Factors Influencing Transplant Eligibility in Patients With MDS

A variety of factors influence the success of a transplant in patients with myelodysplastic syndrome (MDS). No matter how similar 2 people may look, every patient has a unique profile in terms of the histopathologic, cytologic, and molecular features, according to Ronald L. Paquette, MD.

Clinical features including how fit a patient may be for therapy, age, and the number or type of comorbidities also play a role in a physician’s decision-making, Paquette, clinical director, Stem Cell and Bone Marrow Transplant Program at Cedars-Sinai Medical Center and Samuel Oschin Cancer Center explained to Targeted Oncology™. While age seems to be the least important of the factors, patients with MDS tend to be over the age of 70.

This means that the same intensity of therapy cannot be given to older patients as it is given to younger patients. Reduced intensity conditioning is primarily used for older patients who are older and with non-myeloablative conditioning occasionally used. Both practices aim to reduce the risk of relapse for patients who have higher risk disease.

Oftentimes, choosing the best transplant option comes down to identifying which patients with MDS have a high enough risk-level to be selected for transplant.

In an interview with Targeted Oncology, Paquette, discussed MDS and what factors may impact the success of a patient’s treatment when undergoing transplant.

Can you explain which patient-related factors can affect success of transplant in patients with myelodysplastic syndrome?

The first thing that is important is patient selection. I always tell my patients that no 2 patients are alike. The histopathological features, the cytogenetic features, the molecular features are often dissimilar between 2 patients that might otherwise be comparable, and you have clinical features like how fit is the patient, how old is the patient, and what their comorbidities are? Patient selection for transplant is very important and so is identifying the patients for whom the risk of the disease is high enough that a curative option like transplant is appropriate and warranted.

Then, determining which of that population of patients would be successful with a transplant in terms of tolerating the conditioning regimen and the risks of graft versus host disease prophylaxis [is important]. The selection process is convoluted and oftentimes less than a clear cut one, but many variables have to be taken into account in order to determine who might be a suitable candidate for transplant.

What disease-related factors impact the decision making on going to transplant for a patient with MDS?

We still use the time honored, revised, international prognostic scoring system that integrates peripheral blood count abnormalities, bone marrow blasts, and cytogenetic abnormalities. The widespread use of myeloid gene sequencing also contributes additional information that can be helpful when picking patients who are at higher risk. Although the complexity of the molecular mutations hasn't been fully validated, we still take those into account and make decisions about who might be a higher versus a lower risk patient.

Can you discuss some of the advantages and disadvantages of different conditioning regimens, intensities, and donor types in graft source?

The median age of the diagnosis of myelodysplastic syndrome is around 70 or 71 years of age. As a result, the majority of patients who are diagnosed will be of an age group which is just at the borderline of consideration for transplant. The cutoff at our center is arbitrarily set at 75, but I'm looking at the outcomes of patients over the age of 70, who have been transplanted for a variety of different hematologic malignancies. It is apparent that their survival is not dissimilar from that of patients who are younger than 70. That reflects a very careful selection of people who are older who are most fit, but by the same token, age as a discriminating factor seems to be less important than all the other things.

That said, we can't give the same intensity of therapy to older patients and we that we give to younger patients. We primarily use reduced intensity conditioning for the patients who are older. The use of non-myeloablative conditioning is on occasion used for those who are perhaps less fit, but we tend to gravitate towards a reduced intensity conditioning regimen for those patients who have a moderate to high risk of relapse because that's primarily what the intensity is attempting to address. It is reducing the risk of relapse for patients who have higher risk disease.

In terms of graft source, we preferentially use peripheral blood stem cells here because the risk of chronic graft versus host disease requires therapy. At our center it is somewhere around 10%. Using bone marrow to try to reduce the risk of chronic graft versus host disease seems not to be necessary in the age of post-transplant cyclophosphamide.

That leads to graft versus host disease, prophylaxis. Our center uses post-transplant cyclophosphamide for all of our transplants, regardless of if they're fully-matched related donors, unrelated donors or haplo-identical donors. We use all of those graft sources and because myelodysplastic syndrome patients, as I've alluded to, are generally older, we oftentimes will use children as donors. In fact, I think about 85% of our transplants are performed using half-matched donors. The outcomes are perhaps numerically a little bit lower than a fully matched related donor. Someone who is 70 is not going to have a suitable donor, who's a fully matched sibling, so it is a very practical solution to transplanting patients who are older with myelodysplastic syndrome is to use 1 of their children who is haplo-identical.

Can you talk about the transplant related morbidity and mortality risks? How do they maybe differ between the age groups?

Myelodysplastic syndrome patients in general are older. I'm gearing my discussion primarily to the older age group MDS, and of course MDS can happen in younger patients to where there are less concerns about conditioning related morbidity and mortality. What we found is that our transplant related mortality for older individuals is still less than 10% using a reduced intensity conditioning regimen. I think that's reassuring.

What we found however, is that because we're using post-transplant cyclophosphamide as graft versus host disease prophylaxis, the use of alkylating agents as part of the conditioning regimen has led to undue toxicities not just in older age group, but even in younger patients. In our hands, Northland and the conditioning regimen is associated with thrombotic microangiopathy In some patients at a rate that's higher than the use of total body irradiation. We also see pulmonary toxicity with the use of alkylating agents in the conditioning regimen.

Our go to regimen in older individuals is fludarabine with total body radiation at a dose of 800 cGy. That's been our preference recently. We are obviously monitoring the safety and efficacy of this regimen going forward. But we've been able to mitigate the risks of those two particular complications that we previously saw with melphalan containing regimens.

Considering regimen related toxicity, many say that transplant is the best alternative and that is the only Inc curative treatment. What are your thoughts on that?

There have been retrospective analyses in the past that suggested that transplant was suitable for patients only with higher risk myelodysplastic syndrome. What's changed over time is that the risks associated with transplant have been progressively reduced. With 1-year survivors, even in older patients that are approximately 90%, that looks very attractive when you consider that the condition that you're treating is not curable. Since we only tend to place transplant patients with high-risk disease, it looks like a very attractive option in comparison to receiving lifelong therapy until there's no longer a therapy available that offers any chance for continued benefit.

The downside is that patients who go through transplant may have morbidity or mortality, that they would be having with the transplant procedure that would be worse than if they're just getting standard of care therapy with a hypomethylating agent or hypomethylating agent combination. In elderly patients, I think that's an area where we still need to do more study.

Although survival is quite remarkable, it takes older people longer to recover from the toxicities that are associated with the transplant procedure. We've noted this and it's something that we actually have interest in studying prospectively, by further modulating the conditioning regimen or the graft versus host disease prophylaxis to try to reduce the morbidity of the transplant procedure for these older patients with myelodysplastic syndrome. We think there's significant opportunities in that area where we can still make the procedure even safer and with lower toxicities and still be potentially successful.

This is an area where we plan to devote a fair amount of attention and generate clinical trials that will look at the biology of transplantation in older individuals and look and see what happens when you infuse younger stem cells into an older bone marrow microenvironment. We want to look at the cognition of older patients who are undergoing transplant and see how the transplant process affects their cognition and their functional status. We are looking at very different aspects of both biology, physiology, and performance.

We hoped to learn more about what we're doing to the patients in a more quantitative fashion, so that we can address things that might potentially still be improved by modifications in the approach that we're using now. We're very happy that people are surviving longer and being “cured” of the incurable illness, but we think there's still room for improvement in the transplant process.