I do have a discussion with them about the fact that it is a rare disease, and that’s always something we need to talk with the patients about. I personally think the patient should be treated at centers that have some experience using these treatment options and using these agents. That’s a very important point, especially when we are assessing newly diagnosed patients. It is an aggressive malignancy and there is lack of second- or third-line options, and that’s something I talk with the patients about earlier on, and about whether I would refer them for a clinical trial at that point. Those are the things that I bring up talking with patients.

As we’ll talk about, it is a different time that we’re dealing with right now. There is COVID-19 [coronavirus disease 2019] and complications related to that, so we are worried about patients who can develop COVID-19. Usually we are worried about patients with hematologic malignancies and developing infections.

I counsel patients that they need to show up. It’s hard to do telemedicine with a rare disease. You do need to look at the skin. We can’t do that through telemedicine very well. They’re going to be coming in for outpatient therapy. It’s an intravenous drug after all, so it has to be given in an infusion center. I have no experience with its administration in the home. I don’t even know if it can be dispensed that way. Again, you need to check blood counts, and you need to check albumin. There’s no way around this. COVID yes or COVID no, they’re going to have to come into the clinic and see a person. Because they keep getting cycles, and there is no end to it as long as patients respond, at least at the time of administration they can have a medical evaluation. They may not need to have an in-person evaluation midcycle. You could always get counts through home care or through a local laboratory that might be less busy than coming into a busy oncology clinic. But on the first day of the cycle, that’s the time when I see these patients.

The first cycle is inpatient, so that helps in terms of COVID-19 because you’re admitting the patients. The outpatient administration is going to be challenging. You bring up a very important point, that once the patients are in remission and they are getting tagraxofusp on a maintenance schedule, I frequently get asked questions about whether they can stop it for a time period. As you can imagine, because this is an aggressive malignancy and we don’t have good second- or third-line options, I usually tell the patient that I would not stop the therapy, especially given that they’re working. There’s no reason in that circumstance to stop therapy and let the disease progress, and then you have a different problem in your hand.

I agree. They continue to use drug until progression, at which time you either look for an alternative investigational agent or you can go to some acute leukemia–based regimen such as an ALL [acute lymphoblastic leukemia]–based regimen. Any other points to share?

 There are, of course, newer agents being evaluated in clinical trials. They’re all looking at the fact that the CD123 is highly expressed on this tumor, and there are at least 2 promising drugs that are in clinical trial. One is an antibody-drug conjugate, IMGN632, which is using an alkylating agent as a payload and could be used to target this disease. It’s enrolling patients right now. There is a bispecific targeting CD123 as well, and that is still promising. Our initial intuition was that patients who progress with tagraxofusp do not lose the expression of CD123, which allows us to target CD123 with these 2 options. That’s unique about this disease mechanism of resistance to tagraxofusp, in contrast with B-cell malignancies. When we use CD19 and CD22 therapies, the expression of CD19 or CD22 is altered. This allows us to enroll these patients in those clinical trials, and I remain cautiously optimistic about the outcome of those trials.

Great. I appreciate your insights and both of our experiences with tagraxofusp and with BPDCN [blastic plasmacytoid dendritic cell neoplasm].

 Thank you. I thoroughly appreciate your insight as well.

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Treatment Approach Amid COVID-19 Pandemic

I’ve discussed the topic of tagraxofusp, also known as Elzonris. Again, a targeted therapy for a disease for which there was no acceptable or standard therapy. It’s a CD123 monoclonal antibody attached to diphtheria toxin. Because of the risk of capillary leak associated with its use, there was an albumin threshold on the clinical trial, although you can get around that by treating patients—if you have the luxury of time—with supplemental intravenous albumin to the point that they then sustain an adequate oncotic pressure that might mitigate the adverse effects of the drug. What about your experience with trying to get patients to that magic number before they start getting treatment?

You bring up an excellent point about assessment of a patient’s fitness to receive tagraxofusp. As we mentioned, in the clinical trial they used a threshold of serum albumin of 3.2 g/dL, and their idea was to lower the risk of capillary leak syndrome for those patients. Again, if we have ways to improve the serum albumin, that could be helpful in terms of lowering the risk of capillary leak syndrome, because in the study they had seen 18% of patients develop capillary leak syndrome, and there were 1 or 2 deaths that occurred in the clinical trial. One has to closely assess a patient’s fitness in terms of their ability to receive tagraxofusp, so that they are at low risk of developing capillary leak syndrome.

