An Update On The Robust Clinical Activity Of SL-401, a Targeted Therapy Directed To The Interleukin-3 Receptor On Cancer Stem Cells and Tumor Bulk, In Patients With Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Abstract

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.

CD 123 is a membrane biomarker and a therapeutic target in hematologic malignancies

“…Thus, Frankel and coworkers have recently reported the treatment of seven BPDCN patients (some heavily pretreated) with SL-401, an agent targeting the IL-3Rα (this agent is composed by human IL-3 coupled to a truncated diphtheria toxin payload). A single cycle of 5-days treatment with this agent at 12.5mcg/kg IV over 15 minutes elicited a pronounced anti-tumor response inducing clinical remissions in most patients lasting several months to over a year [ 30 ]. These preliminary promising observations represent the basis for future studies involving multiple cycles of treatment and the enrolling in the future of less heavily treated patients.…”

“…Furthermore, the SL-401 administration was well tolerated [ 73 ]. The same compound SL-401 was evaluated also in the context of a phase I clinical study involving eight patients with blastic plasmocytoid dendritic cell neoplasms [ 30 ]. In this group of heavily pretreated patients with advanced disease the treatment with a single cycle of SL-401 was well tolerated and demonstrated prominent antitumor activity, with most of patients achieving a complete response [ 30 ].…”

SL‐401 and SL‐501, targeted therapeutics directed at the interleukin‐3 receptor, inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia

“…The K116W variant DT 388 ‐IL3 molecule (DT388‐IL3[K116W], or SL‐501) exhibited greater IL3R binding affinity and cytotoxic activity against AML progenitors than SL‐401, although SL‐501 also possessed negligible activity against normal bone marrow progenitor cells (Testa et al , ; Hogge et al , ). In a Phase 1–2 clinical trial in patients with advanced haematological cancers, a single cycle of SL‐401 administered as a 15‐min intravenous infusion daily for 5 d induced complete responses in patients with relapsed or refractory AML or blastic plasmacytoid dendritic cell neoplasm, an IL3R + malignancy of plasmacytoid dendritic cells (Frankel et al , ), and a survival signal among AML patients who received this agent as third‐ or later‐line therapy was noted (Konopleva et al , ). In these clinical trials, SL‐401 administration was devoid of myelosuppressive effects.…”

Clinical Activity and Tolerability of SL-401 (Tagraxofusp): Recombinant Diphtheria Toxin and Interleukin-3 in Hematologic Malignancies

“…Because BPDCN is an aggressive tumor, unfortunately, patients have a short survival, irrespective of the intensity of chemotherapy [24]. This accelerated the pathway to move SL-401 from in vitro studies to more early phase clinical trials [13,25]. The first prospective trial in BPDCN using SL-401 published its results and outcomes in 2014.…”