Improving Outcomes With Transplant in Myelodysplastic Syndromes

Sergio A. Giralt, MD

Stem cell transplant is a promising treatment option for patients with myelodysplastic syndrome (MDS). Still, the decision to proceed with transplant should be made in consultation with a qualified health care provider who can assess individual factors and risks.

As research continues to advance, experts like Sergio A. Giralt, MD, believe that further improvements in transplant outcomes and expanded access to this treatment are to be expected.

“I think transplant has a bright future. Now, the big issue is access. Now that we have broken the age barrier and we have broken the HLA barrier, we need to be able to make sure that patients have better access to this treatment,” explained Giralt, professor of medicine at Weill Cornell Medical College, attending physician in the Adult Bone Marrow and Transplant Service at Memorial Sloan Kettering Cancer Center (MSKCC), deputy division head of the Division of Hematologic Malignancies, and Melvin Berlin Family Chair in Multiple Myeloma at MSKCC, in an interview with Targeted Oncology^TM during the 2024 Society of Hematologic Oncology (SOHO) Annual Meeting.

In the interview, Giralt discussed the evolving role of transplant in MDS.

Targeted Oncology: What are the current indications for considering stem cell transplant in patients with MDS?

Giralt: The current indications for transplant in patients with MDS are in anybody with intermediate- to high-risk disease, or patients in which primary therapy is failing and they are still transfusion dependent, in which it is felt that transplant will significantly improve their quality and quantity of life.

Blood cells: © Dr_Microbe - stock.adobe.com

How do factors like disease risk classification and patient characteristics influence this decision?

[It is] essential to be able to risk-stratify patients. We now know that some patients [with low-risk disease], because of molecular abnormalities, are actually patients [with high-risk disease] because [the disease] will have a higher tendency to transform to acute leukemia. Then, we also know that patients [with disease] scored as intermediate-2 may actually have a lower propensity of progressing. We also have to incorporate the patient-specific factors we just heard in this [SOHO] meeting from Mohamed L. Sorror, MD, MSc, [where he] gave us an excellent presentation of the CHARM [composite health risk assessment model] score, where you could look at patients over the age of 65 and try to prognosticate what the risk of mortality is after transplant.

Those types of scoring and risk stratification criteria are essential for both the patients and the physicians taking care of them to decide whether the risk-benefit ratio of transplant is positive or whether the patient is better served by a more conservative approach.

How do you determine which patient is a candidate for transplant?

I think transplant candidacy is something that should be determined in the transplant center by a transplant physician, and they have teams of people who help them make this decision. For older patients, we think geriatric assessment should be the standard of care, because our geriatricians can provide us [with] enormous insight into what the risk of transplant may be for an individual patient. In general, we take into consideration disease risk characteristics and patient risk characteristics, and it is a conversation. We now know everybody has a donor. With posttransplant cyclophosphamide, we can now do mismatched-unrelated donors and mismatched-related donors. In reality, [transplant] used to be a procedure that was only limited to people who had HLA-identical donors within the family, and the registry is now open to everyone.

What is the optimal time to perform a transplant in patients with MDS?

[Patients with high-risk] MDS should probably be transplanted as soon as the diagnosis is made. In patients with intermediate- or low-risk disease, it can be something where you can what the tempo of the disease is. But once again, when these patients develop high-risk molecular abnormalities, the data would show that the earlier they go to transplant, the better it is.

What are the most commonly used conditioning regimens for patients with MDS undergoing transplants?

Currently, most of the patients undergoing transplants are older patients, so many of them are getting reduced intensity conditioning with either fludarabine/melphalan or fludarabine/busulfan. We do know, based on a randomized trial, that myeloablative therapies are associated with better outcomes. So fludarabine/busulfan at full dose or fludarabine/melphalan have been probably the most common ones utilized.

There is important data with fludarabine/treosulfan that seem to be emerging. Treosulfan is now commercially available in the US. Many of us are exploring investigational strategies with myeloablative therapies, combining alkylators like thiotepa with fludarabine and busulfan, or fludarabine and melphalan in conjunction with what we call CD34 engineered grafts. Then, there are the Memorial Sloan Kettering CD34 selection trials that have recently been published.

What are the outcomes for patients with MDS who undergo transplants compared with those who do not?

We know that for patients with high-risk disease, the outcomes with transplants are about 50% long-term disease control. For patients with high-risk disease without transplant, there are very few and far between who are long-term survivors. For patients without p53 mutations, those outcomes are significantly worse, but still, significantly better than patients who do not undergo transplant. There are a lot of investigational strategies being incorporated for maintenance strategies posttransplant with either drugs or cells that hopefully will improve those outcomes.

Are there any challenges associated with finding suitable donors for this patient population?

We now think donor age is an important factor. There are a lot of studies on whether, if [a patient] has an older sibling vs a younger unrelated donor, whether [the transplant physician] should go with the younger unrelated donor. There is data that, for older patients, a younger unrelated donor will result in better outcomes than an older sibling.

Graft-vs-host disease (GVHD) remains a significant challenge for these patients. What are some of the latest strategies for preventing and managing GVHD, and what is the long-term impact?

Posttransplant cyclophosphamide has now become an established standard of care for graft-vs-host disease prevention for patients with a variety of hematologic malignancies, including MDS. It significantly reduces the risk of acute and chronic graft-vs-host disease. CD34 selection and CD34 selection with T-cell add-backs or the Orca studies have also shown to be significantly impactful in reducing the risk of chronic graft-vs-host disease, and we are now exploring the new drugs that are being used to treat chronic graft-vs-host disease, such as ruxolitinib [Jakafi] and belumosudil [Rezurock], and I imagine eventually axatilimab [Niktimvo] is trying to reduce the risk of chronic graft-vs-host disease in patients in the upfront setting, although we do not know the data. But we do know that posttransplant cyclophosphamide and CD34 selection are effective ways of reducing the risk of graft-vs-host disease.

How do you see the role of transplant evolving?

I think transplant has a bright future. Now, the big issue is access. Now that we have broken the age barrier and we have broken the HLA barrier, we need to be able to make sure that patients have better access to this treatment. There is still a lot of physician and patient bias. I always hear that if a patient is too old, they should not get transplanted. But as we heard [at SOHO 2024], we are transplanting patients up to the age of 80 without batting an eye, and one of the largest groups of patients being transplanted are those over the age of 65.

What are the key takeaways from this session?

The main takeaway is that there is a lot happening in the MDS field, and hopefully we will have better strategies to reduce toxicity and reduce the risk of relapse posttransplant.

REFERENCE:

Giralt S. Transplant in MDS. Presented at: 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023). September 9, 2023. Houston, TX.