Naveen Pemmaraju, MD, discusses results from a retrospective study examining the utilization hyper-CVAD, and long-term follow-up data regarding the use of tagraxofusp in patients with blastic plasmacytoid dendritic cell neoplasm.
Despite the rarity of patients diagnosed with blastic plasmacytoid dendritic cell neoplasm (BPDCN), 2 studies examining treatment options for the disease produced encouraging results and safety data, according to Naveen Pemmaraju, MD.
Pemmaraju presented both studies at the 2021 ASH Annual Meeting and Exposition. The first retrospectively investigated the utilization of hyperfractionated cyclophosphamide, vincristine, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD).1 The other presentation centered on subanalyses of age and baseline disease involvement of the phase 1/2 TAG 0114 trial (NCT02113982), which explored tagraxofusp-erzs (SL-401; Elzonris), a first-in-class CD123-targeted therapy, in the treatment of BPDCN.2
“There have been no standard therapies at all for this rare disease. Groups around the world have been borrowing paradigms from other leukemias, [such as] chemotherapy from acute myeloid leukemia [AML], acute lymphoblastic leukemia [ALL], lymphoma,” Pemmaraju said. “Those outcomes have been suboptimal overall, with early deaths, high infection rates, and many of these patients are older, frail, unfit. The background is that new, novel therapy approaches are needed to not only for remission, but long-term cures.”
In an interview with OncLive®, Pemmaraju, associate professor in the Department of Leukemia, Division of Cancer Medicine, the University of Texas MD Anderson Cancer Center, discussed results from a retrospective study examining the utilization hyper-CVAD, and long-term follow-up data regarding the use of tagraxofusp in patients with blastic plasmacytoid dendritic cell neoplasm.
Pemmaraju: BPDCN is a rare, but serious and aggressive, deadly blood cancer that [is diagnosed in] around 500 to 1000 patients in the United States per year. It is an ultra-rare diagnosis, but one that has a great consequence to our patients.
The background is that there have been no standard therapies at all for this rare disease. Groups around the world have been borrowing paradigms from other leukemias, [such as] chemotherapy from AML, ALL, lymphoma. Those outcomes have been suboptimal overall, with early deaths, high infection rates, and many of these patients are older, frail, unfit. The background is that new, novel therapy approaches are needed to not only go for remission, but long-term cures.
In terms of the design of this study for the hyper-CVAD outcomes in BPDCN, over 20 years ago, Hagop Kantarjian, MD, came up with the hyper-CVAD regimen in patients with ALL and that has worked nicely in that aggressive blood cancer. The supposition there is threefold. One is that there are multiagent chemotherapy, so not just 1 drug. Two, you have alternating cycles of chemotherapy, sort of changing the game on the leukemia. Three, you have lumbar punctures, which give the central nervous system protection in case the leukemia travels there, or if it does, then to treat it.
We adapted and borrowed that hyper-CVAD regimen into BPDCN, but we studied it more formally. In a retrospective analysis, we have one of the largest groups of BPDCN patients in the world that come to see us. We then looked at the outcomes in younger and older patients who could either get the main regimen, which is quite intense, or age-adjusted, lower-intensity regimens; and we looked at their outcomes.
[It’s] not only feasible to deliver multiagent intensive chemotherapy to patients with BPDCN, we safely give it, watching for the infections and toxicities. We had a very high response rate. That high response rate carries over into 2 things. One is that when you get into complete remission, the patient’s blood counts improve and it's a more manageable course for them in terms of their disease. Second, we were able to get a lot of these patients to stem cell transplant and have long-term remissions. This is very important in a disease where overall survival expectancy is maybe 1 [to] 1.5 years.
The question now moving forward is if we can prevent the occurrence of the central nervous system relapse, maybe even get people to stem cell transplant or, if they’re older or unfit, make that the disease treatment itself. We believe that the role of older cytotoxic chemotherapy still exists with BPDCN, but that we can combine it with the newer treatments that our group has pioneered, which are called targeted therapies. This develops a multiagent, multiple chemotherapy approach that we're seeing in other diseases, like multiple myeloma and AML.
