Evolving Transplant Paradigms in Hematologic Malignancies

Guenther Koehne, MD

Significant shifts have occurred in stem cell transplant technology over the past decade. While autologous transplants, especially for multiple myeloma, have remained relatively stable, there is noteworthy change that involves considering chimeric antigen receptor (CAR) T cells for patients with residual disease post-chemotherapy instead of autologous transplantation.

Allogeneic stem cell transplants have seen substantial evolution, with a focus on overcoming major hurdles like graft-vs-host disease (GVHD), infections, and relapse. Various strategies aim to reduce graft-vs-host disease. Exciting developments include laboratory manipulations targeting T cells responsible for GVHD, offering potential improvements in patient outcomes and quality-of-life.

In an interview with Targeted Oncology^TM, Guenther Koehne, MD, deputy director and chief of blood and marrow transplantation and immunotherapies, hematologic oncology, of the Miami Cancer Institute, Baptist Health South Florida, discussed how the field has changed and what practice changes are in the pipeline.

Targeted Oncology: How has the field autologous stem cell transplants changed in the past 5-10 years?

Koehne: Autologous transplants have not changed a lot, particularly for multiple myeloma. It is sustainable health care to continue to integrate autologous stem cell transplantation for myeloma [and] for lymphoma, which has also been the standard-of-care, [but that] has changed to some degree.

Now, if there is residual disease after the chemotherapy, patients will likely get CAR T cells at that point rather than undergo autologous transplantation. But once they relapsed, they may still consider [it] if they are chemotherapy-sensitive. So, the relapse occurs, patients get more chemotherapy, and if they get back into a complete remission, because they’re chemotherapy-sensitive, they may still be candidates for autologous stem cell transplant. At this point, we don't treat patients with CAR T cells that have no disease because [we]need to target something with a CAR T-cell. There are these 2 pathways.

How have allogeneic stem cell transplants evolved in the past 10 years?

Allogeneic stem cell transplants have changed over the last 10 years significantly. The focus here has been to reduce the 3 major hurdles to overcome for allogeneic transplantation. Number 1 is graft-vs-host disease, number 2 is infections, and number 3 is relapse after allogeneic stem cell transplantation.

I can say particularly, my center and Memorial Sloan Kettering Cancer Center and others that I worked at before focused on reducing graft-vs-host disease. That can be done by graft manipulation. We do it here at Miami Cancer Institute by selecting the stem cells to CD34-positive stem cells, therefore depleting the donor lymphocytes which are the ones that induce graft-vs-host disease. That is effective in reducing graft-vs-host disease. Alternatively, there is the treatment approach that came from Johns Hopkins Institute. In simple words, to reduce graft-vs-host disease, what has also been effective [are]T cells of the donor proliferate early after the stem cell product has been infused, and the proliferating cells are the ones that get eliminated by the post-transplant [cyclophosphamide]. Those are 2 different approaches.

There is the third one that I think is exciting. That is manipulation by eliminating in the laboratory the T cells that are responsible for inducing graft-vs-host disease, and those are called T-cell receptor alpha beta-positive T cells. We can do this in the laboratory and eliminate the alpha beta-positive T cells and leave everything else in the product. With that, there is also a significant reduction of graft-vs-host disease. Those are the real excitements that I am observing and that I am working on, personally, to improve the outcomes and particularly the quality-of-life of patients.

Patients with chronic graft-vs-host disease are sometimes so sick, that they are [asking] the question, “Is it worthwhile to continue living?” They are in remission, but they have complications from chronic graft-vs-host disease. I personally do not see a reason to not eliminate chronic graft-vs-host disease if there is a possibility to do that and improve their outcome.

How are infections and reinfections being managed in patients who have received allogeneic transplants?

With respect to infections, [they have] been, in the past, driven mostly by viral reactivations. We made some significant progress. One of the viruses is called cytomegalovirus, or for short, CMV. That has been that has improved significantly because now we have a drug called letermovir [Prevymis] which is given prophylactically to reduce the development of CMV reactivation. In the CD34-selected transplant patient cohort, we could reduce CMV reactivation from 63% to 10%. That is a big drop, and therefore, the transplant-related mortality [that] is secondary to viral reactivations could be reduced significantly, which I think is also important and exciting.

How can relapse be managed?

Thirdly, and that is where I am getting excited now, is how to manage relapse. Particularly, the major indication for allogeneic stem cell transplantation is acute myeloid leukemia. With a few exceptions, patients with acute myeloid leukemia all need a donor-derived [allogeneic] transplant, and there is still a very high chance of having relapse [of] disease. Even later afterthe transplant, 2 years, 3 years, when everybody thinks the risk of recurrence is over. Some patients with high-risk acute myeloid leukemia relapse earlier. That is also, I think, a big step forward that we now do not consider acute myeloid leukemia all the same. They are risk-stratified from the beginning. FLT3-positive AMLs, TP53-mutated AML, and some others we know are very high risk of relapse, so they will relapse despite allogeneic transplants.

What is happening there is now we can certainly come in with post-transplantation maintenance treatments, as we do in multiple myeloma. But that is more complicated because the markers that are expressed on the leukemia cell that can be targeted are also expressed on the normal healthy hematopoietic stem cell, and therefore, you would eliminate the healthiest stem cells at the same time as you are trying to knock off the leukemia cell population.

Now, I am proud to say I am a principal investigator of a clinical trial that uses CRISPR technology. That is gene editing of downregulation of the expression of CD33 on the normal hematopoietic stem cells prior to the transplant. If we now have a CD33-negative stem cell product from the donor and infuse this into the patient, then the patients have a normal reconstitution, normal blood production, normal recovery of this white cells [and] platelets, but the cells are all CD33-negative. Now, we can go in with treatments that target CD33 and specifically target the leukemia cell.

We are very active in improving outcomes and immunotherapies [and] are certainly in the lead to specifically targeting the tumor cells. The fact is, we are moving away from more chemotherapy because now we are able to specifically go after the residual or early recurrence of hematologic malignancies with immunotherapies.