Approach to Managing Relapsed Acute Lymphoblastic Leukemia

Richard M. Stone, MD: Let’s discuss relapsed ALL, starting with relapsed Philadelphia-negative ALL. We never like to see that, but we have 3 agents approved in relapsed ALL— blinatumomab, inotuzumab, and at least for younger adults, CAR [chimeric antigen receptor] T-cell therapy.

Bijal Shah, MD: This is something that not everyone is going to agree with me with. Independent of tumor burden, we tend to approach our patients with BLINA [blinatumomab] in the first relapse setting. The main reason for that has been the toxicity that we’ve seen with inotuzumab. Part of that may be a reflection of practice patterns, we’re incorporating INO [inotuzumab] into the later lines of therapy where it’s less likely to be effective and the marrow is more beat up. Because of the low toxicity profile, we tend to favor BLINA for first relapse. If they’re young, CAR T after that. If they’re older, then we’ll end up going down a CVD[cyclophosphamide, vincristine, dacarbazine]/INO or INO-based approach.

Ryan D. Cassaday, MD: I’m less disinclined to consider inotuzumab in first relapse and it speaks in part to the issue of disease burden. Those first relapses are the ones that may come out of the blue with somebody who finished maintenance therapy, only coming in every 2 or 3 months, and all of a sudden their platelets are 6 or their white count is 30. That’s a situation where blinatumomab historically, can work but perhaps not as well and there’s more toxicity. Inotuzumab, on the other hand, works well except on the high ends of disease burden, and is reliable. If you can use it selectively and not expose patients to too many cycles, you can still safely administer that medicine with the goal of getting a patient to a stem cell transplant.

Richard M. Stone, MD: Let’s discuss the trials that might assess if CAR T-cells would be a useful therapy in first relapse.

Jae Park, MD: There was one plan by Novartis, the famous OBERON trial, but it has not taken off yet. It’s a relevant question now as we’re discussing either INO or BLINA, which 1 to use in the second-line setting or the first relapse setting, and among the CAR T-cell therapy, too. We don’t have such an answer. Hopefully, we can get such trials to get going soon. I’m less disinclined to choose inotuzumab being more inclined to use it in the higher burden patients, typically. Even though BLINA can work, the efficacy rate is lower. I’ve been using the mini-CVD/INO combination that allows a slightly lesser dose of inotuzumab, and especially for those who have later relapse, but not on hyper-CVAD [cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone]. In the combination of the chemotherapy and less dose of inotuzumab, we don’t know that for sure, potentially reduce the chance of VOD [veno-occlusive disease] after transplant.

Richard M. Stone, MD: Just because INO beat chemotherapy and BLINA beat chemotherapy doesn’t mean that they’re the best therapy to use. This is why adding chemotherapy to 1 of those regimens, such as mini-hyper-CVD and INO seems to be, there are good responses in the relapsed setting. Let’s address the concerns of using an INO-based regimen, either alone or with mini hyper-CVD for relapse when you’re going to take somebody to transplant.

Ryan D. Cassaday, MD: The biggest concern is a sinusoidal obstructive syndrome or veno-occlusive disease, though there are other forms of hepatotoxicity that can happen with this drug. When it’s been looked at retrospectively, the things that seem to bear out is the highest risks for developing that potentially very serious complication are if you’ve had a prior transplant, if you’re older age, if you’ve had multiple prior lines of therapy, or underlying liver disease. Many of these you can’t do anything about. You can’t undo a patient’s alcoholic cirrhosis or you can’t undo the transplant that they got in first remission.

The things that you can do prospectively to reduce that risk that we know of is less exposure to the drug, avoiding particularly dual alkylator conditioning regimens for the subsequent transplant if the patient goes on to transplant. The data has yet to be borne out for inotuzumab, its related drug gemtuzumab ozogamicin. There’s more experience of providing more of a duration of time from the last treatment to the start of conditioning. Those are the things we typically do to try to mitigate that risk. Fortunately, I would say our experience has fared fairly well in terms of having a low risk of that complication. Ursodiol is another thing that people talk about using, though none of the studies have ever prospectively looked at whether or not that can help.

Bijal Shah, MD: We use ursodiol. We don’t have any qualms about that. We use the mini-CVD combo because it allows for a lower dose of the inotuzumab. We start at the 0.3/0.3 rather than the 0.6/0.3 approach that was taken on the published study, with the goal of trying to reduce that total exposure. In regards to defibrotide during the transplant, it’s not something we commonly do.

Richard M. Stone, MD: Let’s move on to the difference between first relapse before the transplant or first transplant if someone had a transplant during CR1 [complete remission 1].

Jae Park, MD: When working withpatients with a prior transplant, I’ll be less inclined to use inotuzumab or blinatumomab. I would favor CAR T-cells in that patient. I think INO and BLINA at best is a bridge to transplant. For the patient with a first transplant, it may not always be possible to get a second transplant and the efficacy may not always be good, especially if the CR duration from the first transplant was relatively short. I’m looking for more definitive therapy, not that CAR T-cell therapy has been proven to be a definitive therapy. We have a subset of patients with an INO and BLINA, but the more of those patients, a possibility at least with an autologous anti-CD19 CAR T-cell therapy. I’d be more inclined to use CAR T in the post-relapse transplant patients in the setting, whether there’s a bridge to a second transplant, and we’re hoping not, but hopefully as more of definitive therapy for them.

Transcript Edited for Clarity