Management of Blastic Plasmacytoid Dendritic Cell Neoplasm
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare myeloid malignancy, representing only 0.44% of hematologic malignancies, with an incidence of 0.04 cases per 100,000 people in the United States.1,2 BPDCN, which was formerly known as blastic natural killer cell lymphoma or granular CD4+/CD56+ hematodermic neoplasm, was renamed in the 2008 WHO classification with the evolving knowledge of its PDC origin.3,4 In 2016, it was recognized as a unique myeloid malignancy.5 The 2022 WHO classification system considers BPDCN to be a subtype of a group of malignancies known as plasmacytoid dendritic cell neoplasms.6 Pathologically, it is characterized by aggressive proliferation of precursors of PDCs.7,8 The etiology of BPDCN is unknown, but its association with myelodysplastic syndromes or chronic myelomonocytic leukemia in some cases may suggest a related pathogenesis.7,9 BPDCN is associated with a poor prognosis, with a median overall survival (OS) of approximately 8 to 12 months when patients are treated with chemotherapy.8,10 Median age of presentation is 65 to 67 years, with an approximate male-to-female ratio of 3:1. The most frequent clinical presentation of typical BPDCN cases is asymptomatic solitary or multiple skin lesions that can disseminate rapidly without therapy.7,8 Peripheral blood and bone marrow involvement may be minimal at presentation, but tend to develop as the disease progresses. Additional sites of involvement can include lymph nodes, spleen, and other extramedullary organs.4,7,11 Less commonly, patients may present with features of an acute leukemia without skin manifestations.8 Central nervous system (CNS) involvement is not infrequent; approximately 10% of patients who present with neurologic symptoms at diagnosis have confirmed CNS involvement,12 and rates of CNS involvement, both at diagnosis and at relapse, have been found to be in the range of 9% to 26% in several additional studies.8,13,14
Workup
Evaluation and initial workup for suspected BPDCN consists of a comprehensive medical history and physical examination. Laboratory evaluations include a comprehensive metabolic panel and a complete blood cell (CBC) count including platelets and a differential of white blood cells. Analyses of peripheral blasts; bone marrow biopsy and aspirate; biopsy of skin lesions and, if suspected to be involved, lymph nodes; and other tissues are recommended. These analyses should include dendritic cell morphology assessment, immunohistochemistry, flow cytometry, cytogenetic analysis (including karyotyping and/or fluorescence in situ hybridization), and molecular analyses. Analysis of skin lesions often occurs in collaboration with dermatology. It is essential to differentiate the skin lesions of BPDCN from other neoplastic and nonneoplastic skin lesions and rashes, including leukemia cutis associated with acute myeloid leukemia (AML), and analysis by experienced hematopathologists is often required.4 If extramedullary disease and/or lymphadenopathy is suspected, a PET/CT scan is recommended. A lumbar puncture is highly recommended at initial diagnosis to rule out CNS disease, and subsequent intrathecal prophylaxis is strongly encouraged even in the absence of known CNS disease.4
Diagnosis of BPDCN can be difficult due to overlapping morphologic, immunophenotypic, and clinical features of other hematologic malignancies, such as AML.4 This is particularly true when BPDCN presents as isolated cutaneous lesions, because biopsy specimens from cutaneous lesions may not yield sufficient cells for appropriate flow cytometric analysis.4 A diagnosis of BPDCN requires expression of at least 4 of these 6 antigens on malignant cells: CD123 (also referred to as interleukin-3 receptor-alpha [IL3Rα]), CD4, CD56, TCL-1, CD2AP, and CD303/BDCA-2, in the absence of lineage-specific markers.4,7 TCF4/CD123 coexpression has also been found to be a sensitive and specific diagnostic marker for BPDCN.15,16 CD303 is emerging as another marker useful in the diagnosis of BPDCN and may serve as a potential marker for further directed therapy.17 BPDCN must be distinguished from mature plasmacytoid dendritic cell proliferation in which PDCs are morphologically mature and CD56-negative.7 In addition, recurrent mutations in the following genes have been described: ASXL1, IDH1, IDH2, IKZF1, IKZF2, IKZF3, NPM1, NRAS, TET1, TET2, TP53, U2AF1, and ZEB2.4,7,18,19
Induction Therapy for Patients With BPDCN
Given the rarity of BPDCN, no standardized chemotherapy approach has been established.8 Historically, therapeutic approaches have varied widely and have included irradiation for localized skin lesions, lymphoma- or leukemia-type chemotherapy regimens, and hematopoietic cell transplantation (HCT).20 Despite good initial responses to chemotherapy, with response rates of 40% to 90%,4 early relapse rates are high, even among those who achieve complete remission (CR).4,8,20 CD123-targeted therapy with tagraxofusp-ersz has more recently emerged as the preferred treatment option in appropriate candidates.
