Assal Explores the Current Landscape and Future Prospects of BMSCT

Amer Assal, MD

Advancements in bone marrow and stem cell transplant (BMSCT) research have allowed for improvements in safety, applications, and the management of complications associated with these procedures. According to Amer Assal, MD, significant strides have been made in preventing graft-vs-host disease (GVHD), a major complication affecting the quality-of-life and survival of patients who have undergone transplant.

One of the notable successes in treating and preventing GVHD came with the adoption of post-transplant cyclophosphamide (PTCy) and the use of Janus kinase (JAK) inhibitors. However, while various developments have been practice-changing for patients who have undergone a BMSCT, challenges, such as the risk of post-transplant relapse and the need for better prevention and treatment strategies remain.

In an interview with Targeted Oncology^TM, Assal, associate professor of medicine at the Rutgers Cancer Institute of New Jersey, provided insights into the risks and complications associated with stem cell transplants, emphasizing the importance of risk stratification and preventive measures.

Targeted Oncology: What are the latest updates in bone marrow and stem cell transplant research?

Assal: There [have been] a lot of updates and advances recently, especially in recent times. They range from how to make [stem cell transplants] safer and different applications of stem cell transplant. I think the major advances in the field really go into how we treat and prevent graft-vs-host disease. So that's one of the main complications that we have in stem cell transplant, and it affects patients' quality-of-life and affects their survival after transplant, and then there's been increased adoption of use of what we call PTCy, so post-transplant cyclophosphamide. That's giving chemo after the stem cells are in which helps eliminate or modulate the T cells and their function after transplant. That's led to a good reduction in graft –vs-host disease.

Multipotent stem cells in the bone marrow: © Juan Gärtner - stock.adobe.com

Another advance in the field is the use of JAK inhibitors to treat graft-vs-host disease. At [the 2023 American Society of Hematology (ASH) Annual Meeting], there [have] been some abstracts on how they could potentially be used in prevention, even though the main study with that was not a positive study. After years of successful trials, JAK inhibitors have been the main drug that were [in] randomized studies [and] FDA-approved to treat steroid-refractory graft-vs-host disease.

Then we see other things that apply more for non0cancer applications of stem cell transplant. One for example, is gene editing trials. Now we have FDA-approved products where the genes are edited to treat sickle cell disease or other hemoglobin sympathies. Another advance that I am excited to see applied more is to use a non-chemotherapy conditioning regimen. That is where you use a drug, an antibody that targets it. That helps you eliminate the old stem cells and introduce the new stem cells. [At the ASH Annual Meeting], there's an abstract that covers this and I'm excited about that. There's different ways to do this, like different compounds, but it's good because there are a lot of applications for stem cell transplant outside of cancer, and it's nice to see a non-chemotherapy, non-toxic conditioning regimen.

What are the current challenges seen in BMSCT?

For GVHD treatment, we can prevent it better with PTCy. There is another advance, the use of a drug called abatacept [Orencia], and it would be nice to see how we can combine these 2. We need better prevention for graft-vs-host disease [as the] rates are not 0. We need better treatment. Not everybody has a response, especially [patients with] chronic GVHD. Then, making it less toxic with the conditioning regimens. One area of transplant that is a big struggle is post-transplant relapse. After a stem cell transplant, even though it is considered curative therapy, patients are still at risk of the disease coming back. That is the main cause of mortality after a stem cell transplant. There have been some advances in that field, but there is definitely room for more.

What are the risks and complications of stem cell transplants?

When I talk with patients, I tell them the first risk is that they may not be able to achieve a cure, which is unfortunate as it is the only way to obtain a cure. Usually patients are referred for transplant. But the complications include graft-vs-host disease, so that is like an [adverse] effect of therapy. That is when the donor immune system attacks the patient. There is the immune suppression complication, so the immune system is completely or partially eliminated, and it takes a while to reconstitute. We have a high risk of infections, both from inside the body, outside the body, viral, bacterial, any kind of infection really, and then we have the acute toxicity to the organs. The chemotherapy itself is toxic to the gut [and] to the kidneys, to the liver, to the different organs of the body, and then you have other, immunologic endothelial type [adverse] effects to transplant. For example, we have liver toxicity, idiopathic pneumonia syndrome, and other rare complications of stem cell transplant. That is why it's usually reserved for higher-risk patients, patients who are at a very high risk of relapse. The more we improve the complications of transplant, we may offer it to other patients, but what will happen is that we will offer it to older and sicker patients who have more comorbidities and who we would not transplant because of these risks.

How should one manage these toxicities?

