Novel Agents for Managing Patients With Relapsed ALL

At the 2022 Lymphoma, Leukemia & Myeloma Congress in New York, Michal Bar-Natan, MD, Tisch Cancer Institute, Icahn School of Medicine, Mount Sinai, provides an update on the newest agents for management of relapsed acute lymphoblastic leukemia (ALL).

Transcript:

My name is Michal Bar-Natan. I'm a hematologist/oncologist at Mount Sinai School of Medicine in here in New York. I am attending the Lymphoma, Leukemia, and Myeloma Congress, and we were just discussing updates on the newer agents for treatment of relapsed acute lymphocytic leukemia (ALL). Incorporating newer agents in the upfront setting led to a major improvement in patient outcomes. However, relapse remains a main problem. Historically, patients who relapsed with ALL had a very poor prognosis with less than 10% overall survival and a median survival of 6 months. The newer agents that we're going to discuss have improved this outcome very well.

The first agent that we will discuss is inotuzumab, which is an anti-CD22 antibody conjugated to calicheamicin. In the pivotal trial, 80% of the patients achieved remission, which was very remarkable, with many of them having [minimal residual disease)] MRD negativity. Unfortunately, this only translated to a median overall survival of 7.7 months, but that was better than the standard-of-care treatment.

The second agent that we discussed was blinatumomab, which is a bispecific T-cell engager targeting CD19 and CD3. In the pivotal trial with very heavily pretreated patients, 44% of the patients achieved remission, including 75% achieving MRD negativity. These are good results, but they're not enough, and in their own kind of clinical trial, we are trying to incorporate those antibodies together with chemotherapy trying to achieve better remission, deeper remission, and longer remission.

One of these trials was mini-CVD [cyclophosphamide, vincristine and dacarbazine chemotherapy] with inotuzumab with or without blinatumomab. The patients received chemotherapy in combination with the immunotherapy and were able to achieve an overall response rate of 80%, and 47% of them were able to proceed with transplant with a median overall survival of about 13 months. We have many other ongoing clinical trials trying to improve those results, including trying to augment activity of blinatumomab with adding checkpoint inhibitors or having newer antibody drug conjugates with less toxicity.

We also have other newcomers such as venetoclax, which is a BCL [B-cell lymphoma] inhibitor, which is a pro-apoptotic drug, and this has been incorporated with chemotherapy with good results, especially in a subset of T-cell ALL that we don't have many antibodies for.

The newer and very exciting agent that we have recently is the CAR T-cells. CAR T is an engineered T-cell that has a receptor that recognizes the antigen, which could be CD19, for example, where there is an inner part that is T-cell signaling and co-stimulatory molecules. In the last few years, we have had a few clinical trials. The major 2 were the ELIANA trial in younger adults and the ZUMA-3 trial in the older patients. These 2 trials were a little bit different, but both have shown high treatment efficacy. It is important to remember that only about 80% of the patients who were enrolled actually received the drugs because of the nature of the disease, many patients had disease progression, or complications from previous chemotherapy and could not get the actual product. There were also some manufacturing failures.

Overall, the response rate was between 70% to 80% of the infused patients. CAR T-cells are a toxic treatment, with many patients experiencing cytokine release syndrome or neurotoxicity, some of which were very high grade. These 2 trials and many other trials led to an approval of these 2 CAR-T cells, and we have it now available for our patients. In a recent publication from the pediatric population, the real-world data seemed to recapitulate the data from the clinical trials with about an 80% response rate with overall survival at 1 year approaching 75%. Still, patients, especially adults, do less well than the pediatric population. Their overall survival and event-free survival is lower than the pediatric population. Part of this is because 40% of the patient population relapses.

We have a great tool, and we need to make it better. There is ongoing clinical research in trying to improve our CAR-T and the delivery of CAR-T. This research is dealing with neuro-antigen or dual-antigen targeting, trying to produce a different construct with less side effects, having neuro-targets also for T-cell ALL such as CD5 and CD7, and trying to minimize or reduce at least the side effects that we see in a toxic treatment.

One of the things that is important is to try to figure out if CAR T-cells are a destination treatment or a bridging to an allogeneic stem cell transplant. About 40% of the patients on CAR T-cell therapies relapse, and we need to try to figure out who those patients are, so we will know who should proceed with allogeneic transplant, and who can be treated only with CAR T-cells and not need additional treatment after this. The future direction will be: Though all these newer agents improve outcomes in patients, we still have a long way to go. We need to find the right sequencing of those agents and the right combination of these agents. We need to figure out who are the people who need transplants.

Source:

Bar-Natan, M. Updates in the Newest Agents for Management of ALL. Presented at Lymphoma, Leukemia & Myeloma Congress; October 18-22, 2022. New York, NY.