Lower-Risk MDS: Diagnosis and Treatment Options | Aplastic Anemia and MDS International Foundation

Lower-Risk MDS: Diagnosis and Treatment Options

Maria Baer joined the University of Maryland Marlene and Stewart Greenebaum Cancer Center in Baltimore, Maryland in 2007 as director of hematologic malignancies and professor of medicine and molecular medicine, University of Maryland School of Medicine. She previously served as chief of the leukemia section at Roswell Park Cancer Institute and professor of medicine and associate professor of molecular pharmacology and cancer therapeutics at the University at Buffalo School of Medicine and Biomedical Sciences in Buffalo, New York.

In this interview, conducted at the AA&MDSIF Washington, DC Patient & Family Regional Conference, Dr. Baer discusses lower-risk MDS – how it is diagnosed and classified and what treatment options are available.

Can you explain what is meant by lower-risk MDS and how it differs from higher-risk MDS?

The current standard way to defi ne risk in MDS is by using the International Prognostic Scoring System (IPSS). It uses three criteria to assess whether MDS is classified as lower- or higher-risk. The first criterion is the number of low blood counts, specifically defined as hemoglobin level less than 10 grams per deciliter, neutrophil count less than 1,800/uL and platelet count less than 100,000/mm3. The second criterion is the percentage of blasts, or immature white blood cells in the bone marrow, categorized as less than 5%, 5 to 10%, and 10 to 20%. In the current classification, which is the World Health Organization (WHO) classification, 20% blasts or greater establishes a diagnosis of acute myeloid leukemia, rather than MDS. The third criterion is whether chromosome abnormalities are observed in the bone marrow, and, if so, which specific abnormalities are observed. About half of the time, chromosome abnormalities are acquired in bone marrow as part of the disease process in MDS. Chromosome findings may be favorable, unfavorable or intermediate, in terms of risk. Favorable chromosome findings include normal chromosomes, deletion, or loss, of the long arm of chromosome 5 or chromosome 20, or loss of the Y chromosome. Unfavorable findings include chromosome 7 abnormalities, or presence of three or more abnormalities, which is called a complex karyotype. All other abnormalities are considered intermediate.

A score is assigned based on these three factors – number of low blood counts, percentage of blasts in the bone marrow, and chromosome findings. The score will fall into one of four categories. These include the low, intermediate-1, intermediate-2, and high risk categories. The low and intermediate-1 risk categories are considered lower-risk, and the intermediate-2 and high-risk categories are considered higher-risk. The degree of risk refers to whether the patient’s survival time will be adversely affected, and the chance of the disease progressing to acute leukemia over time. So whether survival is likely to be affected as well as the likelihood of MDS progressing to acute leukemia are predicted by the number of low blood counts, the percentage of blasts in the bone marrow, and the bone marrow chromosome findings.

Is it better to use two classifi cation systems to be sure of a correct assessment of disease severity?

We use the IPSS for making decisions about treatment. There is a newer category, the World Health Organization (WHO) classifi cation–based Prognostic Scoring System (WPSS), which takes transfusion dependence into account, along with the three factors in the IPSS, but currently the IPSS lower-risk and higher-risk categorization is the major determinant of which treatments will be considered. It is also important in designing clinical trials and applying the results of clinical trials. We do not take data from a trial involving lower-risk patients and apply them to higher-risk patients, or vice versa.

 

What are the main treatment strategies for lower-risk MDS? Are there advantages and drawbacks to each?

The major problem in lower-risk MDS is low blood counts. In lower-risk MDS, the chance of developing acute leukemia is low, and survival is relatively unimpaired. So the major goal is to improve the blood counts, in order to improve patient safety and quality of life. In assessing treatment options in a patient with lower-risk MDS, the fi rst distinction is to determine the patient’s primary problem. Is it anemia, or a low white blood cell count, or is it a low platelet count?

 

Anemia is the most frequent problem in MDS, affecting 85% of MDS patients. If anemia is the primary problem, there is a specifi c set of treatment options. For lower-risk patients whose primary problem is anemia, the first thing we look at is the bone marrow chromosome analysis, to see if there is loss, or deletion, of part of the long arm of chromosome 5, called “deletion 5q.” These patients have a very good chance of responding to a drug called lenalidomide (Revlimid®), with about a 75% chance of becoming transfusion-independent, if they have been needing red blood cell transfusions. Lenalidomide is a pill that is usually taken every day.

If a lower-risk patient whose primary problem is anemia does not have the deletion 5q bone marrow chromosome abnormality, the next treatment to consider is erythropoietin (EPO). EPO is the hormone that stimulates red blood cell production in the bone marrow. EPO is administered as an injection under the skin, and there are two diff erent preparations of EPO, which are not identical. Procrit® is shorter-acting, while Aranesp® has a longer lasting effect.

