Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy for which there are few treatment options outside of cytotoxic chemotherapy. A new investigational agent, SL-401 (tagraxofusp, Elzonris), may provide an effective targeted therapy for patients with BPDCN, according to Naveen Pemmaraju, MD.
Findings from a pivotal phase II trial presented at the 2018 European Hematology Association Congress showed that SL-401 was active in this patient population and had a manageable safety profile. Overall response rate (ORR) was 90% for patients treated with SL-401 as frontline therapy, reported Pemmaraju.
In August 2018, the FDA granted a priority review designation to a biologics license application (BLA) for SL-401 as a treatment for patients with BPDCN. The agency is scheduled to decide on the BLA by February 21, 2019.
In an interview with OncLive
, Pemmaraju, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed SL-401 and the future of treatment for patients with BPDCN.
OncLive: What is the current prognosis of and treatment for patients with BPDCN?
: Not much is known about BPDCN. Incidence is quite low—we are talking about a disease diagnosed in less than 1000 patients per year. The prognosis overall has been very poor, and most groups have reported a median overall survival (OS) of 8 to 14 months despite using cytotoxic chemotherapy that is usually borrowed from acute myeloid leukemia (AML), acute lymphoblastic leukemia, or lymphoma. That is also including patients who are younger and fit who have undergone stem cell transplant.
The 2 caveats are that it is usually a disease of older adults with a median age range of 68 to 72 years old. That obviously plays a role in overall survival reporting. However, even in younger fit patients, you do see an increase in OS, as you might expect with allogeneic stem cell transplant done in the frontline setting.
But, most of these patients are older, unfit, and cannot do cytotoxic chemotherapy or transplant. It is a disease that has poor OS, and although some patients can go into remission with cytotoxic chemotherapy, they often relapse quickly or transform to an AML-type phase and can die very quickly of multi-organ failure or sepsis. This is what we see a lot in our patients with acute leukemia. Any breakthrough in this field would be urgently needed.
Could you provide some background information on this trial?
This clinical trial centers around an extremely rare hematologic malignancy known as BPDCN. The background is simply that there are no FDA-approved therapies for this rare but aggressive hematologic malignancy. The seminal discovery in the field is that virtually 100% of patients overexpress a particular marker called CD123. The question was, “Can we target that specific marker in these patients?” The only clinical background before the current study was a pilot study that I participated in, which for this field, was a large number of patients. There were responses in 7 out of 9 patients with SL-401, which targets CD123. In that, we had an ORR of 78%, including 5 complete responses. That formed the basis for the current trial.
What is the design of this trial?
This is the first ever multicenter study of a targeted agent that is dedicated to patients with BPDCN. Across several sites, we conducted this study in 3 stages. Stage 1 was a typical dose-escalation phase that started at 7 mg and went up to 16 mg. Stage 2 was an expansion phase, which focused on the identified dose of 12 mg/kg per day. Then, there was a third stage that was done, which focused only on patients at that 12-mg dose [in the frontline setting]—the previous 2 stages included relapsed/refractory patients.
What are the findings?
The findings are quite encouraging. In summary, we found that among patients in stage 1, 2, and 3, the ORR was 90% in the frontline setting. In the relapsed/refractory setting, it was 69%. Importantly, in the frontline setting, 45% of these patients were able to go onto an allogeneic stem cell transplant. This is notable because some of these patients were older—many of them being over the age of 60.
Are there any next steps?
In terms of safety, there were some commonly found events, including hypoalbuminemia, transaminitis, and thrombocytopenia. These were usually restricted to the first 1 or 2 cycles at lower grades. The most significant finding in terms of safety was what was already hypothesized due to the mechanism of the drug, which was capillary leak syndrome. The CLS was seen frequently not only at the lower grades, but also at the higher grades, and there was 1 death out of 114 patients treated across all indications for SL-401 as a single agent at the 12 mg dosing. With the institution of amendment protocols, including watching the albumin, daily weights and fluids status—all of these side effects and the CLS were found to be manageable. From here, the trial is continuing to enroll in a stage 4 further expansion study.
Another exciting avenue would be to combine this drug. These are all single-agent studies, and we have started looking at the first rational combination in an investigator-initiated study. This study is combining it with azacitidine for patients with high-risk myelodysplastic syndrome and AML. Looking for different partners for SL-401, whether they are targeted therapies, hypomethylating agents, or cytotoxic agents, is going to be an exciting next part of this field in the next 5 to 10 years.
What would be your take-home message about this study?
For historically rare tumors, especially cancers that have changed names or do not have a high incidence like BPDCN, the take-home message is that if we continue to search for novel unique targets—targets that are not only specific to the tumor, but amenable to drug therapy—and keep working in small subsets, we might have a chance to identify a targeted therapy. No matter how rare the disease is, or how rare the cancer is, keep trying and approaching new ways to look at it. If you find something that may work in that rare disease, continue to work on the science; then, you may be able to extrapolate to other malignancies. That is what we have found working with BPDCN.
Is there anything else that you would like to add?
As my passion for rare diseases and rare blood cancers has developed, I found that there are different new venues where patients and doctors are getting their information. Some of those include social media like Twitter, which has rapidly exploded among academic physicians and something that I am personally involved in.
is an example of disseminating accurate information rapidly, straight from the thought leaders and opinion makers to the general public, patients, advocates, and caregivers. For a lot of people, a simple Google search is not enough.
The message that I would say is that if you have a rare tumor, you are likely not alone. There are going to be people out there who either have a similar disease type, and there is likely a researcher, doctor, or a clinical trial out there for you. However, it might not always be readily available, so these other mechanisms are good ways to find that information.
Pemmaraju N, Sweet KL, Lane AA, et al. Results of pivotal phase 2 trial of sl-401 in patients with blastic plasmacytoid dendritic cell neoplasm. In: Proceedings from the 2018 European Hematology Association Congress; June 14-17, 2018; Stockholm, Sweden. Abstract 214438.