Transplantation for Myelodysplastic Syndromes (MDS): Who, When and How

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Transplantation for Myelodysplastic Syndromes: Who, When, and How?

Wednesday, October 27, 2021

Presenter: Dr. Nandita Khera, MD, MPH, Associate Professor of Medicine, Mayo Clinc

Presentation is 29 minutes long with 28 minutes of Q & A.

Summary: Myelodysplastic syndrome (MDS) is a blood disorder that can develop into leukemia. There are several treatments for MDS, including stem cell transplantation. This presentation reviews key features of MDS, treatment options and when a transplant is an appropriate remedy.

Highlights:

• MDS patients are categorized into risk groups based on their blood counts, number of abnormal cells, genetic mutations, and chromosomal changes. Patients with low-risk disease rarely develop full blown leukemia, whereas those with high-risk disease will likely develop leukemia.
• Allogeneic transplant (a transplant using donor stem cells) is the only potential cure for MDS.
• All medically eligible, high risk, MDS patients, including older adults, should be evaluated for transplant.

Key Points:

(03:03) MDS involves low blood counts, marrow dysplasia, and genetic mutations.

(03:41) MDS affects about 60,000 people in the U. S, typically older adults.

(05:49) Treatment options depend on the how likely it is that the disease will progress to leukemia and include supportive care, gentle chemotherapy or transplant. 

(09:57) A recent observational study showed comparable survival rates for younger and older patients who received transplants.

(11:09) A recent clinical trial found patients with advanced MDS who received transplants did much better than those who did not.

(14:41) Transplants using half-matched or unrelated donors have comparable outcomes to those with matched donors.

(17:29) Considering all options (including half-matched relatives), most candidates for transplant will have a suitable donor. 

(17:54) Transplant requires conditioning with chemotherapy and radiation to prepare the body for new stem cells.

(21:48) Transplants are more successful if the patient is in remission at transplant; other factors also play a role. 

Transcript of Presentation:

(00:00) [Susan Stewart]    Hello, and welcome to the webinar Transplantation for Myelodysplastic Syndrome: Who, When and How. My name is Sue Stewart, and I will be your host for today's session.

(00:13) Introduction of Speaker. It's my pleasure to introduce to you today's speaker Dr. Nandita Khera. Dr. Khera is an Associate Professor of Medicine in the Mayo Clinic College of Medicine and a consultant in the division of hematology oncology at Mayo Clinic, Arizona since 2012. Dr. Khera treats patients with hematological malignancies, especially those needing a blood stem cell or a bone marrow transplant for their disease. Her research focuses on improving the delivery of care for patients with cancer to help them better prepare for the psychosocial and financial consequences of treatment.

She has published several papers in the area of outcomes, late effects and quality of care after transplant and has held leadership positions in the various organizations and societies in the field of hematology and blood and marrow transplantation.

Dr. Khera was the chair of an advisory group on Financial Barriers to Transplant organized by the National Marrow Donor Program in 2018. And she works closely with other stakeholders to help address issues relevant to access to and quality of care in hematopoietic cell transplantations. She also co-chairs with Dr. Linda Burns Blood and Marrow Transplant Clinical Trials Network Evidence into Practice Taskforce, which is currently working out initiatives to help improve dissemination and implementation of data generated by the clinical trials in this field. Please join me in welcoming Dr. Khera.

(01:58) [Dr. Nandita Khera]          Overview of Talk. Thank you, Sue for the nice introduction and for the opportunity to present here today on this topic. I am going to be presenting on behalf of the CIBMTR and as a co-chair for the Taskforce on Evidence into Practice for BMT CTN, which is the organization that conducts clinical trials in the area of blood and marrow transplant.

I have no disclosures. So for the next 25 to 30 minutes, I will be talking to you about myelodysplastic syndromes and specifically focusing on the role of allogeneic hematopoietic cell transplantation for MDS or the myelodysplastic syndrome. We'll talk a little bit about the transplant process.

I will describe to you the results of the observational study and a recent clinical trial in the space. And finally, I've listed some potential challenges that patients and providers encounter in order to get to transplant. So let's start with what is MDS and how common is it?

(03:03) MDS involves low blood counts, abnormal looking blood cells, and genetic mutations. MDS is a group of bone marrow stem cell cancers, which is defined by low blood counts, marrow dysplasia, which means abnormal looking cells when the pathologist looks at them under the microscope, and chromosome changes or genetic mutations. It is characterized by need for transfusions and risk for infections due to low white blood cell count.

(03:26) MDS can be mild or severe and may transform into leukemia. It's a spectrum of diseases which can range from very low severity, indolent kind of disease to very high severity. And this severity is based on the risk for transformation to full-blown leukemia or blood cancer.

(03:41) MDS affects more than 60,000 people in the U. S. who are typically in their 70s. MDS is uncommon before the age of 50 years. And usually we see it in people who are in their 70s. The number of patients with MDS living in USA currently is estimated to be between 60,000 and 170,000, which is still much rarer than some other cancers like breast cancer or lung cancer.

(04:02) Three factors are used to calculate the risk category of MDS. So then we talk about what are the risks categories as I mentioned for MDS. The risk categories that we calculate is based on three different factors.

The first is which blood counts are low and how low. So it could be just the hemoglobin that's low. It could be white blood cells, it could be platelets, or it could be a combination of the three. It also depends on the number of blasts, which are the abnormal, ugly looking cells seen in the bone marrow biopsy by the pathologist. And it includes the type of chromosome changes, which can range from good risk to poor risk, again, based on their aggressiveness.

