Ronald L. Paquette, MD

Ronald L. Paquette, MD, clinical director of the Stem Cell and Bone Marrow Transplant Program at Cedars-Sinai Medical Center and Samuel Oschin Cancer Center, discusses how age impacts the use of bone marrow and stem cell transplants in patients with myelodysplastic syndrome (MDS).

According to Paquette, the median age of patients diagnosed with MDS is 70 to 71 years old, while patients are often not considered eligible for bone marrow and stem cell transplants beyond the age of 75. This means many patients are close to being ineligible for transplant.

He says that patients over 70 who receive transplants for MDS and other hematologic malignancies generally do not have worse survival than younger patients. While this could be due to these patients being selected for transplant eligibility based on better health and fitness, age is not the most significant factor for a successful transplant.

However, older patients tend to be given reduced-intensity myeloablative conditioning before transplant more often compared with younger patients. Paquette says non-myeloablative conditioning is sometimes used for less fit patients, but less intense myeloablative conditioning is preferred for patients with a moderate to high risk of relapse to improve their outcomes and reduce risk of relapse.

 The median age of the diagnosis of MDS is something 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 obviously 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 that we give to younger patients. We primarily use reduced-intensity conditioning for the patients who are older and the older [patients with] MDS in particular. 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, is reducing the risk of relapse for patients who have higher-risk disease.

Videos

Ronald L. Paquette, MD, discusses how age impacts the use of bone marrow and stem cell transplants in patients with myelodysplastic syndrome.

The Role of Age in Bone Marrow and Stem Cell Transplants for MDS

Ronald L. Paquette, MD, clinical director of the Stem Cell and Bone Marrow Transplant Program at Cedars-Sinai Medical Center and Samuel Oschin Cancer Center, discusses the choice of using bone marrow and stem cell transplants as treatment for patients with myelodysplastic syndrome (MDS).

Stem cell transplant was primarily considered as an option for patients with higher-risk MDS due to the associated toxicities, while lower-risk patients would receive a hypomethylating agent, which is the standard of care. However, the risks associated with transplant have been reduced due to use of prophylaxis for chronic graft-vs-host disease, according to Paquette.

Even for older patients, 1-year survival rates with transplant are at approximately 90%, and transplant has advantages compared with the standard of care since it offers a chance of curing MDS. Patients who do not receive transplant must receive long-term therapy until it no longer offers benefit.

There are increased morbidities and risk of mortality with transplant recipients that could be avoided with hypomethylating agent therapy or chemotherapy, which is a concern in older patients, according to Paquette. In addition, it takes longer for older patients to recover from the transplant procedure than younger patients. More research into the effects of transplant on older patients could improve the availability of curative therapy to these patients.

 There have been retrospective analyses in the past that suggested that transplant was suitable for patients only with higher-risk MDS. What's changed over time is that the risks associated with transplant have been progressively reduced. With 1-year survivors, even in older patients, [there were survival rates of] approximately 90%; that looks very attractive when you consider that the condition that you're treating is not curable. And since we only tend to 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.

What’s the downside? 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.

Ronald L. Paquette, MD, discusses the choice of using bone marrow and stem cell transplants as treatment for patients with myelodysplastic syndrome.

Benefits and Risks of Stem Cell Transplant for Older Patients With MDS

Ronald L. Paquette, MD, clinical director of the Stem Cell and Bone Marrow Transplant Program at Cedars-Sinai Medical Center and Samuel Oschin Cancer Center, discusses the selection of graft source for bone marrow and stem cell transplants in patients with myelodysplastic syndrome (MDS).

Paquette says that his treatment center prefers to perform peripheral blood stem cell transplant over bone marrow transplant because the risk of chronic graft-versus-host disease (GVHD) requiring treatment is only about 10%. Post-transplant cyclophosphamide prophylaxis is used in all transplants at Paquette’s center, whether they are unrelated donors, haplo-identical donors, or fully matched donors, greatly improving outcomes for patients by reducing the risk of chronic GVHD.

