Prof. Naveen Pammaraju:
Hi everyone. Welcome to what’s really an exciting VJHemOnc BPDCN session. We’re really excited to kick off this BPDCN specific curriculum. I’m Professor Naveen Pammaraju, department of Leukemia at MD Anderson and the director of our BPDCN program.
I’m really honored to be joined by my esteemed colleagues and dear friends. First Professor Marina Konopleva from Albert Einstein in New York City. She is one of the world leaders in both leukemia and BPDCN. And her pioneering work in the preclinical, translational, and clinical levels really led to the approvals of these first class of drugs with CD123. Marina, welcome. Thanks for joining us.
Prof. Marina Konopleva:
Thank you, Naveen. It’s a pleasure to be here and talk to you all about BPDCN. Yeah, so as Naveen said, I’m now at the Albert Einstein, but we worked together at MD Anderson for many years. And we launched the BPDCN program, which now took off very successfully with Naveen’s leadership. Excited to be here.
Prof. Naveen Pammaraju:
Oh, wonderful. Thank you, Marina. And also from Europe, from the other side of the pond, we have our very good friend, Professor Emanuele Angelucci who has really worked with me closely over the last several years in defining some of the more, I would say engaging, interesting subsets of patients with BPDCN, often thought to be historically a disease of older men.
And what Professor Angelucci’s work is showing us is that as we’re diagnosing the disease, more and more we’re finding it in females, young patients, infants, neonates across the board. Perhaps a disease that’s been hanging out in plain sight. Professor Angelucci, welcome and I’d like to hear your opening remarks, sir.
Prof. Emanuele Angelucci:
Naveen, good afternoon in Italy. Good morning for Americans. And I’m very happy to be here with you. My name is Emanuele Angelucci, I’m the chair of Hematology and Cellular Therapy Department in Genoa, Italy. We were involved in BPDCN since several years. We were, I believe, the first center in Europe to use tagraxofusp as induction therapy for transplant bridging therapy to obtain a complete remission and to go patient to transplantation. So we have an experience of six patients treated with tagraxofusp and we are very satisfied of this, of the results so far obtained.
We are chairing the European MPP program for tagraxofusp, together with my friend in Germany and my friend in France. And during this experience we particularly focused on CNS involvement and we can a little discuss a little bit more in detail. And we have the opportunity to treat a young patient, a 16 year old patient with and a single… And this patient was treated with tagraxofusp, chemo, and transplantation. And now is one year and a half approximately in complete remission… So will be very happy to share my experience with you.
Prof. Naveen Pammaraju:
Fantastic. Thank you both for joining. So to kick off our discussions, let me start with Marina. Marina, you and I have worked together for a decade plus now really in this CD123 space. I was wondering if you could give the viewers there, now that we have a chance to pause and reflect with the first approved drug tagraxofusp and hopefully working on the second class of drugs, the IMGN drug and others.
If you can give folks a background, what drew you to CD123, Marina? The over-expression of BPDCN? And what do you think about these drugs? And maybe if you can comment on the different ways to target CD123, you’ve been involved in all that. The floor is yours. Go ahead.
Prof. Marina Konopleva:
Yeah, thank you, Naveen. So we learned and realized very early on from the literature, from our own research, and from work of our collaborators, that CD123 is a cell surface antigen that is highly expressed on BPDCN tumor cells. Previously it was known as AML stem cell antigen and it still is from the pioneering work from Monica Guzman and Craig Jordan’s lab.
And we knew that this is very important antigen in AML, but subsequently it was realized that this is actually a hallmark of BPDCN tumor cells. That’s one of the diagnostic criteria. So if you don’t have CD123, then the diagnosis is quite questionable, I would say, of BPDCN. So we started working on that with the initial collaboration with the Art Frankel who was in Texas at that time. And he came up with this, what we now know as tagraxofusp, or at that time as diphtheria toxin conjugated to interleukin-3. Interleukin-3 is a ligand for CD123, so the way the drug works is it binds to the receptor on the tumor cells, let’s say in BPDCN, and then there’s internalization and then there is a toxin release. And the toxin in that case is DT, diphtheria toxin. And then there’s this tumor-specific killing of the BPDCN cells.
