Stemness Inhibitor Tested in Rare Hematologic Cancer

OncologyLiveVol. 19/No. 8
Volume 19
Issue 8

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SL-401, a novel therapy that targets a cancer stemness pathway, is being investigated in patients with blastic plasmacytoid dendritic cell neoplasm in a phase I/II trial.

Andrew A. Lane, MD, PhD

Andrew A. Lane, MD, PhD

Andrew A. Lane, MD, PhD

SL-401, a novel therapy that targets a cancer stemness pathway, is being investigated in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) in a phase I/II trial that may pave the way for its approval for the rare and aggressive hematologic malignancy.

The drug is directed at the interleukin-3 (IL-3) receptor, which is overexpressed on cancer stem cells (CSCs) and/or tumor bulk in many hematologic malignancies, including BPDCN, acute myeloid leukemia (AML), multiple myeloma, and myeloproliferative neoplasms (MPNs).1

Researchers believe that CSCs, which make up about 1% to 5% of the tumor, promote the development of most of the carcinogenic cells in the tumor bulk.2

Stemline Therapeutics is developing SL-401 for patients with BPDCN under the FDA’s breakthrough therapy designation, which provides for an expedited review, and is conducting clinical studies of the drug as a single agent and in combination regimens in AML, multiple myeloma, and MPNs.3 In April, the company initiated a rolling submission of a biologics license application to the FDA in BPDCN.4

Figure. SL-401 in BPDCN

In BPDCN, SL-401 is being studied as a singleagent first-line or later treatment (NCT02113982). Phase II of the trial, which is being conducted in 4 stages, will constitute the largest prospective study for this BPDCN indication, according to Stemline (Figure).3 The Leukemia and Lymphoma Society is collaborating on the trial.BPDCN is a highly aggressive hematologic malignancy with cutaneous manifestations; primary sites of the disease are in the bone marrow and skin, and secondary sites include the lymph nodes and viscera.1 The condition has a poor prognosis, with a median overall survival (OS) of about 12 months from diagnosis.

Patients with BPDCN who are treated with chemotherapy may have a transient response, but most then relapse.5 “[Patients with BPDCN] have been treated in the past by lymphoma doctors, leukemia doctors, whoever they happen to land with, and were treated with various regimens; unfortunately, none of them worked very well,” said Andrew A. Lane, MD, PhD, assistant professor of medicine at Harvard Medical School and director of the BPDCN center at Dana-Farber Cancer Institute. “There really is no standard of care.”

BPDCN affects mostly elderly patients, who may not be able to tolerate chemotherapies, according to Lane, who is the principal investigator at Dana-Farber. SL-401 may have a better safety and toxicity profile for this patient population due to its targeted mechanism of action. The drug is an IL-3 conjugated truncated diphtheria toxin, which essentially delivers diphtheria toxin to cells that have the IL-3 receptor. Many hematologic malignancies have CD123 expression, but BPDCN in particular has characteristically high expression; Lane said it is 1 of the markers required to make the diagnosis of BPDCN.

When the diphtheria toxin penetrates a cell, it binds to and ADP-ribosylates elongation factor 2, a factor necessary for protein translation. When the protein synthesis process is inhibited, the cell dies by apoptosis. “There are some studies that say even 1 molecule of diphtheria toxin inside a cell will kill a cell, so it’s a very potent way to deliver a targeted therapy,” said Lane.

Positive findings from the current trial were presented at the 2017 American Society of Hematology Annual Meeting, where SL-401 demonstrated strong activity in patients with BPDCN. Across 3 stages of the trial, 42 patients received SL-401 at a dose of 12 μg/kg each day. In first-line BPDCN, the overall response rate (ORR) was 90% (26 out of 29 evaluable patients), with a CR rate of 72% (21 of 29). After therapy with SL-401, 45% of patients (13 of 29) were bridged to stem cell transplant (SCT). In patients with relapsed/refractory BPDCN, the ORR was 69% (9 of 13), with a 38% CR rate (5 of 13), and 1 patient was bridged to SCT.

The median OS was not reached in patients who received SL-401 therapy in the firstline setting. In the pivotal stage 3 cohort, the study met its primary endpoint with a 54% CR rate (7 of 13). The ORR was 77% and 46% of patients were bridged to SCT (6 of 13). The most common treatment-related adverse events (AEs) were alanine aminotransferase increase (52%), aspartate aminotransferase increase (50%), hypoalbuminemia (50%), and thrombocytopenia (38%). Capillary leak syndrome was also noted in 19% of patients, which was grade 5 in 1 patient.3

“From a clinical research standpoint, we thought that we might get mostly relapsed/ refractory patients on the study because a patient would get chemotherapy in the first line,” said Lane. “But it turns out that all the investigators saw the efficacy was very high in the first line.”

The most significant AE associated with SL-401, Lane said, is the risk of capillary leak syndrome. During the study, all patients will be closely monitored for signs of capillary leak. “Particularly in the first cycle, patients may have a decreased level in their albumin, fluid retention, and weight gain, and it’s the main side effect that we watch out for. For that reason, on this study, all patients are admitted to the hospital as inpatients for the first cycle, and after that they can be either inpatients or outpatients,” Lane said.

Other AEs associated with the drug are mostly grade 1/2 severity, and include hypoalbuminemia, increases in aspartate and alanine aminotransferase, and thrombocytopenia.1 Lane said the main prophylactic measure taken in the study design is to exclude patients without normal cardiac ejection fraction or those with low albumin.


  1. Pemmaraju N, Sweet KL, Lane AA, et al. Ongoing phase 2 clinical trial of SL-401 in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN): stage 1 and stage 2 results. Poster presented at: the 59th American Society of Hematology Annual Meeting; December 9-12, 2017; Atlanta, GA. Accessed April 9, 2018.
  2. Cancer stem cells. Stemline Therapeutics website. Accessed April 9, 2018.
  3. Stemline Therapeutics presents detailed SL-401 pivotal data in BPDCN at ASH and kicks off its BPDCN awareness campaign; updated results from ongoing trials in additional malignancies also presented [press release]. New York, NY: Stemline Therapeutics, Inc; December 13, 2017. Accessed April 4, 2018.
  4. Stemline Therapeutics announces start of rolling BLA submission for SL-401 [press release]. New York, NY: Stemline Therapeutics, Inc; April 5, 2018. Accessed April 9, 2018.
  5. 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. doi: 10.1182/blood-2014-04-566737.
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