MDS basics | Aplastic Anemia and MDS International Foundation

MDS basics

MDS and Inflammation

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.

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

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.

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

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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.

Making the Most of Office Visits with Your Specialist

Dr. Christopher Cogle is an associate professor of medicine at the University of Florida, Gainesville, Florida. He has clinical and research expertise in the

Interview: 

Communications with a medical team will often contain complex information. What would be the most important questions a patient should consider asking to let the members of the medical team know he/she needs to have concepts and specific instructions explained again?

The first thing the patient should be sure they understand and should ask is, “What is my diagnosis and is this the right diagnosis?”

With bone marrow failure disease, the diagnosis might be a little murky or unclear because of the degrees of various overlap syndromes that can occur with myelodysplastic syndromes (MDS), aplastic anemia, and paroxysmal nocturnal hemoglobinuria (PNH). Sometimes, it truly can be hard to tell where one disease stops and another one starts.

It is ok for a patient to say “I don’t understand. Will you please rephrase or restate the diagnosis in a different way?” I’m encouraged when my patients ask this. It shows that they are engaged and intently listening and want to understand what I have said.

Another thing I encourage, especially on the first few visits, is for a patient to bring a family member or close friend and ask that person to take notes or even make an audio recording of the conversation to capture what the physician and the clinical team are saying. Often, with everything occurring at once, there will most likely be something that the patient missed in the discussion. It’s good to have another person who can remind you of what your doctor said.

What resources are typically available when there is a language barrier between doctor and patient?

Patients have the right to ask for a translator. Clinics have the responsibility of providing a translator, and especially so if a clinical trial is being discussed. Call before the clinic visit and ask that a translator be available. Often times a certified medical interpreter will be on the telephone to help with the visit.

What type of questions should be addressed by the doctor and what questions should be addressed by the nurse?

In day-to-day practice, doctors have a limited amount of time, so they often focus their discussion on diagnosis, prognosis, treatment options and management of complications.

With your doctor, make sure you have a clear understanding of the diagnosis. That being said, your blood disease diagnosis may be a mixture of blood diseases. For example, your MDS may have some elements of aplastic anemia and PNH. When discussing prognosis, ask how your doctor came up with the life-expectancy estimates. Also ask how your prognosis will change with the various treatments. During the treatment discussion, ask about all available options.

For each treatment option ask about the benefits and risks. Your doctor should be able to give you specific percentages based on the published literature. You should also ask your doctor how many patients he/she has treated with each treatment option and what his/her individual experience has been. Finally, your doctor should also explain how he/she would provide blood transfusions, and prevents and treats infections and iron overload.

Nurses typically focus on the important topics of pain, side effects, fatigue, diet/exercise, taking medications, and central venous line maintenance. Social workers can help with accessing resources such as housing, transportation and food assistance. Financial representatives can help explaining your health insurance benefits, limitations, and out-of-pocket payment expectations.

How do you tell your doctor that you want a second opinion?

Signs that you may need a second opinion include: if your doctor has difficulty explaining your disease and treatment, if he/she doesn’t have time to talk with you, if he/she has little experience treating your disease.

Many patients are reticent to get a second opinion because they don’t want to offend their doctor. But in actuality, it’s usually the doctor that initiates the second opinion. In my experience, most doctors welcome a second opinion. For diagnosing and treating blood diseases, more information and perspective is helpful.

My guidance to my patients is that if you’re wondering about getting another opinion, do it quickly. With blood diseases, time is usually of the essence. Thus, the second opinion, if requested, should occur rapidly.

Aplastic Anemia and MDS Overlap Syndrome

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.

Interviews with the Experts MDS Genomics: Providing ‘Street View’ Directions of Disease

Interview: 

Please explain what is meant by genomics and genomic navigation, and how genomics differs from genetics.

“Genomics” is the umbrella term for any study of chromosomes, genes, and DNA in a cell. “Genetics” is a more specific term that pertains to the study of just the 23,000 genes in a cell. The term “genomics” is a better fit when talking about MDS because MDS doctors look at whole chromosomes and specifi c genes when trying to understand each patient’s disease. DNA, housed in the nucleus of each cell, acts as the software program directing how cells grow, divide, sleep or die. Sometimes DNA gets damaged after exposure to toxins or as a normal consequence of aging. If a blood stem cell suffers DNA damage involving a gene important for blood production, then this can result in MDS. By using new machines that read DNA, we have discovered that MDS cells contain multiple genomic problems and that there is great variability from patient to patient on which genes are damaged.

We compare the DNA of MDS cells to the DNA of normal blood cells, and then we notice where the MDS cells have changed or mutated from their normal state. Depending on what DNA in the MDS cells have mutated, this can tell us how aggressive or responsive to treatment the MDS cells will be. Genomic “navigators” such as genetic counselors and doctors with specialized knowledge of cancer gene mutations help patients and other doctors understand the clinical significance of the genomic mutations. They provide information about disease origin, prognosis, treatment options, and risk of passing on blood problems to children.

