Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm.

BACKGROUND: Blastic plasmacytoid dendritic-cell neoplasm (BPDCN) is an aggressive hematologic cancer that is caused by transformed plasmacytoid dendritic cells that overexpress interleukin-3 receptor subunit alpha (IL3RA or CD123). Tagraxofusp (SL-401) is a CD123-directed cytotoxin consisting of human interleukin-3 fused to truncated diphtheria toxin. METHODS: In this open-label, multicohort study, we assigned 47 patients with untreated or relapsed BPDCN to receive an intravenous infusion of tagraxofusp at a dose of 7 µg or 12 µg per kilogram of body weight on days 1 to 5 of each 21-day cycle. Treatment continued until disease progression or unacceptable toxic effects. The primary outcome was the combined rate of complete response and clinical complete response among patients who had not received previous treatment for BPDCN. A secondary outcome was the duration of response. RESULTS: Of the 47 patients, 32 were receiving tagraxofusp as first-line treatment and 15 had received previous treatment. The median age of the patients was 70 years (range, 22 to 84). Among the 29 previously untreated patients who received tagraxofusp at a dose of 12 µg per kilogram, the primary outcome occurred in 21 (72%), and the overall response rate was 90%; of these patients, 45% went on to undergo stem-cell transplantation. Survival rates at 18 and 24 months were 59% and 52%, respectively. Among the 15 previously treated patients, the response rate was 67%, and the median overall survival was 8.5 months. The most common adverse events were increased levels of alanine aminotransferase (64%) and aspartate aminotransferase (60%), hypoalbuminemia (55%), peripheral edema (51%), and thrombocytopenia (49%). Capillary leak syndrome was reported in 19% of the patients and was associated with one death in each of the dose subgroups. CONCLUSIONS: In adult patients with untreated or relapsed BPDCN, the use of tagraxofusp led to clinical responses. Serious adverse events included capillary leak syndrome; hepatic dysfunction and thrombocytopenia were common. (Funded by Stemline Therapeutics and the Leukemia and Lymphoma Society Therapy Acceleration Program; ClinicalTrials.gov number, NCT02113982.).

A non-Darwinian role for mutagenesis in stem cell-derived cancers.

It is clear that mutations cause cancer. The implicated mechanism is Darwinism. That is, a stochastic series of mutations is purported to effect the cellular variability upon which natural selection acts to yield increasingly cancer-like intermediates leading ultimately to malignant clones. It is no wonder then that the neoplastic phenotype is considered "alien," having evolved via random unrehearsed events. Neoplasia, however, has also been depicted as something less than foreign, bordering on familiar. This is because cancer shares proliferative and invasive qualities with the native developmental processes of embryogenesis and adult tissue renewal/repair. A question then arises: If key features of malignancy already naturally exist within well-choreographed programs, why reinvent this phenotype via stochastic multistep schemes rather than reactivate it largely en bloc? Indeed, as will be shown, tissues do harbor a malignant potential capable of reactivation. Specifically, this capability is maintained by stem cells (having inherited such from embryonic precursors)-a phenotype controlled by a microenvironment favoring perpetual rearing by (quiescent) stem cells of proliferative progeny for orderly renewal over neoplasia. Accordingly, normally well-sequestered stem cells, when amid carcinogen/mutagen-induced disruption to local surroundings, produce progeny tending by default toward disorderliness (neoplasia) over renewal. Because such tumor-causing mutations act non-cell autonomously, this cancerous state is potentially reversible but subsequent cell-autonomous mutations can impair particular clonal progeny, already cancerous, from regressing. Thus, a scenario wherein mutations (1) de-repress malignancy non-cell autonomously and then (2) slow its reversion cell autonomously, commonly misinterpreted as Darwinian, may constitute a non-Darwinian mechanism for the genesis of cancers that are stem cell derived.

In vivo enhanced expression of patched dampens the sonic hedgehog pathway.

The sonic hedgehog (SHH)-patched (PTCH) pathway functions in normal embryonic development of the brain, musculoskeletal system, and hair follicles, and in normal post-natal control of hair follicles. Dysregulation of the pathway has been implicated in a variety of neoplasias, including those of skin and brain. Based on the knowledge that generalized, prolonged PTCH expression can inhibit the effects of SHH signaling, we tested the hypothesis that localized transient overexpression of PTCH would inhibit the phenotype of SHH-induced accelerated growth of hair follicles. Adenovirus (Ad)-mediated transient over-expression of Shh (AdShh) in telogen (8 weeks) mouse skin induced anagen hair growth as demonstrated by histology and gross appearance. Strikingly, local intradermal administration of a Ptch-expressing adenovirus (AdPtch), but not a Null control adenovirus (AdNull), 18 hours before AdShh injection, significantly blocked this phenotype, with 100% of AdPtch+AdShh mice failing to advance to anagen compared with AdNull+AdShh mice and AdShh mice (30% and 45% failing to advance to anagen, respectively). Thus, PTCH expression mediated by gene transfer can modulate the SHH signaling pathway in the adult mammal and may serve as a starting point for therapies relevant to clinical conditions resulting from dysregulation of this pathway as well as for strategies to suppress normal SHH-dependent processes, such as hair growth.