CD123-Targeted Therapy
CD123, or IL3Rα, overexpression is present in virtually all cases of BPDCN.11 Tagraxofusp (formerly SL-401) is a recombinant fusion protein made up of the catalytic and translocation domains of diphtheria toxin fused to IL-3 that has shown activity against BPDCN.
The first prospective study of treatment of patients with BPDCN included 11 patients with recurrent or refractory (R/R) BPDCN or who were not candidates for chemotherapy who were treated with SL-401.21 Each cycle of SL-401 treatment was comprised of a 12.5 µg/kg dose administered over a 15-minute infusion every day for up to 5 doses. Of 9 evaluable patients who received treatment, 5 had a CR and 2 had a partial response (PR) after one cycle of SL-401 treatment (78% overall response rate [ORR]). The median duration of response was 5 months (range, 1–20+ months), with responses occurring in all sites of disease, including skin, bone marrow, and lymph nodes. Acute infusion-related adverse effects such as fever, chills, and nausea were mild to moderate in severity and were most commonly seen within the first several hours after SL-401 infusion; however, these symptoms were occasionally noted up to 4 to 8 hours following infusion. Premedications including acetaminophen, diphenhydramine, methylprednisolone, and famotidine were given, likely mitigating these events. Resulting symptoms following infusion responded to additional dosing of acetaminophen, meperidine, antiemetics, and/or H1- and H2-histamine antagonists. These acute infusion-related events may be related to cytokine release from necrotic cells and damaged BPDCN blasts. Most patients experienced one or more symptoms suggestive of vascular or capillary leak syndrome (CLS), such as hypoalbuminemia, edema, hypotension, and hyponatremia. Hypoalbuminemia was the most consistent and early manifestation of CLS (grade 1 in 4 patients, grade 2 in 6 patients). Symptoms of CLS were managed by the administration of parenteral albumin and diuretics. Although several patients experienced grade 3 thrombocytopenia and neutropenia, myelosuppression was generally modest and reversible, potentially reflecting the minimal expression of IL3R on normal myeloid progenitors. Many patients experienced transaminitis without hyperbilirubinemia, with onset typically 5 to 10 days postinfusion and with full resolution typically 15 to 21 days following infusion.
In a multicohort study by Pemmaraju et al,22 84 patients with untreated or relapsed BPDCN were treated with an intravenous infusion of tagraxofusp at a dose of 12 µg/kg on days 1 to 5 of each 21-day cycle. Treatment was given until disease progression or unacceptable adverse effects. Of the 84 patients, 65 received first-line treatment and 19 had received prior treatment. Among evaluable patients who received first-line treatment of tagraxofusp, the primary outcome (CR and clinical CR) was observed in 57% of patients, ORR was 75%, and median OS was 15.8 months. Of the patients who achieved CR or clinical CR following first-line treatment of tagraxofusp, 51% were successfully bridged to HCT (allogeneic HCT, n=13; autologous HCT, n=6) while in remission and the median OS in this subgroup was 38.4 months. Of the 18 patients who achieved CR or clinical CR following first-line treatment who did not proceed to HCT, 4 had duration of responses >6 months. Among the 19 patients who had received prior therapy, ORR was 58% with a median OS of 8.2 months. Among this subgroup, 1 patient was successfully bridged to HCT. Based on earlier data from this trial,11 the FDA approved tagraxofusp-erzs for the treatment of BPDCN in adults and pediatric patients aged ≥2 years in 2018.
