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myelodysplastic syndromes (MDS)

The MDS Research Consortium

Amy E. DeZern, MD, MHS
Interview: 
  • What is it about the original concept (or design) and ongoing function of the CRC that makes it a unique addition or enhancement to traditional MDS research?

This is the first endeavor of its kind in the United States – it’s a wonderful, collaborative effort between six large MDS programs to run trials together in a more efficient way and hopefully bringer new drugs to patients sooner.

  • Are there any CRC studies (completed or underway) that would not have been possible without the scope that CRC participation allows?

There are two good examples of this. One is a research study on CMML, a more rare MDS/MPD overlap. Because it’s an unusual patient population, having the consortium to more quickly accrue enough patients for this study was very helpful. A second example is of a randomized trial, headed by MD Anderson of the two approved MDS drugs, azacitidine (Vidaza®) and decitabine (Dacogen®). Outside the consortium environment this study might not have been approved. It’s going well and with good accrual and I think we’ll have some great results for the field.

One thing to keep in mind is clinical trials have a lot of regulatory aspects –they are paperwork intensive, and not an altogether efficient process, besides all the aspects of patient care.  So, having several centers working in coordination can be helpful.

  • Are there any CRC studies you have a particular interest in?

One that I’m interested in is a on a high-risk type of MDS that comes with the tp-53 mutation, which carries a very poor prognosis – it’s really one of the worst actors in in MDS. There’s a trial run out of Moffit Cancer Center that some of us are participating in that is accruing well. It’s an exciting time in MDS right now and we hope to make progress in developing a drug for this high-risk MDS subtype.

  • Do the participating centers have different roles in the CRC or are they all the same kind or level of participation? Does data sharing play a role?

It’s generally the same although the number of patients vary some by region – but the experience of planning and running the trials is pretty much the same. Data sharing has been useful to have a larger aggregate group to examine results and statistics from. There have been some successful abstracts that benefitted from having this larger pool of rare disease data.

  • This is an example of a creative partnership that combines resources to increase the pace and scope of research? Is it working out has you had hoped and is there any ‘next step’ in a partnership arrangement like this?

Overall it is working very well, and we have been very productive as group since the inception of the MDS-CRC. We are currently exploring all ways possible to maintain the funding to continue this endeavor for years to come.

 

Education Topics: 
myelodysplastic syndromes (MDS)

AAMDSIF Virtual Film Festival

Over the past few years, several documentaries and dramas about people living with aplastic anemia have been created by independent filmmakers and by patients themselves. These depict the everyday lives of patients coping with a diagnosis, the challenges presented by treatment and the hardship caused by inadequate medical insurance coverage.

Whether fictional movies, or stories about actual patients and families, these portrayals bring you into the world of bone marrow failure disease in an uncompromising and straightforward manner.

MDS and Inflammation

Alan List, MD
Interview: 

What is inflammation and its relationship to MDS?

Inflammation is a complex biological response to an injury or an irritant. Inflammatory responses protect the body and cells from specific insults, with the purpose to rapidly neutralize the injury or insult the body has experienced. This could be a pathogen like bacteria, or even result of cell death, where intracellular components are released into the environment. These immediate cellular effectors of inflammatory responses involve white blood cells, immune cells, blood vessels and additional molecular factors. This process reflects what we refer to as the ‘innate immune system’ at work, and which specifically appears to be activated in MDS.

What are MDSCs?

The main cells that seem to be involved in operationalizing the inflammatory response are something called myeloid-derived suppressor cells (MDSCs). We found that these cells are markedly expanded in the bone marrow of MDS patients and their role appears to be to suppress blood formation. They will suppress and kill neighboring cells in the bone marrow and are genetically distinct or separate from the MDS clone. This findings suggests that MDSCs –may have preceded, and drive the emergence of the MDS clone.