(04:44) Low risk groups do well and rarely develop full blown leukemia. As seen on the right-hand side of the slide, the curve shows very well that the disease, the risk groups can be stratified based on how the patients behave. So the ones in very low and low risk groups tend to do very well and have a very low chance of developing full blown acute leukemia, as opposed to the high-risk people who tend to behave worse because of their aggressive disease.

Now, the thing to remember is that as our field advances, there's a lot more data coming about newer genetic mutations and how they may influence the disease trajectory. And so that needs to be included in some of these risks stratification systems for a better idea of how people will do.

(05:28) If people don’t respond to treatment their risk increases and transplant may be considered. The third thing that can also impact risk is the response to treatment. So somebody may start off as a low risk or an intermediate risk, but once they stop responding to treatment, then automatically we would move them to a higher risk category, which is where we would have to consider transplant as a potential treatment.

(05:49) Treatment options include supportive care, gentle chemotherapy, and transplant.  So then how do we treat MDS? There's three main strategies. The first is supportive care, which includes transfusions, growth factors and minimal medical interventions basically to help manage symptoms. And this is usually done for patients with low risk disease or even highest disease if the patient is very frail.

The second strategy is disease modifying treatments, or the so-called gentle chemotherapy. These are treatments that may change the natural history of the MDS, but don't cure it. So what they do is they basically delay the progression. So the patient will do well for 12 to 18 months or sometimes longer, but eventually we know that the MDS will start coming back. The only potentially curative therapy that we have so far is hematopoietic cell transplantation, or also known as bone marrow or stem cell transplant.

(06:45) Four main factors inform decisions about the best treatment for a patient with MDS. How do they decide which treatment approach is best for our patients? So there's four main factors that go into that decision making. The first is patient age and fitness. The second is the risk category as I mentioned, ranging from very low to very high. The third is risk of treatment. And the fourth is what are the patient's goals and wishes.

This is where some of the subjectivity creeps in, and patients can be treated differently based on whether they are being seen at a community center versus an academic center. And what is the availability of treatment options.

(07:22) Allogeneic transplant (transplant using donor stem cells) is the only potential cure for MDS. So let's talk about the allogeneic transplantation for myelodysplastic syndrome, which I mentioned is the only potentially curative therapy so far known. So what is allogeneic HCT? It's a procedure in which the bone marrow that is diseased or damaged is replaced with stem cells from another donor. The rationale of doing a transplant is that the new or transplanted immune system will attack the cancer cells that have survived the chemotherapy or radiation. And this is called graft-versus-tumor effect. In fact, this is the immunologic effect that can bring us the potential of cure with transplant.

(07:58) What are stem cells?  So then the next question is what are stem cells? Stem cells are sort of the grandfather, grandmother cells that are responsible for developing into the mature white blood cells, red blood cells, or platelets. These are the cells that we see in the blood. The stem cells are found in the bone marrow, especially in our older patients only in certain sites, such as pelvis, femur and sternum. In children, they can actually be found more widespread. They're also seen in the cord blood and in small numbers in blood. Although we have medicines now that can actually bring the stem cells from the bone marrow into blood, which we use for various purposes.

(08:43) A stem cell transplant is medically complicated and poses several risks. So, transplant is a medically complicated, very intense procedure. And so there are risks and benefits of it. And for each patient that we see, we have to be able to make a decision based on the fact that the benefits have to be higher than the risks occurring.

(09:03) So what are the risks of transplant? There's a high risk of complications, including infections, graft-versus-disease, which I will talk a little bit later about, and organ toxicity. It can basically damage any organ in the body, kidneys, liver lungs, so forth. Patients who are frail or have poor functional status may be at higher risk for some of these toxicities. Some of the other challenges or risks would be lack of a good donor and insurance coverage because it's, as I mentioned, a very expensive and highly complicated procedure.

(09:37) The benefits of transplant include its potential for cure, especially in high risk patients. The benefits of transplant are it's the potential cure, especially for our patients with high risk MDS and those with poor risk genetic mutations, such as a p53 mutation. And it is also considered to be beneficial for patients who have stopped responding to the non-transplant treatments.

(09:57) A recent observational study showed comparable survival rates for younger and older patients. So in 2010, Center for Medicare and Medicaid Services felt that they did not have enough data to be able to say that transplant was an effective treatment for our older patients with MDS. So what they came up with is this coverage with evidence development program, by which they said, if a patient went on an observational study that was able to then record their outcomes, then they would cover that transplant in terms of the benefits.

So this study, this observational study was conducted by a bone marrow transplant registry and was published recently. What they did was they compared the outcomes of patients 55 to 64 years, versus those more than 65 years with MDS. They enrolled patients from December, 2010 to May, 2014. And basically as the curves on the right show, the survival was very comparable between younger and older patients.

However, as clinicians, we still would like to see some clinical trial data rather than go with an observational study.

(11:09) A recent clinical trial found that high-risk MDS patients who received a transplant did much better than those who did not. So for that, the BMT CTN, which is I mentioned the organization that helps conduct the trials, came up with this trial which is a biologic assignment trial of reduced intensity hematopoietic cell transplantation based on donor availability in patients 50 to 75 years of age with advanced myelodysplastic syndrome. So when I say biologic assignment study, what I mean is unlike most of the trials that you may have heard are randomized controlled trials, where you have a 50/50 chance of ending on the treatment arm versus the non-treatment arm. In this case, it was decided by whether there was availability of a matched related or unrelated donor within 90 days of the patient enrolling on the study.