In the past with MDS, the way we approached it was like taking a trip with a poorly detailed paper map showing only major highways and cities and vast expanses of blank space. Making a decision on which of the few roads to take was simple, but the small number of roads rarely took us where we needed to go. However, with the new genomic information we have, our MDS map is fi lling in, much like what you see with detailed online maps. We now have “street view” images, where we are seeing MDS gene mutations, chromosome breakages, methylation patterns, and other molecular level details like we have never been able to before. Our new MDS maps are much more detailed, specific to the patient, and prompt us to talk about more than the few approved drugs that are available for treating MDS. Another impact of new molecular information is the power it brings in cinching the diagnosis of MDS. In the MDS clinic, we often have a very basic question: does the patient actually have MDS? A simple blood draw could help confirm the diagnosis when using the new DNA reading machines. Finally, this new understanding of MDS genomics is helping predict aggressiveness of the disease and chances of responding to treatment. Certain MDS mutations in genes (like the gene TP53 that is buried in chromosome 17) indicate more aggressive disease and may call for more aggressive treatment such as allogeneic hematopoietic cell transplant.

What specific advantages are there when genomics is applied to MDS?

There are situations where patients and doctors aren’t completely sure if the patient has MDS or not. The patient may have low blood counts, and their physician has ruled out a list of all other possible causes, such as bleeding and deficiencies in vitamins and minerals. The bone marrow biopsy may suggest MDS, but the chromosome testing may not detect an abnormality, which happens in half of MDS patients. In this common situation, patients and doctors are rightfully frustrated about whether MDS is present or not.  Using the new DNA reading machines can help patients and doctors decide whether the patient actually has MDS. Sometimes a simple blood test can pick up MDS gene mutations, and this will confirm the diagnosis.

Once we identify the MDS genetic mutations for each patient, at that point, the enemy is marked and we can follow those enemy clones by looking for their markings in subsequent blood and bone marrow specimens. Enemy identification and tracking is one important facet of ‘personalized medicine.’ Genomics is personalized in MDS because each MDS patient’s DNA damage is different than that of other patients. 

The current MDS classifi cation system, which is largely based on older light microscope technology, tries to lump together the many presentations of MDS into groups that doctors and patients can talk about in a clear manner. The number of classifications has grown steadily over the past several years out of frustration by MDS doctors in trying to honor the newly appreciated personalized nature of MDS with a continuing need for an organized system to clearly communicate the many subtypes of MDS. In the coming years, we will see more MDS genomic information included in the MDS classifi cation system and this will bring even greater value to the MDS classification systems.

Can a patient see the results of this progress in the office/treatment setting?

If an MDS patient has certain genomic mutations in their blood cells that predict for aggressive disease, then those patients will be treated diff erently in the clinic. They may be seen more often in the clinic, have labs drawn more frequently, possibly require more blood transfusions, and may be offered chemotherapy or possibly an allogeneic hematopoietic cell transplant. A patient with lower-risk MDS genomics may be seen less often initially and is provided supportive care until evidence of disease progression. The intensity and activity of the care will be more proactive because of what was learned from the MDS genomic landscape.

What is important for health professionals treating MDS to know about test results from genomic cell analysis?

The fi rst thing they should know is that there are now several pathology laboratories that just in the last few months have created new genetic testing panels for patients who are suspected to have or currently have MDS. I recommend that referring physicians consider sending a patient’s bone marrow aspirate or peripheral blood sample to one of these labs, in the event they want to rule in or rule out an MDS diagnosis. In addition, doctors may find helpful the extra information that MDS genetic testing brings to define prognosis or actionable mutations. As examples, genetic mutations in TP53 portend for a more therapy-resistant MDS, and if a patient has mutations in IDH1 or IDH2, then the patient may qualify for ongoing clinical trials of IDH inhibitors.

If hematology-oncology physicians receive a genomic report that is confusing (and many of them can be), I encourage the physician to contact an MDS specialist at one of the specialized MDS centers. The specialist will help clarify the genomic mutations and help determine if they are clinically meaningful. As an MDS specialist, I’m happy to help interpret reports because it gives me the satisfaction of making sure patients have as much information as possible to make their best treatment decision. I see a day soon when community hematologists-oncologists will be able to access MDS and leukemia specialists from afar for quick online consults and assistance in identifying relevant clinical trials. This could help patients by opening access to the latest data on molecular testing and pointing to cutting edge treatments.

What is most important for MDS patients and families to know about the present and potential applications of genomics in MDS?

It’s important for patients to ask their doctor for their MDS genomics report. Also, they should ask their doctors to spend time explaining how that information informs their diagnosis, prognosis, and treatment. Patients should ask questions to understand at least the broad brush strokes of what these reports mean and how that information forms the basis for a treatment strategy. Many patients are reticent to ask for this time because chromosomes, genes, and DNA can be confusing, and it takes time to explain normal function, let alone mutation, and we respect our doctors’ busy schedules. But patients need to know this information and its significance before they leave the doctor’s office.
Education Topics: 

ASH 2012 - Reviewing MDS Progress from Research and Clinical Perspectives

Dr. Sekeres is Director, Leukemia Program, Department of Hematologic Oncology and Blood Disorders, at the Cleveland Clinic Taussig Cancer Institute Cleveland, Ohio. In this interview, Dr. Sekeres reviews some of the more significant clinical and treatment-related findings presented at the December 2012 American Society of Hematology (ASH) Annual Meeting that would be of interest to MDS patients.