We have also learned that MDSC’s are expanded and activated by a specific inflammatory protein, called S100A9, which together with its binding partner, S100A8, can drive the expansion of these cells. MDSCs and S100A9 also trigger a specific type of cell death. Targeted cells die by a unique process called pyroptosis – this is an inflammatory form of cell death. In the process of cell death, the cells swell and get larger. These are known as macrocytic cells, that are often seen in MDS -- and it also drives their proliferation. They appear to have a very important role in the disease biology and this signaling occurs through a protein complex called the inflammasome.

What are some inflammatory symptoms?

We have known for years that there are increased inflammatory complications in MDS. There was a large Swedish registry study showing that people who sustained chronic inflammation, whether it is asthma, rheumatoid arthritis, or some sort of autoimmune disorder, had a much higher risk of developing MDS. MDS patients can develop rashes, profound fatigue, vasculitis or inflamed blood vessels, and Sweet’s Syndrome which are painful flares in the skin associated with fever and inflamed, swollen joints. There are number of inflammatory symptoms that are all related to activation of innate immunity.

For people who have MDS and experience inflammatory disorders, I think we are on the cusp of having some new therapies that will help suppress this process. I have many patients where their hemoglobin is not low enough to have symptoms, but they have profound fatigue and aches with inflammatory symptoms. These novel kinds of treatment that are coming may have a role in treating all of the symptoms and initiating biological events, and represent an unprecedented opportunity for the future, not just for treatment but also for prevention.

We have heard about gene mutations that can be detected a very low level in the peripheral blood of people who are otherwise hematologically normal, These individuals have about an eleven fold increase in risk for developing MDS later on. If the inflammatory process drives it, it could eventually be as simple as taking a pill to prevent this from occurring. I think there’s enormous opportunity in the future for this.

What are some possible directions for future research?

I think the most important take home message is that understanding this biology which is very new, allows us to target the MDS clone therapeutically in a very specific way that we never could before. The convergence points in this process are the inflammasome, as well as S100A9, the key soluble mediator of expansion of MDSCs or activation of the cell death pathway we call pyroptosis.

We can target this in the laboratory now, by creating a soluble receptor that will neutralize S100A9, and using an inflammasome inhibitor which could be taken as a pill. These agents have been licensed to Celgene for clinical development in the years ahead. In the laboratory they work beautifully to enhance the survival of the cells and the effective production of blood cells.

For future research, the real question is what the mechanism of activation is for this pathway within the cells.  If we can find the specific internal activators, we can make more specific inhibitors to help arrest the process. This needs to be a key priority of research in in the next few years.

Education Topics: 
MDS basics
myelodysplastic syndromes (MDS)

Pregnancy in Bone Marrow Failure Disease

Ellen Friedman, MD, FACP
Interview: 

What is the impact of bone marrow failure disease and its treatment on pregnancy?

Bone marrow failure diseases frequently occur in women who are young and of child bearing age. People with these diseases have legitimate concerns about whether a pregnancy will cause their infants to suffer from the disease or its treatment, or whether their own disease will relapse. But the goal of modern therapy and modern obstetrics is to minimize both maternal and fetal complications.

Experience from published reports suggests that in the past ten years, both maternal health and fetal outcomes have improved in women with aplastic anemia and PNH. However each bone marrow failure disease (aplastic anemia, MDS, PNH) has to be evaluated separately for pregnancy complications. The issues are different for each condition.

Fertility appears to be unchanged in people with these disorders compared to people without them. But in people who have had an allogeneic stem cell/bone marrow transplant, the immunosuppressive medications may affect the ability to become pregnant.

For PNH, has the use of eculizumab in pregnancy been studied?

There are cases of women who have been successfully treated with eculizumab. Recent information shows that with modern obstetric care, women with PNH can successfully give birth to children, but there is an increased incidence of complications compared to people without PNH. The major complication is premature birth. Other complications include the need for blood and platelet transfusions, anticoagulation with blood thinners, thromboses (blood clots) and hemorrhage. However, fetal outcomes are also improved with this drug.

Use of lenalidomide (Revlimid®) during pregnancy is known to be harmful because it can cause birth defects. Does this mean only other drug therapies can be used?

