Activity Transcript

Segment 1

Daniel H. Wiseman, MB, ChB, PhD: Hello, and welcome to this activity, which is called "Linking Inaugural Skin Manifestations with Blastic Plasmacytoid Dendritic Cell Neoplasm: Clinical Pearls for Identification and Management." My name is Dr Daniel Wiseman. I'm a consultant hematologist at the Christie NHS Foundation Trust, in Manchester in the United Kingdom. And I'll be joined for this session by Dr Naveen Pemmaraju, associate professor at the department of leukemia at the University of Texas MD Anderson Cancer Center.

Welcome to the first session. This is going to be on identifying patients with blastic plasmacytoid dendritic cell neoplasm. Now skin manifestations are a common, but underappreciated feature of a wide range of hematologic malignancies. This study here gives a snapshot of the diverse spectrum of skin manifestations in a series of consecutive blood cancer patients that presented to an Italian dermatology department. It's quite interesting that 15% of these were due to direct neoplastic infiltration by a whole range of conditions, both myeloid and lymphoid, and was the presenting feature of the disease in around half of those cases. It's clear that multidisciplinary collaborative approach between hematologists and dermatologists is often crucial.

A range of blood cancers have particular tropism for skin, primary cutaneous lymphomas, other lymphomas, neoplastic eosinophils, and mast cell diseases, histiocytic conditions. All of these have classic skin presentations. Acute leukemias, notably leukemia cutis, is a manifestation of acute myeloid leukemia, can present with classic violaceous lesions like these, either at presentation or relapse.

But today's exercise will focus on 1 rare but important form of dendritic cell cancer, called blastic plasmacytoid dendritic cell neoplasm, BPDCN. BPDCN is a rare, but highly aggressive blastic leukemia and lymphoma. It can present as either. It is thought to represent less than 1% of all blood cancers but it is probably underdiagnosed. The best estimate suggests about 700 patients in the US and about a thousand in Europe annually, but it may well be more. Tends to be a disease of older patients, in the median age of 67. But an important point is that it can occur at any age, including childhood. [It t]ends to affect men with a ratio of about 3 to 1.

And the clinical features can be quite diverse. Most patients, around 90% will present with skin involvement, and around half will have involvements of blood and bone marrow. Other common sites of presentation include lymphadenopathy, hepatosplenomegaly, and central nervous system involvement in a meaningful proportion of patients. It's got generally poor prognosis with a median survival of around 12 to 14 months and interesting overlaps with other myeloid malignancies like myelodysplasia, chronic myelomonocytic leukemia, and acute myeloid leukemia (AML).

Now BPDCN has gone by a large number of names over the years. This list here from a meeting now 17 years ago just shows some of the names that it's gone under previously.

This was before its cell of origin was confirmed to be a plasmacytoid dendritic cell, which is a type of dendritic cell that produces type I interferon, plays important roles in viral response, and important for diagnostic purposes, expresses CD123 to high level, as well as CD4. And as a consequence of this, the name blastic plasmacytoid dendritic cell neoplasm was added as a separate entity in the 2008 World Health Organization (WHO) classification. At that time, it was classified as a subtype of acute myeloid leukemia. In 2016 revision, it moved to its own distinct category, reflecting its different origin from other forms of AML.

So the cutaneous features of BPDCN could also be quite variable. I mentioned that more than 85, 90% of patients will have skin involvement at presentation. If it's not obvious, it will often be there if you go looking. There are these 3 classic patterns of either isolated or a small number of these nodular lesions that tend to be purple, round, raised, and can occur anywhere on the body, often on the face or the trunk or the limbs.

Some patients will present with something that looks more like a typical benign bruise. It's important to recognize that this could be something more sinister. And then there's a minority of patients who have the more classic presentation of disseminated disease with this really striking diffuse bruise like or hyperpigmented red, brown macules. There's a couple of images here. But by no means are these the only ways it can present.

The lesions can vary in size, shape, distribution, color. They're often asymptomatic. And typically, they don't itch. They can become scaly over time. And as I say, they can be atypical. And here's a few images of cases that did have BPDCN that didn't really follow the rules that I introduced before. And I think the important message here is to always consider it as a potential diagnosis.