 So if they had a donor, then they went to transplant using a lower intensity regimen within six months of enrollment. If they didn't have a donor, they went on this gentle chemotherapy or hypomethylating agent or best supportive care, whatever the physician decided to do.

The inclusion criteria for the study included high risk MDS. 50 to 75 years of age, any prior therapy was allowed, but no prior search had to be done. And the patient had to be eligible for lower intensity allogenic transplant from a matched related or unrelated donor.

The primary endpoint of the study was overall survival, which is how many people lived for three years. The secondary endpoints were leukemia free survival, which is how many people lived for three years without leukemia, quality of life and cost-effectiveness.

(12:48) So these graphs here show the clinical outcomes of overall survival and leukemia free survival. There were about 260 patients in the donor arm and 124 patients in the no donor arm. As you can see on the graph on the left, the blue line is the one with the donor arm where patients were able to go to transplant and they did much better than those on the red line, which are the ones that did not go to transplant. And the difference between overall survival was about 20%, with 48% people on the donor arm still living at three years versus only about 27% in the no donor arm. Patients without any leukemia at three years were still better in the donor arm with about 36% patients doing good versus 20% only in the no donor arm.

(13:42) This study established that for higher risk patients with suitable donors, transplant is an integral part of MDS management. We also looked at quality of life using various instruments at multiple time points before and after transplant and chemotherapy, and basically showed that quality of life stayed comparable in both the groups at many time points after transplant. So the study concluded that among patients with higher risk MDS age 50 to 75, having a suitable matched related or unrelated donor leads to improve outcomes, and that transplant should be considered as an integral part of MDS management plan for these patients. And for that, early referral to a transplant center should be recommended.

(14:24) Even half matched or unrelated donor transplant recipients with MDS had comparable outcomes to those with matched donors. Now, a question that comes up is what about patients who don't have a good donor option in the sense, some of our patients with MDS who are older may have siblings that are even older than them, or may not even have siblings. So does the study result not apply to them?

And I would say as a clinical transplanter that that's not the case, because now we know that patients who are able to still get transplant using a half match donor or another type of donor option, such as an unrelated donor, they do quite comparable to those receiving a matched related or unrelated donor.

(15:06) Transplant begins with a referral, then a donor search, and then a comprehensive clinical evaluation of the patient. So what would it mean for you as a patient with MDS? And that could be basically any disease, not just MDS. So once we know that the transplant is a good option for a patient like you, then the first thing that needs to happen is a referral needs to go from your treating doctor to a transplant center. There you will meet with the transplant doctor and the team. The team then works with the treating doctor on a care plan while searching for a donor.

Once the best possible donor option is decided, the dates for transplant can then be decided as well. And once the date is decided, then we work backwards from that date for two to three weeks before that date, which is when they would conduct a very thorough, very comprehensive clinical evaluation, since as I mentioned that transplant is a very complicated, medically complicated procedure. So we want to make sure that your body will be able to tolerate that.

(16:07) Be the Match is an organization that expedites the donor search process. I do want to put in a plug for this program called HLA Today by National Marrow Donor Program, Be The Match, because the goal of this program is to help expedite this whole donor search option. And what they are trying to do is they are actually working with some of our community HemOnc doctors who can then order free swab kits from an NMDP/Be The Match and have that be available for the newly diagnosed patients that then they can swab and send for HLA typing. They can even request family member typing if it is desired and they will receive the report in seven to 10 days. And all this can happen while they are still working on referring the patient to the transplant center for a transplant consult.

So then once the typing is done, the next question is who is that donor going to be? As I mentioned, a match sibling is the most preferred donor with which we have the best results. However, in today's day and age, lack of a donor is no longer considered a major limitation to transplant.

This graph on the right shows the data from our bone marrow transplant registry. And as you see, the orange line is that of an unrelated donor, which is looking at donors in the registry. The other fastest growing group is this green line, which is the half match donors.

(17:29) Considering all options (including half matched relatives), most candidates for transplant will have a suitable donor.  Now, who is a half match? Kids, parents, and 50% of the time siblings will be a half match. And this is definitely becoming a very important and commonly used donor option for a lot of our patients. So what I mean to say is most everyone who needs a transplant will have a suitable donor, even if it's not a matched sibling or a 10 out of 10 matched unrelated donor.

(17:54) Transplant requires conditioning with chemotherapy, with or without radiation, to prepare the body for new stem cells. So then what happens after the donor is decided and the transplant evaluation reveals that everything is good to go? Then the patient is admitted to the hospital where they undergo a conditioning regimen. And conditioning is usually a combination of chemotherapy plus minus radiation therapy. The goal for this is to try and immunosuppress you so that the donor cells can come in and populate in your marrow. And that is then followed by the stem cell infusion from the donor. And then the new cells start to grow.

(18:29) Once the cells engraft, the patient can be discharged from the hospital but will still be closely monitored. Usually it takes between 10 to 18 days for these new cells to start appearing in the blood. And that's when we say the patient has engrafted and we would discharge them from the hospital, but we would still follow them very closely in outpatient clinics for at least the first 100 days, because that's considered to be time for Cetus complications.

 (18:51): Graft-versus-host disease is a potential complication after transplant. And what are these complications? Acute and chronic graft-versus-disease are basically complications that happens because the donor cells decide to attack the body of our patient. They can attack the skin, the GI tract, the liver in the short-term and in the long-term, which is the chronic GVHD, they can attack any other organs. The risk for that is about 40 to 60%. And again, it's dependent on the type of donor that we choose.

