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Blastic plasmacytoid dendritic cell neoplasm

Blastic plasmacytoid dendritic cell neoplasm
Literature review current through: Jan 2024.
This topic last updated: Sep 22, 2023.

INTRODUCTION — Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that most commonly manifests as cutaneous lesions with or without bone marrow involvement and leukemic dissemination.

The nomenclature used to describe this entity has evolved as knowledge of the underlying biology has improved. It is labeled BPDCN in contemporary classification systems after it was shown that this acute leukemia is derived from plasmacytoid dendritic cell precursors [1,2]. Former labels included acute agranular CD4-positive natural killer (NK) cell leukemia, blastic NK cell lymphoma, and agranular CD4+CD56+ hematodermic neoplasm/tumor.

The epidemiology, clinical manifestations, pathologic features, diagnosis, and management of BPDCN are presented here.

Chronic NK cell lymphocytosis and NK cell large granular lymphocyte leukemia are described separately. (See "Natural killer (NK) cell large granular lymphocyte leukemia".)

EPIDEMIOLOGY — BPDCN is a rare form of acute leukemia.

The precise incidence of BPDCN is difficult to estimate because of evolving nomenclature and diagnostic criteria. The incidence has been estimated to be 0.04 cases per 100,000 people in the United States [3,4]. BPDCN represents <1 percent of acute leukemias [3] and 0.7 percent of primary cutaneous skin lymphomas [5], but cutaneous lymphoma registries likely underestimate the true incidence because some cases present without skin lesions [6].

The median age at diagnosis is 65 to 67 years, and there is a male predominance, with a male to female ratio of 3:1 [3,4]. Although most cases present in adults, BPDCN has been reported in all age groups [5,7,8]. It is uncertain if the incidence varies by ethnicity or geography.

BPDCN can occur as an isolated disease or in the context of other hematologic malignancies. Approximately 10 to 20 percent of patients have an antecedent and/or concomitant hematologic malignancy, such as myelodysplastic syndromes/neoplasms, chronic myelomonocytic leukemia, or acute myeloid leukemia [6-8]. When BPDCN occurs with another hematologic malignancy, it is important to distinguish clonal proliferations of mature plasmacytoid dendritic cells that are clonally related to the associated myeloid neoplasm and frequently have RAS pathway mutations [1].

PATHOGENESIS — BPDCN appears to arise from premalignant clonal precursors in bone marrow that migrate to skin, where they accumulate mutations and undergo malignant transformation to BPDCN. The transformed BPDCN cells may later migrate to bone marrow and other sites.

Functional inactivation of TET2 is seen in 70 to 80 percent of cases of BPDCN with biallelic TET2 mutations in most cases [9-11]. Clonal TET2-deficient plasmacytoid dendritic cell precursor cells that migrated from bone marrow to the skin appear to undergo malignant transformation in response to ultraviolet (UV) damage [9]. Mutations of RAS; copy-number loss of tumor suppressor genes (eg, CDKN2A, SETD2, TP53); aberrant signaling from the E-box transcription factor, TCF4; and/or overexpression of FLT3, HES6, and RUNX2 have been implicated in malignant transformation to BPDCN [12-14].

CLINICAL PRESENTATION — BPDCN is a unique type of hematologic malignancy that typically presents with skin lesions, but most patients ultimately develop systemic disease [15].

Most cases of BPDCN are seen in adults, but the clinical presentation at diagnosis is similar in children and adults [16]. Most patients present with cutaneous lesions with or without bone marrow involvement and leukemic dissemination [7]. One-third of cases have no evidence of disease beyond the skin [8]. Some patients present with leukemia without skin involvement [17].

Skin lesions – A series of 90 patients with cutaneous involvement reported that one-half of patients initially presented with localized skin disease with one or two nodules, while one-quarter had multiple nodules affecting one or two areas [8]. Skin lesions were brown or purple nodular lesions in 73 percent, "bruise-like" brown to violaceous infiltrated patches in 12 percent, and disseminated and mixed lesions in 14 percent. The most common areas of localized involvement were on the face or scalp (20 percent), lower limb (11 percent), trunk (9 percent), and upper limb (7 percent).

Other findings – Cytopenias, lymphadenopathy, and/or splenomegaly are present in most patients [6,7].

Involvement of bone marrow, lymph nodes, or blood was seen in 61 percent of cases and central nervous system involvement in 11 percent [6]. Liver involvement appears to be more frequent in patients with extensive bone marrow involvement. Involvement of the tonsils, paranasal cavities, lungs, eyes, and paravertebral disease have been reported [6,7].

A leukemic presentation without apparent cutaneous disease is seen in a minority of patients [17]. Such patients present with abnormal circulating "lymphoid/monocytoid" cells with or without leukocytosis, anemia, thrombocytopenia, hepatosplenomegaly, and lymphadenopathy.

EVALUATION — The initial evaluation of a patient with suspected BPDCN must distinguish it from other cutaneous and leukemic disorders, define the sites and extent of disease, and assess comorbidities that may affect treatment choices. There are no formal guidelines for staging BPDCN.

Clinical/laboratory

Clinical evaluation – History and a physical examination should assess cutaneous abnormalities and lymphadenopathy. Collaboration with dermatology is necessary for cataloguing the extent of cutaneous involvement and measuring skin lesions prior to treatment [18].

Laboratory  

Hematology – Complete blood count (CBC) with leukocyte differential count; a peripheral blood smear should be reviewed, ideally by a hematopathologist.

