Advances in the Treatment of Myelodysplastic Syndrome: Targeting CD47 - Episode 1

An Overview of Myelodysplastic Syndrome

Naval Daver, MD, explains myelodysplastic syndrome, including risk factors and potential complications.

Naval Daver, MD: Myelodysplastic syndrome [MDS] is a hematological malignancy associated with bone marrow dysplastic changes that result in a decrease in production of different bone marrow cellular components, including red cells, platelets, white [blood cell] count. The main complications we see with myelodysplastic syndrome are related to the decreased production of different hematopoietic components. Due to the low white count, patients are at risk of infection, and low hemoglobin will result in anemia, shortness of breath, fatigue, weakness, and then due to low platelets they’re at increased risk of bleeding.

The risk stratification that we have used traditionally for MDS is called the IPSS [International Prognostic Scoring System]. We have used this for the last 14 or 15 years. Now there is an updated version of this called the IPSS-R [Revised International Prognostic Scoring System], and the main components that we are looking for here are 5 different things. One is what we call the bone marrow blasts. The blasts are basically the pathologist identifying abnormal leukemia MDS cells in the marrow, and they give a percentage for those blasts. Anything above 5% is considered abnormal; the higher the blasts, more than 10%, more than 15%, the higher the risk associated for the bone marrow blasts.

The second factor we usually look at are what we call cytogenetics or chromosome analysis. There are certain cytogenetics that are favorable, certain that are intermediate, and certain that are adverse based on known outcomes in patients who have had these cytogenetic abnormalities. Based on that, we assign a score for cytogenetics.

The third and fourth things that we look at are anemia, the degree of anemia, and degree of transfusion requirement. Then the fifth thing that we often look at is the platelet count of the patient. Putting all these together, we come up with a score for that patient depending on what score was assigned for each of these variables, and that helps us know the IPSS-R for that patient.

There are basically 5 different categories in the IPSS-R: very low risk, low risk, intermediate risk, high risk, and then very high risk. Based on that, we know the expected prognosis, median survival and range for a given patient based on thousands of prior patients whose data were used to generate IPSS-R. More importantly, a lot of the therapies in myelodysplastic syndrome, especially the newer combination therapies, are more specifically geared toward the higher blast, higher-risk MDS, so we usually use this IPSS-R for that identification.

It’s also important to note that MDS is a precursor; there’s another condition called acute myeloid leukemia [AML]. The distinction between MDS and AML is usually based on blast percentage. Patients who have less than 20% blasts are considered to have myelodysplastic syndrome, and those who have 20% or more per the WHO [World Health Organization] are considered to have acute myeloid leukemia. Often this may be semantics as we can sometimes see patients with 16% to 18%, 19% blasts; if they’re young, fit and healthy, we may consider treating them as AML, and vice versa. However, in patients who have low-blast MDS, especially less than 5%, or 5% to 10%, there is often a biologically significant difference from those who have true AML. Usually looking at molecular mutation profiles, we can identify these differences. In a nutshell, this is how we identify MDS, what the blast cutoffs are for MDS, and what risk stratification and prognostic scoring systems are being used today for MDS prognosis.

In general, MDS is thought to be a spontaneously occurring disease with very few identified or known risk factors. We think that in about 85% to 90% of patients who develop MDS, this is due to the acquisition of genomic mutations over time with aging. Now, in the recent 10 to 15 years, a lot of work has been done, and we are identifying a few subsets of what we call familial, or genetic MDS. These are often patients who have mutations like GATA2, RUNX1, and may have cytopenias persistent for many years before the development of MDS. Also, heavy exposure to chemicals like benzene, radon, and arsenic, but usually this is very high exposure daily or multiple days a week over years that could put a patient at risk. This is a very uncommon with today’s environmental controls and checks, and we do not see this frequently as a cause of MDS. However, in the past, this was associated with MDS in a few patients.

Now, the big group of MDS that we are seeing more and more of is what we call secondary MDS. These are patients who have had another malignancy: colon cancer, breast cancer, lung cancer, brain tumor, and got chemotherapy and/or radiation for that prior cancer, and often had a remission and even sometimes were cured from that prior cancer. They may unfortunately develop MDS many years later, 4 to 8 to years later, due to the DNA damage from the prior cancer’s chemotherapy and radiation. This is what we call therapy-related MDS. Unfortunately, this type of therapy-related MDS often is associated with difficult and adverse cytogenetics and molecular mutations.

The good news is the incidence of therapy-related MDS is usually low, 1% or 2% of all cancers treated. Of course, we still need to treat the primary cancer because that would be the main cause of mortality, but it’s important to know that 1% or 2% of patients may develop a secondary or therapy-related MDS. For this group, we are now trying to design better or different treatments because this group of patients has historically been resistant to the traditional treatments that work in the de novo or spontaneous MDS.

The main complications of MDS are related to low blood counts. Due to low production of hemoglobin and anemia, patients are at risk for cardiovascular events such as strokes and heart attack. Low platelet counts make patients at risk of increased bleeding, and we do sometimes see patients presenting with MDS with bleeding from the gum, GI [gastrointestinal] tract, and in rare cases even severe intravascular bleeding. This could be in the brain or in the abdomen or other regions.

The most common complication is usually because of a low production of white cells or neutrophils; patients who have neutropenia are at high risk for infection. Probably the most frequent complication we do see with MDS is an increased risk of infection because of immunosuppression from low white cells.

Transcript edited for clarity.