Expert Discusses State of CAR T-Cell Therapy in ALL

Bajil J. Shah, MD

Bijal J. Shah, MD

In March 2017, tisagenlecleucel-T (CTL019) became the first chimeric antigen receptor (CAR) T-cell therapy to enter regulatory review when the FDA granted the treatment a priority review for use as a treatment for pediatric and young adult patients with relapsed and refractory B-cell acute lymphoblastic leukemia (ALL).

The FDA’s subsequently Oncologic Drugs Advisory Committee (ODAC) subsequently scheduled a public hearing for July 12, 2017, to discuss the biologics license application for tisagenlecleucel-T in ALL.

At the recent 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Bijal J. Shah, MD, discussed the success of CAR T-cell therapy in ALL.

“What CAR T-cell therapy is generating in terms of the likelihood of remissions, durability of remissions, and improvements of survival are beyond what we have seen with other agents that have been newly approved in the same space. This gives us a lot of reason for optimism moving forward,” explains Shah.

OncLive: Can you provide an overview of your presentation at this meeting?

In an interview with OncLive, Shah discussed the significant impact CAR T-cell therapy can have on the treatment landscape for patients with ALL.Shah: I wanted to summarize the work that’s been done across the clinical trials in adult ALL. We will hopefully see our first approval in pediatric ALL sometime this year since the data has been submitted to the FDA and is currently under review.

On the adult side, we’re following closely behind. I’ve been heavily involved in the Kite CAR T-cell trial. There are other trials, such as Juno, that have been working very closely in this space, as well. Novartis will likely also be entering this space in the near future.

Are there any reasons as to why this type of therapy has received greater attention in ALL than in other malignancies?

We’re going to have these cellular therapies for ALL, which is very exciting. What CAR T-cell therapy is generating in terms of the likelihood of remissions, durability of remissions, and improvements of survival are beyond what we have seen with other agents that have been newly approved in the same space. This gives us a lot of reason for optimism moving forward. It's because of the poor outcomes that we otherwise observe in patients with relapsed leukemia. We know for patients in first relapse from the MRC ECOG data that their long-term survival is in the range of 3% to 7% at 5 years.

We can improve that to as high as 20% with a transplant for those that are able to get a remission. We haven't improved much beyond that.

We are beginning to improve results further with other novel therapies in this space, but we are still plateauing at 20% long-term survival.

Do we know which patients are most likely to receive this type of therapy or are able to tolerate it better?

Our hope with CAR T-cell therapy is that we can do better. We already have a sense from the earlier studies that we're going to increase progression-free survival. However, we don’t yet know to what extent that will translate into both a short- and long-term survival benefit or the role of allogeneic transplant.On the adult side, we have not tried to limit participation. I can say this for both the Memorial Sloan Kettering Cancer Center (MSKCC) study that was done, as well as the ongoing Kite study.

We have standard inclusion and exclusion. For example, patients cannot come on with kidney failure, liver failure, or severe infections. These are standard inclusion and exclusion criteria that are seen across any trial. I don’t think that that is a good reflection of who benefits or who doesn’t, since it’s more for a standard trial.

A better way to think about it is magnitude of benefit. We know from the NCI data, the Fred Hutchinson data, and the MSKCC data, that those who are treated with CAR T-cell therapy who have minimal residual disease (MRD), have much better outcomes.

The data from MSKCC were very pronounced in those regards. The survival for those who underwent a transplant is slightly less but there is going to be more morbidity that comes from a transplant. I don't think anyone will say that a patient with relapsed leukemia should not receive a transplant. However, the magnitude of benefit that was seen in this low-disease burden population is interesting. Again, similar findings were observed at Fred Hutchinson and NCI, when they looked at patients who came in with MRD.

We know that the toxicity is a reflection of T cell expansion and the T cells are going to expand when they encounter that CD19 on the leukemic cells.

What’s interesting is that there was a concern that we wouldn’t see enough T cell expansion if there were too few leukemic cells. I don't know the answer but I can certainly say that comparing their data with MSKCC, it’s clear that even those who had very low disease burden faired very well. 100% survival is hard to overlook.

What are the important takeaways from your talk on CAR T-cell therapy?

The next broad category is child versus adult. One of the reasons I wanted to focus this presentation on adult ALL is that we do know adults with relapsed leukemia do worse. There is a debate that is ongoing regarding whether we should be using pediatric-inspired therapy for these patients and whether that will improve the outcomes. In my own opinion, this is not relevant since I think that adult ALL is biologically distinct. It is important to understand the biological difference, since the mutations that drive leukemia in adults versus children can also inform the success of therapies in the relapse setting.CAR T-cell therapy is the most promising therapy we have for relapsed leukemia. Although there are toxicities, such as cytokine release syndrome, neurotoxicities, and cerebral edema, it’s important to understand that it’s manageable for the majority of patients.

The risk of dying of these toxicities is exceptionally low, at less than 5%. The way I present CAR T cells to my patients now, is that the risk of death and toxicity is in line with an autologous transplant. There are unique toxicities, but they are manageable for the overwhelming majority.