplasm.
• Explain the management of blastic plasmacytoid dendritic cell neoplasm.
• Describe the multidisciplinary approach for blastic plasmacytoid dendritic cell neoplasm management.

Introduction

Blastic plasmacytoid dendritic cell neoplasm is a rare, clinically aggressive hematologic malignancy characterized by cutaneous lesions, bone marrow involvement, and leukemic dissemination. Blastic plasmacytoid dendritic cell neoplasm terminology has evolved over decades along with the underlying pathophysiology process. It was previously known as acute agranular CD4-positive natural killer (NK) cell leukemia in 1995.[1] After the World Health Organization (WHO) discovered that it originated from plasmacytoid dendritic cells in 2008, the term blastic plasmacytoid dendritic cell neoplasia was coined.[2]

Etiology

No known environmental or genetic risk factors predispose to the development of blastic plasmacytoid dendritic cell neoplasm. Blastic plasmacytoid dendritic cell neoplasm can occur as an isolated neoplasm or in conjunction with other hematologic neoplasms.

A prior history of hematologic malignancies, such as myelodysplastic syndrome, chronic myeloid leukemia, chronic myelomonocytic leukemia, and acute myeloid leukemia, has been reported in 10 to 20% of patients diagnosed with blastic plasmacytoid dendritic cell neoplasm.[3][4][5] Despite this, the association between blastic plasmacytoid dendritic cell neoplasm and other myeloid malignancies remains elusive.

Epidemiology

Blastic plasmacytoid dendritic cell neoplasm is a rare hematologic neoplasm, and the exact incidence is unknown. Estimating blastic plasmacytoid dendritic cell neoplasm incidence is difficult due to changing nomenclature and lack of defining criteria before the 2008 WHO classification system. Blastic plasmacytoid dendritic cell neoplasm represents 0.7 percent of primary cutaneous skin malignancies.[6] However, the incidence could be underestimated as it could present without skin involvement.[3] 

Blastic plasmacytoid dendritic cell neoplasm affects people of all races and geographic regions. Blastic plasmacytoid dendritic cell neoplasm has been reported in patients of all ages, but it is most prevalent in adults; most patients are older adults, with a median age of diagnosis of 65 to 67 years. There is a slight male predominance, with a male-to-female ratio of about 2.5:1.[6][4][5]

Pathophysiology

The progenitors of plasmacytoid dendritic cells were identified as the normal variant of blastic plasmacytoid dendritic cell neoplasm in 2008.[7][8] Further research revealed that blastic plasmacytoid dendritic cell neoplasm is related to myeloid resting plasmacytoid dendritic cells.[9]

Normal plasmacytoid dendritic cells can be derived from either myeloid or lymphoid lineages. Both common dendritic cell progenitors and common lymphoid progenitors can differentiate into plasmacytoid dendritic cells and produce type 1 interferons (IFN-I). Still, only myeloid-derived plasmacytoid dendritic cells can process and express the antigen.[10]

An intricate transcriptional network generates common dendritic cell progenitors and common lymphoid progenitors from bone marrow hematopoietic stem cells (HSCs). During this process, progressive lineage commitment results in the acquisition of alternate cell pathways.[11]

The commitment to plasmacytoid dendritic cell lineage is regulated by various transcription factors governing the differentiation of myeloid and lymphoid hematopoietic progenitors.[12] TCF, BCL11A, and IRF8 have been identified as the primary transcription factors determining plasmacytoid dendritic cell formation. TCF4, an E-box transcription factor, regulates both differentiation and maintenance of the plasmacytoid dendritic cell lineage.[13]

The protein known as B-cell lymphoma/leukemia 11A, or BCL11A, is required to form plasmacytoid dendritic cells. BCL11A, in combination with the transcription factor TCF4, is used to distinguish the gene expression profile of plasmacytoid dendritic cells from that of myeloid dendritic cells, which lack the BCL11A protein but express a high level of the BCL6 protein.[14] The IFN regulatory factor 8, IRF8, promotes early dendritic cell lineage commitment in lymphoid-primed multipotent progenitors and common dendritic cell progenitors, and its expression is upregulated during this transformation.[12][15] 

IRF-8 regulates different hematopoietic lineages and, if mutated, may cause plasmacytoid dendritic cell cytopenia and immunodeficiency.[16] As normal plasmacytoid dendritic cells, blastic plasmacytoid dendritic cell neoplasm cells express BCL11A and TCF4, while IRF8 may be mutated or mis-spliced.[11] The functional effects and the tumor's propensity to produce IFN-I due to this repercussion remain unknown. 