So to Art’s credit, he made this drug in his lab and he took it all the way to clinic. And he has done the first pilot study in relapsed/refractory BPDCN, which we contributed to. And he showed very high response rate, about 70% in patients who failed other therapies. So I think that began the journey of targeting CD123 and BPDCN. It was recognized that this is a great target, is somewhat tumor-specific. Again, there’s some CD123 on normal stem cells, but the levels are very low. So you actually do not get a lot of myelosuppression when you target CD123 with tagraxofusp. And then eventually it led to the clinical trials that were led by Naveen and Elaine, myself, and the many other collaborators in US and abroad with what we call now TAG, in the relapsed/refractory BPDCN and subsequently in newly diagnosed BPDCN
So this study, so initial paper was published in New England Journal of Medicine in 2019. It showed again high response rates of about 60%. And it is still a disease of more older patients and many of them are not able to tolerate intensive chemotherapy because in the past the Hyper-CVAD was perhaps a standard of care or any other chemotherapy, ALL type or AML type was standard of care. So the response rate was close to 60, 65%. The overall response rate was above 70% and there was a quite significant extension of survival in these patients. So this led to the approval of this drug as a first targeted therapy in BPDCN. Because this is such a rare disease, this did not require the Phase III study. So it was based on the Phase II data, but since then there have been a lot of real world experience confirming the efficacy of this agent in this otherwise deadly disease. Now it comes with some side effects as any drug does, and the particular side effect of TAG is what we call capillary leak syndrome or CLS, which we think is really related more to the toxin, not so much to the antigen. So we developed the guidelines how to recognize early and manage the CLS. And that was really instrumental in this drug moving forward because if left untreated can be quite deadly. But I’m not going to talk too much about that. But since then of course we recognize that there are other ways of targeting CD123. And in the last few years there have been quite a few trials with the antibody-drug conjugate, which we now call PVEK from ImmunoGen, IMGN632. So this is again antibody conjugated to the toxin, which is in that case is alkylator, proprietary alkylator to the company. So induces DNA damage specifically in the tumor cells, it’s been tested for both BPDCN and AML. And what we found that again similarly to TAG, it’s a very effective drug perhaps with a similar activity, but the side effect profile is I would say a bit more benign. So we don’t see capillary leak syndrome with this agent. There’s some [inaudible] edema and some myelosuppression if given in combination, but overall it’s quite safe drug. And the schedule is given I think every three weeks now or weekly. So it doesn’t require an admission necessarily. So it’s not yet FDA approved, but we are certainly hoping that this will be considered for FDA approval for patients who are intolerant to TAG or who have failed at TAG.
And maybe on the last note, there have been also attempts to make the CAR-T against CD123, both autologous and allogeneic CAR-T cells. And my lab has published preclinical work with the product from Cellectis with allogeneic CAR-T cells, where we showed extremely high activity of the CAR-T in the BPDCN models of patient derived xenografts in vivo and also in vitro. So the CAR-T trials are of course they’re associated with the CAR-T associated toxicities. And I think they’re still ongoing. They haven’t really led yet to the approval. But I think eventually we’ll probably have CD123 CAR that hopefully can be used, we can we can use for our patients. So maybe I’ll pause here and we can come back to that later in the discussion.
Prof. Naveen Pammaraju:
Wow. No, wonderful. It’s targeting the PDC with CD123. I think that’s the theme of what Dr. Konopleva is summarizing. Wonderful summary of the past decade. Professor Angelucci, as we turn to you, you’ve been leading the charge with CD123 targeted therapy in Europe, particularly with the TAG as you mentioned. A nice series of patients that you and colleagues have shown, showing the real-world feasibility. Minding the fact that it can cause vascular leak, capillary leak syndrome, but really I think being well managed and prevented by you and colleagues. So I wanted to ask you your European experience with the TAG agent as you alluded to in your earlier comments. And then also I’m going to ask you perhaps if you would like to answer as well, what we’re missing with the TAG is, as Marina was mentioning, the CNS involvement. This is something that you’ve made a very key set of observations. So maybe if you want to comment on the practical aspect beyond the TAG? So lumbar punctures, radiation. The floor is yours, Professor Angelucci.