(19:21) Patients will be monitored for graft-vs.-host disease (GVHD), infections, and late effects up to five years after transplant. Another complication has been no occlusive disease, which is severe liver damage that can be life-threatening. However, with the improvement and the advances that have been made the risk for this is now as low as three to 4%. We have medicines that can help protect liver, which the patient can be put on even before transplant.

The risk for infections, bacterial viral and fungal infections can range from 10 to 60%. And again, it's dependent on a lot of factors in terms of the intensity of the regimen that is given, in terms of how much immunosuppression the patient is and so forth.

And then there are late effects such as cardiac complications, second cancers, thyroid issues, heart problems. All of these can happen anytime after one year to five years sometimes. And basically what I tell my patients is consider transplant as changing the trajectory of, or changing the conditions that you have from a life-threatening disease to some chronic health conditions for which they will need almost lifelong monitoring.

(20:28) GVHD can mild to life-threatening and acute or chronic. So just going back to graft-versus-disease that occurs because of the differences between the cells of your body and the donor cells. The severity can range from mild to life-threatening. And it does have two types, acute and chronic. Acute usually will develop in the first 100 days, but can occur later also. And usually it presents with a skin rash, nausea, diarrhea, or liver test abnormalities.

(20:53) Chronic GVHD usually develops three to six months after transplant, but can appear earlier or later, and it can involve most organ systems in the body like skin, eyes, lungs, joints, et cetera. And the main problem with this is that it is a quality of life issue rather than really a mortality issue, other than possibly the lung graft-versus-disease.

(21:17) Late effects include chronic health conditions and lower physical functioning. Other than graft-versus-disease, there are other late effects also as I mentioned, and multiple studies have shown that they can adversely impact a patient's quality of life, their health and functional status. Survivors with late effects, chronic health conditions tend to have lower physical functioning, lower likelihood of returning to full-time work or study, a higher likelihood of limitations in their usual activities, and a higher incidence of overall distress.

(21:48) Transplants are more successful if the patient is in remission at the time of transplant; other factors also play a role.  So what determines the success of transplants? In general transplants are most successful if MDS, or whatever disease you're getting the transplant for, is in remission at the time of transplant and has not transformed to an aggressive condition. Good organ function, optimum functional status, having no major uncontrolled infections and good psychosocial support are some of the other factors that will have a great impact on improving the success, the chances of success with transplant.

(22:22) How can a patient increase the likelihood of a successful transplant? So as a patient, you can say, how do I prepare for transplant? How do I improve my chances of a successful outcome? You can do that by getting more information about risks and benefits of transplant by attending a webinar like this. I would also say that it's a good idea to explore non-transplant options such as clinical trials, especially because there is a lot of advances going on in that area as well.

(22:48) Plan to live close to the transplant center for 100 days after transplant. If you do decide to move forward to the transplant, we would recommend that you select a transplant center that is easy for you to be able to live close to because most transplant centers would require you to live within an hour driving distance for at least the first 100 days after the transplant. In addition, you have to look at what is in network for your insurance and what has good outcomes. For a lot of these centers, that outcomes data is published in as a public document that you can look at or talk to your insurance case manager about.

(23:26) Other things that you can do is continue to optimize your functional status, your nutrition while the plan for transplant is going on, select and decide about a caregiver plan.

(23:37) Recruiting a caregiver and clarifying financial issues is also important. Now, a caregiver is a very important facet of this whole transplant journey because you would need a caregiver the first 100 days. And so having a good caregiver plan is very important for the success of transplant and planning.

Your finances are important because it's a very expensive procedure and the expenses can last not only pre-transplant, but also post-transplant ,depending on the complications that may happen.

I know BMT InfoNet has a goldmine of information about some of these options and even individual presentations about each of these points.

(24:18) Caregivers can provide medical, financial and emotional/social support for transplant recipients. Some of you may be caregivers here. And so your question is what can you do as a potential transplant caregiver? So there's three main areas of support that we would require you to provide.

Medical support, meaning gathering more information, talking to the doctors and helping care for your patient. Financial help in terms of, again, talking to the insurance company, helping manage the costs and daily household finances. And the most important is emotional and social support, which means providing, listening, and supporting your patient during this very difficult time of their life.

What is also important is that you have to be able to take care of yourself while caring for your loved one. You cannot run on empty. So that's why it's very important for you to be careful about yourself as well. And there's many resources, again, I think BMT InfoNet has a lot of these resources available for caregiver wellness as well.

(25:13) Currently only about 15% of MDS patients go to transplant though more could benefit from it. So despite the signs showing that allogeneic transplant is a potential cure for MDS, there's only about 15% of patients with MDS that actually end up going to transplant. We hope that the number will increase with this new data that's become available. However, we recently identified some potential challenges that can occur at the patient level and provider level for somebody to be able to go to transplant.

(25:43) There are several barriers to transplant that may need to be overcome before people can receive a transplant and its benefits. Some of the patient perceived challenges include perceptions of high risk of transplant, but without being put in a context of benefits. And that is because the discussion may be held only with the referring hematologist oncologist who doesn't really understand the advances in the transplant field.

There may be social barriers. There may be a need for transportation and lodging. Lack of caregiver, lack of insurance and lack of optimal donors can be some of the other patient perceived challenges.

