LDH and ECOG Performance Tests

Transcript:

David Miklos, MD: Loretta, please share your thoughts on the JCO [Journal of Clinical Oncology] publication 2 weeks ago. What are the predictors of how patients did on simple things such as LDH.

Loretta J. Nastoupil, MD: When you have this available in your toolkit, you’re going to start to apply it in [populations that are] sicker, frailer….And so, 43% of patients would not have met the eligibility criteria in ZUMA-1 [NCT02348216]. Despite that, the safety looks good. When we try to predict who did best, meaning who had the best outcomes, LDH at lymphocyte depletion and ECOG performance status were very robust clinical prognostic factors, which tease out those patients [who] have highly proliferative tumors that you don’t have the luxury of time or a cellular therapy that you’re manufacturing from an autoproduct.

Stephen J. Schuster, MD: David has a blood test for performance status, don’t you, David? Do you want to tell us about that?

David Miklos, MD: We don’t have a blood test for performance status. One has often said that I never get much below 2. But we do have a blood test looking at the tumor burden, which is another part of this discussion of how much disease somebody has. There was work produced by Dr Matthew Frank in our group and Dr Fredrick Locke and at ASH [American Society of Hematology], where we looked at circulating tumor DNA using the soluble DNA in the plasma blood using the clonoSEQ (assay) from the company Adaptive Biotechnologies. In that 80-patient study, it was highly informative, both looking at the amount of tumor going in, much like LDH pre-LD-amount of tumor, or some of the diameters of the tumor, or I hear metabolic tumor volume at Dr Locke’s group now. There [are] a lot of ways to read out how much patients [with tumors] have going in. And then, of course, it tells a lot about modality of when patients are losing the benefit of the CAR T, which is the most important thing about this frequent measurement, because we could see in that analysis that everybody was hitting the nadir of tumor at 21 to 28 days, arguing that, what you said, Steve, hitting them hard up front might be a very important thing for axi-cel [axicabtagene ciloleucel]. It may be different in other CAR T-cell therapies. But with axi-cel, you needed to get the big bang up front.

Matthew J. Frigault, MD: Going back to something Loretta said, too, that it’s important that a good number, if not half of these patients would not have met the criteria. And we’re still seeing efficacy. And even in the patients who had poor prognostic factors, patients still did benefit. The question of selecting patients, at least in my opinion, it’s more about an optimization question than an exclusion, they’re acting on the considerations in terms of how are we paying for these therapies. But benefit was seen across the board. And I don’t think there was a specific population that uniformly did horribly 100% of the time.

Stephen J. Schuster, MD: Quite frankly, Matt, the toxicity in the real world is lower than the toxicity in the clinical trials. What does that mean? It means history is important. We’ve learned something over the years. And the patient selection, as Caron can tell us, the patients had very poor characteristics in relatively speaking to the clinical trial patients. And yet toxicities were lower than expected. Maybe in the real world, doctors don’t see toxicities and report them.

Caron A. Jacobson, MD: I don’t even know that we’re just improving toxicity. If we take a look at some of the real-world data, we may even be improving in efficacy, as well, because when you do tease out the patients [who] were eligible versus ineligible for clinical trials, the group that’s eligible is actually lifting as a whole, they’re the same. But when you tease it out by 2 different groups, the group that was eligible is actually lifting up the curve, or it’s looking better in multiple series now, compared [with] the pivotal clinical trials. To Matt’s point, we’re not only getting better at toxicity, we can treat people with more comorbidities, but we’re also getting better at selecting the patients and getting patients in faster, which I think is a really important point…to meet these patients earlier in their disease course, earlier in their relapse, so that we can get them in and get their cells faster when they’re in the best position to respond.

David Miklos, MD: Three studies showed that [women] who are over 65 or 70 do the best. Isn’t that something?