Prof. Emanuele Angelucci:
Okay, thank you. Let me discuss a little bit what is our approach. Okay, we started our approach with tagraxofusp, particularly we are basically transplant center. So basically it’s a bridge to allogeneic transplantation in the concept that allogeneic transplantation is the only curative, really curative approach for this very aggressive disease. So the purpose was to have a bridging therapy able to induce complete remission with limited toxicity, only at least limited toxicity for a transplant point of view. This is particularly chemotoxicity. So we know that and we learned that tagraxofusp toxicity is a capillary leak syndrome. But this at least in our experience, doesn’t make impact on transplant platform. That for example, in all our experience, none of the patient developed capillary leak syndrome after transplant… even if that involved TCLS with tagraxofusp.
So the aim was to induce a complete remission. In order to have a transplant in complete remission we need to limit pre-transplant toxicities. We treated six patients, three of them were elderly patients, not able to go to transplantation. Three were eligible for transplant. And one of them was a complete remission, marrow and scan, complete remission [inaudible] after one transplantation.
The other two were with a minimal residual disease after tagraxofusp treatment. And they were, we obtained a complete remission with chemotherapy and then they underwent transplantation. And so far all of them are in complete remission. The last one is a very, very short follow up. Since then, we look into the literature of our preferred approach conditioning regimen for transplantation in..[inaudible].. total body irradiation based and we induced total body irradiation for these patients. And since the beginning of our experience in our standard approach, we include the CNS diagnosis if possible involvement of the BPDCN, the blastic cell in CNS, even for asymptomatic patients on the neurological point of view. And I have to tell you that on six patients, two were negative, two were clearly positive on a morphological point of view. Only one has mild syndrome. And two were positive, but only by flow analysis. So if you consider patients with the minimally involved [inaudible] determined by flow, the flow cytometry, we have four, about six patients positive for presence, at least presence of the blastic cells in the CNS. We treated all the positive patients with the ALL schedule every week to do during the treatment, every week if possible of course. And even the patients with minimal positivity by flow. And all of them responded well and were in complete remission at least regarding CNS involvement. The two patients with negative examination were treated with prophylactic lumbar puncture, following typical schedule for ALL. And we didn’t register any particularly side effects, any particular problem in combination with intrathecal chemotherapy. And so far we are very satisfied with this experience that we suggest to anyone first to check, to make a diagnostic lumbar puncture at the beginning. And if negative, to treat patients with [inaudible] prophylactic chemotherapy. And at the moment, without more specific evidence, we suggest an ALL schedule. And to treat patients with positive CNS in liquid examination, and also in this case to treat them with classical acute lymphoblastic leukemia schedule.
If in the follow-up, will be defined more specific schedule, of course. We will follow more specific schedule. But so far the only evidence available is the evidence of ALL. What is more important, my point of view, is the CNS involvement has to be looked at, even in asymptomatic patients.
Prof. Naveen Pammaraju:
Right. Well said. I just wanted to applaud you because you made so many practice-changing, lifesaving observations there. I mean I really want to emphasize for our viewers, the CNS rate is much higher than I expected it to be in BPDCN. So even in our own MD Anderson series led by myself, Dr. Konoplava, Dr. Kantarjian, exactly as you said. I would say rather shockingly in the modern era, we are reporting something like 20 to 30% CNS rate. This is frontline and relapsed/refractory. So some people think it’s only at relapse. Almost all of these patients are asymptomatic occult. You can only find it by doing the LP. And because it’s so prevalent and so frequent, let’s say AML, all comers maybe less than 5%. It’s more than ALL, AML. This is more like Burkitt’s, leukemia, lymphoma, something like that. We are at our institution doing eight lumbar punctures. So two for the first four cycles, alternating IT Ara-C, IT-methotrexate. So eight total, like a high-risk, ALL paradigm. And then I’m even recommending four more post-transplant. We can get into that. In addition to that, as you said nicely, if you are positive or symptomatic, then you’ve got to think about triple intrathecal LP, more frequent LP, radiation. This is a really tough situation. But early recognition, asymptomatic lumbar punctures, and in our paradigm, prophylactic chemo, has been I think life-saving. So I’m really happy you brought that up. Great observation. Marina, we’ll turn it back to you. So as Professor Angelucci was saying, we think that most of these approaches are not curative alone. So whether it’s chemotherapy, it’s CD123, you and I have started to do the combinations. We have to talk about stem cell transplant. But interestingly in our field, as you and I have done before, it’s not just allo transplant, there is a question of auto 2transplant as well, which may be a kind of interesting wrinkle in the BPDCN story.