About 85% of transplants in Paquette’s experience are performed using half-matched donors. While stem cell transplants from fully matched donors such as siblings have better outcomes for patients with MDS, older patients may not have healthy siblings who are suitable donors, and more often patients’ children who are haploidentical are used as donor, still offering good outcomes due to GVHD prophylaxis.

 In terms of graft source, we preferentially use peripheral blood stem cells here because the risk of chronic GVHD that requires therapy at our center is somewhere around 10%. And so using bone marrow to try to reduce the risk of chronic GVHD seems not to be necessary in the age of post-transplant cyclophosphamide.

That leads to GVHD prophylaxis. Our center uses post-transplant cyclophosphamide for all of our transplants, regardless of if they're fully matched related donors, unrelated donors, or haploidentical donors. We use all of those graft sources, and because MDS patients, as I've alluded to, are generally older, we oftentimes will use [their] children as donors. In fact, I think about 85% of our transplants are performed using half-matched donors. Although 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 MDS is to use 1 of their children who is haploidentical.

Ronald L. Paquette, MD, discusses the selection of graft source for bone marrow and stem cell transplants in patients with myelodysplastic syndrome.

GVHD Prophylaxis Expands Graft Source Options for MDS

Ronald L. Paquette, MD, clinical director, Stem Cell and Bone Marrow Transplant Program at Cedars-Sinai Medical Center and Samuel Oschin Cancer Center, discusses the transplant related morbidity and mortality risks and how they differ between the age groups for patients with myelodysplastic syndrome (MDS).

According to Paquette, patients with MDS are generally older. His research has shown transplant related mortality for older individuals to be consistent with previous data when using a reduced intensity conditioning regimen.

Fludarabine with total body radiation at a dose of 800 cGy is the current preferred regimen used to treat these patients, but the safety and efficacy are continuously being examined to make sure this method is best.

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.

Ronald L. Paquette, MD, discusses how transplant related morbidity and mortality risks differ between age groups for patients with myelodysplastic syndrome.

Reduced Intensity Conditioning Leads to Less Transplant-Related Mortality for Older Patients With MDS

Ronald L. Paquette, MD, clinical director, Stem Cell and Bone Marrow Transplant Program at Cedars-Sinai Medical Center and Samuel Oschin Cancer Center, discusses

 characteristics of myelodysplastic syndrome and how they may impact a patient’s success in undergoing stem cell transplant.

According to Paquette, each patient has a different profile in terms of the histopathologic, cytologic, and molecular features. Moreover, clinical features like a patient’s fitness for therapy, age, and the number and type of comorbidities all impact a physician’s decision-making.

Choosing to transplant often comes down to identifying which patients with MDS have a high enough risk-level to be selected for transplant.

 Well, the first thing that is important is patient selection. So, I always tell my patients that no 2 patients are alike because of the histopathological features, the cytogenetic features, the molecular features are often dissimilar between two patients that might otherwise be comparable. And you have clinical features like how fit is the patient, how old is the patient, and what are their comorbidities?

 And so, patient selection for transplant is very important and identifying the patients for whom the risk of the disease is high enough that a curative option like transplant is appropriate and warranted. And then determining which of that population of patients would be able to be successful with a transplant in terms of tolerating the conditioning regimen and the risks of graft-versus-host disease prophylaxis.

 So that's it, the selection process is convoluted and oftentimes less than clear cut one but many variables have to be taken into account in order to determine who might be a suitable candidate for transplant.

Ronald L. Paquette, MD, discusses characteristics of myelodysplastic syndrome and how they may impact a patient’s success in undergoing stem cell transplant.



Ronald L. Paquette, MD | Authors

Articles

The Role of Age in Bone Marrow and Stem Cell Transplants for MDS

Benefits and Risks of Stem Cell Transplant for Older Patients With MDS

GVHD Prophylaxis Expands Graft Source Options for MDS

Reduced Intensity Conditioning Leads to Less Transplant-Related Mortality for Older Patients With MDS

Factors Impacting Success of Transplant in Patients With MDS