The lag time from lesions developing to a diagnosis being secured has been estimated to more than 6 months for the majority of patients, indicating there's more we can do to recognize this disease early, and a skin biopsy is critical for making the diagnosis. Importantly, this skin biopsy needs to include the deep dermis because the epidermis is typically spared. And in many patients, the diagnosis will be made on a skin biopsy by immunohistochemistry. And here are some of the markers that tend to be positive, particularly CD4 and CD56.

But CD123 is arguably the single most important marker in securing a diagnosis of BPDCN. CD123 is the α-chain of the interleukin-3 receptor. In normal tissue, its highest expression is on plasmacytic dendritic cells (pDCs). And we know it's overexpressed in a variety of cancers, but it's highest in BPDCN, and the pattern of expression with these other markers, with particularly CD4 and CD56, which is an aberrant expression pattern. CD56 is not normally expressed on pDCs. This gives you the classic triad of CD4, -56, -123. There are other markers that can be helpful in differential diagnosis, particularly CD303, CD304, and a variety of others.

Now I mentioned half of patients present with blood and bone marrow involvement. So there are cases diagnosed by the hematologist down the microscope. This is a monomorphic blastic disease often with quite a high infiltrate. The blasts tend to be medium sized, undifferentiated, and agranular with an irregular nucleus and usually at least 1 nucleolus. And morphologically, it tends to resemble an undifferentiated acute leukemia or an acute lymphoblastic leukemia.

Again, the diagnosis in these cases would usually be secured on flow cytometry, looking for the classic triad, the CD123, CD4, and CD56, which has led to the moniker "Think 123456." And other markers, again, that can be done by flow cytometry on blood or bone marrow, can be helpful at discriminating this disease from other blastic leukemias. The blasts usually fall within the classic blast gate, but they tend to be in almost all cases, CD34 negative. Again, a useful discrimination from most AML subtypes.

Cytogenetics are helpful, but there's nothing pathognomonic or unique to this diagnosis. Notable lesions involve genes like RB1, ETV6, and TP53. And a range of mutations have been identified involving a lot of the usual epigenetic, signaling, and transcription factor genes and splicing genes that we see in other myeloid malignancies. But there's nothing that will in itself lead to a diagnosis of BPDCN.

So, just finally, there are some important differential diagnoses to consider, and there are other skin tumors that can present with similar-looking lesions. Again, it's the immunophenotype that will lead to the correct diagnosis.

And the most important differential here is acute myeloid leukemia. And it's vital to distinguish these 2 conditions to direct patients to appropriate therapy. Again, CD123, 4, and 56. When the triad is present, that's essentially enough to confirm the diagnosis. There are some markers that will exclude the diagnosis. So it's important to include in panels of the T- and the B-cell markers, panmyeloid markers. And as I say, immature markers like CD34 and 117 tend to be negative.

There is no 1 marker that's perfect. All of these markers can be expressed in AML, but they tend to be expressed only in a minority. And the combination is what is usually enough to clinch the diagnosis. So I'd like to thank you for participating in this activity and direct you to continue to view the next chapter when my colleague will discuss management of BPDCN.

Segment 2

Naveen Pemmaraju, MD: Hi, everyone. I'm Dr Naveen Pemmaraju, associate professor and director of the BPDCN program at MD Anderson Cancer Center in Houston, Texas, and it's truly my honor to join my colleague, Dr Dan Wiseman, on this topic of BPDCN, and my talk will be on focus on managing patients with BPDCN.

Blastic plasmacytoid dendritic cell neoplasm, or BPDCN, is truly a clinically aggressive hematologic malignancy, which tends to affect almost every part of the body. Outside of the cutaneous manifestations, bone marrow, lymph node, and even the central nervous system are common areas for BPDCN, and so in this manner it distinguishes itself from both AML and acute lymphocytic leukemia (ALL) and really represents its own unique entity, and therefore we hypothesize that it should have its own unique therapies. While cytogenetics and molecular mutations can be quite heterogeneous, the overexpression of CD123, or interleukin 3 (IL-3) receptor alpha, appears to be a target for our targeted therapy approaches.