Histopathology

Blastic plasmacytoid dendritic cell neoplasm is most commonly characterized by a widespread, monomorphous infiltration of medium-sized blasts with irregular nuclei, fine chromatin, and single to multiple nucleoli.[6][4][17] Giemsa staining typically reveals a narrow, grayish-blue, and agranular cytoplasm rim. The number of mitoses varies, and the Ki-67 rate ranges from 20 to 80%.[11]

There is substantial dermal infiltration in the skin, which extends into the subcutaneous fat. In most cases, the epidermis and adnexa are not involved.[18] There is diffuse involvement of the interfollicular regions and medulla in lymph nodes, with B-cell follicles being more commonly unaffected. Bone marrow involvement could range from slight infiltration to extensive marrow replacement.[6] Neoplastic cells could exhibit cytoplasmic microvacuoles and pseudopodia on peripheral blood and bone marrow smears.[4]

History and Physical

The most prominent characteristic of blastic plasmacytoid dendritic cell neoplasm is skin lesions, followed by involvement of the bone marrow and lymphadenopathy.[4] (Figure 1)

Skin is the most common and first affected organ, although blastic plasmacytoid dendritic cell neoplasm is rarely present without skin involvement. Skin lesions range from brown to violaceous bruise-like lesions, plaques, or nodules.[5] Lesions on the skin could be solitary or widespread. It has been hypothesized that the skin may serve as a protective barrier against the initial transmission of disease.[19]

The production of skin-migration molecules such as cutaneous lymphoma-associated antigen (CLA) and CD56 by tumor cells has been associated with the dermatological phenotypic expression of blastic plasmacytoid dendritic cell neoplasm.[11]

The other signs and symptoms of blastic plasmacytoid dendritic cell neoplasm include cytopenias, lymphadenopathy, hepatomegaly, and splenomegaly.[3][4] There have also been reports of involvement of the mucosal membrane, tonsils, paranasal cavities, lungs, eyes, and central nervous system (CNS).[3][4]

Evaluation

Skin biopsy with routine histology and immunophenotype is an essential diagnostic step in evaluating blastic plasmacytoid dendritic cell neoplasm in any patient with skin lesions. However, the absence of skin lesions does not preclude the diagnosis, as a subset of cases could present without skin involvement. As a result, a blastic plasmacytoid dendritic cell neoplasm diagnosis should be considered in any patient with poorly differentiated leukemia and an uncertain immunophenotype.

The diagnosis of blastic plasmacytoid dendritic cell neoplasm necessitates a biopsy and morphologic evaluation of the affected tissue and immunophenotypic tests by flow cytometry or immunohistochemistry. In addition, patients with leukemic dissemination should undergo a bone marrow biopsy to rule out the presence of other hematological malignancies.

Immunohistochemistry or flow cytometry can be used to confirm the immunophenotype of blastic plasmacytoid dendritic cell neoplasm. The tumor cells are positive for CD4, CD56, CD123 (alpha-chain of interleukin-3) (figure 2), BDCA-2/CD303 (blood dendritic cell antigen-2), TCF4, TCL1, and SPIB.[20][18][21][22][23]

Terminal deoxynucleotidyl transferase (TdT) expression is seen in up to 40% of cases and is expressed in 10 to 80% of tumor cells. In the Golgi zone, CD68 expression is reflected by a dot-like positivity.[18][6] CD7 (an antigen on T cells) and CD33 (an antigen on myeloid cells) are also frequently expressed. However, expression of the Epstein-Barr virus-encoded RNA (EBER), CD19, CD20, CD79a, CD3 or CD5 (both T cell antigens), myeloperoxidase, CD117, lysozyme, CD13, CD16, and CD34 is not seen. Notably, uncommon cases lacking CD56 expression have been described, and blastic plasmacytoid dendritic cell neoplasm can be diagnosed if tumor cells express CD4, CD123, and TCL.

