Centering discussion on a recent study, experts Thomas Leblanc, MD, and Bhumika Patel, MD, reflect on long-term data with tagraxofusp in BPDCN.
Thomas Leblanc, MD: Why don’t we get into discussing some of the details of the article in question here?
Bhumika Patel, MD: As we are discussing this article, the objective of this study design was to evaluate tagraxofusp monotherapy in adults with treatment-naive or relapsed/refractory blastic plasmacytoid dendritic cell neoplasm [BPDCN]. The study design was that patients with BPDCN were assigned to receive tagraxofusp in 4 stages. Stage 1 was the dose-escalation phase, stage 2 was the expansion phase, stage 3 was the pivotal and confirmatory phase, and stage 4 was the continued access phase. Tagraxofusp was administered as a daily IV [intravenous] infusion on days 1 through 5 of each 21-day cycle. The primary efficacy end point was complete remission [CR] and clinical CR.
Thomas Leblanc, MD: One thing to underscore for our listeners is that this is a therapy that has to be given in the hospital for at least the first cycle. That’s something that’s even recommended clearly in the NCCN [National Comprehensive Cancer Network] guidelines, and the reason is because of the risk of capillary leak syndrome. You can give this in an outpatient setting after the first cycle depending on tolerability, but at first you need to have these folks in the hospital and watch them closely because this can be a pretty serious or even potentially life-threatening toxicity.
Bhumika Patel, MD: Dr Leblanc, just to add to that, would you consider looking at their albumin levels, their liver enzymes, and everything before even considering tagraxofusp therapy?
Thomas Leblanc, MD: Yes. It’s really important to do that. When patients have capillary leak syndrome, what we commonly see is a precipitous drop in their albumin level, and significant third spacing of fluids, they can have rapid weight gain and peripheral edema. We even see organ function changes like significant transaminitis and changes in the creatinine and creatinine clearance, probably due to hypoperfusion because of the capillary leak. A patient has to have a certain baseline threshold level of albumin in their peripheral blood studies before you even give this treatment, and there are pretty clear parameters in the package insert around what you do depending on what the level of the albumin is. Sometimes we end up having to supplement the patient’s albumin to enhance the tolerability depending on what that level looks like when they’re starting a cycle, and sometimes we even end up having to delay cycles depending on what’s going on with some of these toxicities.
In terms of the patients who got into this study, the typical table 1 demographics are pretty reflective of who gets this disease. There is definitely a male predominance for reasons that we don’t understand, but about 80% of the patients in this study were men. These patients were generally on the fitter side; ECOG [performance status] was 0 to 1 overwhelmingly, and most of them, about 80% to 90%, had skin involvement. As we described at the beginning, that’s typically what happens with this disease, but around half or a little more had bone marrow involvement as well. And what you see is that in the table that breaks down the first-line vs relapsed or refractory patients, you see that there’s more marrow involvement in the patients with relapsed or refractory disease. This is something where I’ve seen this clinically, where many of the patients seemed to present initially with just skin disease, and as their disease becomes more aggressive or as they live longer with this disease, you can start to see marrow or peripheral blood involvement later. So to me, that may be a sign of progression for some patients. And looking at those who have had prior therapies, more than half of them had had at least 1 prior line of therapy, but a number of them had 2 or 3 or 4 or more lines of therapy.
What did this study show about efficacy, Dr Patel?
Bhumika Patel, MD: When you look at efficacy, the overall response was pretty significant, around 75%, for these patients when you look at the first-line setting. Overall when you look at that, I think that’s fantastic, and I think they were able to get a percentage of these patients, once in CR, to transplant subsequently. But what I’m really curious about, which has not been reached, is the median duration of response. We know that the durability, even with the prior therapies before the approval of tagraxofusp, the median durability of responses was short lived if it wasn’t piggybacked with allogeneic transplant. So I’m really curious to see what your thoughts are with your clinical practice of using tagraxofusp. Have you seen that the durability of response has been improved compared to what we see here? They’re saying probability is up to 50% to 60%, median overall, as time goes on; the median overall duration of response is actually long with tagraxofusp utilization.