On the other hand, provider perceived challenges are again around lack of awareness. So a lot has happened in the transplant area that is very hard for the hematologist oncologist to keep up with. And so they may not be able, or they may not think that a patient could be a transplant candidate, even if they are. Sometimes the outside providers also worry about potential revenue loss, because when the patient goes to a center, a transplant center, they may decide to stay there for the rest of their treatment.

There's lack of care coordination. There are financial barriers and there's lack of clarity on post-transplant care, which again can be barriers in terms of the providers referring patients to a transplant center.

(26:56) Better patient education, coordination of care, and social support services can reduce these barriers. So what can we do as doctors, as hematology oncology providers? We can educate our patients about all treatment options, go over the risks and benefits of each of the options to help them decide, we can help improve access to transplant for eligible patients by advocating both at the patient level and at the federal level to policy changes. We can partner with referring doctors to ensure that there is an early referral for all newly diagnosed patients for transplant consult.

(27:28) We can help develop strategies that can help with rehabilitation and social support for some of our older patients who at first glance may not seem to be a good candidate. However, if we can work on some of those gaps, then they may become an appropriate candidate for transplant. And we can continue to do research to improve both non transplant and transplant approaches to get best clinical outcomes.

(27:52) All medically eligible, high risk MDS patients should at least be evaluated for transplant. So to conclude, who should get an allogeneic transplant for MDS? All patients with high risk MDS who are medically eligible should at least be seen by a transplant center to determine whether they are candidates for transplant. When? A referral to transplant center as early as possible in the disease course, but the transplant actually should happen when the disease is under the best possible control and the patient is otherwise considered to be fit by the transplant team.

And how? As I showed you, it's a complicated multi-step procedure involving a lot of people with the need for a lot of coordination and prolonged follow-up. That is the importance of getting all the information, having discussions with your family, your loved ones and your treatment team to decide whether this is an option for you is very, very important.

With that, I will conclude, and I would like to thank National Marrow Donor Program, Be The Match, the registry CIBMTR, and BMT CTN leadership. And Dr. Linda Burns, my co-chair for Evidence Into Practice Taskforce. And I'll be happy to take any questions.

(29:04) [Susan Stewart] Q. & A. Thank you, Dr. Khera. That was a wonderful presentation, very clear. We do have a number of questions. And again, if you want to ask a question, type it into the chat box on the left side of your screen.

(29:16) And we'll start with the first one, do people with MDS have to get into remission with chemotherapy before they go to transplant or not? And if they do, can you explain what that chemotherapy or treatment is that people usually need to have in order to get into remission?

(29:36) [Dr. Nandita Khera]          Sure. As I mentioned, the best chances of success are if your disease especially MDS in this case is in remission. So yeah, we would want you to have as best a chance possible. And for that, less than 5% blast and clearance of the genetic abnormalities is what we would consider to be the best in terms of deciding on timing for transplant.

The chemotherapy that we usually use, it depends a little bit on what is the blast percentage. And so sometimes if we feel that the blast percentage is high and approaching the acute leukemia levels then, and if the patient otherwise is fit, we may do very strong induction chemotherapy in the hospital.

More frequently what we do is the gentle chemotherapy plus an oral agent or if you have any targeted markers, then we do the targeted medicine for that to try and get you into remission, which is the less than 5% blast and clearance of the genetic markers.

(30:44) [Susan Stewart] The next question is about caregivers. This person wants to know why a patient needs a caregiver for 100 days. What exactly is that family or friend going to be doing? And if the patient doesn't have a caregiver, can he or she still go to transplant?

(31:03) [Dr. Nandita Khera]          That's a great question, and that's actually something that we struggle with as the treatment team a lot of times. Studies have shown that our patients who don't have a good caregiver do not do very well because what happens for these first 100 days is that the patient can get very sick very quickly. So we need to have somebody who can help manage their medications, who can bring them back and forth to their appointments, who can bring them to the hospital at night if they have any kind of a fever or any other complication happens. So for that reason, having a good caregiver plan is one of the prerequisites at most of the transplant centers.

There can be more than one caregiver. And as long as you have a good plan, and most transplant centers have social workers that work with our patients to be able to develop that plan, that should be okay then to move to transplant.

(32:02) [Susan Stewart] All right. The next person wants to know, is there an absolute upper age limit for transplant?

(32:10) [Dr. Nandita Khera]          That's a million dollar question as well. I have to say there is no age cutoff per se. That being said, so for instance, my program, we do not transplant people above 75 years of age. So it's more than the physiologic age. It's more than that in the sense we look at the comorbidities somebody has, we look at their overall performance status. We look at what is their chances of getting this risky, complicated procedure by doing what we call geriatric assessments? And then based on that, we decide on whether we would take someone to transplant or not.

I do know some of the bigger transplant centers may even take people up to 80 years of age as long as they are in good shape and we feel that they will be able to go to this extremely complicated transplant. And that's fair. The good thing is that our field has been able to develop these low intensity regimens that because of the immunological effect will still work in order to control the disease and provide that potential of cure.

(33:20) [Susan Stewart] All right, the next one is from a woman who says that she has an RUNX1 mutation and has been diagnosed with MDS. She lost her son to AML, acute myeloid leukemia, which is how she discovered that she had the RUNX1 Mutation. She just turned 40 and has an eight year old son. What treatment would you recommend?

 [Dr. Nandita Khera]        For the patient or for the son?

 [Susan Stewart]               For her. One son was lost to AML, she has another.