Lenalidomide is a derivative medication of the drug thalidomide. In the late 1950s and early 1960s, thalidomide was used as an anti-nausea medication during pregnancy. This caused babies to be born with abnormal body parts, and significant birth defects are associated with its use.

Lenalidomide is used in people with low-risk stages of MDS, and particularly in the 5q-MDS subtype, but it must be stopped if pregnancy is even being considered. This applies to both men and women! Other medications or transfusions can then be used to treat the anemia.

The company that manufactures lenalidomide maintains a risk evaluation and mitigation strategy program (REMS) which requires that in a series of interviews, patients taking lenalidomide are carefully screened and strongly encouraged to prevent pregnancies.  In addition, pharmacists and doctors are all asked to assess their patients for careful use of this medication.

What is most important for patients to know and remember about fertility and pregnancy in bone marrow failure?

Much progress has been made, and modern obstetrics is able to support both mother and fetus through high-risk pregnancies. However, there are still significant issues in people with bone marrow failure diseases that can affect successful pregnancies. The mother is still considered to be in a high-risk pregnancy even though the majority of these pregnancies are able to be successfully managed with current techniques.

Problem areas that remain are in high-risk MDS and fertility in people who have received an allogeneic stem cell transplant. There is a risk of relapse of aplastic anemia during pregnancy, although the response rate to treatment for relapse has been good. Eculizumab can successfully be used during pregnancy to control PNH.

Education Topics: 
aplastic anemia
myelodysplastic syndromes (MDS)
paroxysmal nocturnal hemoglobinuria (PNH)
pregnancy

Therapies

There are many therapies and approaches doctors use to treat bone marrow failure disease patients. Some treatments are used for several different diseases. Others are used only for aplastic anemia, MDS or PNH. Every person's condition is unique, and each situation is different. That's why your health care team must look carefully at your specific case before recommending what's right for you.

What MDS Patients Should Know About Clinical Trials

Mikkael Sekeres, MD, MS

Dr. Sekeres is Professor of Medicine, Director of the Leukemia Program, and Vice Chair for Clinical Research at the Cleveland Clinic Taussig Cancer Institute.  He earned his medical degree and a

Interview: 

Do you find that some patients don’t understand what clinical trials are?

There’s a wide range of patient knowledge and opinions about clinical trials. I have some patients who ask me about them because they want to be part of the latest research and latest opportunities to try new drugs or drug combinations for MDS. I also have patients who want nothing to do with them, saying in effect, “I don’t want to be a guinea pig,” – not wanting to be part of any kind of experimental study. 

Do some patients feel when clinical trials are recommended that this is a ‘last resort’ treatment option?

There are a wide variety of clinical trials, and it also depends on what the patient’s philosophy is on engaging in them.  Some reserve clinical trials for when all other options are exhausted –when there’s nothing else available for them. This isn’t really a last resort, though – I consider this another option when available therapies either aren’t appropriate or haven’t worked, after which there’s nothing but blood and platelet transfusions to turn to.

At present we have only a limited number of FDA approved drugs available for people with MDS. These are lenalidomide (Revlimid®), azacitidine (Vidaza®), and decitabine (Dacogen®). We use a few other drugs off-label, such as erythropoiesis stimulating agents (ESAs) like erythropoietin or darbepoeitin, or immunosuppressants like anti-thymoctye globulin, (ATG).  My approach is that we’ll always have those three approved drugs to fall back on. But if we have a trial that is available and right for the patient, let’s try that first and if there’s no success we can always go back to those available therapies.

Can you describe some current areas of MDS clinical research?

Clinical research runs the spectrum of a person’s individual experience with MDS. I try to think about research from a patient’s perspective –how we can improve this person’s experience from the very moment he or she is diagnosed. In a way, clinical trials are designed to answer these intrinsic questions. How can we improve a person’s quality of life? For this, we engage in research about quality of life issues. How can we help patients minimize the number of blood or platelet transfusions they receive? Here, we conduct research that looks at supportive care issues. How can we improve treatments for a patient’s lower-risk or higher -risk MDS?  Should we look at developing drugs specifically for those conditions? How can we develop drugs for those who have been exposed to other therapies that didn’t’ work for them? We call this refractory MDS, where there was no improvement after 4 or 6 months, or recurrent/relapsed MDS, where there is initial improvement, but then MDS returns to its original state. Ideas for clinical trials are built around areas of inquiry like these.