Let's take a deeper look. CD123 is on the surface of 100% of BPDCN cells, and so an agent, tagraxofusp, or SL-401, was hypothesized to have activity specifically in patients with BPDCN. It consists of a truncated diphtheria toxin payload fused a human recombinant IL-3 receptor, and with this IL-3 approach, it actually has its own data in vitro in the lab for BPDCN, and not just extrapolating it from AML, myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia (CMML) or other related diseases.

In a pilot study that we conducted with our colleague, Dr Arthur Frankel, we found that in this phase 1 experiment, the majority of patients had a response, 78%, 7 out of 9, and 5 of these patients had complete remissions, and these results were published in 2014.

This then led to a major paper, which was really a prospective multicenter stage 1, 2, 3, 4 approach in which we took this agent, tagraxofusp, into the clinic for multiple cycles for patients with BPDCN. In this experiment, a total of 47 patients were treated. All patients of course had CD123 expression, and the agent yielded an overall response rate of 90% with this intravenous (IV) drug, 72% of which were complete remissions and 67% in the relapsed/refractory setting.

This novel agent therefore was approved by the FDA in December of 2018, making it not only the first targeted therapy drug approved for BPDCN, but actually the first CD123-targeted agent in all of hematology/oncology. Furthermore, tagraxofusp has now been approved in the EU for BPDCN adult first-line treatment, and both agencies correctly noted the potentially deadly toxicity of the capillary leak syndrome occurring in patients treated with this agent.

In the clinic, this agent has led to remarkable response. One such patient is shown here. This is a 70-year-old patient who is treated with tagraxofusp, and had a remarkable skin response in the first cycle of therapy which was durable, and then going on to an allogeneic stem cell transplant. This illustrates the agent's activity, not only at the level of the bone marrow and skin, but also of the ability to get patients to stem cell transplant, even in the older patient population.

As with any novel drugs, you have to be on the lookout for novel toxicities. As I mentioned, the capillary leak syndrome is the notable toxicity for this new agent. While there were 2 deaths recorded in the induction period as documented in our New England Journal [of Medicine] paper and leading to the black box warning by the FDA, there are successful cases where patients can have capillary leak syndrome. They are treated and rechallenged with the agent with successful outcomes. One such patient was one of my own young patients who is now alive and well 2 years later after capillary leak syndrome, successful rechallenge, allogeneic stem cell transplant.

Moving on in the field, there are other ways to target CD123. One of the lead agents in this space is the IMGN632 compound, which we showed these results at the American Society of Hematology meeting. With this novel agent IV given every 3 weeks, you can see responses in not only multiple relapsed/refractory BPDCN patients, but also those who had prior tagraxofusp, making this the first time that we've been able to show sequential CD123-based targeted therapy with safety and efficacy results.

Now moving outside of CD123, B-cell lymphocyte 2 (BCL-2) has proven to be a target in both lymphoid and myeloid diseases, and the oral venetoclax agent has shown activity both in the lab and in patients for BPDCN therapy. As a monotherapy, it showed modest results, but we've been able to combine the venetoclax in clinical trials with chemotherapy, as shown here. This is with hyper-cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) and venetoclax leading to responses, but also in hypomethylated combinations, that's azacitidine and decitabine, and notably, these approaches have been able to be used across the world where CD123-based therapies are not yet available.

In the clinical trial space, we've been able to put all this together, particularly for older unfit patients, to go for a doublet, and now even a triplet approach, combining tagraxofusp (SL-401), so CD123 based, hypomethylated, and venetoclax BCL-2, in an ongoing clinical trial at several sites here in the United States.

As I think about the future of BPDCN, we still have to think about 2 components: the role of chemotherapy and the fact that the disease can appear in the central nervous system. In a recent study that we published in Blood, to our surprise, BPDCN commonly has cerebrospinal fluid (CSF) positivity, 22%, mostly asymptomatic occult disease. And now based on these results we've started to incorporate prophylactic intrathecal lumbar puncture chemo in all patients with BPDCN, similar to how we do an ALL or Burkitt's leukemia lymphoma.