(33:54) [Dr. Nandita Khera]          Oh, so this mutation does have a chance of what we call familial predisposition, meaning it can run in the families, which seems to be the case here. In terms of treatment for her, it would depend, as I mentioned, on the risk stratification system. So you would have to look at not just this mutation, but also her other markers in the sense, how many of her counts are low? What is the last percentage? And things like that.

There are centers which are starting to look at some of our patients who have mutational markers, but not other manifestations, and try to follow them and try to come up with ways to prevent this from happening. But in general, right now, the standard of care is if she does not have documented MDS but only the mutation, then we would just follow her carefully unless she met criteria for treatment in terms of the clinical features.

(34:56) [Susan Stewart] All right. This gentleman said that he has MDS as a result of having six years of chemo to treat multiple myeloma primarily with Revlimid and Velcade. He did have one stem cell transplant to treat the myeloma but it did not reach remission. So he's been on Venetoclax with Dex as right now, and he wants to know how having myeloma as the source of his MDS affects his outcome after treatment.

(35:28) [Dr. Nandita Khera]          Unfortunately, we are starting to see a lot of our patients who have been on Revlimid maintenance after myeloma and after an autotransplant for myeloma come up with the secondary cancers, including MDS. In general, again, how he will do will depend a little bit on all his other risk factors in the sense, what are the other mutational markers he has. How he responds to treatment.

If he is able to go into remission, which means the blasts decrease to less than 5% and his counts are somewhat more recovered, the mutations are clearing up, then he may be a candidate still for an allogeneic transplant. I'm assuming the first one that he had was an auto transplant where people would get their own cells because that's what we do for multiple myeloma. But if he's in a good shape, and as I mentioned, some of the things about what are the markers for success, then he should be able to get to an allogeneic transplant for potential cure of the MDS and even myeloma, if there is any remaining.

(36:36) [Susan Stewart] All right. We actually have two other questions related to myeloma and an autotransplant. First one is, what's the difference between an autologous and an allogeneic transplant?

(36:48) [Dr. Nandita Khera]          So autologous transplant is where somebody gets their own cells back. And usually the rationale there is that it just allows us to give patients high doses of chemotherapy, which would otherwise, if we didn't have stem cells to give them back, it would lead to their bone marrow not working at all. So that's an autotransplant. It usually is done for patients who have multiple myeloma or lymphoma like Hodgkin's or non-Hodgkin's lymphoma.

The allotransplant is where we give cells from somebody else. And in this case, it's not just the chemotherapy that is helpful, but also this immunological effect, as I mentioned, the graft-versus-tumor effect, which can help provide a potential cure for any of the disease for which the transplant is being done. And this is usually, we use it for leukemias and even for lymphoma if they relapse after an autotransplant, then we would consider them for allogeneic transplant.

(37:50) [Susan Stewart] All right, and then the follow-up question to that was what's the difference between multiple myeloma and myelodysplastic syndromes?

(38:00) [Dr. Nandita Khera]          So they're both targeting different cell lines. And so the myelodysplastic syndromes, as I mentioned, is basically affecting the cell line that helps give rise to these cells in the blood. The lymphoid cell line is usually the one that will be affected and especially something called plasma cells, which are the cells that help make antibodies when you get an infection. That is the one that is affected in multiple myeloma. Multiple myeloma can affect bones, kidneys, can affect cones.

The myelodysplastic syndrome usually will be only in the blood, will be manifested only in the blood.

(38:47) [Susan Stewart] Okay. This person is concerned about graft-versus-disease. First of all, wants to know if graft-versus-disease ever goes away. And second, whether there are any affordable medications for chronic graft-versus-disease?

(39:05) [Dr. Nandita Khera]          So the hope is, yes, it will go away at some point because the hope is that... So graft-versus-disease happens because the donor cells continue to think that they are not in a, or they are in an enemy body and they continue to fight. We know that eventually they will settle down. Eventually they will recognize the patient's body as their own, but that can take a long time, especially if somebody has already had graft versus host disease.

There's been some nice studies from Fred Hutch that looked at kind of the duration or how much time a patient needed to be on immunosuppression for graft-versus-disease. And the median there was about two years. Now, patients who get peripheral blood for their stem cell source tend to have longer duration of needing immunosuppression, longer duration of chronic graft-versus-disease as opposed to those that have received bone marrow cells.

The other thing is I have had patients that are six, seven, eight years out, and some of them are still struggling with graft-versus-disease. Even if it's not active GVHD, it's the scarring. It's the sequela that GVHD leaves, especially in the eyes or sometimes in the skin that can continue to be a quality of life issue for a long, long time.

(40:29) [Susan Stewart] The next person wants to know, how do you differentiate between intermediate and high-risk MDS? The graph she showed earlier showed transplanted versus non transplanted for high risk. How big of a difference is there in the outcomes if you have intermediate risk or high risk when you go to transplant?

(40:51) [Dr. Nandita Khera]          That's a great question. So in general as I mentioned, we have a risk scoring system that can help us decide whether you are in the intermediate risk group or high risk group. And so I hope you can see these graphs here. And basically what it shows is that there's a nice separation between the high and the intermediate risk groups in terms of how they will do in survival, as well as being free from evolving into an acute leukemia.

In terms of the outcomes after transplant, if you receive it for intermediate versus high risk, a lot will depend on what is the status actually going into transplant? Even if you are a higher, the very high risk but we have been able to control your disease and get you into remission with clearance of all your genetic markers, then your chances are your success will probably be the same as somebody who's coming in with an intermediate disease and is in remission. So that's the most important thing, is what is the disease status at the time of transplant that will determine the outcome rather than the category of diagnosis, so to say.