Who are the primary sponsors of clinical trials?

Trials can be sponsored by a number of different sources. A trial can be born in the institution where the patient is receiving care. The primary investigator may be the patient’s doctor, or perhaps this doctor wrote the trial. It could be for a drug that was developed in the cancer center that is finally reaching MDS patients. The National Institutes of Health (NIH) can also be a sponsor. Here at Cleveland Clinic, we just  last year completed a randomized study called the North American Intergroup study where trial participants -- people with higher risk MDS -- received either azacitidine alone, azacitidine and lenalidomide, or azacitidine combined with vorinostat.  I wrote this study under the auspices of the Southwest Oncology Group, which is one of the National Cancer Institute’s (NCI) cooperative groups.  We participated in this trial along with the Eastern Cooperative Oncology Group, the Alliance Oncology Group (which are all sponsored by NCI), and the National Cancer Institute of Canada. So, in this case, four government-sponsored cooperative groups participated in one study funded by the NIH.

Another common source of sponsorship are the drug companies themselves. Many drugs are discovered or developed by these companies, and they will conduct trials to see if the drug is safe and effective enough to be approved by the FDA – the majority of drugs have this point of origin.

What can an MDS patient in a clinical trial expect to learn?

Every clinical trial that is conducted in the US is registered in the clinicaltrials.gov domain, so the results will be reported there. It may take years before a clinical trial is finished, but the final results are always reported and those results are intended to be publically available. So patients have a great resource to learn about many clinical trials – their purpose and their actual progress.

Why is it important for MDS patients to consider participating in a clinical trial?

There are different reasons. My patients tell me one reason they will participate is the strict, rigorous schedule that is adhered to. Everyone has access to the standard level of care, but some are receiving care far beyond current standards. They may have access to a drug that works for them years before it’s approved by the FDA and widely available. Some participate for completely altruistic reasons – they really do want to help the next generation of MDS patients. But all patients know that there’s a chance they can’t be included in the trial and that even if they are, they may not benefit from the drug regimen being tested.

It’s an exciting time for MDS research, but we need MDS patients for the many clinical trials that are being planned or are in process. That’s the only way new treatments can result from the progress being made in basic research.
Education Topics: 
MDS basics
myelodysplastic syndromes (MDS)
clinical trial

Clinical Trials: What Are Phases, and What Happens in Each One?

Mikkael Sekeres, MD, MS
Interview: 

Clinical Trials: What Are Phases, and What Happens in Each One?

Generally, clinical trials go through three phases.

A Phase 1 study may represent the first time a drug has ever been used in human beings, but for our purposes, it’s more common that it’s the first time a drug has been used in someone with MDS. Frequently the drugs we use in a Phase 1 setting are ones that have been used for other conditions, and we’re now trying to find out if they are safe or have any effect at all in MDS.

The goal of a Phase 1 study is basic – just to determine the best dosages, and/or the best schedule for taking the drug, and that the drug is safe to give. Most people who enter a clinical trial are most interested in whether a drug works, though, which is counter to the express purpose of these trials! Drug efficacy is actually a secondary aim in Phase 1 trials, though sometimes we are pleasantly surprised at how effective even a Phase I trial drug can be. Everyone in a Phase 1 trial gets the drug.

A Phase 2 trial is often similar to a Phase 1 trial in that everyone in the trial gets the drug. There is often no placebo arm of this trial. This is called a ‘single arm’ study. However some newer Phase 2 designs do have a control arm, whether it is a placebo or another therapy – and this is known as a two-arm study. By ‘control therapy’ we often mean a known, existing therapy in use that is being tested against the new drug being evaluated. The primary goal of a Phase 2 study is to see whether or not the drug works. In MDS, this could mean eliminating blood transfusions or improving blood counts.