And then of course for the younger fit patient, chemotherapy itself is still playing a role. This is our recent results with the hyper-CVAD Kantarjian ALL-based regimen still showing high response rates. Of course, in younger patients, good median overall survival for this deadly disease, and of course it already has built in the incorporation of the intrathecal chemotherapy.

So again, the question we ask, can we incorporate all of these maneuvers into a total therapy-based regimen, similar to our colleagues in multiple myeloma or AML, and this is our ongoing clinical trial approach to do that, combining elements of the CD123, chemotherapy, venetoclax, even for the young fit patient.

There's still a role for curative allogeneic stem cell transplant in 2022 and beyond. This is our series of patients with BPDCN and stem cell transplant. Very good outcomes, as you can see, in terms of progression-free survival (PFS) and overall survival (OS), but the caveat is these are younger patients. The median age of this study is 39, roughly half the age of what most of us see in the clinic for this aggressive disease.

And so, in summary, thinking about the current and future approaches for BPDCN, what we are looking at in the frontline setting is a number of different options I'm very pleased to see, many of which we didn't have 5 years ago. And so, in the younger fit patient, we can think about chemotherapy-based approaches plus or minus venetoclax, the SL-401 (tagraxofusp), CD123 with its high rates of response, the IMGN clinical trial, which is open for frontline patients with BPDCN, and for all patients we're incorporating central nervous system (CNS)-directed therapy as well as allogeneic stem cell transplanting at first remission.

In the older patients, we're incorporating the hypomethylating agents, venetoclax, and the CD123 drugs, and of course as I mentioned to you, I believe the future are these triplets and quadruplet combinations, still focusing on eradication and prevention of central nervous system disease, and even allogeneic transplant in the older patient who can go for it.

In the relapsed/refractory setting, unfortunately, it still remains a very aggressive disease with urgent unmet medical need. Clinical trial, clinical trial, clinical trial is always the way to go if you have access. If not, then some combination of these drugs that we mentioned, with particular emphasis on venetoclax, hypomethylating agents, and other CD123 approaches, including chimeric antigen receptor (CAR) T-cell clinical trials, for your consideration.

And with that, I'd like to turn it back over to my colleague, Dr Wiseman, for the remainder of the program.

Segment 3

Daniel H. Wiseman, MB, ChB, PhD​: Welcome to the final parts of today's program. I'm joined by my good friend and dear colleague, Naveen Pemmaraju, for a general discussion on clinical management of BPDCN in the real world. And Naveen, I wanted to start by just asking, there's so many options for treating BPDCN these days, and it's a nice place to find ourselves, but outside of the trial setting, obviously if you're not living close to MD Anderson, if you are young and fit, what would your preferred first-line option be?

Naveen Pemmaraju, MD​: I think this is the most important question of the modern era. We have to be realistic. It's great that we were able to get the CD123 drug approved and more coming, more in clinical trials. But the reality is for most of our colleagues across the world, they may not have access to these drugs. So I really have favored 2 approaches that have really worked not only for myself, but our colleagues across Europe, Asia, Africa, other places.

Number 1, try to divide it up into younger vs older, fit vs unfit. In the younger patient, I still think there's a role for chemotherapy. Most of us favor the ALL-based approach, which is what I personally favor, but some also use AML, acute myeloid leukemia-based approach, so 7+3 induction, and then some groups do favor a cyclophosphamide-doxorubicin hydrochloride-vincristine sulfate-prednisone (CHOP) or lymphoma-based approach, particularly for older unfit.

Then the spin I think I showed in the slides was, I add the venetoclax agent, which has been very active in BPDCN. But in the older unfit, and I think that's the most common real-world patient that you and I see, I do favor the hypomethylating agent (HMA)-based venetoclax (VEN) approach, which now we know is actually approved for older AML, but not extrapolating from the AML. We have our own data in the lab and in patient, that this is a way to go. So I think those are kind of 2 realistic approaches in the absence of CD123, Dan.