Chemistries – Basic metabolic panel; kidney function tests; liver function tests, including lactate dehydrogenase (LDH), uric acid.

Infectious – Serologic evaluation for hepatitis B and human immunodeficiency virus (HIV).

Human leukocyte antigen (HLA) typing should be performed for patients who may be candidates for hematopoietic cell transplantation (HCT).

Pathology – Evaluation of skin lesions should include dendritic cell morphology, immunohistochemistry, flow cytometry, cytogenetic analysis (including karyotype and/or fluorescence in situ hybridization [FISH]), and molecular analysis. Analysis of isolated skin lesions may yield limited cellular material with insufficient cells for flow cytometry. Evaluation of skin lesions and pathology may benefit from consultation with a dermatologist or dermatopathologist.

Lymph nodes or other sites of suspected involvement should be evaluated, if possible.

Pathologic features and diagnostic criteria for BPDCN are described below. (See 'Pathologic features' below and 'Diagnostic criteria' below.)

Bone marrow examination – Unilateral bone marrow aspiration with biopsy should be performed in all patients and evaluated as described below. (See 'Pathologic features' below.)

Imaging – Positron emission tomography (PET)/contrast-enhanced computed tomography (CT) should be performed if there is clinical suspicion for extramedullary disease and/or lymphadenopathy.

Fertility – People of childbearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures.

Neurologic evaluation — A lumbar puncture must be performed for all patients with BPDCN, given the high incidence of occult central nervous system (CNS) involvement [19]. LP should be performed at the time of diagnosis, suspected relapse, or whenever there is clinical suspicion for CNS involvement. Patients with neurologic abnormalities should also undergo magnetic resonance imaging (MRI) or CT evaluation for meningeal disease or CNS bleeding.

Cerebrospinal fluid (CSF) should be evaluated by cytology (morphology of stained cytospin slides) and flow cytometry.

Approximately 10 percent of patients who present with neurologic symptoms at diagnosis have confirmed CNS involvement [19]. Other studies have reported 9 to 26 percent of patients with CNS involvement at diagnosis and/or relapse [6,7,20].

Medical fitness — Fitness is judged by severity of organ dysfunction and performance status.

The following may be required, based on planned treatments (see 'Management' below):

Albumin – Serum albumin must be ≥3.2 g/dL for patients who may receive tagraxofusp because of the risk of capillary leak syndrome. (See 'Tagraxofusp' below.)

Heart – Echocardiogram or radionuclide ventriculogram (RVG) to demonstrate adequate heart function should be performed in patients who will receive an anthracycline. (See 'Other treatments' below.)

Transplant eligibility – Eligibility for allogeneic HCT generally requires adequate heart, lung, kidney, and liver function. Many institutions limit allogeneic transplantation to patients <65 years. Transplant eligibility is discussed in greater detail separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

Performance status – Functional capacity should be evaluated by performance status (table 1).

PATHOLOGIC FEATURES

Morphology

Skin – Skin biopsies of involved areas demonstrate an infiltrate of medium-sized cells that spare the epidermis but can extend to the subcutaneous fat (picture 1) [21]. There is no coagulative necrosis, angioinvasion, or inflammatory cells within the infiltrate. When the subcutis is infiltrated, "rimming" of adipocytes can be seen.

The tumor cells are usually monomorphic, poorly differentiated, intermediate-sized blasts with fine chromatin and two to three nucleoli [5,7,22,23]. The nuclei are most commonly round or oval but may be irregular (notched, folded, bilobed). The cells typically have scant blue-gray, agranular cytoplasm on Giemsa-stained preparations. Mitotic activity is usually infrequent.

Lymph nodes – Lymph node involvement is sinusoidal, interfollicular, and medullary, with sparing of the follicles (leukemic pattern); the infiltrating monomorphic cells resemble those seen in the skin [21]. Diffuse involvement may be seen late in the disease. Coagulative necrosis and angioinvasion are not present.

Blood/bone marrow – Circulating blasts can be detected by microscopy or flow cytometry of peripheral blood in 60 percent of cases, but the number of circulating malignant cells is extremely variable. Morphologically, the blasts are monomorphic, poorly differentiated, and intermediate-sized, resembling those seen in the skin (picture 2). The most common hematologic findings are thrombocytopenia (78 percent), anemia (65 percent), and neutropenia (34 percent) [7].

Bone marrow involvement is present in more than 80 percent of patients, and diffuse involvement is common. However, the number of blasts in bone marrow varies, and special studies may be required to identify these cells. The tumor cells may show microvacuoles along the cell membrane ("pearl necklace" appearance) and pseudopod-like extensions.

Immunophenotype — The immunophenotype of BPDCN must be confirmed by immunohistochemistry and/or flow cytometry.

Tumor cells express CD123, CD4 and/or CD56, and one or more plasmacytoid dendritic cell (pDC)-associated antigens (ie, TCF4, TCL1, CD303, CD304) [21]. CD7 (a T cell antigen) and CD33 (a myeloid antigen) may be expressed, but there is usually no expression of CD19, CD20, CD79a (all B cell antigens); CD3 or CD5 (T cell antigens); and CD34. Similarly, myeloperoxidase, CD117, lysozyme, CD13, and CD16 are not expressed. Epstein-Barr virus encoded ribonucleic acid (RNA; EBER) is not detected. Atypical cases of BPDCN with aberrant expression of B, T, or myeloid antigens have been described.