A phase 3 study is always randomized and always has a control arm, whether a placebo or standard therapy. The primary goal of these studies is to see whether a new therapy or a new combination of therapies, works better than an established therapy, or a placebo. These trials are frequently used for registration purposes, meaning for a drug to be approved by the FDA.
Education Topics: 
aplastic anemia basics
MDS basics
PNH basics
aplastic anemia
paroxysmal nocturnal hemoglobinuria (PNH)
myelodysplastic syndromes (MDS)
clinical trial

Aplastic Anemia and MDS Overlap Syndrome

Amy E. DeZern, MD, MHS

Significant attention has been paid to

Interview: 

How common is one of these diseases coexisting with the other?

This is a complicated topic because the bone marrow failure overlap syndromes are in fluid motion in the diagnostic pathway. Classically, MDS has a hypercellular marrow – too many cells. In contrast, aplastic anemia has a hypocellular marrow, showing a very low number of cells. But there is a subset of MDS called hypocellular MDS. This means there’s a low number cells, but it is still more like MDS than aplastic anemia – and the two diseases are closely linked. What is most often thought of as the defining difference between hypocellular MDS and aplastic anemia would be the presence of chromosomal abnormalities observed when the karyotype of the bone marrow is examined, with MDS being far more likely to have these chromosomal abnormalities. Aplastic anemia has these more rarely.

Are there overlapping symptoms of these two disease that would initially be cause for confusion or misdiagnosis?

Despite the difference I mentioned, the symptoms of both are very similar. Patients with either disease often have low red cells, low white cells, and low platelets. Thus, the confusion could lie in the similar blood counts, but the reason for these low blood counts is different. In aplastic anemiam there are no cells to make new blood, but in MDS,  there are too many bad cells that are not effective in making blood,crowding out the good ones. 

Are cases as a dual diagnosis such as these counted along with the individually diagnosed cases or are they regarded as a separate category?

This is an area of a lot of scientific debate. Usually, they’re more often as classified as MDS if they have the chromosomal abnormality I have mentioned. Aplastic anemia, with a normal karyotype and an empty marrow, is really the only condition that is categorized this way.  Once there has been an evolution – a changing of the chromosomes, this moves away from aplastic anemia to MDS, some call that the overlap syndrome but they are usually treated more as an MDS patient. Hypocellular MDS is often treated initially like aplastic anemia,  with immunosuppressive therapy.

Is treatment each disease any different than when they appear separately?

The first line treatment for an older adult with pure aplastic anemia is immunosuppressive  therapy. In older adults with hypocellular MDS, immunosuppressive therapy could be considered, but would never be considered in MDS where the standard of care should be hypomethylating agents, azacitidine (Vidaza®) and decitabine (Dacogen®), which of course are not used in aplastic anemia.

Should patients who have been diagnosed for one of these diseases be tested for the other?

The testing is same for both. A bone marrow biopsy is performed and chromosomal abnormalities are looked for in both. The observation of dysplasia would be checked for in both diseases.  Measurements of the earliest progenitor cells (or blasts) that are CD34 positive can be helpful to distinguish as well.
Education Topics: 
aplastic anemia basics
MDS basics
aplastic anemia
myelodysplastic syndromes (MDS)

Resistance to Hypomethylating Agents in the Treatment of MDS

Hetty Carraway, M.D.
Interview: 

How common is MDS that is found to be resistant to treatment with the commonly used hypomethylating agents (HMA), azacitidine (Vidaza®), and decitabine (Dacogen®)?

The overall response rate to HMA based therapy is about 40% to 60%.  The landscape is changing slightly, particularly with the use of combination therapies, where we are getting closer to 60% to 80% overall response rates for MDS patients in clinical trials. But that still means about 25% or more patients are experiencing no improvement with these agents. This of course applies mostly to higher-risk MDS patients, because we don’t usually treat lower-risk category patients upfront with these agents. However, we have learned that patients that have not responded to HMA directed therapy (whether they are low or high risk MDS) have poor outcome/survival.

