How to Handle CLS From Tagraxofusp and Maintain Treatment in BPDCN

Commentary
Article

During a Case-Based Roundtable® event, Thomas W. LeBlanc, MD, MA, MHS, discusses the adverse events, like capillary leak syndrome, that come with the use of tagraxofusp when treating patients with blastic plasmacytoid dendritic cell neoplasm in the second article of a 2-part series.

Targeted: How have the survival results from the phase 1/2 0114 study (NCT02113982) of tagraxofusp-exrs (Elzonris) changed the outlook for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN)?
THOMAS W. LEBLANC, MD, MA, MHS: Everybody has been very excited about this therapy, but [the survival curve] is still rather sobering. The median [overall survival (OS)] is more than...12 months [at 15.8 months (95% CI, 9.7-25.8)] and there are a lot of people still alive at 1 or 2 years out, which we wouldn't expect to see with other therapies.1 If you look at results from a European Named Patient Program, which is a term in Europe for compassionate-use therapy, there is a pretty meaningful OS out to 12 to 24 months in these patients, [with an overall median OS of 20.2 months (95% CI, 9.5–not estimable)].2 This was especially so for patients who underwent transplant, but even with non-transplant patients [there were good OS outcomes]. It's clearly active and effective, not a complete home run, but better than what we've had historically.

Thomas LeBlanc

Thomas W. LeBlanc, MD, MA, MHS
Associate Professor of Medicine
Hematologic Malignancies and Cellular Therapy
Associate Professor in Population Health Sciences
Duke University School of Medicine
Duke Cancer Institute
Durham, NC


What were the adverse events (AEs) seen with this therapy?
It's a nice improvement over the status quo, but there are toxicities here. [When we look at the AEs], 2 out of 3 patients will have significant transamination issues, about half will develop hypoalbuminemia, and almost half will have fatigue and pyrexia.1 There was also a significant amount of thrombocytopenia…and capillary leak syndrome [CLS] was seen in about 21% of these patients [on the trial of tagraxofusp]. However, most of these AEs don't lead to a discontinuation; that was only seen in 7% of patients, however, dose interruption was done in 69% of patients. That's usually because of the transamination issues, low albumin, or weight increase. If we look at more severe AES...[those are] often either thrombocytopenia or the transamination issues, and sometimes that's the issue that's going to require you to interrupt the dose [when they’re severe cases].1

What is the impact of CLS when giving tagraxofusp to patients with BPDCN?
This can be a significant toxicity. There have been a couple people who've died because of this, probably before we knew how to manage it when this therapy was initially being given. At Duke, when I was a fellow during the early phase trials bringing [tagraxofusp] to market, I treated many people on this therapy and it was scary at the beginning when we would see hypotension, rapid weight gain, and peripheral edema. What happens [with CLS] is...when you treat patients with BPDCN using tagraxofusp, you get this cytokine storm almost. It's a bit akin to cytokine release syndrome that we see with bispecific drugs that are coming out now or with chimeric antigen receptor T-cell therapy. You get this leakiness of the capillaries…and some of that may have to do with the diphtheria toxin as well, and you lose protein rich fluid from the capillaries.3 That decreases the patient's oncotic pressure, and then the patient can develop hypotension, they can get acute renal injury, which is sort of a hypoperfusion...but generally, when you volume resuscitate these patients will improve.

However, they can get pleural effusions, pulmonary edema, acute respiratory distress syndrome, intestinal edema ascites, and in rare cases, things like muscle edema and rhabdomyolysis. So it's not a treatment that you mess around with and give it in the clinic and send them home, we [have to put the patient] in the hospital for the first round of therapy. Once they're tolerating this treatment, in cycle 2 and especially cycle 3 and beyond, they usually get outpatient treatment and you just monitor their albumin levels, and you supplement it accordingly.

What are some methods to handle cases of CLS?
This theory of toxin causes a sepsis-like syndrome is the way that I think about it when I'm managing [CLS due to tagraxofusp]. If you don't get a good enough response with aggressive bolus crystalloids, you can go up to vasopressors [and then] you can consider giving albumin at that point.3 Usually, you don't have to do [anything beyond] fluid boluses and then maybe add in vasopressors, but most of the time you don't have to do that either as long as you're choosing the right [patients for this drug], giving them fluid, and supplementing their albumin, then usually you do OK.


REFERENCES:
1. Pemmaraju N, Sweet KL, Stein AS, et al. Long-term benefits of tagraxofusp for patients with blastic plasmacytoid dendritic cell neoplasm. J Clin Oncol. 2022;40(26):3032-3036. doi:10.1200/JCO.22.00034
2. Angelucci E, Deconinck E, Manteigas D, et al. Durable outcomes with manageable safety leading to prolonged survival with tagraxofusp for treatment-naive patients with blastic plasmacytoid dendritic cell neoplasm: updated results from a European Named Patient Program. Blood. 2023;142(suppl 1):547. doi:10.1182/blood-2023-178734
3. Siddall E, Khatri M, Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, and management. Kidney Int. 2017;92(1):37-46. doi:10.1016/j.kint.2016.11.029
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