So also we should let the viewers know you also have clinical experience in stem cell transplant as well. What are your thoughts on allo, auto? When do we do it in BPDCN? Is there a day we can get rid of it and only do combination therapy? Marina, what are your thoughts on transplant for BPDCN?
Prof. Marina Konopleva:
Maybe I’ll start and then Dr. Angelucci can continue because he’s a transplanter and I’m not. But I think that the approach, as you said, we are taking it. Pretty much everybody who can should proceed towards stem cell transplant because we don’t think that this regimens, despite the efficacy, are curative on their own. Even in the skin only BPDCN, we feel that the transplant is indicated and that’s really the curative path as Dr. Angelucci mentioned. So I do think that the path forward is to do induction chemotherapy plus hopefully tagraxofusp, which is a targeted therapy. And then followed by allogeneic stem cell transplant. Now the autologous stem cell transplant has been reported by Japanese colleagues and they had small series relatively, as a rare disease, they did show that the data quite compelling seem to be a quite long overall survival in those patients. But I think here in US, we mainly practice allogeneic stem cell transplantation because we know that BPDCN is a systemic disease. We now know that patients who have skin only disease, they already have bone marrow mutations and lesions in the bone marrow. So we do think that originating source is still the bone marrow disease. So I think to me, allogeneic stem cell transplantation remains to be a standard of care. Now how many cycles you need to do before going into transplant? I think it’s an open question and I try to ask many different experts. I think on average I heard the numbers between two and four. I think perhaps four would be a safe bet and then followed by allogeneic stem cell transplant. We also attempted to do the maintenance post-stem cell transplant at MD Anderson as you know, with the same agent. But these are early studies which preliminarily show safety and we need longer follow-up to see how effective that will be. But that’s at least our US approach.
Prof. Naveen Pammaraju:
Yeah, that’s perfect. Professor Angelucci, your thoughts on transplant in BPDCN? You’ve really led the way on a lot of these approaches. What are your thoughts on the latest here?
Prof. Emanuele Angelucci:
Well my center has a huge experience in allo transplant. So we transplant, let’s say regular to transplant patient at the age of 65 and even patient at the age of 70. So in this case, usually I do not consider autologous transplantation for this approach. For example, for a 70-year-old patient, we try to see if it’s eligible to allo transplant maybe with a reduced toxicity regimen. Otherwise, we do not consider autologous transplantation. But let’s say this is an experienced center and treating a 70-year-old patient must be in good clinical condition with a low comorbidity index. This is a very center-specific procedure. If the patient is not transplant-eligible, in Europe outside clinical trial, we cannot do combination therapy except for intrathecal chemotherapy of course. So far we treat patient with TAG until progression. And then we use depending by age, by clinical status, methylating agent. In one case we used lenalidomide, but we try a sort of sequential chemotherapy after failure of first line tagraxofusp. In my idea, a combination treatment, I know you are a trial on this, it will be a much better choice for this category of patients. In summary, if a patient is eligible to transplant, even borderline, our approach is induction and transplantation. Otherwise, we must use TAG single/anti-CD123 single agents.
