Efforts Continue to Enhance Stem Cell Transplants

Carlos R. Bachier, MD

Even with recent significant advances in the treatment of hematologic malignancies, such as chimeric antigen receptor (CAR) T-cell therapy, investigators are still focused on improving one of the field’s longest-established therapies—stem cell transplant.

From discovering the peripheral blood as a source for stem cells to allowing a wider criterion for donors with the introduction of chemotherapy, there are growing opportunities for patients with hematologic malignancies to benefit from stem cell transplantation, according to Carlos R. Bachier, MD. Looking ahead, prior treatment with CAR T-cell therapy may even enhance outcomes in patients who are candidates for transplant, he adds.

OncLive: Please discuss the evolution of stem cell transplants.

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Bachier, program director of Sarah Cannon Center for Blood Cancer, Sarah Cannon Research Institute, discussed the evolution of stem cell transplantation as a treatment for patients with hematologic malignancies.Bachier: There has been an evolution in the way that we treat transplant patients. Forty or 50 years ago, we started just using bone marrow as the source of stem cells. Now, we can obtain stem cells from the peripheral blood. This has benefited patients in the autologous setting, where the recovery of blood counts is much faster. It is the same in the allogeneic setting, where we use donors.

The most important space has been supportive care. When we do transplants, particularly allogeneic ones, these patients can develop reactions such as graft-versus-host (GVHD) disease and infections. Over the last few decades, we have developed much better therapies that have made transplant easier, less toxic, and have improved survival. We have made significant advances in supportive care; however, stem cell transplant is still associated with toxicities. We still struggle, especially in relapse. We still have patients who will relapse after allogeneic transplant. We are actively investigating and developing strategies that will decrease the relapse rate after transplant.

Can you address some of the common toxicities that patients may experience following stem cell transplant?

There has been a significant number of new drug discoveries in different blood cancers. We now have targeted therapies for leukemias and lymphomas, which has had a secondary effect on patients who go on to have transplant. For example, we now have this drug midostaurin (Rydapt), which is a targeted therapy for FLT3 mutations. What we have learned is that if you give midostaurin to patients prior to transplant, their outcome after transplant will be much better. We have had the beneficial influence of these new drugs, which have made transplant much better. It is mostly related to toxicities in the allogeneic transplant setting. Patients receive a transplant through donors, and while these donors are immunologically similar to the recipient, there are still differences between them. When the cells are infused into the recipient, the immune cells may think, "What am I doing here? This is not my body.” They will then attack the recipient’s body. If that happens, patients will develop a complication called GVHD. This is one of the most serious complications that a patient can have after transplant. We have been looking at developing new therapies that can effectively prevent and treat GVHD, although it is still a problem that we face.

Are there any tools currently being used to assess what patients are at risk for relapse before they undergo transplant?

The other area that has affected the incidence and severity of GHVD are the different donor sources that we have now. It used to be that we couldn't use donors that were not a complete match. Now, we have learned that by giving chemotherapy after transplant, such as cyclophosphamide on day 3 and 4 after transplant, we can eliminate the alloreactive T cells from mismatch donors. This has allowed us to use a large pool of donors as a source of stem cells, such as children or mismatched siblings, because we know they will be a half-match. In fact, when we have done these transplants, we have seen that the incidence of acute and chronic GVHD is much less. This is a benefit that is another recent advance in the stem cell transplant field.We have characteristics of diseases that can help us determine whether patients are at high risk for relapse. For example, in acute myeloid leukemia (AML), we know that patients who are FLT3-positive will have a higher relapse rate. We are also now taking advantage of minimal residual disease (MRD). There have been discussions during many of the recent medical meetings on the use of MRD to determine therapies and to see how good patients are responding to new treatments. We have now been able to use MRD as a tool, both before and after transplant. We have learned that there are diseases, such as acute lymphoblastic leukemia (ALL), where it is important to get patients to a MRD-negative state for transplant to be more effective.

Cellular treatments, such as CAR T-cell therapies, are making their way through this space, with some deeming it a modern approach to stem cell transplant. Could you share your thoughts on that?

Similarly, we are starting to measure MRD in AML and ALL after transplant. We have learned that those patients who remain in a MRD-positive state after transplant are at a relatively high risk for relapse, and we are now investigating therapies for these patients to help prevent relapse. The area of immune effector cells, including CAR T cells and T-cell receptor immune cells, is an area that is very exciting. It is tied to what we do with stem cell transplant. CAR T-cell therapy and other immune therapies are going to continue to move forward in the treatment sequence for many diseases. But, can these CAR T cells be used as a bridge to transplant? Is it possible to get these patients into very deep remissions with CAR T cells or immune effector cells so that stem cell transplant can then be effective?

That concept is being developed and tested in ALL, where we know there is still an incidence of relapse after CAR T-cell therapy. But, [CAR T cells] can also put patients into very deep clinical remissions. This can make stem cell transplant even more effective. These CAR T cells and T-cell receptors are working and potentially curing patients on their own, but we should be investigating how we can integrate them into the stem cell transplant world. By combining them with transplant, we may be able to cure patients in higher numbers.