If patients are producing suffi cient levels of erythropoietin on their own, there is a much lower chance of responding to EPO therapy. But if patients are anemic and have low EPO levels, there is a better chance that this therapy will help. The chance is even higher if they are not requiring frequent transfusions. If their EPO level is high and/or they need frequent transfusions, the chances of success with EPO therapy are diminished.

There is also a small group of patients who respond to immunosuppressive treatments. In aplastic anemia, there is a high response rate to a drug called antithymocyte globulin (ATG), usually given with cyclosporine, which is a T cell suppressor. Some MDS patients respond to this treatment. The major predictors of success with this approach are having a certain tissue type known as HLADR-15, being younger, and having a shorter history of transfusions.

If the primary problem is a low white blood cell count and the increased risk of infections that comes with it, or a low platelet count which can cause bleeding problems, lower-risk MDS is approached diff erently. For patients with a low white blood cell count and/or a low platelet count the treatment of choice is a demethylating agent, either azacitidine (Vidaza®) or decitabine (Dacogen®). Also, for patients with anemia for whom the treatments mentioned earlier are not working or stop working, the best treatment is a demethylating agent.

When does active treatment take over from watchful waiting or supportive care?

If a lower-risk MDS patient’s anemia is getting worse, with fatigue, shortness of breath, and loss of energy compromising their quality of life, and they need transfusions or are approaching that point, it is time to intervene. Significant decrease of the white blood cell count or the platelet count is also an indication for beginning treatment. It should be noted that treatment with demethylating agents can depress blood counts for an initial period before they start to come back up, so that is another consideration to be aware of in terms of when to start treatment.

If stem cell transplantation is the only potential cure for MDS, why don’t we do them for all patients instead only the high risk patients? Does degree of risk play a part in this decision?

Transplant does have the potential to cure MDS, and as far as we know, it is currently the only curative approach. We have patients with long-term disease control using demethylating agents, but this will likely not last indefi nitely, and the disease will eventually become resistant to this treatment and become active again. Transplant is an approach that can result in a cure, but it is also a high-intensity treatment that can result in complications. There are some potential negative outcomes with transplants. One complication is graft vs. host disease which can be chronic illness that is associated with a very poor quality of life. Transplant can also be associated with fatalities. So it can shorten life rather than lengthen it.

One very important research study looked at transplant outcomes in patients in each of the IPSS risk categories. On average, people with lower-risk disease who did not have a transplant lived longer than those who did. This is because lower-risk MDS has less of an impact on survival. However, among patients with higher-risk disease, those who had transplants lived longer than those who did not. The data in this research study clearly show why we do not recommend transplants for all MDS patients.

These are general guidelines, and treatment decisions have to be individualized. There are definitely exceptions to the general guidelines. Lower-risk MDS patients can have treatments with varying degrees of success, but those with low platelet counts can experience a real safety risk. In this case, if other treatments have not worked, then a transplant for these lower-risk patients can be very appropriate. We also have to recognize that patients are different, having different outlooks and sets of life circumstances, so advantages and disadvantages all have to be weighed for each patient.

Are new treatments taking the place of existing treatments or just adding to the ‘therapeutic arsenal’ of resources available to low-risk MDS patients?

We are getting good responses to drugs and therapies that we use now, for example a 60 to 70% chance of responding to demethylating agents. So we would generally not withhold a drug known to work pretty well, even if a new one was available. A new drug may be tried in combination with an existing one, or used in cases where existing drugs were tried and had little or no effect, or worked well for a while and then stopped being effective. This is where the clinical trials come in – trying a new drug in patients who have not responded to the established treatments, or adding a new drug to an existing treatment.

What are the most important things to remember a patient who has been classified as lower-risk?

First, they should make sure that they understand their disease -- what it is and how it works. They should also be observant and attuned to the symptoms that they have, in order to explain them to their treatment team, and they should be involved by keeping track of their blood counts, at the very least. They should also be sure they have had the appropriate testing in order to make the correct diagnosis made and that they have appropriate professional advice in understanding their options for treatment. Remember, lower-risk MDS is a rare disease. Also, once the diagnosis is established and treatment options are appropriately addressed, it is important to try not to become overly focused on the disease, as this can reduce quality of life.

Interviewee: 

Maria Baer. MD

Lead Photo
Position / Title: 
Director, Hematologic Malignancies Program
Institution: 
University of Maryland School of Medicine.

Maria Baer joined the University of Maryland Marlene and Stewart Greenebaum Cancer Center in Baltimore, Maryland in 2007 as director of hematologic malignancies and professor of medicine and molecular medicine, University of Maryland School of Medicine. She previously served as chief of the leukemia section at Roswell Park Cancer Institute and professor of medicine and associate professor of molecular pharmacology and cancer therapeutics at the University at Buffalo School of Medicine and Biomedical Sciences in Buffalo, New York.