Terminal deoxynucleotidyl transferase (TdT) expression is observed in up to 40 percent of cases [24]. When present, TdT expression is variable and can be seen in 10 to 80 percent of cells in the tumor. CD68 expression can be seen in up to one-half of cases, but it may be weak or represented by a dot-like positivity in the Golgi zone [5].

Diagnostic immunophenotypic criteria for BPDCN are described below. (See 'Diagnosis' below.)

Genetic features — Most cases of BPDCN have genetic abnormalities, but there is no typical or diagnostic cytogenetic finding. T cell receptor (TCR) genes are usually germline.

An abnormal karyotype has been reported in 50 to 66 percent of patients [6,25]. While not specific, the karyotype is significant for presence of gross genomic imbalances represented mostly by loss of genetic material [25]. Certain chromosomes are preferentially targeted: 5q, 12p, 13q, 6q, 15q, and 9 [25], but these abnormalities are also seen in other myeloid and lymphoid malignancies. Monoallelic deletion of NR3C1 at 5q31 is a recurrent abnormality in 28 percent of patients and is associated with a poor clinical outcome [26].

Loss of genetic material is much more frequent than additional genetic material. Cell cycle regulators are preferentially targeted [27,28]. CDKN2A/CDKN2B on 9p21.3 is frequently lost, and when biallelic, this deletion is associated with poor outcomes. Other frequently deleted regions include 13q13.1-q14.3 (RB1), 12p13.2-p13.1 (CDKN1B), 13q11-q12 (LATS2), and 7p12.2 (IKZF1) [27].

Gene expression studies identified overexpression of FLT3, HES6, and RUNX2 independently of genomic amplification [13]. Mutations in TET2 and TP53 were seen in 53 and 38 percent of cases analyzed [29].

DIAGNOSIS — The diagnosis of BPDCN should be suspected in patients who present with brown to violaceous bruise-like lesions, plaques, or tumors. It may also be suspected in patients who present with a poorly differentiated acute leukemia with an ambiguous immunophenotype.

Skin biopsy is the most valuable diagnostic material, but the absence of skin lesions does not rule out the diagnosis since a minority of cases present with leukemia without skin involvement. Collaboration with dermatology and/or dermatopathology may be useful for classification of cutaneous involvement and measurement of skin lesions [18].

Diagnostic criteria — The following diagnostic criteria are required by the World Health Organization classification of myeloid neoplasms 5th edition (WHO5) [1] and the International Consensus Classification (ICC) [2]:

Histology – A diffuse, monomorphous infiltrate of medium-sized blasts that may resemble either lymphoblasts or myeloblasts [21]. The nuclei have irregular contours with fine chromatin and one or more small nucleoli. Cytoplasm is usually scant, grayish-blue, and agranular. Mitoses are variable in number.

Immunophenotype – Expression of the following by multicolor flow cytometry and/or immunohistochemistry:

CD123

CD4 and/or CD56

At least one of the following plasmacytoid dendritic cell (pDC) markers: TCF4, TCL1, CD303, or CD304

The following antigens are usually negative: CD3, CD14, CD19, CD34, lysozyme, and myeloperoxidase.

Alternatively, the immunophenotypic diagnosis can be made if ≥3 pDCs are expressed with absent expression of all expected negative markers [1].

Differential diagnosis — The differential diagnosis includes malignancies with cutaneous manifestations and various leukemias. Accumulations of mature pDCs may be seen with some reactive conditions, such as Kikuchi disease.

The differential diagnosis includes other malignancies with cutaneous manifestations.

Acute myeloid leukemia – Acute myeloid leukemia (AML) with monocytic differentiation can express CD4, CD56, and CD123 and may be difficult to distinguish from BPDCN. AML can be distinguished from BPDCN based on the diagnostic pattern of antigens described above. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

Some cases of BPDCN express CD33, which is common to AML. However, unlike BPDCN, most cases of AML demonstrate positivity for myeloperoxidase and express other myeloid antigens such as CD13, CD15, and CD117. RUNX1-mutated AML can show significant accumulations of pDCs, but pDCs in AML show maturational continuity with the myeloid blasts by flow cytometry, and there is a distinct interstitial distribution of pDCs in the bone marrow biopsy [30].

Chronic myelomonocytic leukemia – Chronic myelomonocytic leukemia (CMML) is a clonal malignancy with features of both myelodysplastic syndromes/neoplasms (MDS) and myeloproliferative neoplasms. Malignant cells of CMML can be distinguished from BPDCN because they are CD56 negative. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis".)

Mature pDC cell proliferation – Mature pDC cell proliferation (MPDCP) can be associated with rash, macules, papules, or nodules along with infiltration of lymph nodes or bone marrow. However, the pDCs in MPDCP are morphologically mature and CD56 negative, and the condition is invariably associated with CMML, AML, or MDS.

Nasal-type extranodal natural killer/T cell lymphoma – Both nasal-type extranodal natural killer/T cell lymphoma (ENKTL) and BPDCN can present as cutaneous lesions that express CD56 and CD4. Unlike BPDCN, the histology of nasal-type ENKTL is characterized by a polymorphous lymphoid infiltrate that invades vascular walls, producing fibrinoid necrosis of vessel walls and coagulative necrosis of surrounding tissues. ENKTL is associated with Epstein-Barr virus (EBV), which can be demonstrated by in situ hybridization for Epstein-Barr virus encoded RNA (EBER); EBV is not associated with BPDCN. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type".)

