Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients

Abstract

This is the first prospective study of treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy derived from plasmacytoid dendritic cells 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. Because BPDCN blasts overexpress the interleukin-3 receptor (IL3R), the activity of SL-401, diptheria toxin (DT)388IL3 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 12.5 μg/kg intravenously over 15 minutes daily for up to 5 doses; 3 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 9 evaluable (78%) BPDCN patients had major responses including 5 complete responses and 2 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 trial is registered at clinicaltrials.gov as #NCT00397579.

© 2014 by The American Society of Hematology.

Figures

Figure 1

SL-401 concentration-time curve for patient 3 on day 1. Drug concentrations assayed by a previously described bioassay. The Cmax and t1/2 values were 22 ng/mL and 40 minutes, respectively.

Figure 2

Photographs of skin, PET/CT scan, and bone marrow biopsy, pre– and post–SL-401. (A) Involved skin of patient 7 photographed before treatment and 4 months after treatment. (B) PET/CT images for patient 6 scanned before treatment and 1 month after treatment, demonstrating enlarged and PET-avid left inguinal node (1.2 × 1.6 cm; standardized uptake value Max 3.5) and right inguinal node (0.7 × 1 cm; standardized uptake value 2.3) before treatment. These inguinal nodes regressed and were no longer PET-avid at 1 month after treatment. (C) Immunostaining for CD123 on a bone marrow aspirated from patient 1 before treatment and at 1 month after treatment. Pretreatment showed 10% positive cells and after therapy showed <1% to 2% positive cells. Magnification pretreatment microphotograph is ×20; magnification post-treatment microphotograph is ×40.