What is the difference between MDS that is refractory to hypomethylating agents and recurrent MDS that returns after successful or partially successful treatment?  Is there any understanding of why some MDS is initially resistant to these drugs and why other MDS shows an encouraging response at first, but becomes less effective later?

It is important to identify what we mean when use the words ‘refractory’ and ‘resistant’. My view is that there is a difference, and MDS that is refractory to hypomethylating agents means that patients do not respond to the treatment at all no matter how long they have been exposed to the therapy. In that scenario, we often refer to such patients as ‘primary refractory’ patients. If there has been some response to treatment with a hypomethylating agent with a meaningful benefit (such as transfusion independence) or a larger benefit (like complete remission) with subsequent loss of that response, that is defined as resistant MDS.  Biologically, there may be some difference in the MDS that is refractory versus that which initially had a response and then became resistant to treatment. I would say that the biology of refractory MDS dictates that those clinical situations are harder to treat and have worse clinical outcome(s).

Is it known why some MDS is resistant to these two quite similar drugs? Are there instances where one drug fails and the other does not?

We are trying to get a better understanding of this resistance. One of the ways I like approach this is to consider what the mechanisms of action is for the two HMA drugs.  Both 5-azacitidine and deoxy-azacitdine are thought to cause reversal of DNA methylation as well as disruption of DNA synthesis by disruption of the dNTP (deoxyribonucleotide triphosphates: dATP, dCTP, dGTP, and dTTP)  pool (building blocks of DNA).  One difference between the two agents is that azacitidine is known to preferentially incorporate into RNA, and as a result it has a direct cytotoxic effect by inhibiting protein synthesis. Both drugs enter the cell and require a special enzyme to cause phosphorylation that results in its activation For azacitidine, that enzyme is called uridine cytidine kinase (UCK), and for decitabine, it’s called deoxycitadine kinase (DCK). So these kinases causing serial phosphorylation are distinct. We have also learned that using high doses of these agents cause direct cytotoxicity and damage and using lower doses with longer exposure are optimal for the mechanism of reversal of DNA methylation.  This reversal of DNA methylation results in gene re-expression (re-expression of genes that suppress tumor growth) and directly results in killing cancer cells.

There are a few ways to envision the mechanisms of resistance to hypomethylating agents (HMA). One is that there is a decreased transport of either drug into the cell. The transporter used for this is a human nucleoside transporter, known as an hNT.  If a cancer cell wants to avoid the toxicity of the agent, then it will find a way to mutate the transporter and thus, decrease the ability of the agent to get into the cancer cell.  Another mechanism of resistance would be inactivation of the drug by disruption of key enzymes needed to activate the drugs when they enter the cell that we mentioned earlier (UCK and DCK). If the cancer cell inactivates that key enzyme (UCK/DCK) needed for drug activation, then the agent won’t be activated and therefore won’t be able to kill the cancer cell.

Cells can also learn how to increase the elimination of the HMA drug. If the cancer cell increases the ability to break down the active HMA by increasing cytadine deaminase (CDA) levels, the cancer cell can decrease its exposure to the drug by directly eliminating it, and then the cancer cell has a growth advantage and can avoid the threat from the HMA. There are some researchers that believe there are differences in men and women with regard to CDA activity and that gender affects the likelihood of response to these agents.

Other things to consider are epigenetic mechanisms of resistance. If there’s heavy methylation on the DNA strand, the HMA drug don’t work as well in that setting because it’s so cumbersome and hard to reverse the methylation burden. It is also thought that these agents can work through immune modulation through up-regulation of PD-1, PD-L1, and up-regulation of regulatory T cells. This may come into play, but is still an area of active investigation.

Is there a way to predict what patients may be refractory to treatment with hypomethlyating agents?

