Blastic plasmacytoid dendritic cell neoplasm

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Acute myeloid dendritic cell leukemia
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Blastic plasmacytoid dendritic cell neoplasm
CD4+ CD56+ lymphoma

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy. It was initially regarded as a form of lymphocyte-derived cutaneous lymphoma and alternatively named CD4+CD56+ hematodermic tumor, blastic NK cell lymphoma,[1] and agranular CD4+ NK cell leukemia.[2] Later, however, the disease was determined to be a malignancy of plasmacytoid dendritic cells rather than lymphocytes and therefore termed blastic plasmacytoid dendritic cell neoplasm. In 2016, the World Health Organization designated BPDCN to be in its own separate category within the myeloid class of neoplasms.[3] It is estimated that BPDCN constitutes 0.44% of all hematological malignancies.[4]

Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy with features of

lymph nodes, central nervous system, or other tissues. The neoplasm occurs in individuals of all ages but predominates in the elderly; in children, it afflicts males and females equally but in adults is far more common (~75% of cases) in males.[5]

Blastic plasmacytoid dendritic cell neoplasm typically responds to chemotherapy regimens used to treat hematological malignancies. All too often, however, the disease rapidly recurs and does so in a more drug-resistant form.[5] Furthermore, the disease may occur in association with the myelodysplastic syndrome or transform to acute myeloid leukemia.[4] Consequently, BPDCN has a very low 5 year survival rate.[5] Current translational research studies on treating BPDCN have therefore focused on non-chemotherapeutic regimens that target the molecular pathways which may promote the disease.[6]

Presentation

Blastic plasmacytoid dendritic cell neoplasm occurs in children,

neonates,[7] but is more common in adults, particularly those between the ages 60–80.[5] BPDCN usually (i.e. 61%[5] to 90%[8] of cases) presents with skin lesions, i.e. nodules, tumors, red or purple papules, bruise-like patches, and/or ulcers that most often occur on the head, face, and upper torso.[2] The lesions are due to diffuse infiltrations of the skin by malignant pDC. In one large study, this presentation was accompanied by swollen lymph nodes, usually in the neck, due to malignant pDC infiltrations (~50% of cases); enlarged liver (~16% of cases) and/or spleen (26% of cases), also due to malignant pDC infiltrations;[5] increased levels of malignant pDC in blood (i.e. >2% of nucleated cells) (~40% of cases), bone marrow (~65% of cases) and cerebrospinal fluid (47% of childhood cases but less often detected in adult cases).[5] More advanced or severe cases may present with extreme organ and/or lymph node enlargements, skin lesions in virtually any site, and clinical evidence of malignant pDC infiltrations in the breasts, eyes, kidneys, lungs, gastrointestinal tract, bone, sinuses, ears, or testes.[5] About 10% of individuals with BPDCN present with a leukemia-like disease,[4] i.e. they exhibit circulating malignant pDC, anemia, thrombocytopenia, and/or leukopenia due to extensive malignant pDC infiltrations in the bone marrow.[4] A leukemic phase of the disease is a common feature of end stage and post-therapy relapsing BPDCN.[2]

Pathophysiology

There are three types of

NK cell lineages.[11]

Blastic plasmacytoid dendritic cell neoplasm typically arises after the serial acquisition of multiple genetic abnormalities in pDC or their precursor cells.

SUPT3H on the short arm of chromosome with MYC on the long arm of chromosome 8, or KMT2A on the long arm of chromosome 11 with MLLT1 on the long arm of chromosome 19;[12] and 4) duplication or loss of entire chromosomes, particularly chromosomes 9, 13, or 15.[4] Laboratory studies indicate that malignant pDC have a pathologically overactive NF-κB pathway that promotes their survival and production of various cytokines) that stimulate their own proliferation.[8] Presumably, these genetic abnormalities lead to the activation of the NF-κB pathway and/or other cellular activation pathways which promote the survival, proliferation, and/or other malignant phenotypic traits in pDC and thereby cause BPDCN.[12]

Diagnosis

BPDCN is suggested by a biopsy of skin lesions which reveals the infiltration by medium-sized blast (i.e. immature) cells into the

CD11c, and CD163 which are unique to AML, TCLL, or NKL blasts.[4] Two other studies recommended assaying somewhat different sets of marker proteins.[2][12]

Treatment

There have been no controlled studies to define the optimal treatment for BPDCN.

L-asparaginase, idarubicin, and dexamethasone followed by allogenic or autologous bone marrow transplantation in 26 participants newly diagnosed with BPDCN is planned but not yet in its recruiting phase.[13]

While few studies have reported on the treatment of BPDCN that has recurred following initial therapy, donor lymphocyte infusions coupled with alternative chemotherapy treatments have induced second complete or partial remissions in a few patients.[4]

Tagraxofusp-erzs

eukaryotic elongation factor 2).[citation needed
]

Prognosis

Due to the high rates of recurrence following initial therapy and the short overall survival times of individuals with BPDCN, prognosis of the disease is poor. However, further study of treatment regimens that include intrathecal chemotherapy and hematological stem cell transplantation in initial treatment regimens (see previous section) and newer non-chemotherapeutic drug treatments (see next section) may improve this situation.[8]

Research

UCART123

UCART123#CAR-T cancer treatment).[15] The suspension was lifted in November 2017 after the trial used reduced amounts of the cells and with additional conditions were applied.[16] A new phase 1 clinical trial is now recruiting 76 new patients to study the safety and efficacy of UCAR123 in treating BPDCN. The study began in June 2017 and is scheduled to end in December 2021.[17]

Venetoclax

BCL-2 is a cellular protein that can act to inhibit cell death due to apoptosis. The BCL-2 gene appears to be one of the most up-regulated (i.e. overactive) genes in BPDCN. Venetoclax inhibits the apoptosis-inhibiting action of BCL-2 and proved active in treating two patients with relapsed or refractory BPDCN.[8] A phase I clinical trial testing the safety and efficacy of the drug in BPDCN is planned but not yet in its recruiting phase.[18]

References

  1. S2CID 23625855
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  2. ^
    PMID 29760611
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  3. PMID 27069254
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  4. ^
    PMID 27913457
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  5. ^
    S2CID 11799428
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  6. S2CID 207330989
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  7. PMID 29806701
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  8. ^
    S2CID 3627886
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  9. ^
    PMID 29313948
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  10. ^
    PMID 29444460
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  11. ^
    S2CID 47003308
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  12. ^
    S2CID 13993911
    .
  13. ^ "Combination Chemotherapy (Methotrexate, L-asparaginase, Idarubicin and Dexamethasone) in Patients with Newly Diagnosed Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)". 19 November 2019.
  14. ^ "FDA approves first treatment for rare blood disease" (Press release). Food and Drug Administration. December 21, 2018.
  15. ^ a b McKee, Selina (2017-09-05). "FDA holds trials of Cellectis' cell therapy after patient death". www.pharmatimes.com. Retrieved 2017-10-08.
  16. ^ Melão, Alice (9 November 2017). "FDA Lifts Clinical Hold on Cellectis' UCART123 Trials in AML, BPDCN".
  17. ^ "Phase 1, Open-label Dose-escalation and Dose-expansion Study to Evaluate the Safety, Expansion, Persistence and Clinical Activity of a Single Dose of UCART123 (Allogeneic Engineered T-cells Expressing Anti-CD123 Chimeric Antigen Receptor), Administered in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)". 29 July 2019.
  18. ^ Lane, Andrew (6 May 2021). "Phase 1 Study of Venetoclax, a BCL2 Antagonist, for Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)".
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