The most common adverse effects noted in the study by Pemmaraju et al22 were increased levels of alanine aminotransferase and aspartate aminotransferase, hypoalbuminemia, fatigue, fever, thrombocytopenia, nausea, and peripheral edema. In addition, CLS was observed in 21% of patients (8 of which were grade ≥3 and 3 of which were grade 5 resulting in death), primarily in the first cycle of treatment. Median time to onset of CLS was 6 days (range, 3–51 days), with a median duration of 6 days (range, 3–69 days). CLS was managed by withholding further doses of tagraxofusp, administering intravenous albumin or glucocorticoids, and careful management of volume status.
Chemotherapy
In a retrospective multicenter study, 41 patients with BPDCN received induction treatment with AML-type regimens (n=26) and acute lymphoblastic leukemia (ALL)/lymphoma-type regimens (n=15).8 The AML-type treatment protocols included MEC (mitoxantrone/cytarabine/etoposide), ICE (idarubicin/cytarabine/etoposide), standard-dose cytarabine + anthracycline (7 + 3), FLAG (fludarabine/cytarabine/granulocyte colony-stimulating factor), and FLAG-IDA (FLAG + idarubicin). The ALL/lymphoma-type regimens included hyper-CVAD (alternative cycles of hyperfractionated cyclophosphamide/vincristine/doxorubicin/dexamethasone/methotrexate/cytarabine), GIMEMA ALL trial therapy (association of doxorubicin/vincristine/prednisone/asparaginase), CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone), and CHOEP (CHOP + etoposide). There were patients who required additional therapy based on extramedullary disease (4 received intrathecal chemotherapy for CNS involvement and 2 received radiation therapy for skin lesions); 14% of patients underwent allogeneic HCT at some point in their course of therapy. After induction, the overall CR rate was 41%, with 7 patients achieving CR after AML-type induction, and 10 patients achieving CR after ALL-type induction. Median OS was 8.7 months (range, 0.2–32.9 months), and patients who received ALL-type chemotherapy appeared to have longer OS compared with those treated with AML-type chemotherapy (12.3 vs 7.1 months, respectively; P=.02). In addition, the median OS of patients who received transplant was significantly higher than nontransplanted patients (22.7 vs 7.1 months, respectively; P=.03). Age was also noted to be a significant prognostic factor, with a median OS of 12.6 months in patients aged <65 years compared with 7.1 months for those aged >65 years (P=.04). Relapses occurred in 35% of patients at a median of 9.1 months.
An additional retrospective study analyzed the impact of 4 different chemotherapeutic approaches: (1) local therapy or systemic regimens less aggressive than CHOP, (2) CHOP and CHOP-like regimens, (3) acute leukemia regimens, and (4) allogeneic or autologous HCT.20 Therapies less intensive than CHOP were a heterogenous group, including local radiation, systemic steroids, and supportive care, but were mostly cyclophosphamide-based chemotherapy regimens. Although this group had a high ORR of 80% (68% CR), only 7% of patients had a sustained CR and the median OS for evaluable patients was 9 months. Patients in the CHOP and CHOP-like regimens arm had similar results despite therapy being more aggressive, with an ORR of 70% (55% CR) and only 1 case of sustained CR. Intensive acute leukemia regimens resulted in a CR rate of 94%, with approximately one-third of patients experiencing a sustained CR. There were 10 evaluable patients in the HCT arm (6 allogeneic, 4 autologous). Median OS was 38.5 months in the allogeneic arm compared with 16.5 months in the autologous arm. At the time of publication, all but one patient who had undergone allogeneic HCT in first remission remained disease-free.
