Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm

Plasmacytoid dendritic cell expansion defines a distinct subset of RUNX1 mutated acute myeloid leukemia

“…Based on the clonal origin and possible pro-leukemic activities of pDCs in AML, we reasoned that targeting pDCs may have therapeutic benefit in pDC-AML. The proof-of-principle experiments demonstrated efficacy of tagraxofusp in eliminating pDCs, consistent with the clinical efficacy in patients with BPDCN (49). Tagraxofusp has previously shown objective responses as a single therapeutic agent in a small subset of AML patients (69).…”

“…Tagraxofusp, a fusion protein consisting of interleukin-3 fused to a truncated diphtheria toxin payload with high affinity and avidity for the interleukin-3 receptor-α (CD123), has shown substantive therapeutic efficacy in and therefore is FDA-approved for the treatment of BPDCN (49). Since pDCs are increased in the patients with pDC-AML and the leukemic blasts also expressed higher levels of CD123 compared to AML with no pDC expansion (median of MFI: 1773 vs 1008, p=0.0003) (Figure 1D), we hypothesized that CD123 targeted therapy may have efficacy in pDC-AML.…”

The lenalidomide/bortezomib/dexamethasone regimen for the treatment of blastic plasmacytoid dendritic cell neoplasm

“…High‐dose acute leukemia‐like induction chemotherapy and then consolidation with allogeneic hematopoietic stem cell transplantation (HSCT) has resulted in better outcomes for eligible young patients but the relapse rate is still high . No specific targeted agents are currently approved in an indication of BPDCN, though preclinical and early clinical studies have revealed that CD123‐directed therapies are very effective and might therefore improve outcomes in patients with BPDCN …”

“…1,2 No specific targeted agents are currently approved in an indication of BPDCN, though preclinical and early clinical studies have revealed that CD123-directed therapies are very effective and might therefore improve outcomes in patients with BPDCN. 3 Along with targeted therapies, immunomodulatory approaches are being investigated in preclinical studies. A therapeutic effect of lenalidomide has been demonstrated in a mouse xenograft model, using primary bone marrow cells from a patient with BPDCN; slower tumor growth was associated with an increase in apoptosis and cell cycle arrest, and a decrease in tumor cell engraftment and tumor vascularization.…”

Cutaneous blastic plasmacytoid dendritic cell neoplasm arising in the context of TET2 and ZRSR2 mutated clonal cytopenias of unknown significance, secondary to somatic copy number losses involving CDK2NA/2NB and MTAP

“…8 On the other hand, MTAP (5 0 -methylthioadenosine phosphorylase), commonly co-deleted with CDKN2A/B due to chromosomal proximity, participates in the methionine salvage pathway that metabolizes methylthioadenosine (MTA) to adenine and methionine, and has been shown to have an independent effect in cell migration and invasion. 9 In addition, the recent US FDA approval of Tagraxofusp, a CD123-directed cytotoxin consisting of recombinant human interleukin-3 fused to a truncated diphtheria toxin has revolutionized the management of BPDCN, with overall response rates of 90% in previously untreated patients 10 ; substantially improving outcomes. However, this drug is not curative, and especially for transplant ineligible patients, there is a strong need for additional, more definitive rationally derived therapies.…”