As with any rare disease, there are multiple challenges and barriers. One is the obvious, which is finding the appropriate patients. Pathology diagnostic standards have improved, we're able to make the diagnosis, compared with maybe a lymphoma or leukemia. [Second], a lot of these patients in the clinic are older and unfit for intensive chemotherapy. In those patients, can we smartly deliver chemotherapy? [This includes] reduced doses, targeted agents, or combinations that work for older patients.
Third, can we at some point eliminate the need for a stem cell transplant [by] curing through chemotherapy alone?
It’s a multicenter effort led by us at MD Anderson and it is the long-term follow-up data of our pioneering study with tagraxofusp, which was the first and only approved CD123 targeted agent.
This is an interesting scientific story. It turns out that BPDCN cells express or overexpress the surface marker target in 100% of patients. All patients have this. But targeting it has been somewhat challenging scientifically and clinically. We were able to lead this trial from start to FDA approval exactly 3 years ago.
Now, I’m starting to present, on behalf of my group, the 2, 3-year follow-up data. This presentation focused on subgroup analysis by age and disease involvement because it's a heterogeneous disease.
As with any novel agent, tagraxofusp, now approved, carries some element of [adverse] effects and toxicities that come with all of these new agents. The most important is the so-called US FDA black box warning for a toxicity known as capillary leak syndrome [CLS]. It’s not new or specific to this agent. We’ve known about this entity for decades with cytotoxic agents, other targeted agents, even disease processes themselves.
But CLS is important. It could be fatal in some patients and it leads to a fluid buildup around the heart and lungs. Education is important to doctors, health care workers, pharmacists, nurses, patients, a patient’s family, and caregivers. Everyone should know about this. What we did on the clinical trial is what we're doing in the real-life experience on the package label insert.
There are certain things you can do to mitigate against CLS. We admit all the patients for cycle 1, watch them closely for fluid status, creatinine, kidney function, and liver tests . If the patient tolerates treatment well, then you have the option to do it as an outpatient [administration] in the second cycle. If a patient develops CLS, we have some maneuvers that we can give to treat the patient.
Lastly, the albumin level, that’s the protein level in the body. It’s important to know at baseline if this patient should receive this drug or not. If it goes down, you can replace it with intravenous albumin.
You have to know the toxicities of novel agents in anything. Once you understand [and] know how to deal with it, then you can watch for it. We’ve actually been able to successfully rechallenge patients with this drug who've had that toxicity, as it largely occurs in the first cycle of therapy.
[In] patients with BPDCN, the median age is close to 70 and it’s rare to have pediatric patients present with this disease. [An important question is], can you give this new targeted agent to older patients? On clinical trials, we enrolled patients young, teenagers, 20-year-olds, and all the way up to mid-80-year-old patients. There are patients who've received the drug on compassionate use or other basis in the very young, pediatric setting. Young or old can get this agent.
You’re watching for CLS, you’re watching for other more common [adverse] effects like thrombocytopenia and elevated liver function tests. But the good news is we have been able to safely deliver it in even older patients. You have to watch out for the albumin levels, heart and lung function at baseline. Not every drug is for every patient with a disease, so you need to follow the package label insert and the team’s advice for each patient.
One is that this agent has a fairly well-known [adverse] effect profile. Three years after its US FDA approval, it's now approved in the EU for frontline adults as of 2021. It is nice to see that the [adverse] effect toxicity profile that we observed [and] predicted is the same that you’re seeing in the real-world setting, and that the drug is efficacious, young or old…whatever compartments of disease are involved.
The second aspect is that it started a blossoming new field in hematologic oncology, which is the CD123 targeted era. We have several other drugs now. The phase 1/2 IMGN632 trial [NCT03386513], which we’re also leading at MD Anderson, and several other trials, which are using different modalities and platforms to hit the same target in not only BPDCN, but also host of other leukemias including AML.
It's an exciting time for our patients, for their caregivers, for their families. Let’s keep working together, because at the end of the day, it doesn't matter how rare your disease is. There are people at places like MD Anderson, my team, myself, who are dedicated to these areas to help.