Subcutaneous panniculitis-like T cell lymphoma – Patients with subcutaneous panniculitis-like T cell lymphoma (SPTCL) typically present with one or more painless subcutaneous nodules or poorly circumscribed indurated plaques. BPDCN can be differentiated from SPTCL based on the immunophenotype and molecular studies. Unlike SPTCL, T cell receptor (TCR) genes in BPDCN are usually germline, and the tumor cells express CD56 but not cytotoxic molecules (TIA-1, granzyme B, and/or perforin). (See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma".)

Cutaneous T cell lymphoma – Like BPDCN, cutaneous T cell lymphoma may express CD4 and cutaneous lymphocyte-associated antigen. However, unlike BPDCN, cutaneous T cell lymphomas do not express CD56, CD123, and BDCA2. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

MANAGEMENT — Optimal management of BPDCN is not well defined. We encourage enrollment in a clinical trial and treatment at a center with specialized expertise.  

Initial management of BPDCN involves the following aspects of care:

Central nervous system management – All patients require evaluation and management for possible central nervous system (CNS) involvement. (See 'Neurologic evaluation' above and 'Central nervous system management for all patients' below.)

Induction therapy – Induction therapy is stratified by age and medical fitness:

Medically fit adults – Intensive treatments generally require ECOG (Eastern Cooperative Oncology Group) performance status ≤2 and no severe comorbid illnesses. We do not consider age, per se, as a measure of fitness.

Induction therapy also requires adequate serum albumin for treatment with tagraxofusp or good cardiac function that includes an anthracycline, as discussed below. (See 'Induction therapy' below.)

Less-fit adults – Patients who do not meet the features of medical fitness require lower intensity treatments. (See 'Less-fit adults' below.)

Children – Management for patients ≤18 years is discussed below. (See 'Children' below.)

Postremission management – Consolidation or maintenance therapy is a consideration after achieving remission with induction therapy. (See 'Postremission management' below.)

Monitoring – Surveillance for relapse is discussed. (See 'Monitoring' below.)

Our approach to management is consistent with that of the North American BPDCN Consortium (NABC) [31].

Central nervous system management for all patients — All patients with BPDCN should be evaluated at diagnosis for CNS involvement.

Based on the findings from cerebrospinal fluid (CSF), patients should receive either prophylaxis or treatment for active CNS disease. (See 'Neurologic evaluation' above.)

No central nervous system involvement demonstrated – For all patients without documented CNS involvement, we suggest intrathecal (IT) chemotherapy as CNS prophylaxis, based on the high incidence of occult involvement.

We generally treat with IT chemotherapy twice per month for a total of at least eight doses. Examples include alternating IT cytarabine and methotrexate or triple IT therapy (cytarabine, methotrexate, corticosteroid). Some experts continue IT therapy (eg, once or twice per month).

Preferred agents and regimens for CNS prophylaxis vary among institutions. CNS prophylaxis for acute myeloid leukemia (AML) is discussed separately. (See "Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)", section on 'Intrathecal chemotherapy'.)

Documented central nervous system disease – For documented CNS involvement, we suggest IT treatment twice weekly until CSF is clear by cytology, continued IT therapy for ≥4 treatments, and then twice monthly for ≥8 doses. IT treatments may be continued once or twice per month, if desired

It may be preferable to place an Ommaya reservoir for intraventricular chemotherapy. Patients with cranial neuropathy should be considered for whole-brain irradiation, as described separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'CNS management'.)

Medically fit adults — Fit adults with BPDCN require induction therapy, CNS management, postremission care, and surveillance for relapse.

Induction therapy — For induction therapy in medically fit adults with BPDCN, we suggest tagraxofusp (CD123-directed cytotoxin) rather than intensive leukemia- or lymphoma-based treatments or other regimens. Outcomes with tagraxofusp are similar to those with intensive chemotherapy induction regimens, but it is less toxic; lower-intensity regimens are less efficacious.

Administration – Prior to treatment with tagraxofusp, serum albumin should be ≥3.2 g/dL, and patients should receive prophylaxis for capillary leak syndrome (CLS), as described below. (See 'Tagraxofusp' below.)

When tagraxofusp is not available or suitable, alternative acute leukemia-type induction regimens are described below. (See 'Other treatments' below.)

No randomized trials have directly compared tagraxofusp with other treatments for BPDCN, but overall survival (OS) and progression to hematopoietic cell transplantation (HCT) are similar to those with intensive induction regimens, while tagraxofusp is better tolerated.

Tagraxofusp versus other treatments

-There were no significant differences in OS or duration of remission (DOR) using various induction regimens for treatment of BPDCN in 100 patients, as reported in a retrospective multicenter study [32]. Response rates differed between treatments, but analysis of outcomes should recognize that demographic and other prognostic features differed substantially between the treatment groups. Treatment with hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) was associated with an 80 percent rate of complete remission (CR), compared with 59 percent with tagraxofusp and 43 percent with other regimens. However, there were no significant differences in other outcomes; the median OS and DOR in 35 patients treated with hyper-CVAD were 28 months and 39 months, respectively; a 14-month median OS and median DOR was not reached in 37 patients treated with tagraxofusp; and a 23-month median OS and 10-month median DOR in 28 patients treated with other regimens. One-half of patients in the hyper-CVAD and tagraxofusp groups were able to proceed to HCT, compared with 38 percent with other treatments.

