CAR T-Cell Therapy for R/R DLBCL

Ian W. Flinn, MD, PhD: Amit, I want to get back to you. Let’s switch gears and focus on CAR [chimeric antigen receptor] T cells. In which patients are you using CAR T cells on a routine basis?

Amitkumar Mehta, MD: That’s a great question. Both of the products that are approved and the 1 that is going to be approved soon are approved in second-line and beyond settings. Patients have to have failed 2 lines of treatment to be considered for CAR T. As we were discussing about frontline treatment of large B-cell lymphoma, those who are at high risk, high IPI [International Prognostic Index] patients, or double hit, double expressors are the patients who tend to relapse early. If I start a treatment in a patient with double-hit lymphoma, they are on my radar to consider for CAR T down the line. But currently, the FDA indication is a failure of 2 lines of treatment.

The only difference between the tisa-cel [tisagenlecleucel] and axi-cel [axicabtagene ciloleucel] is that axi-cel [axicabtagene ciloleucel] allows for primary mediastinal B-cell lymphoma because those patients were part of the study. That’s the only difference in the label. A high-risk patient that I’m starting treatment on is on my radar for the CAR T treatment down the line. 

Also, it is important to know how they are relapsing. We cannot put every lymphoma case in the same bucket. Some patients have a low burden of disease, some have a high burden of disease, some also have CNS [central nervous system] involvement, for some their LDH [lactate dehydrogenase] is high and the velocity of their progression is high. This is important because CAR T is a process, right? You have a collection, and then you have, depending on the product, 2 to 3 weeks before that product will be ready. We have to see, in that perspective, whether the patient can be held, so to speak, during that time. If they explode between the collection and the infusion, they cannot successfully get the CAR T. All those factors are important.

Also, like transplant, it is important that they have social support. For 8 weeks, maybe they cannot drive. All those are factored in when we consider using CAR T-cell therapy. It also depends on the patient’s insurance status, whether they have good social support, and how their financial systems are. Those all factor into decisions regarding use of CAR T.

Ian W. Flinn, MD, PhD: Loretta, Amit just nicely outlined a few of the issues, but there are some real issues in regard to delivering CAR T cells to patients, from financial barriers to logistical issues. You hear some people say, “If he couldn’t get a transplant, there’s no way he’s going to get CAR T cells.” Do you find that to be true? What are your thoughts on that?

Loretta J. Nastoupil, MD: It’s grossly underutilized because the logistics are challenging. It requires referral, and it requires commitment from the patient and family members. That being said, when you have a patient who you know would be dead and now they’re cured with this treatment—this is a onetime treatment, though I recognize it includes 6 weeks weeks leading up to it and another several months post infusion where you’re monitoring and adjusting things—it is really rewarding when we see it work.

Where I struggle is, can you actually optimize patients who you’re concerned about? I see the discussion often happening in referrals to me when hospice is offered vs CAR T. I don’t think it should be utilized in that setting where it’s a last-ditch effort. The logistics are so challenging, just as Amit mentioned, so you need a patient who has disease stability while you’re undergoing manufacturing, at least for these auto products. But I still think it should be considered, at least at some point in the disease course for any patient with relapsed/refractory large B-cell lymphoma. You cannot utilize the same criteria we apply to identify transplant candidates.

Ian W. Flinn, MD, PhD: So you don’t have a litmus test. You’re not requiring every patient to have an echocardiogram and have an EF [ejection fraction] of 50%, or pulmonary function tests, or something like that, is that correct?

Loretta J. Nastoupil, MD: You have to use your physician eyeball test that you already have heard about. You have to be able to predict that they’re going to tolerate the therapy if they have severe CRS [cytokine release syndrome] or severe neurotoxicity. You have to predict that they’re going to have the pulmonary, cardiac, renal, and hepatic reserve to get through that. But it’s not the same stringent criteria we utilize to identify who’s going to tolerate high-dose chemotherapy. You don’t have the whole notion of, “They have to have chemotherapy-sensitive disease—step 1. Step 2, make sure they don’t have comorbidities that would predict for bad outcomes.” That part is still very fuzzy to me because we looked at ejection fractions of less than 50%, and we looked at renal insufficiency and liver insufficiency. So far none of those has held up as being a really strong factor associated with either safety or efficacy.

Transcript Edited for Clarity