(42:03) [Susan Stewart] All right, the next question is about the immune system. Are there ways to build up your immune system after transplant?

(42:12) [Dr. Nandita Khera]          The main thing is because after transplant you are on immunosuppression to try and keep those donor cells from fighting against your body, that is the main risk factor that makes someone immunosuppressed after transplant. There's really no ways to build immune system other than to say that what we tell our patients is that they need to follow all sorts of infection precaution things. They need to receive vaccinations when they are due for it. So our usual vaccinations after transplant will start anywhere between six months to a year. With the COVID vaccine, the recommendations are to start it at three months after transplant. The flu vaccine needs to be done whenever the flu season starts.

And so if we can do some of those things to try and prevent an infection from happening, that would be the best. Unfortunately, there's no other immune builders as such that we can do because a patient would need to stay on immunosuppression to prevent graft-versus-disease for some time after transplant.

(43:17) [Susan Stewart] And speaking of vaccines, this person wants to know, is it safe to get the COVID-19 vaccine while undergoing chemotherapy and while the immune system is suppressed?

(43:29) [Dr. Nandita Khera]          That is what our current guidelines from the society are, is that it is okay for somebody to get the vaccine. The issue usually with vaccines is that we don't like to do live vaccines in our patients post-transplant unless they meet certain criteria, which is they have to be more than two years out. They have to be more than a year off of their immunosuppression. But for COVID vaccine, it's not a live vaccine. So yes, anyone who is still immunosuppressed, who is on treatment should be able to get it.

The only problem is that we don't know how well they would respond to it. So usually what I tell my patients, even if they've gotten their two doses and the booster, is to continue to be careful in terms of masking, social distancing with the hope to prevent it from happening. But absolutely, you can get it even by you're getting chemotherapy. The only thing I would say is maybe have a gap of like two weeks between the chemo and getting the vaccine if it is all possible. And if not, then it should still be fine.

(44:34) [Susan Stewart] All right, thank you for that. This individual has said, when I was diagnosed in 2019 with MDS, I had the TP-53 gene mutation and was given a poor prognosis. At first, the transplant looked like a failure, but after four months, the donor cells kicked in. We are so fortunate. In your experience, can the TP-53 gene mutation stay away forever after transplant?

(45:02) [Dr. Nandita Khera]          First of all, congratulations for doing so well. TP-53 is definitely a very bad marker. And in general, our outcomes for patients who have that even with transplant are relatively poorer than others. So in your case, it sounds like if you are several years out, then the likelihood that you're cured and that the TP-53 is gone is very high. And usually we would say that if you make it to five years after transplant without having the disease come back, you would be considered cured and you would be considered... Your chances of the MDS coming back would probably be the same as somebody in the general population developing it as a new issue. So the hope is yes, you're cured if you've been free from this mutation for so many years.

(45:55) [Susan Stewart] All right. The next question is from a woman who said that she's two years post-transplant, is still on tacrolimus and sirolimus, presumably for graft-versus-disease. And wants to know, is it possible that she'll have to be on these immunosuppressants for the rest of her life?

(46:16) [Dr. Nandita Khera]          Again, I would say that the chances are probably high. Even if it's not lifelong, it would still be for somewhat of a long time. Again, in that study from Fred Hutch, what they showed was seven years was the maximum that somebody was either continued on immunosuppression or had another complication that would happen. So in general, yes, if you are still on immunosuppression, the chances that you will be on it for a little bit longer even up to five, six, seven years is high. Hopefully it's not lifelong though.

(46:55) [Susan Stewart] Great. This person wants to know about other treatments for MDS other than transplant. Is there anything new that's being explored that looks promising?

(47:06) [Dr. Nandita Khera]          Again, a great question. There's definitely a lot happening in this area. So as I mentioned, the standard of care is the hypomethylating agents, something called azacitidine and decitabine. There's a medicine called Venetoclax, which we are commonly using in combination with these chemotherapies, especially for our patients with P53 disease.

In addition, there are oral chemotherapies and targeted agents that are being looked at. Again, mostly a lot of them are in the P53 area. The issue has been that some of these studies have had great results in phase two, but when they've been looked at in a randomized controlled fashion then the results don't appear that attractive. But that being said, yes, a lot is happening in this area with a lot of oral chemotherapies and targeted agents that are being assessed for MDS.

(48:07) [Susan Stewart] All right. The next question is what are the advantages and disadvantages of using different types of stem cells for transplant? Is one better than the other, bone marrow, peripheral blood stem cells, cord blood?

(48:20) [Dr. Nandita Khera]          So as I mentioned, peripheral blood is the most commonly used source. I would say it's used for about 70% of our transplants. The problem with that is because there are more, what we call T-cells, the incidence of graft-versus-disease is slightly higher with peripheral blood. But in general, especially for our patients who will have high risk disease and we want that graft-versus-tumor effect, they tend to do better with the peripheral blood.

The bone marrow graft, especially again, one of the big studies from BMT CTN showed that bone marrow graft was better in terms of having a lower incidence of graft-versus-disease because of the lower level of T-cells, although the survival was comparable. And so that should be preferred for our patients who are receiving unrelated donor transplants, but that's not really happened because of a lot of issues.

And then in terms of the cord blood that's the least commonly used source so to say, and only a few centers in the country use that. It's used very frequently in our pediatric population, but for the older adults, there are complications and there are center specific practices that the cord blood is used in a very limited number of centers. But in general, the results in those centers, especially with other sources, is quite comparable.

