Download The IL-3Rα-Targeted Drug SL-401 Selectively Kills Blastic

614. Acute Lymphoblastic Leukemia - Therapy, excluding Transplantation: Poster II
The IL-3Rα-Targeted Drug SL-401 Selectively Kills Blastic
Plasmacytoid Dendritic Cell Neoplasm Cells
Fanny Angelot-Delettre, PhD*,1, Arthur E. Frankel, MD2, Jen Sing Liu, PhD*,2, Estelle
Seilles, PhD*,1, Sabeha Biichle, Bsc*,1, Bernard Drenou, MD, PhD*,3, Mark L. Jacobson,
MA*,4, Thomas P. Cirrito, PhD*,4, Arkam Yazid, MD*,3, Eric Deconinck, MD, PhD*,1,
Christopher L. Brooks, PhD*,4, Philippe Saas, PhD1 and Francine Garnache Ottou, PhD*,1
1
INSERM U645, Besancon, France,
Scott & White Memorial Hospital, Temple, TX, USA,
3
Departement Hematologie, Centre Hospitalier de Mulhouse, Mulhouse, France,
4
Stemline Therapeutics, Inc., New York, NY, USA
2
Abstract 2588
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive neoplasm
derived from plasmacytoid dendritic cell precursors that involves the skin and invariably leads to
aggressive leukemic dissemination (Garnache Ottou et al., 2007). The incidence is more
frequent in men and elderly subjects, but BPDCN may occur in young adults and even in
children. Current treatment options are not codified, and although conventional chemotherapy
often induces an initial response, relapse is frequent and rapid. The prognosis is poor, with a
median overall survival of 9–13 months whatever the initial presentation was. Allogeneic
hematopoietic transplantation is currently the only potentially curative treatment, but this is not
an option for most elderly patients. Therefore, there is an urgent need to develop novel therapies
that can specifically target this tumor type. Since BPDCN cells express high levels of the
interleukin-3 receptor (IL-3R) α-chain (CD123), we tested SL-401, a novel biologic conjugate
that targets IL-3Rα (Konopleva et al. 2010 and Frolova et al. 2010), against 2 BPDCN cell lines
(GEN2.2 and CAL-1) and 6 primary BPDCN cells isolated from 5 patients (P#1-5). Cells from
P#2 were tested at diagnosis (#2d) and at relapse (#2r). A CD123+ cell line (TF-1/H-ras)
sensitive to SL-401 and a CD123– cell line (Daudi) were used as controls. Cytotoxicity was
assessed by MTT assay as well as flow cytometry (FC) after Annexin-V (AV) and 7-AAD
staining. Primary BPDCN cells were cultured with IL-3 alone (to maintain survival) or IL-3 in
combination with SL-401 for 24 h (FC) or 48 h (MTT) (Figure 1). All BPDCN cell lines and
primary cells were found to be sensitive to SL-401 by MTT assay (Figure 1A). These results
were confirmed by FC with a dose-dependent decrease in cell viability observed for the GEN2.2
and CAL-1 lines, (47 ± 10 to 2 ± 2%, n = 4, and 90 ± 7 to 11 ± 5%, n = 4, respectively) when
treated with SL-401 compared to untreated cells (48 ± 9% and 88 ± 5%, for GEN2.2 and CAL-1
respectively). Cell viability decreased for all the 6 primary cells tested by FC (Figure 1B). The
Daudi negative control cell line was resistant to SL-401 (Figure 1A), which confirmed SL-401
specificity.
This is the first study evaluating the in vitro sensitivity of BPDCN using the IL-3R targeted drug
candidate, SL-401, which is currently being evaluated in clinical trials of patients with acute
myeloid leukemia (AML), myelodysplastic syndrome, and chronic myeloid leukemia.
Importantly, the highest concentration of SL-401 evaluated in these in vitro studies was ten times
lower than the peak plasma concentration achieved in AML patients (Frankel et al, 2008). Since
all BPDCN patients evaluated to date express high levels of CD123 (Garnache Ottou et al,
2009), these results suggest that BPDCN patients may clinically benefit from SL-401 therapy.
This new strategy should be evaluated in a clinical trial.
A. Percentage of viable cells from BPDCN patients (#1, #4, and #5, n = 1) or of viable CAL-1
and GEN 2.2 cells (n = 3) assessed by MTT assay after incubation with different concentrations
of SL-401 or without drug (cells only). Untreated cells were considered as 100% viable cells.
The Daudi cell line (CD123–) was used as a negative control (n = 3). B. Percentage of viable
cells (AV and 7-AAD negative, as measured by FC) after incubation with different
concentrations of SL-401 or without drug (cells only) for 24 h. The histogram represents a mean
of 3 (P#1), 4 (P#2d), and 6 (P#2r) independent experiments. Samples (P#3- 4, and- 5) were each
tested once.
Disclosures: Frankel: Stemline Therapeutics: Patents & Royalties, Research Funding.
Jacobson: Stemline Therapeutics, Inc: Employment, stock Options. Cirrito: Stemline
Therapeutics, Inc: Employment, Equity Ownership, Patents & Royalties. Brooks: Stemline
Therapeutics, Inc: Employment, equity options.