Blastic plasmacytoid dendritic cell neoplasm frequently shows occult central nervous system involvement at diagnosis and benefits from intrathecal therapy

Abstract

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive myeloid neoplasm which shows a high rate of central nervous system (CNS) recurrence and overall survival (OS) of <1 year. Despite this, screening for CNS involvement is not routinely performed at diagnosis and intrathecal (IT) prophylaxis is not regularly administered in BPDCN. Here, we prospectively evaluated 13 consecutive BPDCN patients for the presence of CNS involvement by flow cytometry. Despite none of the patients presented with neurological symptoms, occult CNS involvement was detected in 6/10 cases evaluated at diagnosis and 3/3 studied at relapse/progression. BPDCN patients evaluated at diagnosis received IT treatment -either CNS prophylaxis (n = 4) or active therapy (n = 6)- and all but one remain alive (median follow-up of 20 months). In contrast, all three patients assessed at relapse/progression died. The potential benefit of IT treatment administered early at diagnosis on OS and CNS recurrence-free survival of BPDCN was further confirmed in a retrospective cohort of another 23 BPDCN patients. Our results show that BPDCN patients studied at diagnosis frequently display occult CNS involvement; moreover, they also indicate that treatment of occult CNS disease might lead to a dramatically improved outcome of BPDCN.

Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms

“…Larger prospective studies will be required to address the relationship, if any, between NR3C1 haploinsufficiency, residual disease, and the presence of central nervous system involvement at diagnosis which has been implicated in rapid disease recurrence in BPDCN patients. 56 As proposed recently, 55 restoring normal GCR levels from the intact NR3C1 allele might represent a route to overcoming glucocorticoid-based therapy failure in NR3C1-haploinsufficient BPDCN. Of note in this context is the finding that thalidomide appears to specifically benefit patients presenting with multiple myeloma and low GCR expression.…”

LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis

“…The CNS may represent a blast cell sanctuary in BPDCN patients with leukemic presentation both at diagnosis and at relapse. 4 Efforts are currently being made to generate new synthetic agonists with increased specificity for the LXRb isoform, expressed by BPDCNs, to limit steatosis 19,49 and/or to stimulate LXR specifically in a target tissue. 50,51 Our study supports a new approach for BPDCN treatment using these new synthetic LXR agonists.…”

“…2,3 It has been recently proposed that the frequent relapse after treatment and the poor prognosis can be related to the fact that the involvement of the central nervous system (CNS) is frequently undetected. 4 Recently, BPDCN was classified by the World Health Organization (WHO) as a distinct entity in the group of "acute myeloid leukemia (AML) and related precursor neoplasms." 2,5 Extensive characterization of this malignancy is still limited and diagnosis overlap may exist with immature AML, monoblastic and undifferentiated leukemia.…”

Treatment of blastic plasmacytoid dendritic cell neoplasm

“…12 Recent literature brought attention to the high percentage of primary CNS involvement (10%) at diagnosis or during relapse of disease (30%) observed in BPDCN, suggesting that the CNS is a sanctuary for cells in patients with primary leukemic presentation and perhaps all BPDCN, given the high incidence encountered in relapse. 31,46 In support of this concept, patients treated with ALL-type regimens, which include aggressive CNS prophylaxis followed by allo-SCT, seem to do better. Upon validation with an additional retrospective cohort of 23 patients, Martín-Martín et al 46 demonstrated that patients receiving prophylactic intrathecal therapy (5 of 23) had both prolonged CNS recurrence-free disease and OS.…”