Another retrospective study evaluated the diagnostic flow cytometry pattern and outcome of 9 patients with BPDCN after frontline treatment with hyper-CVAD.23 In this group, 7 patients received induction treatment with hyper-CVAD and had a CR of 67% and ORR of 86%. Of the 6 patients whose disease responded to therapy, 5 received planned allogeneic HCT. With a median follow-up of 13.3 months, the 1-year disease-free survival (DFS) and OS rates for all patients were 56% and 67%, respectively. The 1-year DFS for those who received allogeneic HCT was 80%. The 1-year OS for patients who received allogeneic HCT was 80%, compared with 50% in those who received chemotherapy alone. Median OS was 7.9 months for those who received chemotherapy alone.
A more recent retrospective study compared outcomes of 100 patients with BPDCN treated with frontline hyper-CVAD–based therapy (n=35), tagraxofusp (n=37), or other therapies (n=28).24 The highest CR rates were seen with hyper-CVAD–based therapy (80%), followed by tagraxofusp (59%), and finally other regimens (43%) (P=.01), although there was no significant difference in OS (28.3 vs 13.7 vs 22.8 months, respectively; P=.41) or remission duration probability (38.6 months vs not reached vs 10.2 months, respectively; P=.24) noted between the 3 arms. In the hyper-CVAD–based group, 51% of patients were bridged to HCT, compared with 49% of patients in the tagraxofusp group and 38% in the other regimens group, respectively (P=.455). This study suggests a continued role for hyper-CVAD–based regimens in the targeted-therapy era.
Venetoclax-Based Regimens
The antiapoptotic protein B-cell leukemia/lymphoma-2 (BCL2) is overexpressed in a majority of patients with BPDCN.25 Venetoclax is an oral selective BCL2 inhibitor approved in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of newly diagnosed AML in patients aged ≥75 years or for those who are otherwise not candidates for intensive remission induction therapy.26 In vitro, BPDCN cells were found to be uniformly sensitive to venetoclax in a study that measured direct cytotoxicity, apoptosis assays, and dynamic BH3 profiling.27
A retrospective study assessed the efficacy of venetoclax combinations in a total of 43 patients with R/R myeloid malignancies, including 2 patients with BPDCN.25 The most common treatment regimens included venetoclax with decitabine (53%), azacitidine (19%), and low-dose cytarabine (19%). Patients had been previously treated with a median of 3 prior lines of therapy, including allogeneic HCT in 12%. Although ORR was seen in 21% of patients, neither of the 2 patients with BPDCN who were evaluated achieved a response by formal criteria, although one patient had a major response by PET/CT, bone marrow blast reduction of >50%, and improvement in cutaneous lesions. The other patient with BPDCN also had a significant improvement in cutaneous lesions. All patients who received venetoclax combination therapy experienced grade ≥3 neutropenia and 72% developed a grade ≥3 infection, most commonly pneumonia, bacteremia, cellulitis, invasive fungal infections, and urinary tract infections. All patients were given allopurinol for tumor lysis syndrome prophylaxis, and none developed hyperuricemia that required rasburicase.25 Venetoclax in combination with hypomethylating agents appears to have efficacy in BPDCN, but larger and more formalized studies are necessary to confirm these observations.