My experience is that we would assess the patient, and even though the patients are receiving the first cycle, we administer it in the hospital and closely monitor their vitals, their liver function tests, serum creatinine, and body weight. We’re closely assessing, and at any of those early signs, we would start treatment them with the administration of IV [intravenous] albumin and use steroids and other measures that they were taking in the clinical trial. It has to be closely monitored.

The incidence of capillary leak syndrome was just seen in the first cycle mostly, and there was less chance of developing capillary leak syndrome with the second cycle onward. With the second cycle, we allow administration of tagraxofusp as an outpatient because the incidence is much lower. We closely monitor these patients for the things that I mentioned earlier. In terms of toxicity, they did see elevation of liver function tests and thrombocytopenia, so those are the other things that need to be closely monitored. What has your experience been in terms of administration of tagraxofusp?

Yes, you must give the first cycle as an inpatient. Patients do require close observation. The toxicity can be seen quite a bit of time after the administration of the first dose, so they need to be followed. They also need to be followed for things that may or may not be on the label, such as tumor lysis and pancytopenia. With subsequent cycles, we have no trouble administering in the clinic. The challenge with the registration trial is that there is no end point. For my older patients who are over age 75 and not eligible for allogeneic transplant at our institution, we continue to use tagraxofusp for long periods of time, until disease progression. That’s a little frustrating, but that’s the best we got because that’s the registration trial and that’s the label, and there is no precedent, at least not that I’ve seen published, for stopping therapy when it’s been effective. Would you agree?

I agree. You also brought up the fact that there are the other unusual toxicities. In the study, they did see thrombocytopenia, and a subset of patients with BPDCN [blastic plasmacytoid dendritic cell neoplasm] do have underlying myeloid malignancies, and there could be myelodysplastic syndrome or chronic myelomonocytic leukemia. Those patients are more vulnerable to the cytopenia adverse effect of the tagraxofusp as well. It’s somewhat challenging in terms of the clinical use in real life vs in the clinical trials.

You don’t need a separate hematologic neoplasm. This neoplasm itself can occupy blood and marrow. When you have an effective therapy, pancytopenia would be expected; it’s not such a surprise. But that is often a first-cycle phenomenon, and some patients need to be watched closely.

Novel Agents for BPDCN Management

What would you consider in terms of stem cell transplantation? Who gets that and when?

For the fit patients, if they achieve complete remission, allogeneic stem cell transplantation should be offered for those fit patients who are in remission. In the clinical study that was published in the

, 47% of patients who were newly diagnosed with BPDCN [blastic plasmacytoid dendritic cell neoplasm] were able to undergo transplantation. Interestingly, there were 13 patients who underwent transplantation, and 3 of 13 patients underwent autologous stem cell transplantation, and there have been some data about use of autologous stem cell transplantation. However, allogeneic stem cell transplantation offers better results as compared with autologous stem cell transplant, and there is a scarcity of data for use of autologous stem cell transplantation.

Getting back to the median age of the disease, it is important to realize that it is in the late 60s, and we are not able to offer allogeneic stem cell transplantation for most of those patients. That is a big limitation in terms of performing stem cell transplantation for BPDCN. In terms of the outcome, the best outcome that we have for this disease is based on the patients who were able to undergo transplantation for BPDCN. I certainly would offer for patients who are fit and are in first remission.

Things may change. There are clinical trials for the anti-CD123 CAR [chimeric antigen receptor] T, which is something on the horizon. CAR T-cell therapy is an attractive option for a lot of B-cell malignancies and is 1 myeloid disease where the CAR T cell has a promising option. That would be something that I’m looking forward to in the future, to see the results from the clinical trial.

 You were careful. You almost said a promising potential, and that’s all you could say about a CD123 CAR because there might be a lot of off-target toxicity. Even with a novel agent, you see some toxicity that is capillary leak, and that’s why the albumin threshold was placed on the original trial. I hope you’re correct that engineered cell therapy will have a role, but that’s something completely investigational now.

The University of Texas MD Anderson Cancer Center trials with anti-CD126 CAR T have been closed for enrollment because they had some undesired results in their early data. But it’s a promising option for patients who have relapsed disease and enrolling in a clinical trial allows us to evaluate other options.

Second-Line Treatment Options

What is your current standard of care treatment for blastic plasmacytoid dendritic cell neoplasm?