We have risk stratification. We won't transplant a patient aged 80 [as it is] really a hard cutoff for transplant for most people. At the upper ages, 76,77,78, people have transplanted them and [we may] see them in trials, but we try to prevent the complication by risk ratification, so high incidence of comorbidities. There's the HCT-CI, so the amount of hematopoietic stem cell transplant comorbidity index. Patients with baseline dysfunction in kidneys, liver, lungs, and high age, we avoid transplanting them or use a lower toxicity conditioning regimen. That's 1 way. The other is prevention. We give prophylactic antibiotics. We do prophylaxis for graft-vs-host disease. PTCy is an example of prophylaxis. After transplant, we have intensive monitoring. We see the patients twice a week for some time after transplant and we monitor the organ function. Also, we are looking for infections and graft-vs-host disease.

What have been some of the most significant and recent findings/research in this space?

We had a presentation on the use of axatilimab,which is a [colony stimulating factor-1 receptor(CSF-1R)]- directed monoclonal antibody. That has shown advances in the treatment of refractory chronic graft-vs-host disease. Again, the nickname [for GVHD] was that it was the graveyard of drugs, because many drugs were studied in this field, and nothing was successful. Now, we have 2 FDA-approved drugs. In the chronic space, we have ruxolitinib [Jakafi], belumosudil [Rezurock], and then ibrutinib [Imbruvica] is also approved, though it has not been popular in use, even though it is FDA-approved. The fourth potential drug now is axatilimab. I am excited about this because it is a whole different novel mechanism and reflects a good understanding of the immune system and the role of different immune cell subsets and graft-vs-host disease. In this case, it's macrophages, and the company is planning to study it. The presentation was in refractory chronic respiratory disease, and they're trying to move it more frontline, but it's exciting.

Other studies [are a] work in progress. We use cyclophosphamide, initially developed for haploidentical transplants, where there is a large [human leukocyte antigen (HLA)] disparity. It needs extensive immune suppression. Because it was so successful there, it has been studied in matched or mismatched, unrelated, where there is not such a large HLA disparity or no disparity in the case of match unrelated donors. The question now is, do we need that much cyclophosphamide? Can we decrease the dose because it has its own [adverse] effects and toxicities? There are some [studies] where they have attempted to do that and show good results. Then, it will be interesting to see if people have thought about this. I have done this, combining it with drugs, and I think seeing more of those results is encouraging.

The microbiome story is another that was center stage in previous meetings, but we keep seeing more data from there. We have not learned how to target that therapeutically, but we do see more advances. There was something interesting where T cells directed at the bacteria contribute to graft-vs-host disease. Basically, the bacteria are not seen as a neutral resident of the gut. They are very active in the immune system, which we knew from the non-transplant setting, but now we are seeing that they are active in a transplant setting as well. Then there were some presentations on more intelligent selection of T-cell specificities to different antigens that could cause graft-vs-host disease. That story is in the early stages of being read, but that is super interesting.

What are the implications of these new findings on clinical practice?

We would like to decrease the dose of PTCy cyclophosphamide. That could be potential [of what] we start implementing in our patient care, using less cyclophosphamide, a lower dose, especially in the matched setting. Then perhaps adding abatacept with it. That could be an immediate or quick application in the near future. In terms of graft-vs-host disease, we are comfortable and we use JAK inhibitors all the time. Now that we are comfortable using them, it would be nice to see us now have access to axatilimab to treat chronic graft-vs-host disease because chronic is, as the name implies, chronic. It takes time for the disease to respond. Then people live with it for a long time, and it affects quality-of-life. It would be nice for us to have another agent to treat this condition.

What are the next steps for research in this space?

It would be nice to see if we can target the microbiome to come up with therapies based on our understanding of the microbiome. There is going to be a lot more work to be done in acute or chronic graft-vs-host disease, newer targets, [and] further understanding of how we can use these agents. For example, there was a negative study for itacitinib in the initial treatment of graft-vs-host disease, the GRAVITAS trial [NCT03139604]. We are seeing more smaller studies where prophylaxis actually does have some advantage. There is a lot more work to be done in detailing the use of these drugs and transplant.

[In the relapse setting], it will be nice for us to have more studies there. I think it is the leading cause of mortality after transplant. We often present it as a cure, and we want to decrease the incidence of relapse. More study in that area is warranted, whether we use it in drugs, post-transplant, or better understanding of the immune reconstitution and the graft-vs-leukemia effect. There is a graft-vs-host disease where the immune system is attacking the donor, but that same immune system could attack leukemia. Separating the 2 or the prioritizing 1 vs the other is the holy grail of transplant. We would love to see more work there.

What are you most looking forward to seeing in this space this year?

I am excited about transplants and more applications. We may see the use of transplant or [chimeric antigen receptor] T and like non-malignant conditions using how it suppresses the immune system. For example, like rheumatologic indications, there is not too much work being done in that area, but people have been interested in this. As we make transplant a lot less toxic, we can start to think more about using it in non-malignant and non-hematologic conditions, even though that may take a long time to convince people to do a transplant. It is something that we could see in the future.