Prof. Naveen Pammaraju:
A really wonderful discussion. I agree with both of your points, which is kind of three practical points for the viewers. One, BPDCN is a life-threatening hematologic malignancy. The historical rates before we all got into this field were like eight to 14 months median overall survival. So whatever you do, hyper-CVAD-based regimen, some of our colleagues have been using AML or myeloma-based. Of course now with CD123, we recommend allo transplant in CR1. There’s no doubt about it. You’re right. In very selected cases, Marina and I and others have done the auto transplant. They’re usually older, frail, unfit patients. Possibly skin-limited disease, maybe thinking that the marrow was never involved, but we still need to iron out the science of that. And then the last aspect, as you both mentioned, is the number of cycles before, we have never adjudicated. So on the TAG trials it was exactly as Marina said, two to four cycles, we were able to get the majority of patients to transplant. I’ll also say that some patients who’ve come to us in their 70s, you would’ve never given them cytotoxic therapy, PS of two. They actually improve the performance status as they attain remission with TAG, with whatever you’re giving, and then you’re able to bridge them to transplant. I find that to be a remarkable part of our field. It kind of suggests to me that there is a cytokine element that some of these patients actually are not feeling and doing well. They get effective therapy, steroids, TAG, chemo, whatever they’re getting, and they feel better. So maybe make sure it’s a dynamic assessment, transplant or not. Early consultation and then dynamic assessment. You never know, someone could become eligible when you thought they were ineligible. Marina, I want to turn it back to you. One thing that both of you made me think of is this concept of can we eliminate stem cell transplant? But what I mean by that is can we go for a cure with these combinations with CD123 with chemotherapy? And I wonder, you’ve been one of the leading experts in the field with microenvironment, MRD, you and I talk about this all the time. But what questions would you pose to the field? How do we get to the point where we can assess MRD and BPDCN, maybe like you’re doing in AML and ALL so that we can tell we’ve really cured this patient? What do you think? What do we need to do for the next 10 years? To put you on the spot with that question.
Prof. Marina Konopleva:
I think that’s a great question. I don’t know if I know the answer to that. As far as measuring MRD, obviously for somebody who has bone marrow disease, that’s fairly standardized, similar to AML. For people who have skin-only disease, if you do the skin biopsy before the transplant and they’re MRD positive, I think that’s telling us something. And I think many of them are MRD positive in my experience. And then the question becomes do you give them alternative therapy before they go for transplant? Or you give maintenance post-transplant? Of course we don’t have a great maintenance regimen as of right now. So I think it’s an open question. Ideally, as we are all saying, the combination therapy would be a way to go upfront to try to eliminate this minimal residual disease. And here we can not only use CD123 targeted agents, but also hypomethylating agents, but also BCL2 inhibitors. Venetoclax has been shown by Andy Lane and our work has been an extremely important agent for BPDCN because the BPDCN cells depend on BCL2. So I think some of the combinations of chemotherapy plus venetoclax, like what we’re doing for ALL and AML or hypomethylating agents plus venetoclax perhaps followed by CD123, like antibodies or TAG, which probably my guess will work best in the minimal residual disease setting, would be the way to go. Are we confident at this point that it’s going to work? I think no. So we still feel that the transplant is the curative approach. But I think that eventually we will also lead the studies and see if using some of these alternating approaches. And for people who are unable to go for a transplant, if we can track the minimal residual disease. And if they’re MRD negative, if we can continue on that rotating schedule and then consider maintenance strategies like what we do for AML. There are data now that if they’re maybe MRD negative, then maybe you don’t need FLT3 inhibitors long term. Who knows, right? It’s still not standard of care. But I think some of those paradigms we can utilize in BPDCN as well, but time will tell.
Prof. Naveen Pammaraju:
Wow, I really love that. I love what you said, which is the best answer for MRD is to prevent it from happening in the first place. This is an amazing concept. Our multiple myeloma colleagues are doing it, AML, ALL. And it is in fact the argument, which is why if you have a monotherapy, which has a fairly high rate of response, which we are fortunate to have now in our field, the problem as Marina is saying is that you still have a high rate of relapse after monotherapy. We may not be curing anyone.
And so can you add more drugs upfront to prevent the recurrence, CNS recurrence, systemic recurrence? And eventually can we do it even in the absence of stem cell transplant? That’s awesome.
Professor Angelucci, back to you. Most of the focus has been on older patients because that’s historically what we found, median age of 68 to 70. But some of your work has been shedding a light that infants, kids, teenagers, adolescents, young adults, not only get BPDCN but may behave differently. I wondered if you could comment on that from your experience, observations from that, treatment paradigms? Why were we missing that before? Were these patients being diagnosed as leukemia NOS, Professor Angelucci?
