Emerging Therapies in BPDCN


Shared insight on a number of novel therapies and treatment modalities being investigated in patients with blastic plasmacytoid dendritic cell neoplasm.


Naveen Pemmaraju, MD: Let’s move into the final portion of our discussion, which is looking to the future. You both nicely summarized for us what’s going on in the pathology lab and in the clinic. I put together a few slides for our discussion. One of the most promising aspects of BPDCN [blastic plasmacytoid dendritic cell neoplasm] is building on the success of the CD123 fields with the tagraxofusp agent. What’s really exciting, which I’m helping to co-lead, is the IMGN632 program. It has a name now, pivekimab sunirine.

In the relapsed/refractory BPDCN setting, as we showed at ASH [American Society of Hematology Annual Meeting] a year or 2 ago, this next-generation CD123 antibody-drug conjugate is showing some nice safety and efficacy results early on in the relapsed/refractory setting. This is a sample of the first 29 patients treated, ages 72 with a median of up to 82 years. James mentioned the median age of the prior experiences, so it’s in line with that. The majority were men, as we’ve come to expect. You can see the skin, bone marrow, lymph node involvement, and prior therapies shown here. Almost half the patients had prior tagraxofusp.

With this novel antibody-drug conjugate, in this experience, we saw no capillary leak syndrome. That’s a notable thing compared with the prior experience. There were no drug-related discontinuations or deaths in these first 29 patients during the induction period. Among the common adverse events, they were fairly manageable with some thrombocytopenia, neutropenic fevers, and hyperglycemia—approximately 10% each. As you think about the new agent, it’s an IV [intravenous] drug given every 3 weeks, as 1 dose every 3 weeks, and it can be administered in the outpatient setting.

The efficacy results are shown here. This is a very heavily pretreated group of patients, but you do see a 29% to 30% overall response rate. This was granted the BTD, or breakthrough therapy designation, for the relapsed/refractory cohort. Based on these very promising results, the study is open enrolling in the frontline setting in United States and Europe, known as the CADENZA study. I’m the lead PI [principal investigator] for this, and this is active and enrolling in the United States and Europe, giving patients another option for their BPDCN therapy.

In addition, CAR [chimeric antigen receptor] T-cells [therapy] is starting to take over every field, with lymphoma leading the way, but many of our other fields are markedly far behind in terms of developing therapies. That’s suggested in laboratory and phase 1 testing only. There are CD123 CAR T cells being developed across the world. Usually, they involve both AML [acute myeloid leukemia] and BPDCN. Some are BPDCN specific, but the concept is targeting CD123. Can you get cell kill in the BPDCN without affecting the normal hematopoietic stem cell compartment? That’s the problem and issue with CD123 therapy.

Multiple groups are trying for combination therapies. Our group, Dana-Farber [Cancer Institute], and City of Hope have opened a doublet and now a triplet trial with CD123 if you can believe it. [The trial for the combination] tagraxofusp, venetoclax BCL2, and azacitidine, is open and enrolling in frontline and relapsed/refractory BPDCN. It’s usually centered on older patients and those unable to get cytotoxic chemotherapy, but you have to be able to get this triplet.

As James mentioned, with the occurrence of CNS [central nervous system] disease, we’re doing lumbar puncture [LP] in all our patients. It’s changed the way we look at BPDCN, think about it, and think about it at relapse. In the publication our group put out last year, I was surprised to see that we reported 22% CSF [cerebral spinal fluid] positive at some point during their BPDCN course. This is a retrospective analysis. The number is higher if you’re systematically looking for it. What we’ve done is adopt an ALL [acute lymphoblastic leukemia] Burkitt-type model for LP. In AML, only 3% to 5% of patients have CNS involvement. Here it’s much higher, so we need to be thinking about that and incorporating it into our therapies.

At The [University of Texas] MD Anderson [Cancer Center], a lot of our clinical trials for BPDCN are up and running. We’re trying to put all these concepts together and move toward a more total-therapy, triplet-therapy approach. Alejandro mentioned multiple myeloma and some of these other aggressive hematologic malignancies that have moved from a more acute emergent presentation to a more chronic disease over time. This is 1 clinical trial that’s trying to put everything together: hyper-CVAD [cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone], CD123, venetoclax, lumbar punctures, getting correlative testing, and maybe eliminating stem cell transplant in the future.

I have 1 last important concept to bring to our audience. As rare as BPDCN is, it often appears with another hematologic malignancy, most commonly MDS [myelodysplastic syndrome] and CMML [chronic myeolomonocytic leukemia], but I’ve seen cases of MPNs [myeloproliferative neoplasms] and T-cell ALL. While you’re distinguishing them, remember that you could have more than 1. You could have 2 diagnoses at the same time, so that may alter what you do.

The last concept is that we’re trying to distinguish BPDCN from AML. Our colleagues from [Memorial] Sloan Kettering [Cancer Center], led by Ross Levine and Wenbin Xiao, showed that there’s a small entity between BPDCN and AML. They termed it PDC [plasmacytoid dendritic cell]–AML. That’s quite compelling. Usually 3% to 5% of cases are associated with RUNX1 mutation, which may lead to an upregulated PDC. They did have more skin lesions and worse overall survival, and CD123-targeted therapy may help. Alejandro, maybe you can comment on the elucidation of these in-between entities. Where do you think the field is going?

Alejandro Gru, MD: This is an excellent part. I had a case of this 2 weeks ago. I was talking to your colleague, and I said, “Let me email Naveen and tell him about it.” It’s a peculiar entity because the blasts have the same morphology. These cases have an interesting phenotype. They’re often CD123-positive, CD4-positive, with the same level of brightness and intensity you see in BPDCN. Interestingly, a lot of times they’re CD56-negative. In this case they lack CD56 expression. They have myeloblast markers like CD34. It’s not common to see in BPDCN, but it could happen. It’s not a diagnosis of exclusion.

The last thing is that there are very interesting data. I haven’t seen the numbers, but they were published in a paper in Haematologica 2 years ago. It looks like these cases are TCF4 positive. As you know, because you were part of the paper, which looked at TCF4 expression across a spectrum of hematologic myeloid and lymphoid malignancies, it appeared from the study that all cases of AML were negative for TCF4. Perhaps this might be the sole exception. I love what you mentioned about how this might be an in-between entity because it has TCF4 expression. Our case was diffusely positive for TCF4, but it had an unusual phenotype. It had RUNX1 mutation, and about 10% or 20% of these cases have either trisomy 12 or trisomy 13. That’s also an accompanying feature that you see. This is an entity in which we’re going to study more and separate from BPDCN if there is a true separation. The older literature mentioned that RUNX1 mutations aren’t very common in BPDCN. ASXL1 is a coexisting mutation in this entity, but RUNX1 appears to be much less frequent. This is a unique and intriguing entity, and we need to learn more about it.

Transcript edited for clarity.

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