What treatments are available for BPDCN?
I'll divide it out into maybe three aspects. So historical, maybe current, and then future directions. Historically, because BPDCN was a not understood, misunderstood, you know, sort of rare, elusive entity, it was sort of treated and I think appropriately so at that time as what was the biological understanding at the time. For example, if you look at our historical literature, if you presented a skin predominant, folks gave skin directed therapies, including maybe even topical, those largely did not work as the disease would come rippling back because of marrow disease, leukemia, and ultimately fatal disease.
The second aspect of historical therapy was systemic therapy, usually multi-agent chemotherapy, usually borrowed from the existing more common blood cancers. So just to give a quick example to some of the viewers out there that know this program well, multiple myeloma therapies, which have been around for a while. So that's been used in BPDCN to varying degrees of success. ALL, acute lymphoblastic leukemia protocols, AML, acute myeloid leukemia protocols, lymphoma protocols, so on and so forth. So the basic theory is it's an aggressive disease with poor overall survival, as it just mentioned, less than a year. Multi-agent chemo potentially CNS penetrating, etc. Unfortunately, those had mostly suboptimal outcomes. And again, usually older frail patients who are susceptible to infection, sepsis, multi-organ failure.
Then as you move more into the current era, you know, I think we have this emerging story, which I've been fortunate to be the world leader in, which is CD123 targeted therapy, a kind of an amazing story in this rare disease, poor overall survival with cytotoxic kind of generic general therapy. The major finding was that CD123, which is a protein surface marker IL-3 receptor alpha, it expressed ubiquitously so 100% of BPDCN cases should have it, should be attractive for therapeutic pharmacological chemo immunotherapy targeting. But we didn't have a drug until the one you mentioned earlier which is tag or tagraxofusp.
So this DT IL-3 molecule serves as a homing device, if you will. That takes a truncated or modified diphtheria toxin payload and infused it to a human IL-3 recombinant version. And then this is then I.V. injected into patients and then it will home to the receptor site for IL-3 which is CD123 out the receptor alpha, thereby causing directed damage to the BPDCN CD123 bearing cells. Well, this was a breakthrough because what we were able to do in frontline patients, as well as even relapsed refractory, is have a very high response rate. Ultimately, getting the drug FDA, US FDA approved in December of 2018, ages two and older, so including the majority of pediatric patients and then ultimately even in the EU European association in January of 2021 for adults with BPDCN.
So that marked a major milestone, that offers a new modern, if you will, the first targeted therapy for just BPDCN and the first ever drug approved just for this rare indication. There are other CD123 therapies actively in clinical trial. The next one that's in the latest stage of development is that of Pivekimab sunirine or IMGN632, which I have presented publicly a couple of years ago as a positive phase two clinical trial, the EHA meeting in Frankfurt, Germany, a year or two ago. And so we await those trial data to mature. Outside of these two with CD123 agents, there's a number of other molecules that have been tested and are being tried—bispecific CD123 monoclonal antibodies and CAR-Ts.
Outside of that, there is the venetoclax agent, which our group and others have shown activity. This is the anti-BCL2, which has already been approved in AML and lymphoid malignancies. And again, either as a single agent or in combination with CD123 and other chemotherapy has showed benefit for a number of our patients. And then finally as we think about future directions, you know, we're starting to test formally in the clinic triplet combinations. So CD123, BCL2, and chemo—ALL based chemo for example. And then CD123, BCL2 targeted and then hypermethylation either aza or decitabine. And those are active ongoing clinical trials that folks can look up online.
Finally, I want to mention stem cell transplant, a huge important part of this disease thus far. As in many other aggressive myeloid malignancies, transplant in what we call first year, first complete remission appears to be the way to go. We've done a limited number of autologous—from the patient themselves—stem cell transplants. But the majority of what we're doing and have done is allogeneic stem cell transplant—a donor from someone else to the patient.
Finally I have to mention CNS prophylaxis and CNS treatment. The vast majority of patients who will have CSF positivity and then BPDCN will be asymptomatic. That's a good thing. So usually we can treat with intrathecal chemo to reduce that and go back to negative. But a small fraction of patients will have symptomatic disease. So we try to catch that early as I mentioned. And if it needs treatment, triple intrathecal chemo for the spinal taps and then radiation and other things if and when needed. That's a small fraction of cases.
Finally, I'd like to also mention there are a number of active clinical trials ongoing, both here at M.D. Anderson, across the U.S. and across the world, that are either trying to test novel targets that I have not mentioned here, or different combinations of therapy, ALL based and others, either with the newer agents or with older agents. Again, the goal trying to be to eradicate the disease before it gets to the relapsed refractory setting, or once it's already there to treat it so it can be treated in different ways. I'm not sure that there's a firm standard of care way of treating it. I think what is attractive in 2025 is targeted therapies like tagraxofusp, the anti-CD123 directed diphtheria toxin. So that's an immunotherapeutic approach.
Historically we've used combination chemotherapies, combinations like HYPER-CVAD. And also we're now increasingly seeing rational therapies like hypomethylating agents plus BCL2 inhibitors like venetoclax. So there are different ways. And I think you tailor the treatment depending on the patient profile and their ability to, you know, be able to handle intensive therapy versus less intensive therapy. So there's a lot of factors that might about the patient, not even just the disease, that might influence the decision making.
HealthTree
