Sequencing Therapies in Relapsed/Refractory ALL

Ibrahim Aldoss, MD: When would you recommend CAR [chimeric antigen receptor] T-cell therapy versus blina vs inotuzumab [blinatumomab vs inotuzumab]? My approach, for CAR T cells, I tend to recommend it for someone who relapsed after transplant, or transplant is not an option, because between all these 3 options, the one that has the best record and durable remission is CAR T cells. I tend to recommend CAR T cells more in someone with extramedullary disease, since patients with extramedullary disease tend to be refractory to blinatumomab. CAR T cells, of course, require fit patients. It’s only approved for age 25 and younger, and hopefully soon, we’ll have approval for older patients after the ZUMA-3 study data were presented. There are still many studies available even for older patients at this time. For blinatumomab, it usually works better in low disease burden. I try to avoid it in high disease burden unless we give cytoreduction. I tend to avoid it in extramedullary disease because we have seen decreased response in this setting. We tend to use blinatumomab as bridging therapy for transplant because durable remission in relapsed/refractory disease, durability tends to be short, and patients tend to relapse without transplant. For inotuzumab, one of the concerns is VOD [veno-occlusive disease]. We try not to start with it as first-line therapy before transplant. We save it more for CD19-negative disease, if a patient has high disease burden, not eligible for CAR T cells. From a logistics standpoint, it’s easier to give inotuzumab than blinatumomab than CAR T cells. If someone lives far away, someone who has comorbidities, it’s easier to give inotuzumab. For someone with CNS [central nervous system] disease, not leukemia related, or there is the concern of neurotoxicity with the blinatumomab, with the CD19 CAR, we tend to recommend inotuzumab. Any thoughts, James?

James K. McCloskey, MD: I agree with that almost entirely. The bottom line is, from an objective standpoint, in many ways, especially if we remember CAR T and talk about blinatumomab vs inotuzumab, if we’re going to be strict and by the book from an effectiveness standpoint, they’re very similar. They’re hard to tease apart, and you mentioned many of the criteria that we look at as well, disease burden and extramedullary disease, potentially being patients who are less eligible for blina [blinatumomab] salvage. But even those data are not so concrete, and here we’ve looked at those data, and it didn’t turn out to be statistically significant in our patient population. It’s hard because those extramedullary patients are not often making up a large cohort in any of these trials, but we tend to follow that as well, as patients who might be better candidates for ino [inotuzumab]. I think, to be very clear, across the board, we would use ino [inotuzumab] or blinatumomab as salvage rather than chemo [chemotherapy], and that’s important to mention. Then, for us, just like you said, our transplant division particularly does have concern for the potential for VOD. It was rare in clinical trials, especially with our approaches to transplants, and by potentially sparing patients chemotherapy after chemotherapy, before taking the transplant, that may even be less of an issue. To boil it down, a lot of it comes down to logistics like you mentioned. At the end of the day, some of it comes to how frequently the patient can come visit you, can they go a period without driving as they need to on blinatumomab? And some of it will just boil down to logistics in the end. Certainly, for MRD [minimal residual disease] clearance, we use blinatumomab on label. But I think a lot of it is still at a physician’s discretion because you can make lots of arguments either way until we have good head-to-head data. Then for CAR T, likewise, we often utilize that in patients who’ve already failed stem cell transplant. That’s particularly our go-to if we have a patient who is eligible, but not as much in our adult patients as bridging to first transplant because we, typically, would salvage it with something else.

Obviously, as you’ve mentioned, we’d all prefer to avoid transplant if possible. The more appealing and the obvious route, given what we’ve talked about with MRD clearance and the potential to cure patients early, like we’ve said multiple times, moving some of these other therapies into the earlier phases of chemotherapy, so chemotherapy, immunotherapy, sequential agents like we’re exploring in an Alliance [for Clinical Trials in Oncology] protocol looking at sequential blina and ino [blinatumomab and inotuzumab] post-induction. This may be the best strategy that is right before us to avoid transplant.

Transcript Edited for Clarity