Treatment / Management

Pre-treatment evaluation includes complete blood counts, liver and kidney chemistries, lactate dehydrogenase, hepatitis B, and HIV. Human leukocyte antigen (HLA) typing should be performed on stem cell transplant candidates. Peripheral blood flow cytometry is essential, along with peripheral smear evaluation by pathology. Unilateral bone marrow biopsy and aspirate are recommended for all patients. Computed tomography (CT) with contrast to evaluate for lymphadenopathy and hepatosplenomegaly. Patients with neurologic signs or symptoms should have imaging studies and cerebrospinal fluid evaluation. 

Remission induction with Tagraxofusp (CD123-directed cytotoxin consisting of recombinant human interleukin-3 fused to a truncated diphtheria toxin) is recommended for adults with blastic plasmacytoid dendritic cell neoplasm over regimens used for acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL). The U.S. FDA approved Tagraxofusp in 2018 for use in adults and children over two years of age as the initial treatment of blastic plasmacytoid dendritic cell neoplasm and relapsed disease.[24] The overexpression of CD123 by blastic plasmacytoid dendritic cell neoplasm led to the development of tagraxofusp.[25]

In the prospective, open-label, multicenter cohort of 29 patients with untreated blastic plasmacytoid dendritic cell neoplasm, tagraxofusp resulted in a combined rate of complete remission (CR) and complete clinical remission in 21 (72%) patients. Survival rates at 18 and 24 months were 59% and 52%, respectively. Elevated liver enzymes, capillary leak syndrome, and hypoalbuminemia were among the most common adverse effects. Tagraxofusp is given intravenously once a day at a dose of 12 mcg/kg on days 1-5 of a 21-day cycle. Treatment is continued until the disease progresses or significant toxicity occurs.[26]

In contrast, ALL/LBL, non-Hodgkin lymphoma (NHL), and acute myeloid leukemia (AML) regimens are associated with poorer response rates, considerable toxicity, and poor long-term outcomes.[27] However, in instances where tagraxofusp is unavailable, an ALL/LBL-like regimen is a suitable alternative treatment. In addition, all adults should undergo CNS prophylaxis or treatment for the confirmed disease, as CNS involvement with blastic plasmacytoid dendritic cell neoplasm is prevalent.[28]

Alternate remission induction regimens for blastic plasmacytoid dendritic cell neoplasm could vary by institution. Most individuals treated with ALL/LBL-like induction therapy relapsed after two years; nevertheless, ALL/LBL-like regimens were reported to produce favorable outcomes.[4][3] In a retrospective study, patients who received ALL/LBL-like or other aggressive NHL treatment (e.g., hyper-CVAD, CHOP) were more likely to achieve complete remission and had considerably longer overall survival than patients who received AML-like treatment.[27]  

Regarding the role of hematopoietic stem cell transplantation in blastic plasmacytoid dendritic cell neoplasm therapy, multiple studies have found that allogeneic stem cell transplantation (Allo-SCT) produces better results in durable remissions and relapse rates than autologous stem cell transplantation. Allo-SCT has been shown to result in long-lasting remissions with overall survival rates ranging from 58% at three years to 40% at ten years, depending on the length of follow-up.[29][30]

Allo-SCT consolidation produces the best results when performed in the first complete remission, with rates reaching 74 to 82% in 3-4 years.[30][31] Relapse rates appear to be comparable between reduced intensity conditioning and myeloablative regimens.[30]

Management in children: It is recommended that children (age 2 to 18 years) diagnosed with blastic plasmacytoid dendritic cell neoplasm undergo remission induction therapy with either tagraxofusp or an ALL/LBL-like regimen followed by observation rather than allogeneic HCT in the first remission stage. Allogeneic HCT is associated with significant toxicity and outweighs any potential longer-term favorable outcomes. However, because tagraxofusp is not FDA-authorized for children under two, treatment with an ALL/LBL-like regimen is recommended.[32][33][34]

