[Show abstract][Hide abstract] ABSTRACT: Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy derived from plasmacytoid dendritic cells. Today, no standard of care is accepted to treat blastic plasmacytoid dendritic cell neoplasm, and therapeutic strategies have never been prospectively evaluated. Since blastic plasmacytoid dendritic cell neoplasm cells express high levels of IL-3 receptor α chain (IL3-Rα or CD123), antitumor effects of the IL-3R-targeted drug SL-401 against Blastic plasmacytoid dendritic cell neoplasm were evaluated in vitro and in vivo. Cytotoxicity of SL-401 was assessed in patient-derived blastic plasmacytoid dendritic cell neoplasm cell lines (CAL-1 and GEN2.2) and in primary blastic plasmacytoid dendritic cell neoplasm cells isolated from 12 patients using flow cytometry and an in vitro cytotoxicity assay. Cytotoxic effects of SL-401 were compared to several relevant cytotoxic agents. SL-401 exhibited a robust cytotoxicity against blastic plasmacytoid dendritic cell neoplasm cells in a dose-dependent manner. Additionally, the cytotoxic effects of SL-401 were observed at substantially lower concentrations than those achieved in clinical trials to date. Survival of mice inoculated with a blastic plasmacytoid dendritic cell neoplasm cell line and treated with a single cycle of SL-401 was significantly longer than that of untreated controls (median survival, 58 vs. 17 days, p <0.001). These findings indicate that blastic plasmacytoid dendritic cell neoplasm cells are highly sensitive to SL-401, and support the rationale to further evaluate SL-401 in patients suffering from blastic plasmacytoid dendritic cell neoplasm.
[Show abstract][Hide abstract] ABSTRACT: This is the first prospective study of treatment for patients with blastic plasmacytoid dendritic cell neoplasm-BPDCN, an aggressive hematologic malignancy derived from plasmacytoid dendritic cells-PDCs that typically involves the skin and rapidly progresses to a leukemia phase. Despite being initially responsive to intensive combination chemotherapy, most patients relapse and succumb to their disease. Since BPDCN blasts overexpress the interleukin-3 receptor-IL3R, the activity of SL-401, DT388IL3 composed of the catalytic and translocation domains of DT fused to IL3, was evaluated in BPDCN patients in a phase 1-2 study. Eleven patients were treated with a single course of SL-401 at 12.5mcg/kg IV over 15 minutes daily for up to 5 doses; three patients who had initial responses to SL-401 received a second course in relapse. The most common adverse events including fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia and transaminasemia were transient. Seven of nine evaluable (78%) BPDCN patients had major responses including five complete responses and two partial responses after a single course of SL-401. The median duration of responses was 5 months (range 1 - 20+ months). Further studies of SL-401 in BPDCN including those involving multiple sequential courses, alternate schedules and combinations with other therapeutics are warranted. This study was registered at clinicaltrials.gov, identifier: NCT00397579.
[Show abstract][Hide abstract] ABSTRACT: STUDY QUESTION: How can leukemic cells be detected in cryopreserved ovarian tissue? SUMMARY ANSWER: Multicolor flow cytometry (FCM) is useful to evaluate the presence of viable leukemic cells in the ovarian cortex with a high specificity and a robust sensitivity. WHAT IS KNOWN ALREADY: Storing ovarian tissue is an option to preserve fertility before gonadotoxic radiotherapy or chemotherapy treatments. However, transplantation of cryopreserved ovarian cortex to women cured of leukemia is currently not possible due to the risk of cancer re-seeding. STUDY DESIGN, SIZE, DURATION: We developed an automated ovarian cortex dissociation technique and we used eight-color FCM to identify leukemic cells with a series of dilutions added to ovarian single cell suspensions obtained from healthy cortex. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Healthy ovarian cortex originated from women between 23 and 39 years of age undergoing laparoscopic ovarian drilling for polycystic ovary syndrome. Blood or bone marrow cells were collected in acute lymphoblastic leukemia (ALL) patients at diagnosis. MAIN RESULTS AND THE ROLE OF CHANCE: The tissue dissociation technique yield was 1.83 ± 1.49 × 10(6) viable nucleated cells per 100 mg of ovarian cortex. No cell exhibiting a leukemic phenotype was present in the normal ovarian cortex. Added leukemic cells were detected using their leukemia-associated phenotype up to a dilution of 10(-4). When specific gene rearrangements were present, they were detected by real-time quantitative PCR at the same dilution. The ovarian cortex from two leukemia patients was then used, respectively, as positive and negative controls. LIMITATIONS, REASONS FOR CAUTION: Making available minimal residual disease (MRD) detection techniques (multicolor FCM, PCR and xenograft), that can be used either alone or together, is essential to add a fail-safe oncological dimension to pre-autograft monitoring. WIDER IMPLICATIONS OF THE FINDINGS: This approach can be performed on fresh ovarian tissue during cryopreservation or on frozen/thawed tissue before reimplantation and it is currently the only available technique in cases of ALL where no molecular markers are identified. This new perspective should lead to studies on ovarian tissue from leukemia patients, for whom the presence of MRD should be established before autograft. STUDY FUNDINGS/COMPETING INTEREST(S): The study was supported by the BioMedicine Agency, the Committee of the League against Cancer, the Besançon University Hospital, DGOS/INSERM/INCa and the regional Council of Franche-Comté. There were no conflicts of interest to declare.
Human Reproduction 04/2013; DOI:10.1093/humrep/det126 · 4.59 Impact Factor