Historically, for BPDCN [blastic plasmacytoid dendritic cell neoplasm], chemotherapy has been the backbone of most of the treatments. We have used both AML [acute myeloid leukemia]– and ALL [acute lymphoblastic leukemia]–like regimens in treatment of BPDCN. However, those AML- or ALL-like regimens cannot be used for the majority of patients. When I am assessing a patient with BPDCN, I’m assessing whether patients are fit or frail. Usually, my treatment algorithm follows that assessment initially. I assess if the patients are fit. I consider 2 options. One is using tagraxofusp, which is the new drug therapy approved by the FDA for treatment of BPDCN. The other is intensive chemotherapy, which ALL-like regimens have been using in the past with success. However, although those do lead to a good response rate, the responses tend to be transient, and one has to follow those regimens with allogeneic stem cell transplantation. The treatment has been changed by the approval of tagraxofusp. I would assess looking at the eligibility criteria for the patients enrolled in the clinical trial. One of the major factors that played in terms of enrolling these patients was the serum albumin. If the patient’s serum albumin is less than 3.2 g/dL, I would not consider using tagraxofusp for those patients.

The second factor that excluded patients for the treatment of tagraxofusp was CNS [central nervous system] involvement. Patients who have CNS involvement may not consider using tagraxofusp unless someone wants to add CNS therapy along with the tagraxofusp, which has not been studied for that combination.

For the failed patients, it’s more challenging because the median age of the disease is in the late 60s. Unfortunately, that could be a significant proportion of our patients who get evaluated, and for those patients we may consider enrolling them on a clinical trial. For some patients who are very frail, we may consider just local therapy, and in that sense radiation could be a useful modality just for cutaneous involvement. We may consider using radiation or steroids for those failed patients who are not candidates for tagraxofusp or not candidates for even any intensive chemotherapy. What do you think about the second-line therapy?

 I view tagraxofusp as the first-line therapy. I’m certainly old enough to remember when we used ALL-like regimens, and we also occasionally used cytarabine and daunorubicin, an AML regimen, and our response rates were not particularly good. You’re right the way that you framed it, looking at eligibility criteria for the clinical trial, and those who fall outside the eligibility criteria are, in some ways, upon them is conferred a need for another therapy, and you have no choice but to go back to something older.

On the other hand, patients who have had an initial response to tagraxofusp, either alone or after allogeneic transplant, who sustain relapse, again are potential candidates for an ALL-like regimen. But response rates are not particularly good, and survival is not particularly long. Your best chance is when you’re treating patients initially. If they’ve never been exposed to the monoclonal antibody and have achieved a remission through a vincristine-based regimen followed by allotransplant, then of course you would use tagraxofusp in the second-line setting. But in the first-line setting, it would be better to go with the novel agent. It has a specific indication, and the alternatives are not particularly desirable.

Standard of Care for BPDCN Treatment

® presentation, “Targeted Therapy in Blastic Plasmacytoid Dendritic Cell Neoplasm.” We’re going to discuss the advanced treatment of BPDCN [blastic plasmacytoid dendritic cell neoplasm]. I’m Gary Schiller, and I’m the director of the hematologic malignancy stem cell transplant program at the David Geffen School of Medicine at UCLA Medical Center in Los Angeles, California. Today I am joined by my colleague Dr Salman Fazal, from West Penn Hospital in Pittsburgh, Pennsylvania.

 I’m the director of transplant at the Allegheny Health Network in Pittsburgh, Pennsylvania, and specialize in myeloid malignancies.

 We’re going to discuss blastic plasmacytoid dendritic cell neoplasm. This is a myeloid malignancy. It is not common. It’s been considered quite rare, and it was underdiagnosed in the past. It will take more data and a few more years of patient presentation to get an accurate assessment as to how common this myeloid neoplasm is. A typical patient profile is the reason that the disease is underdiagnosed. Often the patients are older, although there is no specific age distribution, and they present to a dermatologist with skin lesions. It is very common that patients will present with a variety of skin lesions, typically papular ecchymotic skin lesions on the trunk but also on the extremities. They’re often palpable, can sometimes be on the face, and can sometimes be macular. Given time, patients will go on to develop pancytopenia as this neoplasm will invade the marrow and produce hypoproliferation of normal marrow elements.The typical work-up depends on where the patient presents. If a patient presents in a dermatologist’s office, the skin biopsy may lead to a diagnosis. If the patient’s pancytopenia is associated with complications such as neutropenic fever or thrombocytopenia, that patient might present in an emergency department, in an internal medicine ward, or hopefully on a hematology service, and a bone marrow might be the way the diagnosis is made. The most important thing in making a diagnosis is histopathologic confirmation and working with an hematopathologist, because it’s a tricky diagnosis. It’s not easy, and a hematopathologist needs to be involved from the skin biopsy all the way through the bone marrow biopsy. Otherwise it will be underdiagnosed or misdiagnosed as some other primary dermatologic neoplasm.

Salman Fazal, MD, West Penn Hospital

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