Dr Wiseman: Yeah. So, I mean, my next question was going to be about how to manage the older, less-fit patient. And I guess, I mean, my attitude to this is often to, the first point would be to decide if your patient is on a transplant track or not. And I don't know whether you would agree with this, but I would take a different view to management if a patient were clearly not a transplant candidate and, in those patients, would it be correct to say that you would favor a hypomethylator with venetoclax if they were available in that context, if you couldn't get access to CD123?

Dr Pemmaraju: Right, yes, exactly right. I think this is the right way. So whatever words that we use, older, fit, unfit, younger, this is right, what you said, which is, we still believe the allogeneic stem cell transplant is still part of the curative regimen for most of these patients, even if you're older. And I think that's a great point. I have transplanted patients out of what you and I would consider a lower-intensity or medium-intensity regimen, like you said, so hypomethylator venetoclax-based or chemotherapy, but I think your point is a good one, which is, you can be older, but still fit for transplant. So you can come in with a performance status (PS) of only 1 or 2, get hypomethylator venetoclax, chemo, and then improve your PS, right Dan? To 0 or 1, and then still go for the transplant.

But the other point I was going to ask you, you and I have talked about this before, some of these patients have been put forward for autologous stem cell transplant, which you and I don't commonly do right in our myeloid leukemias, what's your stance on that approach?

Dr Wiseman: I mean that there is good data out there for the autologous transplant, not something that we tend to do in our center, and I don't think it's widely applied in the UK, but certainly some of our European colleagues would definitely recommend it. And I think that's one of the challenges of BPDCN management really is, that there are these choices and there's no head to head. You're not going to get head-to-head data for such a rare disease. So, it's choosing between these options that I think is a real dilemma, facing a lot of the clinicians in the clinic.

I wanted to ask you about a topic that I know is something you are very interested in, which is the CNS disease. And if you've got any advice for clinicians on how to go about screening and managing CNS disease? I'll mention your paper from last year in Blood, which really very elegantly showed that it's much more common than we thought. Would you include a diagnostic lumbar puncture at the start for all patients?

Dr Pemmaraju: Yeah, Dan, excellent points. And I really loved in particular, a couple of your slides where you basically are reminding us that in order to diagnose something, you must first think about it. I really appreciated that from your discussion. And that's the same thing I would say about the CNS journey that we've been on with our patients. I am personally very surprised to see how common it is once we started doing systemic lumbar punctures.

And so, yes I would give 3 kind of practical points from that academic work. One is what you said, which is now that we know for sure this is pretty common, let's all add a diagnostic lumbar puncture, as you said. And again, we do that in certain other diseases as well. We do not do it right routinely in AML, where it's been regularly shown what less than 5% of AML patients routine will have.

Number 2, what, however you're treating, whether it's VEN HMA, CD123, or chemo, let's remind ourselves that we don't know about the blood-brain barrier (BBB) transmission or connection of a lot of these agents, particularly newer targeted agents. So let's include prophylactic lumbar punctures (LPs). Now, how many, which type? Okay, fine, let's debate and discuss, but I've basically borrowed from the Kantarjian ALL hyper-CVAD regimen, which is 2 per cycle for the first 4 cycles, so that's 8. Now, if you wanted to do more of a Burkitt's or Philadelphia positive, maybe you can do more.

And then the third principle is if you have symptomatic central nervous system disease, this is very important, so early imaging, in additional lumbar puncture, consultation for radiation oncology, looking for palsies, and you may need to incorporate a radiation therapy in those patients. So I think these are the central tenants, and we must bring in what we've learned from lymphoma ALL Burkitt's into this space and not assume it's infrequent, like we see in AML, Dan.

Dr Wiseman: That's really great advice. I'm sure it'll help a lot of people in the clinic. Switching gears slightly, obviously tagraxofusp and other CD123-targeting drugs have revolutionized the treatment landscape for this disease, it's given us a fantastic tool, the targeted therapy. What are the key messages that you'd want to convey about how to use tagraxofusp safely in the clinic?

Dr Pemmaraju: Perfect, Dan, this is important, especially as the drug is now approved in the EU and compassionate use cases are being given all over the world. I can think of 4 practical tips for folks out there who are listening to this program.

