Hematologic Oncology Update, Issue 3, 2016 (Video Program) - Video 6Clinical approach to CAR-T therapy and management of associated cytokine release syndrome
4:11 minutes.
TRANSCRIPTION:
DR NASTOUPIL: So we’ve seen cytokine release, and we’ve also seen some neurotoxicity. We’ve seen some neurotoxicity at our site with some of the other CAR T agents. So seizure activity is not infrequent. Confusion/change in the mini mental status exam is not infrequent. Generally, these have all been reversible. But the cerebral edema is what I think we worry the most about. DR LOVE: Can you kind of walk us through what happens when a patient gets CAR T therapy? For example, this patient, and how this patient specifically tolerated it. DR NASTOUPIL: Correct. So generally speaking, first we have to collect their CAR Ts. And so patients are undergoing a phoresis, which is not the most complex, but again, at our center it’s generally a multidisciplinary approach where we have to have collaboration with our Transplant and Phoresis Center. Once the CAR Ts are sent off, there are usually central manufacturing sites, again depending on the — near the sponsor of the study. And the turnaround time in terms of when those CAR Ts are actually available to infuse into the patient is anywhere from 2 to 5 weeks. And if you have a highly proliferative tumor, that can be a very challenging time period to manage these folks so that they don’t get into significant trouble before you can actually treat them. Once you know the CAR Ts are available, then you generally will give them T cell-depleting therapy. And that’s been slightly different across the studies. That usually will go on from anywhere from 2 to 5 days of outpatient chemotherapy, and then they’re admitted to the hospital. They receive their CAR Ts. Generally speaking, the most challenging aspect is getting them to the T-cell infusion without them either progressing rapidly or becoming too ill to participate in the study. Once they’re admitted to the hospital, within a few hours after the T-cell infusion, it’s not uncommon to see the cytokine release syndrome start. It seems to peak around day 4 to 7, and then it generally gets better from that time point forward. The neurotoxicity is a little bit less predictable, at least in my experience. And so the onset can be anywhere from 4 days in to last sometimes — so this particular patient had significant neurotoxicity. DR LOVE: Really? What happened? DR NASTOUPIL: So all of the patients we’ve seen so far have had fever. So he had fever. And in the midst of fever, we were looking into a source of infection. He was having difficulty with word finding. He was having difficulty with orientation. And it progressed to the point where he was essentially somnolent. He had no seizure activity, but he was prophylaxed with levetiracetam and monitored very closely from our neurology colleagues. DR LOVE: What did his brain look like on MRI? DR NASTOUPIL: So no abnormalities have been seen on MRI, which is striking. Even in patients that have severe neurotoxicity, we’ve not identified any changes in the brain MRI. We have picked up some patients that have subclinical seizure activity, and we’ve had patients that have had status epilepticus. So it’s a big spectrum there. We’re generally thinking about prophylaxing every patient with levetiracetam. The cytokine release syndrome, though not to minimize that concern, generally speaking, I think we’re successful at identifying patients that become hemodynamically unstable. We can manage them appropriately. I think the neurotoxicity is a little bit more challenging, in my opinion, because it’s more unpredictable and it’s a little bit harder to tease out what is the cause. Is it seizure activity? Is it just global brain dysfunction? We don’t know if it’s the CAR Ts that are compromising the blood-brain barrier and causing cytokine release within the brain or if it’s something else. So those are questions that are still being teased out. But this particular patient had — so he improved in terms of alertness. So he was alert, he was awake, but he could not use his cell phone or a remote control for approximately 3 months. DR LOVE: Three months! Did you ever give him corticosteroids? DR NASTOUPIL: He did not have corticosteroids, because he was not seizing. So we have grading that will determine when we give toci or when we give steroids. And even though it was a change from his baseline, it wasn’t severe enough to warrant those things. Now, he did get levetiracetam, and he was one a very long taper of levetiracetam, but he didn’t receive steroids and he never received tocilizumab. DR LOVE: Let me see what else I want to ask you about him. So you say it really took almost 3 months for the neurologic symptoms to go away. DR NASTOUPIL: Correct. DR LOVE: Interesting. What an amazing case. |