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References1 Riaz W, Zhang L, Horna P, et al. Blastic plasmacytoid dendritic cell neoplasm: update on molecular biology, diagnosis, and therapy. Cancer Control 2014; 21: 279-289. 2 Frankel AE, Woo JH, Ahn C, et al. Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients. Blood 2014; 124: 385-392. 3 Sun W, Liu H, Kim Y, et al. First pediatric experience of SL-401, a CD123-targeted therapy, in patients with blastic plasmacytoid dendritic cell neoplasm: report of three cases.

7029^ Background: SL-401 is a novel biologic targeted therapy directed to the interleukin-3 receptor (IL-3R). IL-3R is overexpressed on cancer stem cells (CSCs) and tumor bulk relative to normal hematopoietic cells in a wide range of hematologic malignancies including AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Since SL-401 targets both leukemia blasts and CSCs, tumor regression and improvement in long-term outcome is expected. The clinical activity and side effect profile of SL-401 were evaluated in a multicenter Phase I/II trial of patients with advanced hematologic cancers. Methods: Eighty-one patients with advanced hematologic cancers, including relapsed or refractory AML (n = 59) and heavily pretreated BPDCN (n = 4), have been enrolled. Patients received a single cycle of SL-401 via 15-minute IV infusion to determine the maximum tolerated dose (MTD) and assess antitumor activity. Results: A single cycle of SL-401 demonstrated single agent activity in relapsed or refractory AML patients, including 2 durable CRs of 8 and 25+ months duration and multiple cases of blast reductions. SL-401, when delivered at therapeutically relevant doses, was associated with > 3-fold greater median overall survival (OS) in AML patients who received 2+ prior lines of treatment relative to historical results. In addition, 3 heavily pre-treated patients with BPDCN, an uncommon malignancy that expresses high levels of IL-3R and is ultrasensitive to SL-401 (IC50 values in the femtomolar [10-15 M] range), had CRs, with durations of 5, 3+ and 1+ months. The MTD was 16.6 µg/kg/day; the dose-limiting toxicities of hypoalbuminemia and edema, which are manifestations of capillary leak, occurred at 22.1 µg/kg/day. Other ≥ Grade 3 adverse events included transient transaminase elevations. There was no treatment-related myelosuppression. Conclusions: SL-401 was well tolerated and demonstrated single agent activity in patients with relapsed or refractory AML and BPDCN. Based on these findings, single agent SL-401 given in multiple cycles will be advanced into pivotal studies of AML (3rd-line) and BPDCN. Clinical trial information: NCT00397579.

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is an aggressive hematologic malignancy derived from plasmacytoid dendritic cells. The clinical presentation of BPDCN typically involves the skin at outset and invariably progresses to a leukemic phase with or without lymph node and splenic involvement. BPDCN blasts have a distinctive phenotypic appearance with ubiquitous overexpression of CD4, CD56, and CD123 (interleukin-3 receptor [IL-3R]). Although rare, BPDCN has been estimated to affect at least two thousand patients in the United States and Europe annually. There is no standard therapy for BPDCN, but treatment usually incorporates intensive combination chemotherapy, occasionally with allogeneic stem cell transplant. Treatment-naïve patients generally respond to these measures, but disease-free survival is brief, and most patients relapse with chemo-resistant disease. Despite aggressive upfront therapies, BPDCN has a dismal prognosis with estimated median survival of 9-14 months. SL-401, a novel biologic targeted therapy directed to IL-3R, is being developed to treat BPDCN, acute myeloid leukemia (AML), and several other IL-3R-expressing hematologic malignancies. SL-401, which is comprised of IL-3 conjugated to a truncated diphtheria toxin, a potent inhibitor of protein synthesis, has demonstrated ultra-high anti-tumor potency against BPDCN cell lines and primary BPDCN tumor cells, with IC50 values in the femtomolar (10-15 M) range and robust activity after treatment of an in vivo model of human primary BPDCN cell engraftment (Angelot-Delettre et al; ASH 2013). This report serves to update the results of SL-401 treatment in BPDCN patients who are participating in a Phase 1/2 study of SL-401 administered as a single cycle (15 minute infusion daily for 5 days). To date, 6 subjects with BPDCN (5 male/1 female; ages 35-72 years) received a single cycle of SL-401. The BPDCN blasts of all 6 patients expressed CD123 (IL-3R) as well as CD4 and CD56. Five patients had failed previous chemotherapy regimens, with 3 of these subjects also having received allogeneic stem cell transplantation, whereas one patient was treatment naïve. There have been no serious adverse events. Two patients had SL-401-related Grade 3 liver function test (LFT) elevations that recovered to Grade ≤2 within 24 hours and one patient had a brief episode of SL-401-related Grade 3 neutropenia and thrombocytopenia; all other SL-401-related adverse events (AEs) were Grade ≤2. One patient was not evaluable for response. To date, 5 (100%) of the 5 evaluable patients have had major responses. All five responding patients were treated with SL-401 at 12.5 µg/kg/day for 5 days, and experienced either a complete response (CR; 4 patients) or a partial response (1 patient). The CRs included disappearance of BPDCN in the skin, bone marrow, peripheral blood, spleen, and lymph nodes. As of August 2013, CR durations following a single cycle of SL-401 treatment are 11+ (ongoing), 5, 3, and 1 months; the PR duration is 1 month. Given these promising clinical responses to this targeted therapy, additional BPDCN patients are being accrued to this study and a pivotal program will begin in 2014. Disclosures: Frankel: Stemline Therapeutics: Research Funding. Woo:Angimmune: Patents & Royalties, Research Funding. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Szarek:Stemline Therapeutics: Employment, Equity Ownership. Bergstein:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. Rowinsky:Stemline Therapeutics: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.