Stephen J. Schuster, MD: ...That may be, as we were saying earlier, a niche that autotransplant couldn’t serve, which is you’re talking about not only does CAR T-cell [therapy] save some patients [who] relapse after autotransplant, but now you’re talking about niches of patients [who] might not be eligible that you can treat. Clearly, and the real-world data are showing this. I’m waiting for Caron’s abstract next year. I want to see if this holds up in the telehealth world, whether we get these same good results.

Matthew J. Frigault, MD: It is shifting our transplant practice. When you look at the patients who are having what we would now consider suboptimal responses or partial responses following salvage therapy, we’re thinking about those patients differently now in the world of CAR T. The trials don’t necessarily reflect that, and some of the randomized studies that’ll be coming out and the phase 3 studies. But overall, moving forward, we are shifting the needle in terms of transplant versus CAR T in this population, just knowing the burden of treatment and taking a patient who may still have chemorefractory disease.

Caron A. Jacobson, MD: I’m eagerly awaiting the results of the randomized studies in second line, because for some of these patients [who] we don’t think are transplant-eligible, right now, the label makes us treat them with a second line of chemotherapy, and it would be nice to be able to take those patients directly to CAR T cells. We have 3 randomized studies looking in the second line, and I think that those will be important to further this along.

Stephen J. Schuster, MD: I agree 100% with Caron. I agree because I’m a convert to this opinion that you just expressed. I totally thought this would just get rid of autotransplant completely. I was so impressed with how well we were doing with CAR T cells nowadays, and how poorly our outcomes have become in the rituximab era with autotransplant. And most of our patients are progressing in a year, and they do terrible, but guess what? Okay, so we’re expressing opinions. I’m going to share observations. These come from my practice. I have patients in my practice [who] were part of 1 such trial, who progressed after getting CAR T second line and went on for salvage by transplant. And I have early [University of Pennsylvania] data on that exact situation, progressing and failing CAR T cells despite expansion, and then having a splenectomy and go. Because this particular patient, that was probably 1 of the reasons he was failing. And getting an autotransplant, he’s 5 years in remission now. And then the converse is the patients [who] have an autotransplant and stay in remission. When you do this randomized study, I think we need these studies to be done, because there is going to be a subpopulation of patients [who] will still benefit from transplant, even autotransplant, as primitive as it sounds. And…I know for a fact that it will even salvage some CAR failures. So we’ll wait and see.

Matthew J. Frigault, MD: I think we’ve all had those. Whether you resensitize a tumor to chemotherapy following CAR or whatever the different selection pressures are, we’ve all probably taken a couple patients to allo[transplant] following a CAR T failure once you’re able to get the patient back into remission. And there are people who are still walking around doing that.

Stephen J. Schuster, MD: But I’m talking auto, not allo, Matt. And in this particular case, the CAR T-cells were probably being sequestered in a massive spleen. And taking the spleen out was the key.

David Miklos, MD: The point is, keeping score is very important. Sponsor randomized trials are very powerful. But having real-world data and CIBMTR [Center for International Blood and Marrow Transplant Research] registry data going forward where we can track the people who were on those trials, who went on to another trial, and [then] went on to another trial. We’ve been talking in our own center about the problem of competing risks. This is a good problem to have. In the old days, competing risk was if the therapy didn’t work, and you died of something, we blamed the therapy. Now…we’re becoming multiple myeloma docs, right? We have multiple therapies, and patients are benefiting, living longer. Good news for the patients.

Matthew J. Frigault, MD: This is also going to be a paradigm for multiple myeloma. We’ve all seen the patients who are getting to the CAR T therapies with BCMA [B-cell maturation antigen] and other antigens. They receive average 5, 6, 7 lines of myeloma therapy. Just like we can with patients prior to going to CAR T with lymphoma, we can do the same thing in myeloma. And if it does hold true, that we do get durable responses in myeloma eventually, moving it up in earlier lines is only going to benefit patients.

Stephen J. Schuster, MD: It’s pretty difficult to think of 11 lines of therapy for lymphoma. But I agree with what you said.

Transcript Edited for Clarity