Prof. Emanuele Angelucci:
Yeah, so I’m not a pediatrician, I’m an adult hematologist. But we had the opportunity to treat a 16-year-old female, which were referred to us particularly for our TAG experience. So there were not pediatric center in Italy, experts in anti-CD123 treatment. So this patient was referred to us. And in Italy an adult center can treat an adolescent patient. So we decided it was a patient with the single large lesion in the leg. Large means seven, nine centimeters, very large and very dense. And this patient was of course it’s a long story because in the beginning as usually [inaudible] was lost. And this patient was treated if I remember well as lupus erythematosus. But received steroids, topical steroids. And then the patient, the specimen, the biopsy was referred to Professor Pilleri and the damage was done. The patient lost six months in waiting for the definitive diagnosis. So at this point, even because this patient was a young female, 16 years old, we decide to treat as intensive treatment as possible. So we had a very short, three courses of CD123, and then immediately followed with transplantation. The patient had no systemic involvement, no CNS involvement, no nodes. Just a single large cutaneous lesion with a persistent minimal residual disease after three cycles of TAG, at the single minimal residual positivity and the same lesion on the leg.
So we decided to add chemotherapy cycle, local radiotherapy on the lesion, and then transplantation with an haploidentical donor. I forget to discuss in my previous discussion that I think that in a young patient, the allogeneic transplantation has to be done whichever is the donor.. The fastest possible donor, even if is haploidentical. Time is more important, than complete HLA compatibility in this case.
This situation was particularly complex because we found a completely matched unrelated donor, but the transplant was held at the last moment because the donor resulted to be COVID positive. And so it was not possible to harvest their stem cells at that point. Because the patient was very young because it was in complete remission, we decided not to wait more time to have the donor available for donation.
But we look for the father as an haploidentical donor. And this we decided this strategy because BPDCN is a very aggressive disease, and you cannot lose time waiting the optimal donor. In fact, my opinion say timing is more important than compatibility.
Prof. Naveen Pammaraju:
Wonderful.
Prof. Emanuele Angelucci:
So we decided for this strategy and so far patient is well.
Prof. Naveen Pammaraju:
That’s wonderful.
Prof. Naveen Pammaraju:
Yeah, it’s really fantastic pearls you’re giving. Reminding us and our viewers, it’s a very highly aggressive disease. The window for remission and cure is so difficult with BPDCN, even with the newer agents and newer paradigm. I loved your reminder. And also you’re reminding us, Marina, another observation that we’ve made as well, which is this younger BPDCN AYA. This is anecdotal, just our own observations as experts. It possibly may be, guys, a little bit different of a disease. The older paradigm is UV light exposure, smoking, TET-2 mutations, CHIP. But you heard from Professor Angelucci, Marina, that a lot of these young patients can be female. They may not have these CHIP mutations, they’re younger. What do you think about that as far as open questions for the field? I mean this is a very intriguing dichotomous paradigm that I never thought we would see.
Prof. Marina Konopleva:
Yeah, I agree. I think we need to study the biology of young patients and what’s causing the BPDCN. Of course we don’t know for sure, but we have seen the younger people with BPDCN. It’s hard to tell if the disease is more or less aggressive in those, but I think the fact that they don’t have CHIP mutations. And perhaps less frequently have a secondary like MDS, MPN type of core disease, I think that perhaps make them, their disease more curable. Of course, again, with the same very aggressive approaches including allogeneic stem cell transplantation. But I agree, I think we need to understand better the difference in biology and perhaps therapeutic approaches to these two distinct age conditions.
Prof. Naveen Pammaraju:
Well, thank you very much to both of you. This concludes our program. I just want to thank Professor Marina Konopleva from New York City, Professor Emanuele Angelucci in Italy and Europe for your time, your expertise. And also thank you for taking care of these patients who oftentimes have such a rare diagnosis that the local doctor may have never heard of it or can pronounce the name of the disease.
And so what it reminds us is even if you have a rare disease, it’s not rare to you, to your mother, to your spouse, to your brother, your sister. It’s a disease and it’s scary. It’s something you’re facing. So I’m so happy to know that we now have a network, a community all across the world, as you’re seeing here. So let’s continue to work together and collaborate on BPDCN and try to once and for all, go for a cure for this disease. Thank you both so much for your time. See you all next time.