Outcomes with tagraxofusp

-In 65 patients with previously untreated BPDCN, tagraxofusp was associated with a 16-month median OS and 75 percent overall response rate (ORR), including a 57 percent CR [33]. One-half of patients who achieved CR were able to proceed to HCT. Although 94 percent of patients had at least one grade ≥3 adverse effect (AE), these were largely laboratory abnormalities and reversible; toxicity is favorable compared with AEs associated with intensive induction therapy for acute leukemia.

Outcomes after transplantation are presented below. (See 'Postremission management' below.)

-An earlier study reported that tagraxofusp was associated with a 90 percent ORR and 54 percent complete response in 13 treatment-naïve patients; median DOR was not reached after a follow-up of 19 months (range 1 to 42 months) [18].

Tagraxofusp — Tagraxofusp is the first-in-class CD123-targeted therapy comprising human interleukin-3 fused to truncated diphtheria toxin.

Tagraxofusp is approved by the US Food and Drug Administration (FDA) as an initial treatment of BPDCN and for relapsed disease in patients ≥2 years.

AdministrationTagraxofusp is administered at 12 mcg/kg intravenously over 15 minutes daily on days 1 to 5 of a 21-day cycle; the optimal number of cycles is not currently defined. If dose delays occur, five doses can be given over a 10-day period.

Treatment with tagraxofusp requires baseline serum albumin ≥3.2 g/dL. Albumin should be infused before each treatment if the level is <3.5 g/dL or if it declines ≥0.5 from baseline.

The first treatment cycle should be administered in the inpatient setting, but subsequent cycles of tagraxofusp may be given in the inpatient or appropriate outpatient setting.

Prior to treatment – Vital signs, weight, serum albumin, transaminases, and creatinine should be checked prior to each treatment.

Premedication – Premedication before each treatment should include an H1-histamine antagonist, acetaminophen, corticosteroid, and H2-histamine antagonist.

Indications to withhold doseTagraxofusp should be held for any of the following, which may herald the onset of CLS:

-Serum albumin <3.5 g/dL or a reduction ≥0.5 g/dL from baseline

-Body weight ≥1.5 kg over previous day

-Edema, fluid overload, and/or hypotension

-Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 x upper limit of normal

-Serum creatinine >1.8 or creatinine clearance (CrCl) ≤60 mL/min

-Systolic blood pressure ≥160 or ≤80 mmHg

-Heart rate ≥130 beats per minute (bpm) or ≤40 bpm

-Temperature ≥38°C

Adverse effects – AEs associated with tagraxofusp include:

Capillary leak syndrome – Severe cases of CLS may be life threatening (table 2). Typical manifestations of CLS are hypotension, hypoalbuminemia, edema, weight gain, and hemoconcentration.

Management includes withholding tagraxofusp until resolution; indications for withholding treatment are presented above. Other management includes administering intravenous albumin and/or corticosteroids and careful management of volume status before resuming therapy. Other clinical manifestations and management of CLS are described separately. (See "Idiopathic systemic capillary leak syndrome" and "Common terminology criteria for adverse events".)

Episodes of CLS are most prominent in the first treatment cycle, with a median time to onset of six days (range 3 to 51 days) and median duration of six days (range 3 to 69 days) [33]. CLS was observed in 21 percent of patients, but two-thirds of cases were grade 2 and resolved; all but one event occurred in the first treatment cycle. A decrease in serum albumin during the first days of treatment appears to be the most consistent predictor of CLS [18].

Other adverse effects – Elevated liver function tests (ALT and AST) may occur, with typical onset 5 to 10 days postinfusion and full resolution 15 to 21 days after infusion [33].

Myelosuppression is generally modest, reversible, and limited to the first or second treatment cycle; there was no cumulative hematologic toxicity with continued treatment [33].

Infusion-related events may be related to cytokine release from necrotic cells and damaged BPDCN blasts.

Other treatments — When tagraxofusp is not available or the patient is not suitable, we suggest intensive induction therapy for acute leukemia rather than less intensive treatments, based on limited data.

There is no consensus, and the preferred regimen varies among institutions. Options include:

Acute lymphoid leukemia/lymphoblastic lymphoma-type therapy – Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) is most often given, but other acute lymphoid leukemia (ALL)/lymphoblastic lymphoma (LBL) induction regimens have been used [6,15,32,34,35].

ALL/LBL induction regimens are discussed separately. (See "Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults", section on 'Chemotherapy'.)

Some institutions favor CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOEP (CHOP plus etoposide), especially for older patients or those with moderate comorbidities.

Acute myeloid leukemia-type therapy – Standard cytarabine plus anthracycline ("7+3" therapy) is most often given, but MEC (mitoxantrone, cytarabine, etoposide), ICE (idarubicin, cytarabine, etoposide), FLAG (fludarabine, cytarabine, G-CSF), and FLAG-Ida (FLAG plus idarubicin) have been used [6,15,34,35].

AML induction regimens are discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Induction therapy'.)

Small retrospective studies indicate that outcomes are better with intensive chemotherapy compared with less-intensive treatments. Studies that compared ALL/LBL-type regimens versus AML-type therapy have yielded mixed results. Although initial treatment of BPDCN is associated with favorable rates of CR, most patients relapse within two years unless they receive postremission management, as discussed below. (See 'Postremission management' below.)