There’s one group of scientists that hypothesized that a cancer cell harboring mutations to decrease incorporation of HMA into the cells would be most likely to be refractory to therapy.  This group went on to examine the expression of genes encoding the nucleoside transporter proteins and metabolizing enzymes involved in the metabolism of 5-azacitidine  (5AC) in samples from primary MDS patients and correlated the data with response to 5AC and clinical outcomes.

The researchers wanted to know if the expression of the enzymes that activate azacitidine (UCK1 and UCK2) predicted clinical response(s) to azacitidine. They looked at a cohort of 57 MDS patients, and their data showed there was a higher UCK 1 mRNA expression in those patients who responded to azacitidine, as compared to those patients who did not.  They also found that patients with a lower UCK1 expression had a shorter median overall survival than high UCK 1 expression -- 19 months compared to 49 months. This seemed to be a valuable way to evaluate and predict who may have a longer response or improved survival to HMA directed therapy. Confirming this hypothesis in a prospective manner will help support this research and may help us direct therapeutic choices for our future patients.

It would be great to have markers that help us identify which patients are going respond to specific therapies. We need to do more research with regard to this. We currently have tools like the International Prognostic Scoring System (IPSS) and (IPSS-R), which help with the prognosis for a patient with MDS. Mutation status of specific genes is another tool that is coming to the forefront for evaluating patients with MDS.  For example, MDS that harbors a p53 mutation has a worse prognosis than those without a p53 mutation.

We are incorporating these molecular tools in prospective studies for our MDS patients so we can better understand prognosis and hopefully better guide treatment selections for our patients. 

What follow-up treatments are there for MDS that resists therapy with hypomethylating agents, and does the next type of treatment selected depend on the risk category or classification of the MDS?

We know that for patients who fail treatment with hypomethylating agents (HMA), there aren’t great options at the moment.  This is an area of high investigational interest in pharmaceutical research and for many researchers – as it is a current unmet need. The most important thing for these future studies is to accurately define ’failure with hypomethylating agent’. We have to be able to demonstrate that the first line HMA therapy has not been effective. One important reason is that, as mentioned earlier, we think there are some differences between azacitidine and decitabine. For some patients that remain on HMA therapy but ’switch agents’ (i.e., from 5AC to DAC), it is very challenging to understand if patients have truly ’failed’ the first HMA therapy rather than the fact that they simply had continued prolonged exposure to any “HMA” therapy.

We know that high risk patients have poor outcomes after failing hypomethylating agents, and poor outcomes in the low and intermediate categories have also recently been demonstrated. For those patients, what can we do? Some patients go to a higher dose of HMA therapy, or just switch to the “other HMA” hoping that using a different kinase pathway (UCK/DCK) will help. Some patients are progressing from MDS to AML and they move to a more aggressive approach like intensive induction chemotherapy with the hope to get to bone marrow transplant.  And for other patients, enrolling onto a clinical trial is available to them and offers a therapy that they would not otherwise have access to.

Clinical trials that are focusing on novel combinations may be the best options for patients with refractory or relapsed MDS. (i.e.; PD1 inhibitor plus an HMA or single agent PD1 inhibition). All the options should be discussed with each individual patient if appropriate. It is really the patient and his/her physician’s choice to figure out what is best to for that individual patient.

What is most important for patients to remember if hypomethylating therapies aren’t successful?

First, be sure that HMA therapy is really not effective and isn’t working. Be sure that it truly has gotten its best chance, so don’t stop HMA therapy too soon. Hypomethylating agents take a while (four months) to have an effect, but patients want to know right away if it’s working. Patients should stay on the schedules exactly as prescribed and for the full duration -- don’t settle for an educated guess. The mechanism of action of the HMA is different than classic cytotoxic agents that have far fewer rounds of therapy where treatment stops much sooner. Hypomethylating therapy can go on for four, five, or six months before any improvement is seen, and if there’s a clinical response, we keep giving the HMA as long as it working. It we stop too soon, there will likely be relapse. We know that response is less likely and less robust when therapy is restarted a second time. It may work, but not as well -- so it’s really a lost opportunity if you stop your initial treatment early.
Education Topics: 
myelodysplastic syndromes (MDS)
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