(49:43)  [Susan Stewart] All right, the next question comes from a gentlemen who wants to know what are high risk mutations? What are they?

(49:54) [Dr. Nandita Khera]          So P53 is the most aggressive mutation with a very aggressive course. And then there are others like ASXL1 that can be bad. And in general for MDS usually these are the ones that are considered bad. In AML or acute leukemia, we have other mutations that can be, or other genetic markers that can be considered poor markers, such as FLT3. But they're not usually seen in MDS. MDS mostly it's the P53 and the ASXL1 that I would say are the bad ones. The other common ones, the DNMT3A or TET2. The data is very conflicting about if they're really poor or really don't affect it that much.

(50:51) [Susan Stewart] All right. The next question goes to, how many donor cells should you have in your blood after transplant? She said, what is considered a good mix of donor and patient cells? I've been holding steady at 94% donor and 6% my own cells, but I've been as low as 92% donor cells and as high as 100% donor cells. What causes it to black slide? And at what point does it become an issue that requires some additional care?

(51:24) [Dr. Nandita Khera]          This is something that we are still trying to learn and understand. What you're talking about is mixed chimerism which means, especially with some of these lower intensity regimens that will not wipe out completely your marrow, you may still have some level of your own cells with the recipient cells. In general as long as you're staying steady at that, so 90/10 or close to that, or even 80/20, and as long as your disease is in control, everything should be fine.

It's usually not one value that we worry about. It's the trajectory. So in case someone starts with 90/10 and then they dropped down to 60/40 and then dropped down to 50/50, that's when we worried that they're losing their graft or the donor cells are being lost. And that if we don't do anything, then the chances that their MDS or the leukemia would come back would be high. That being said, I personally have a few patients that have stayed at that low level for a long, long time. I have them on maintenance treatments and their disease is still staying under control. So I am just watching them.

What can be done, though if these chimerism continue to decline is a donor lymphocyte infusion. We would give you more cells from your donor to try and sort of kickstart your graft again so that it can continue to fight your disease process.

(52:54) [Susan Stewart] The next question is from someone who has graft-versus-disease. She wants to know whether there's a way to reduce, repair or resolve the fibrosis, skin fibrosis in scleroderma that sometimes happens after transplant.

(53:11) [Dr. Nandita Khera]          That's a good question. I wish I had a more favorable answer. It is very hard to reverse depending on how bad it becomes, if it becomes what we call hidebound where the skin is just stuck to the underlying tissue and the bone. The reversal can be extremely difficult. That being said there are newer medications. There's one that was approved very recently called belumosudil which showed some excellent response rates in patients with the scarring type of, or skin tightening kind of graft-versus-disease.

And so what I usually tell my patients is that there's two things that have to happen when you have that scarring type of GVHD. One is that we have to be able to control the active disease process or the cells that are continuing to produce the scar tissue. And once that happens, then we have to give the body the time to resolve that scar tissue. And that can take a long, long time. That being said, it's not impossible. I've had a few patients that have been successful in getting better with treatment, but then I've had an equal number of patients that we have not been able to control despite multiple different agents. So it's a complication that we are still studying very closely and trying to understand better and improve on.

(54:37) [Susan Stewart] This woman has myelofibrosis and she wants to know, are there bad genetic markers for this particular type of disease?

(54:45) [Dr. Nandita Khera]          Yes, there are. And again, myelofibrosis, we not only look at the genetic markers, we also look at same some of the similar things as to what the blast percentage is. We also look at what the constitutional symptoms are. We look at what the white count is and how much is the hemoglobin. So all of those factors, then again, help us calculate the score, which we can then determine whether you are a high risk person or somewhat of a lower risk category.

(55:18) [Susan Stewart] All right, this individual developed asthma and thyroid problems after transplant and wants to know if these are temporary. Do they ever go away?

(55:29) [Dr. Nandita Khera]          Thyroid, probably not, depending on what kind of conditioning you got. Asthma, I'm not sure if it's asthma or if it's lung graft-versus-disease. That would need to be looked at to decide whether you can be treated for it and it can get better.

(55:47) [Susan Stewart] All right. This individual wants to know if we know what causes MDS?

(55:59) [Dr. Nandita Khera]          In general, we would say that it's a combination of genetic and environmental factors. So definitely any kind of exposure to what we call carcinogens, any chemicals as part of occupation. Or I recently saw this patient who had been in Russia during the time of the nuclear accident at Chernobyl. And so it's usually conditions like that or factors like that that would increase the chance of MDS.

Sometimes, as we just talked about, multiple myeloma, chemotherapies that patients may have received for other cancers can also increase the chance of myelodysplastic syndrome because of the genetic mutations.

(56:46) [Susan Stewart] Okay, and I think we have time for one more question. We'll take this one from a person who has the 20q12 mutation 10 years after a myeloma transplant. Is he a high risk?

(57:02) [Dr. Nandita Khera]          In general, we don't consider that as a high risk. However, that's where it becomes kind of dicey, f we think that this could be something that's treatment-related after the auto transplant for myeloma or because of the treatments that you've got for myeloma. So I think that's where we would have to look at the other factors as well, or other clinical markers as well to decide whether your high-risk or low-risk.

(57:26) [Susan Stewart] Closing.  And with that, I think we need to wrap up the session. I want to thank everyone who attended the session for your excellent questions and definitely thank Dr. Khera for an excellent presentation and very helpful answers to the questions that you posed.