Studies that compared outcomes with various initial treatments for BPDCN include:

A retrospective study compared outcomes with BPDCN using various approaches [34]. Among 15 patients who received intensive acute leukemia induction regimens (either ALL/LBL-type or AML-type), the CR rate was 94 percent, with one-third experiencing a sustained CR. Among 38 patients treated with less-intensive chemotherapy (eg, CHOP or CHOP-like regimens), the ORR was 70 percent (including 55 percent CR), but only one patient had a sustained CR. For 19 patients who received other treatments (eg, local radiation, systemic steroids, supportive care), the ORR was 80 percent (including 68 percent CR), but the median OS was nine months, and only 7 percent had a sustained CR. Outcomes for patients in this study who underwent HCT are discussed below. (See 'Postremission management' below.)

In a multicenter study of 41 patients who had a leukemic presentation of BPDCN, 35 percent were treated with an ALL/LBL-type regimen, while 60 percent received an AML-type induction regimen [6]. ALL/LBL-like therapy was associated with better survival (median OS 12 versus 7 months) and a higher rate of CR (67 versus 27 percent), but there were more relapses (60 versus 0 percent).

Progression-free survival (PFS) was better for 32 patients treated with intensive regimens compared with those who received moderate or nonintensive therapies in a multicenter study of 59 patients with BPDCN [15]. There was a trend toward better PFS for 35 patients treated with lymphoid-type regimens compared with 9 patients who received AML-type regimens. However, comparison of regimens was not possible, as 22 different front-line treatments were used.

Response assessment — Response to induction therapy is assessed by a review of peripheral blood, bone marrow, CNS, and any other sites of extramedullary involvement.

Response criteria for BPDCN are the same as those for AML, as discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Remission status'.)

Patients in CR proceed to postremission management. (See 'Postremission management' below.)

Patients who do not achieve CR are managed for refractory disease. (See 'Relapsed/refractory disease' below.)

Postremission management — For fit adults in first complete remission (CR1), we suggest allogeneic HCT, autologous HCT, or maintenance therapy with tagraxofusp, rather than observation alone, based on the high relapse rate with BPDCN. The choice of management should be made by shared decision making between the clinician and patient, with consideration of age, comorbid illnesses, and patient preference in choosing an approach.

Postremission management for patients ≤18 years is discussed below. (See 'Children' below.)

We favor myeloablative allogeneic HCT for eligible patients, based on long-term outcomes reported in small retrospective studies. Patients who are not candidates for myeloablative HCT may be considered for reduced-intensity conditioning (RIC) or autologous transplantation [36,37]. Management is evolving because long-term outcomes for patients treated with tagraxofusp are not well defined; some experts treat with tagraxofusp until disease progression rather than pursuing HCT. Most adults who receive no postremission therapy relapse within two years [7].

No randomized trials have directly compared approaches in this setting. Transplantation outcomes are reported in retrospective studies and case series.

Hematopoietic cell transplantation versus no transplantation – Uncontrolled retrospective studies indicate better survival for patients who undergo transplantation compared with observation. Examples include:

In a systematic analysis and review of the literature, outcomes were better for patients (including adults and children) who were transplanted compared with observation [16]. Among 211 patients who were transplanted in CR1 (58 allogeneic, 8 autologous), the 18-month disease-free survival (DFS) was 76 percent, compared with 49 percent 18-month DFS in 145 patients who were observed.

In a multicenter study, the median OS was 6.6 years for 25 patients who were transplanted, compared with 2 years for the entire cohort of 59 patients [15]. Among transplanted patients, there was no difference in OS between patients <60 years versus ≥60 years.

Among patients who achieved CR with tagraxofusp, 6 underwent autologous HCT and 13 underwent allogeneic HCT [33]. For transplanted patients, the 24-month OS was 66 percent (38-month median OS). By contrast, only 4 of 18 patients who achieved CR but were not transplanted experienced >6 months remission.

Among seven patients treated with hyper-CVAD, patients transplanted in CR1 had 67 percent one-year OS and 56 percent one-year DFS, compared with 50 percent one-year OS and an eight-month median OS for patients who were not transplanted [38].

In a multicenter study, the median OS for transplanted patients was 23 months, compared with 7 months for patients who were not transplanted [6].

Autologous versus allogeneic hematopoietic cell transplantation – Outcomes are generally better with allogeneic HCT in CR1 compared with autologous HCT, but the choice of approach and risk factors were not controlled in these studies.

Outcomes were similar with allogeneic HCT versus autologous HCT in a retrospective study of adults who were transplanted for BPDCN; among 162 patients, 78 percent were in CR1 at the time of transplantation [39]. For 146 patients who underwent allogeneic HCT, the one-year OS was 66 percent and one-year PFS was 62 percent, compared with 70 percent one-year OS and 66 percent one-year PFS for 16 patients who received autologous HCT. Among those who underwent allogeneic HCT, 54 percent received myeloablative conditioning (MAC) and 46 percent received RIC regimens. Total body irradiation (TBI) was associated with better outcomes compared with other conditioning regimens (95 percent two-year PFS with MAC/TBI, 82 percent for MAC without TBI, 41 percent for RIC/TBI, and 60 percent for RIC without TBI).

A systematic analysis and literature review of children and adults with BPDCN reported better DFS with HCT compared with observation [16]. Among 211 patients who were transplanted in CR1, the 18-month DFS with HCT was 76 percent, compared with 49 percent in those who were not transplanted.