Thomas Leblanc, MD: Yes, it’s been really impressive to see this high overall response rate of about 75% in the first-line patients, which is better than anything we’ve seen with other standard therapies that we talked about earlier, the AML [acute myeloid leukemia], the ALL [acute lymphocytic leukemia], the lymphoma kinds of therapies that have all been used. And those are probably more intensive treatments too with a lot more hospital time and probably more risk with cardiotoxicity of some of those agents, issues with neuropathy with some of them, significant risk of sepsis and febrile neutropenia and other infections. As you said earlier, with targeted therapies being the hot new thing, it looks like you get better efficacy here, but probably better tolerability too, other than needing to be really careful about a capillary leak, especially at the beginning.
This median duration of the CRs and CRhs [complete remissions with partial hematologic recovery] being about 25 months is quite impressive, with the upper bounds of the confidence interval not even being reached. Some patients get on this therapy and take it for a few years, and it controls their disease and they do well. That’s probably a minority of patients; this is really a bridging therapy ideally for most people. If we can get you to transplant and if you’re a transplant candidate, I view this treatment as a way to control the disease more effectively to get you to that curative intent allogeneic stem cell transplant that gives you the best shot at durable remission. Probably any treatment we give, including tagraxofusp, ultimately is a palliative treatment for this disease. So although the numbers here are a lot better around median overall survival, duration of response, and response rates in all, clearly this is an advance, but it’s still an incremental one around potentially curing patients. We still need that transplant.
Bhumika Patel, MD: Just to add to that, I think what would be really interesting is as we get maturity of the data on median duration of response, we know that with standard regimens, with the ALL, AML regimens, the median overall survival of these patients was less than 2 years. We’re at the 2-year mark now; it’ll be interesting to see as the data mature where we are going to be because I think we’ll probably see some really great data. To your point, I agree. I think this is a bridging therapy and patients who are eligible for transplant would be great candidates for that. I think they will get durability of response and a potential cure.
Dr Leblanc, we just briefly discussed the long-term efficacy data of tagraxofusp in the frontline setting for patients with BPDCN. In which patient population do you consider tagraxofusp? Being at an academic center, you know the cost of the drug can be a limiting factor for some patients. And which do you consider chemotherapy for? What has your experience been like at Duke [Cancer Institute]?
Thomas Leblanc, MD: With this being such a rare disease, nobody sees all that much of this outside of maybe a couple of centers around the country that have been established to be key centers where people with this disease come for clinical trials. But we did participate in the earlier studies that led to tagraxofusp’s approval, so I’ve seen a lot of these folks come through our inpatient service and some through the clinics, and have been really impressed, frankly, with how poorly everything else works for this disease. I’ve used and seen used AML and ALL regimens, the lymphoma regimens, even salvage ALL regimens like asparaginase-containing regimens with steroids and things like that. You get responses most of the time, but they tend to either not be complete responses or the complete responses tend to not last very long. Once we started to get experience with tagraxofusp and see that the response rate is so high and that so many of them are complete responses and the durability seems to be quite a bit longer than what we’ve seen with all of the other kinds of standard cytotoxic chemotherapy regimens, this is by far my first, second, third recommended kind of treatment for any particular patient.
It’s pretty unlikely that I would want to give or recommend a chemotherapy-based treatment up front. The areas where you might need to do that or think about that would be the patients where you are really concerned that they could not tolerate maybe even mild to moderate capillary leak syndrome. If you have somebody with significant liver disease for example, if they already have transaminase problems, or especially if they are starting with hypoalbuminemia due to some other disease like a chronic liver disease, that might be somebody you can’t safely give tagraxofusp to. Or maybe somebody who has significant cardiac disease where they’ve had heart failure, and those fluid shifts are not going to be a good experience for that patient and you think you might harm them with this therapy. That might be somebody else for whom I would think twice about whether I could safely give it and whether it might be the right thing.
Then of course, anyone who’s just not willing to be hospitalized to start this treatment probably shouldn’t get it because I don’t think it’s safe to give this treatment in the outpatient setting, at least at first until you prove that they can tolerate it. When people live really far away from a center that is comfortable with treating this disease, and that happens to a lot of people because there isn’t as much treatment of this rare disease in community settings, where most people live. Then sometimes that means they can’t get this therapy or they decide not to because they don’t want to drive 4 hours to be admitted at a larger medical center. So like anything in cancer care, it becomes a shared decision-making kind of scenario. But by far, most people will get this therapy up front now in our practice because it’s just so much better than what we’ve had historically.
Transcript edited for clarity.