Tagraxofusp Treatment for BPDCN: Clinical Efficacy and Monitoring
James Foran, MD, discusses the clinical efficacy and unique monitoring requirements of tagraxofusp, a frontline treatment for BPDCN, emphasizing its role in achieving durable remissions and potential combination therapies.
Transcript:
James M. Foran, MD: So, to get back to this case, I’ve mentioned this already, but I agree with this treatment decision. An 87-year-old patient with symptomatic, leukemic manifestations, abnormal CBC [complete blood cell count], and who is starting tagraxofusp [is] a patient [for whom] you wouldn’t want to consider intensive chemotherapy; it would be hard to do that. It’s a CD123 fusion protein, linked to the truncated diphtheria toxin. So really, that is the payload. It’s given intravenously and binds to CD123, which is the IL3 receptor, and so it’s an IL3 fusion protein that binds to the IL3 receptor and delivers the toxin, the truncated diphtheria toxin. It really is targeting the malignant cells, the BPDCN [blastic plasmacytoid dendritic cell neoplasm] cells, and the acute leukemia cells in this group of patients.
It’s indicated in the first-line treatment of patients with BPDCN aged 2 [years] or older. There is literature [on treatment] in children and young adults as well. And I’ll tell you, some would question, “What is the most suitable patient in the frontline setting?” And I would almost flip that to ask, “Who’s not appropriate for tagraxofusp in the frontline setting?” The more mature data and long-term follow-up show the overall response rate is 75%. This was published [in 2022] in the JCO [Journal of Clinical Oncology]. Fifty-seven percent [of patients] achieve a complete remission or a composite complete remission, where there’s residual skin abnormality not indicative of active disease. So these are high response rates.
The drug is well tolerated but has unique [adverse] effects. The most common are elevated transaminases and hypoalbuminemia; most are in the first cycle and most are transient. The key toxicity to monitor is capillary leak syndrome, which occurs in about 20% of patients.
Most of the time, it’s grade 1 or 2. Seven percent [of patients] will have grade 3 or higher capillary leak syndrome. It’s important in the daily dosing of the medication that you’re monitoring the albumin daily, you’re monitoring the weight daily so that when you’re seeing capillary leak manifest by hypotension, manifest by anasarca, manifest by pleural effusion, and manifest by hypoalbuminemia, you’re monitoring those and the patients are getting appropriate fluid replacement, that you’re maintaining adequate hemoglobin for colloid, and that you’re giving, when necessary, albumin to supplement hypoalbuminemia, or even holding a dose.
There are very good recommendations in the package insert and in the protocol from the published manuscripts that you can reference for how and when to hold a dose, or more, of tagraxofusp as needed, and how to monitor the daily albumin and supplement albumin when giving it. This sounds harder than it is. This is something you can easily train yourself and your team to do. But it means tagraxofusp is not a hands-off treatment.
It means you do, particularly in the first 1 to 2 cycles, have to be watching carefully. We typically start the first cycle in the hospital because of the monitoring needed, and to look for evidence of capillary leak syndrome, which occurs in about 20% of patients…. And rarely, but sometimes [there are cases of] grade 3 or higher.
I do believe tagraxofusp is an appropriate frontline single agent for patients with BPDCN. There are studies being done. An important question is, “Can you achieve the same responses with acute leukemia regimens?” The answer is yes. If you look at a younger patient getting hyper-CVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone], for instance, it has a relatively high complete response rate. It doesn’t appear that the duration of responses is as attractive; hyper-CVAD has its own toxicities as a heavy inpatient regimen. But the intent for somebody getting intensive chemotherapy is to really move them to allogeneic transplant.
That’s also true of tagraxofusp. The true long-term benefit of these treatments is to get a remission in younger adults, even mature adults [younger than] 75 [years] who have a donor or are transplant eligible, to find a donor, get a best remission, and then move them into allogeneic transplant. So tagraxofusp is a first-line agent; it’s the preferred first-line agent in our practice.
But there are some [cases] where starting intensive chemotherapy can also be alright. Now there are combinations being developed to see if you can do better with both. I would say that’s…an off-label thing to do; that’s not a casual decision. I think we need robust clinical trial data to support the right dosing, the right regimen, and the right monitoring for combinations.
The pivotal trial was relatively small. There were 84 patients in the study, 65 in the long-term follow-up, with 65 being treatment naive and 19 relapse refractory. The patients received the FDA-approved dose of tagraxofusp at 12 μg/kg/day. And there is now an almost 3-year follow-up in these patients. In this study, they were identified by the classical CD123, CD4, and CD56 markers for this aggressive malignancy and treated with single-agent tagraxofusp.
It’s remarkable that you can get FDA approval with a small study like this, with fewer than 100 treatment-naive patients and with a single agent. But I think it speaks to the difficulty of identifying these patients and the rarity of the disease. It took a community to do that. And I acknowledge the FDA recognized the difficulty and clinical value of the response rates, a response rate–driven end point, and now the duration of responses.
The median duration of response was almost 2 years, a little over 22 months. And half of the patients who went into remission were bridged to a stem cell transplant, almost all allogeneic. So it shows that a small trial can get results, response rate–driven results, and, with maturity of the data, show that the responses can be durable. It’s a bridge to transplant, which is our intent with this treatment in younger adults or transplant-eligible patients.
Transcript is AI-generated and edited for readability.