I think it's good to just educate ourselves, the patient, the family, the nurses, pharmacists, caregivers, give people a heads up, "Hey, in the next 3 days, we're admitting this patient for this new drug. Let's let people read about it and know about that."

Number 2 is prevention is the key, what we found in the trial and what I'm still doing in real life for this very effective agent is albumin, the major protein in the body. If the albumin is too low at baseline, and we have numbers on the package insert, don't give the drug, right? We are doing what we do in the trial and then if the albumin drops suddenly or too low, then there are parameters on how to hold a drug, give IV albumin, and watch the fluid status. I actually think this is really important that I can tell you as a leader of the study, what we did on the trial is what I still do in real world and it really helps a lot of patients.

Number 3 of 4, Dan, is there are other parameters that matter with the drug. You want to watch the daily fluid status and weight, creatine, and liver function tests and there are stop wire functions for the drug giving parameters on that. And then fourth, if the capillary leak syndrome does occur, a tachycardia, hypotension, fluid overload, recognizing it early can be life-saving. So I think these are the fundamental tenants.

Dr Wiseman: That's great. Thank you. And I suppose the final thing I wanted to discuss with you is, just ways that we can improve the recognition and cut down that time from presenting symptoms to clenching the diagnosis. And I guess my take on that would be the importance of including CD123 on diagnostic panels. I don't know if you have comments on that. I don't know if in the US, this is something that's widely done, but I know in the UK, it's not always there, and whether you think this is a more common disease than the epidemiology would indicate.

Dr Pemmaraju: Oh, I love this question. It's maybe the passion of my life, what you just asked. I think, Dan, that people get in their minds that a rare disease is so rare that they've never heard of it, they've never seen it, they never will see it. And they think it's medical esoteric or trivia. But what you and I know is 2 fundamental principles. One, this particular disease, BPDCN, is not as rare as people think it is. The name has changed a dozen times in the last 30 years. So people have likely seen it in a long career, blastic natural killer (NK)-cell lymphoma, et cetera, et cetera. So the nomenclature change can confuse people, both pathologists and clinicians, even the most up to date.

And then the second concept that I know you and I believe passionately, is a rare disease is not rare to you if you have the disease, it's not rare to your mother or your sister, your wife, your brother, your husband, it's a disease. And so it does not matter if it affects 200 people or 200,000 people. BPDCN, as you and I have shown us an aggressive deadly disease that if not recognized early, and even if treated early, in many cases, can still lead to an early demise.

You just showed us that people have recognized this entity from at least the 70s. So in the pathology standpoint for our dermato- and hematopathologists colleagues out there, think about BPDCN, include the immunohistochemistry (IHC) and the flow testing when you're ruling out complex blood cancers, particularly with skin involvement, as you beautifully showed us. And then the second concept for clinicians is, if you have an AML NOS diagnosis, not otherwise specified, or AML leukemia cutis, Dan, I was wondering your thoughts on this, maybe add some of these markers and do a little bit more workup. I think there's more BPDCN out there that people think, Dan.

Dr Wiseman: I certainly think that's the case and something that interests me and I know interests you is the overlap with other conditions. And I think a really important point is to consider this, when your MDS or CMML patient transforms. And we all see patients who transform and with a blastic transformation, the immunophenotype may not be typical, it might be CD34 negative. And rather than just being a curiosity, maybe it's telling you that this is a different type of disease.

We've published on this, that transformation from CMML is relatively common considering how rare both diseases are. And it does seem to be 1 mode of transformation of that disease and if you don't go looking, and if you don't do CD4, CD56, CD123, you run the risk of missing it and missing a really important treatment option with CD123 targeting treatments.

So I hope that as awareness, as the disease largely driven by all the outstanding work you've done, I hope that as the awareness increases, we'll be seeing more people diagnosed more quickly and being given the very best treatment. I just want to thank you for a great discussion, I really enjoyed it and your important pearls of wisdom.

Dr Pemmaraju: Thank you, Dan. Great to be here with you.

Dr Wiseman: Yeah. So with that, I just want to thank you for participating in this activity.

This is a verbatim transcript and has not been copyedited.