Hematopoietic Cell Transplantation
Due to the rarity of BPDCN, there have been limited established standardized therapeutic approaches.28 HCT seems to generate durable remissions, especially if given in first CR, as indicated by the studies discussed in the chemotherapy section, as well as others.3,8,20,23,28,29 However, it is worth noting that data are limited to small case series and retrospective registry studies, and larger prospective studies are needed to elucidate the role of HCT in BPDCN.29
A retrospective analysis from the Japan Society for Hematopoietic Cell Transplantation aimed to clarify the role of allogeneic or autologous HCT in treating BPDCN.3 In this analysis, 25 patients were identified, with 14 having undergone allogeneic HCT and 11 having undergone autologous HCT. All patients who underwent autologous HCT were in first CR, whereas 12 of the 14 patients who underwent allogeneic HCT were in first CR (2 were not in remission). With a median follow-up of 53.5 months, the OS rates at 4 years for patients who underwent autologous and allogeneic HCT were 82% and 53%, respectively (P=.11) and the progression-free survival (PFS) rates were 73% and 48%, respectively (P=.14). Data suggest that receiving autologous HCT in first CR may substantially enhance survival. OS outcomes in the allogeneic HCT subgroup did not differ significantly between myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) regimens.
A North American multicenter retrospective study analyzed the outcomes of BPDCN patients treated with allogeneic HCT (n=37) or autologous HCT (n=8).29 Allogeneic HCT recipients had a 1-year and 3-year OS of 68% (95% CI, 49%–81%) and 58% (95% CI, 38%–75%), respectively. Receiving allogeneic HCT in first CR yielded improved 3-year OS versus allogeneic HCT not in first CR (74% [95% CI, 48%–89%] vs 0%; P<.0001), and outcomes were not impacted by conditioning type (MAC vs RIC). The 1-year OS for autologous HCT recipients was 11% (95% CI, 8%–50%).
A more recent retrospective study evaluated 162 adults with BPDCN who underwent first HCT (allogeneic HCT, n=146; autologous HCT, n=16), 78% of whom were in first CR.30 Among the allogeneic HCT group, 54% received MAC, 46% received RIC, and 59% received in vivo T-cell depletion. Total body irradiation (TBI) was used in 61% of MAC transplants and 26% of RIC transplants. Comparable 1-year OS and PFS rates were seen following allogeneic and autologous HCT (OS, 66% vs 70%; PFS, 62% vs 66%). TBI as the conditioning backbone in allogeneic HCT led to significant improvements in OS and PFS compared with all other conditioning regimens. Adjusted 2-year PFS for MAC + TBI was 95% compared with 82% for MAC without TBI, 41% for RIC + TBI, and 60% for RIC without TBI, respectively.
NCCN Recommendations
For patients who are candidates for intensive remission induction therapy, the panel recommends tagraxofusp-ersz as the preferred option, and other options include AML-type (standard-dose cytarabine + anthracycline using 7 + 3), ALL-type (hyper-CVAD), and lymphoma-type (CHOP) regimens. If CNS disease is documented at diagnosis, intrathecal chemotherapy should also be given. If CNS disease is not present at diagnosis, prophylactic intrathecal chemotherapy is strongly encouraged.
Tagraxofusp-ersz should be administered as an intravenous infusion at 12 µg/kg over 15 minutes once daily on days 1 to 5 of each 21-day cycle. Alternatively, 5 doses can be administered over a 10-day period, if needed for dose delays. It is important to note that patients must have a baseline serum albumin of ≥3.2 g/dL to be able to start treatment with this agent. The most serious adverse effect associated with tagraxofusp is CLS, which can occur during the first cycle of treatment and can be life-threatening.11 A decrease in serum albumin during the first days of treatment seems to be the most consistent predictor of CLS.11 Management includes delaying or withholding additional tagraxofusp doses, administering intravenous albumin according to prespecified measures, administering glucocorticoids, and close management of volume status.11 The panel recommends replacing serum albumin if <3.5 g/dL or if there is a reduction of ≥0.5 g/dL from baseline. The panel also recommends premedication with an H1-histamine antagonist, acetaminophen, corticosteroid, and H2-histamine antagonist prior to each infusion to help reduce the risk of hypersensitivity reaction.