Interview: 

Were there any presentations at ASH 2012 on the clinical aspects of MDS that you think patients might find particularly interesting?

There is some evolution in the classification systems used for MDS. For years, we have used the International Prognostic Scoring System (IPSS) as the standard system for prognostication.  IPSS risk classifications help predict survival and determine what kinds of treatments will be used. The IPSS was recently revised – and there is a new system called the IPSS-R, signifying this revision. There were a number of abstracts presented that validated the IPSS-R, applying it to MDS patients in international medical centers to see if it could accurately predict survival in those patient groups. In fact, it worked in a variety of patient groups around the world!

One abstract that interested me was from a French group that took the IPSS-R and applied it specifically to patients who were on azacitidine (Vidaza®). This is important because both the IPSS and IPSS-R were developed around patients who did not receive any therapy for their MDS. So the goal was to find out if either of these systems could be used in patients who are receiving active treatment for their MDS. This French group showed that IPSS-R can be used to predict survival in patients who are treated with azacitidine, thus it is valid for a patient who is about to start azacitidine to use IPSS-R to predict how long that person will live.

However, keep in mind that IPSS-R is a new system, and doctors have to get used to using it just as much as patients need to get used to using it. In time, it may come to replace the IPSS,  but that would be a least a couple of years away, and quite possibly longer, before it is widely used.

What presentations on specific therapies did you find interesting?

One interesting report was an update about the drug romiplostin (Nplate®) which has been FDA-approved for patients with idiopathic thrombocytopenic purpura (ITP). Patients with ITP have a low platelet count, not because of a bone marrow problem, but due to an autoimmune problem in which the immune system is attacking the platelets.

This drug had been earlier studied in patients with MDS who also have a low platelet count and in the largest study, it was found that romiplostin did improve platelet counts in about 40 to 50% of MDS patients with low platelet counts.  This is good news, since we now have a drug that works for platelets in the way that growth factors like erythropoietin (Procrit®) or darbepoetin (Aranesp®) work for low red blood cell counts. Romiplostin can be considered a platelet growth factor, also called a thrombopoietic growth factor (TPO).

The problem was that while the randomized Phase 2 study was in progress, the data safety and monitoring board noticed that the patients receiving romiplostin seemed to have an increased blast percentage, and some of these patients progressed to leukemia. So the study was closed earlier than would have normally happened, and the last patients admitted to the study could not be fully evaluated as to whether they responded to romiplostin.

What I found significant was that the follow-up presented this year of patients from the original study who did or did not receive romiplostim reported that the percentage of patients progressing to leukemia was no different in the romiplostin group and the group treated with a placebo. In other words, with additional follow-up, there actually did not appear to be a higher risk of leukemia among MDS patients treated with romiplostim, compared to MDS patients not treated with the drug.

In a companion study from our group, we developed and validated a model to predict response in patients treated with romiplostin, based on prior platelet transfusion needs and blood levels of the hormone TPO. So just as there is a model to predict patient response for red blood cell growth factors such as erythropoietin, we now have a model to predict patient response with rominplostin. 

One of the more common drugs used to treat MDS is azacitidine, or Vidaza®. This is given as a shot under the skin or into the vein through an IV line. More recently, a pill form of azacitidine has been developed and studied in patients with lower-risk MDS. A clinical trial update on oral azacitidine in lower-risk MDS patients showed that approximately 40-50% of patients had improvements in their blood counts and/or in their requirements for red blood cell transfusions. This is an important preliminary study that has set the stage for the study that will determine whether oral administration of azacitidine will be FDA approved for treatment of lower-risk MDS.

What do you think patients would most want to know about the state of MDS treatment as it was presented and discussed at ASH 2012?

As we get better at discovering and defining the genetic underpinnings of MDS, the next step will be to see if patients with certain genetic abnormalities are more likely to respond to some drugs than other ones.  We are becoming more sophisticated at selecting patients who are more likely to respond to a certain drug.

There were presentations on new genetic abnormalities found in MDS, some validating findings previously reported and some identifying new findings. One of the major ones was an international collaboration reporting on over 700 patients with MDS, MDS/MPN overlap, or AML that had evolved from MDS. This study found that 20% of the patients had a genetic abnormality (called SETBP1) that happens to be the same found in a rare congenital syndrome of infants born with retardation and skeletal abnormalities. This was typical of discoveries in MDS presented at ASH 2012.

What do you think MDS patients would most want to know about the state of research as it was presented and discussed at ASH 2012?

I think it is important to point out that the quality and number of presentations on MDS were higher at this meeting than any ASH meeting I have attended over the past 20 years. Patients should fi nd it encouraging that there is so much good work going on in this fi eld. Although it will take time for these new discoveries to be translated into improvements in diagnosis and treatment for MDS, there is good reason to be optimistic that outcomes for our patients will improve in the coming years.