A retrospective study compared 37 patients who underwent allogeneic HCT with 8 who received autologous HCT [40]. Allogeneic HCT recipients in CR1 had 74 percent three-year OS, compared with 11 percent one-year OS with autologous HCT. Outcomes with allogeneic HCT did not differ between MAC and RIC regimens.

Another retrospective study compared outcomes with autologous HCT versus allogeneic HCT among 25 patients with BPDCN in CR1 [41]. For 11 patients who underwent autologous HCT, the four-year OS was 82 percent and four-year PFS was 73 percent, compared with 69 percent four-year OS for 12 patients who underwent allogeneic HCT. For those who underwent allogeneic HCT, outcomes did not differ between MAC and RIC regimens.

Other studies reported similar outcomes with transplantation for BPDCN [34,42].

Less-fit adults — Management for less-fit adults is guided by symptoms, disease distribution, and patient preference.

Localized cutaneous involvement – For localized BPDCN or disease limited to cutaneous involvement, palliative treatment options include surgical excision or focal radiation.

Symptomatic systemic disease – For patients with symptomatic systemic disease who are not candidates for more intensive treatments, we suggest venetoclax (BCL2 inhibitor) combined with a hypomethylating agent, based on limited data. Other options include corticosteroids and/or supportive care to alleviate symptoms.

A retrospective study of 43 patients who received venetoclax combinations included two patients with relapsed/refractory BPDCN [43]. One of these patients had a major response by positron emission tomography/CT, >50 percent reduction of bone marrow blasts, and improvement in cutaneous lesions, while the other patients also had a significant improvement in cutaneous lesions. BCL2 is expressed in most cases, and BPDCN cells are uniformly sensitive to venetoclax in vitro [14].

Treatment with venetoclax plus a hypomethylating (ie, azacytidine or decitabine) agent is discussed separately. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'HMA plus venetoclax'.)

Children — We distinguish treatment for children (≤18 years) from that for adults.

Remission induction – The choice of remission induction therapy in children is stratified by age:

Children ≥2 to ≤18 years – Induction therapy using either tagraxofusp or an ALL/LBL-like regimen is acceptable.

Administration of tagraxofusp is described above. (See 'Induction therapy' above.)

Preferred ALL/LBL-like regimens vary among institutions/trial groups and are described separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

Treatment with tagraxofusp for children ≥2 years old is extrapolated from data in adults [44].

The largest study of pediatric BPDCN was a retrospective analysis of 29 children (<18 years) [45]. With a median follow-up of 30 months, OS and event-free survival rates were 72 and 64 percent, respectively. Among 14 children treated with ALL/LBL-like therapy, 12 achieved CR and 2 achieved partial response. By contrast, four of six children who received CHOP achieved CR, while all five children treated with AML-like therapy died from progressive disease or therapy-related complications.

Children <2 years – We suggest treatment with an ALL/LBL-like regimen.

Central nervous system management – Children have a high risk for CNS involvement by BPDCN.

Most reports of BPDCN describe CNS involvement in approximately 10 percent of patients, but estimates vary, and most studies are dominated by adult patients [6,19,20,46]. In one report, CNS involvement was reported in 47 percent of 36 children who were evaluated [16].

Management of CNS involvement in children varies among institutions/cooperative groups. Management in adults is described above. (See 'Central nervous system management for all patients' above.)

Postremission – For children with BPDCN who achieve CR, we suggest observation rather than allogeneic HCT. Children with BPDCN have a better prognosis than adults, and we consider that the toxicity of allogeneic HCT in first remission outweighs the potential improvement of longer-term outcomes.

In a systematic review, relapse rates were similar for children who received HCT compared with those who were not transplanted [16]. In another report, HCT did not impact survival in children [45].

In children, transplantation is generally reserved for patients who relapse [16].

MONITORING — Following completion of consolidation therapy, we monitor as follows:

Complete blood count with manual differential count every one to three months for the first two years, then every three to six months for up to five years.

Bone marrow evaluation should only be performed if cytopenias develop or the blood smear is abnormal, rather than as routine surveillance at fixed intervals.

Routine whole-body skin exams should be performed, including rebiopsy for any suspicious skin or extramedullary lesions.

For patients with prior extramedullary disease, we perform positron emission tomography/CT to document remission and for suspected recurrent disease.

RELAPSED/REFRACTORY DISEASE — Optimal treatment of relapsed or refractory (r/r) BPDCN is poorly defined. We strongly encourage enrollment in a clinical trial, when possible.

Patients should be treated to control symptoms and should be evaluated and treated for possible central nervous system (CNS) involvement. Patients who achieve a response to salvage therapy should proceed to allogeneic transplantation, if possible.

Central nervous system – All patients with suspected r/r BPDCN should be evaluated for CNS involvement with a lumbar puncture (LP). CNS prophylaxis or treatment should be administered according to findings from the LP [19]. (See 'Central nervous system management for all patients' above.)

Systemic therapy – Salvage therapy is guided by prior therapy. During administration of any treatment option, a donor search should also be started in appropriate patients, if no sibling donor has been identified.

No prior tagraxofusp – For patients who were previously treated with a chemotherapy regimen, we suggest salvage treatment with tagraxofusp.  