With all treatment options, if CR is observed, allogeneic or autologous HCT should be considered. If tagraxofusp-erzs was given as an initial treatment and HCT is not feasible, additional cycles of tagraxofusp-erzs should be continued until disease progression. If disease progresses or does not respond to induction therapy, patients should be considered for a clinical trial (preferred) or regimens used for R/R disease.
For patients with low performance and/or nutritional status (ie, serum albumin <3.2 g/dL) or for those who are not candidates for intensive remission induction therapy or tagraxofusp-ersz, treatment options are limited. If disease is localized or isolated to cutaneous involvement, palliative treatment options include surgical excision or focal radiation. If disease is systemic, palliative options include low-intensity therapy with venetoclax-based regimens, steroids, and supportive care.
Postremission Surveillance for BPDCN
Following completion of consolidation therapy, it is recommended to monitor a CBC, including platelets, every 1 to 3 months for the first 2 years, then every 3 to 6 months thereafter for up to 5 years. Bone marrow evaluation should be performed only if cytopenias develop or if peripheral smear is abnormal, rather than as routine surveillance at fixed intervals, unless the bone marrow evaluation is being performed as part of a clinical research protocol. For patients with prior evidence of extramedullary disease, a repeat PET/CT scan is recommended. In addition, routine thorough skin examinations with a rebiopsy should occur for any suspicious skin or extramedullary lesions.
Management of R/R BPDCN
Upon relapse, the NCCN AML Panel recommends evaluating for CNS disease and administering intrathecal chemotherapy prophylaxis.12 Management options for R/R BPDCN include clinical trial (preferred), tagraxofusp-ersz (preferred, if not already used),11 chemotherapy (if not already given), local radiation to isolated lesions, systemic steroids, or venetoclax-based regimens.25,27 During administration of any treatment option, a donor search should also be started at first relapse in appropriate patients if no sibling donor has been identified.
Summary
BPDCN is a rare myeloid malignancy that often initially presents with asymptomatic skin lesions but with peripheral blood and bone marrow involvement developing as the disease progresses. Less commonly, patients present in a leukemic phase without skin manifestations. Prognosis is poor, with median OS of 8 to 12 months when treated with chemotherapy.8,10 Decisions about diagnosis and management of BPDCN should involve multidisciplinary consultation at a high-volume center with use of appropriate interventions, and referral to an academic institution should be considered. For fit patients, current treatment options include the targeted therapy tagraxofusp-erzs and chemotherapy, whereas patients with low albumin and/or comorbidities should receive localized therapy or supportive care. For patients who achieve CR with tagraxofusp-erzs or chemotherapy, allogeneic or autologous HCT should be considered. Studies suggest that being in first remission during receipt of allogeneic HCT significantly enhances median OS.8,23,28 Treatment options for R/R disease include clinical trial (preferred), tagraxofusp-ersz or chemotherapy if not already used, local radiation to isolated lesions, systemic steroids, and venetoclax-based therapies.
Despite the development of tagraxofusp-erzs and high ORRs, relapses are still common and outcomes for patients with R/R BPDCN remain dismal. Additional novel therapies, targeting both CD123 and other targets, are being actively investigated. In addition, a collaborative initiative, the North American BPDCN Consortium (NABC), made up of a group of experts from multiple areas of expertise, has been formed to define the current standard of care for management of BPDCN and to identify future areas of research.31
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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their application or use in any way.
The complete NCCN Guidelines for Acute Myeloid Leukemia are not printed in this issue of JNCCN but can be accessed online at NCCN.org.
© 2023, National Comprehensive Cancer Network® (NCCN®). All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
Disclosures for the NCCN Acute Myeloid Leukemia Panel
At the beginning of each NCCN Guidelines Panel meeting, panel members review all potential conflicts of interest. NCCN, in keeping with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself.
Individual disclosures for the NCCN Acute Myeloid Leukemia Panel members can be found on page 513. (The most recent version of these guidelines and accompanying disclosures are available at NCCN.org.)
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