Relapsed or refractory cases: The optimal treatment for relapsed or refractory blastic plasmacytoid dendritic cell neoplasm is not well defined. Treatment should occur within a randomized controlled trial framework as much as possible. Tagraxofusp salvage therapy followed by allogeneic HCT for patients who had previously received an ALL/LBL-like regimen and an ALL/LBL-like regimen or repeat treatment with tagraxofusp for individuals previously treated with tagraxofusp is the recommended option. Venetoclax, bendamustine, and biweekly CHOP chemotherapy are other therapeutic options.[35][36][37]

Differential Diagnosis

• CD56+ acute myeloid leukemia
• T cell lymphoma/extranodal natural killer cell lymphoma
• Subcutaneous panniculitis-like T-cell lymphoma
• Cutaneous T-cell lymphoma/mycosis fungoides 
• Kaposi sarcoma 
• Sezary syndrome
• Drug eruptions

Prognosis

Younger age is indicative of a more favorable outcome.[4][38][39] Patients with just cutaneous disease have shown slightly more excellent complete remission rates and a similar advantage for acute lymphoblastic leukemia-like induction treatment. Lastly, there appears to be a correlation between the maturity of tumor cells and their responsiveness to therapy, with immature cells being more receptive to treatment than mature cells.[40]

Complications

Blastic plasmacytoid dendritic cell neoplasm and its treatment can have complications. The clinical course of this malignancy is lethal without appropriate treatment. Despite treatment, relapses can happen. Therefore, close clinical monitoring and surveillance are recommended. The treatment for this malignancy can lead to pancytopenia, liver toxicity, renal dysfunction, capillary leak syndrome, and an increased risk of infections. 

Capillary leak syndrome, characterized by low albumin, weight gain, edema, and hypotension, is a well-known and life-threatening complication of tagraxofusp.

Deterrence and Patient Education

Patients must be counseled about the clinical course of blastic plasmacytoid dendritic cell neoplasm, the various treatment options, complications, and the risk of cancer recurrence. In addition, the patient must be well-informed on the disease's prognosis, and treatment adherence should be prioritized. In the event of unfavorable treatment effects, the patient must be strongly encouraged to promptly contact their oncologist and undergo a comprehensive evaluation. In recurrent blastic plasmacytoid dendritic cell neoplasm, the possibility of participating in ongoing clinical trials should also be considered.

The contraceptive and lactation needs of female patients should be explicitly reviewed. Patients should be instructed to weigh themselves daily and use the same scale. Women of childbearing age receiving tagraxofusp should use an effective method of contraception during therapy and at least a week after completing their last treatment. Female patients who become pregnant should contact their doctor to seek alternate treatment choices. It is recommended to wait at least 48 hours following the previous dose before restarting breastfeeding. Although no studies on pregnant women have been conducted, there is a possible risk to the fetus.

Enhancing Healthcare Team Outcomes

An interprofessional healthcare team strategy is required for the most effective treatment of blastic plasmacytoid dendritic cell neoplasm, which includes a hematologist-oncologist, oncology nurse practitioner, oncology pharmacist, infectious disease physician, emergency physician, primary care physician/internist, dermatologist, pathologist, blood bank specialist, case manager, psychiatrist/psychologist, occupational and physical therapist. The prompt referral of the patient to a specialist and open communication among the various specialists involved is essential to achieving the best possible outcomes for the patient.

All clinicians will need to contribute each from their specialty as part of a holistic approach to patient care. Given the first-in-class nature of tagraxofusp, a specialized oncology pharmacist will be a valuable adjunct consult, in addition to performing usual medication reconciliation and patient medication counseling. Nurses will administer the drug and be responsible for reporting to the clinical team on patient response and possible adverse events, as well as counseling the patient. The team should be mindful of cultural inclusion as it pertains to the patient and other team members. The interprofessional team approach will yield the best outcomes with the fewest adverse events. [Level 5]