Among 19 patients with r/r BPDCN, tagraxofusp was associated with a 58 percent overall response rate (ORR) and eight-month median overall survival (OS); one patient was successfully bridged to hematopoietic cell transplantation (HCT) [33]. In another study, tagraxofusp was associated with a 67 percent ORR and nine-month median OS in patients with r/r BPDCN [18].

Prior tagraxofusp – For patients previously treated with tagraxofusp, there is no consensus. Options include:

-For fit patients, intensive regimens are described above. (See 'Other treatments' above.)

-Venetoclax-based regimens achieved significant responses in patients with relapsed BPDCN [14,43].

-Bendamustine achieved a complete remission (CR) in one of five patients, and the remission was maintained for >7 months [47].

-Biweekly CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) was associated with a CR that lasted 16 months [48].

Localized management – Radiation therapy or systemic steroids can provide temporary palliative symptomatic relief.

Postremission – Patients who achieve CR with r/r BPDCN should undergo allogeneic HCT, if possible, as the only treatment with the potential for longer-term disease control.

CLINICAL TRIALS — We strongly encourage participation in a clinical trial for patients with BPDCN. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

PROGNOSIS — Prognosis is generally poor because of the high risk of relapse and central nervous system (CNS) involvement with BPDCN.

Age – Outcomes with BPDCN are most closely associated with age. A systematic review that compared 74 children with 283 adults (≥19 years) with BPDCN reported that children had more favorable outcomes [16]. Compared with adults, children had higher rates of complete remission (CR; 86 versus 52 percent across chemotherapy types) and a better mean disease-free survival (DFS; 12 versus 7 months).

Among adults, age >60 was associated with inferior outcomes [16,34].

Other features – Outcomes do not appear to differ between patients who present with skin-only disease compared with systemic involvement; even patients with localized disease have an aggressive course and poor outcome [15]. MYC rearrangements have been associated with adverse outcomes [15,49-51], but prognostic importance has not clearly demonstrated with other genetic features. Outcomes are similar with various types of intensive induction therapy, as described above. (See 'Medically fit adults' above.)

SUMMARY AND RECOMMENDATIONS

Description – Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that predominantly affects older males. It arises from plasmacytoid dendritic cell (pDC) precursors in bone marrow that undergo malignant transformation in skin in sun-damaged regions. (See 'Epidemiology' above and 'Pathogenesis' above.)

Clinical presentation – Most patients present with cutaneous lesions, with or without leukemic dissemination. Some have lymph node or central nervous system (CNS) involvement. Cytopenias, lymphadenopathy, and/or splenomegaly are present in most patients, and occasional patients present with leukemia without skin involvement. (See 'Clinical presentation' above.)

Evaluation – All patients require lumbar puncture (LP) to assess CNS involvement and a bone marrow examination. Medical fitness and performance status (table 1) should be assessed. (See 'Evaluation' above.)

Pathology.

Microscopy – Skin biopsies reveal an infiltrate of medium-sized, poorly differentiated cells that spare the epidermis but can extend to subcutaneous fat. Blasts are usually, but not always, detected in blood and/or bone marrow. (See 'Morphology' above.)

Immunophenotype – Tumor cells express CD123, CD4 and/or CD56. (See 'Immunophenotype' above.)

Diagnosis – Diagnostic criteria include characteristic morphology (described above) together with expression of CD123; CD4 and/or CD56; plus one or more pDC-associated antigens by flow cytometry and/or histochemistry. (See 'Diagnostic criteria' above.)

The differential diagnosis includes other hematologic malignancies with cutaneous manifestations. (See 'Differential diagnosis' above.)

Central nervous system – LP to evaluate CNS involvement should be performed in all patients with BPDCN. Management is guided by the findings from LP. (See 'Central nervous system management for all patients' above.)

No central nervous system involvement demonstrated – We suggest CNS prophylaxis using intrathecal (IT) chemotherapy for all patients (Grade 2C).

Documented central nervous system disease – We suggest IT chemotherapy as detailed above (Grade 2C).

Treatment of fit adults.

Remission induction – For medically fit adults, we suggest tagraxofusp (CD123-directed cytotoxin), rather than leukemia- or lymphoma-based induction regimens (Grade 2C). (See 'Induction therapy' above.)

Treatment with tagraxofusp requires serum albumin ≥3.2 g/dL and prophylaxis for capillary leak syndrome. (See 'Tagraxofusp' above.)

If tagraxofusp is not available, acceptable alternatives include acute leukemia-type induction regimens; there is no consensus regimen, as discussed above. (See 'Other treatments' above.)

Postremission – For adults with BPDCN, we suggest allogeneic hematopoietic cell transplantation (HCT) over autologous HCT or maintenance therapy with tagraxofusp, rather than observation alone (Grade 2C). (See 'Postremission management' above.)

Less-fit adults – Management of less-fit adults is guided by symptoms, disease distribution, and patient preference, as described above. (See 'Less-fit adults' above.)

Children. (See 'Children' above.)

Remission induction – Stratified by age:

-≥2 to ≤18 years – Induction therapy using either tagraxofusp or an induction regimen for acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) is acceptable.

-<2 years – We suggest treatment with an ALL/LBL-like regimen (Grade 2C). Tagraxofusp has not been approved in this population.

Postremission – For children in remission, we suggest observation rather than consolidation with allogeneic HCT (Grade 2C).

Relapsed or refractory BPDCN – Participation in a clinical trial should be prioritized; other treatment options are influenced by prior therapy. (See 'Relapsed/refractory disease' above.)

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References

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