A review of the diagnosis process for myelodysplastic syndrome, followed by insight on appropriate risk stratification.
Amer Zeidan, MBBS, MHS: The diagnosis of myelodysplastic syndrome [MDS] has evolved over time because myelodysplastic syndrome is largely in older patients. For a long time, this was so much of a neglected disorder largely because we did not have many active therapies. Many times, patients would have some myelolipoma, which is the most common manifestation of MDS, and many physicians or even some hematologists would decide against doing a bone marrow biopsy because they think of it as an invasive procedure, and there was not much you could do about it. This has changed substantially over the last 10 to 15 years because we have more effective therapies. We understand that establishing diagnosis is very important, and bone marrow biopsy is not a difficult procedure. We do it very routinely without significant problems in the vast majority of patients. The first step in diagnosis generally involves ruling out other causes of low blood counts and cytopenias. Those could be vitamin deficiencies, other medications, other clinical conditions such as immune conditions, or other blood conditions. All these could [mean] MDS.
The diagnosis would also, in some situations, include ruling out some rare abnormalities such as paroxysmal nocturnal hemoglobinuria or copper deficiency, things like that. Once all these are ruled out, generally the next step is doing a bone marrow biopsy, and the diagnosis is open established based on the bone marrow biopsy in conjunction with a review in the blood and a bone marrow smear. This is usually how the diagnosis of MDS is established. This is usually done by a hematologist after the patient is referred from their primary care physician who would usually be the first person to spot the low blood counts. Sometimes the patients would not have any symptoms, but blood counts are picked up on a routine screening or physical exam bloodwork. Sometimes the patient could have significant symptoms related to bleeding from low platelet infections, low neutrophils, or symptoms of anemia related to the low hemoglobin.
After the diagnosis of myelodysplastic syndrome is established, the attention will turn to risk stratification. Risk stratification or prognostication is extremely important in myelodysplastic syndrome because those conditions occur on a wide spectrum in terms of the outcomes of patients. Some patients can live for many years with minimal symptoms, for which you check their blood counts every few months all the way to very aggressive forms that almost resemble acute myeloid leukemia in terms of complications related to infections, bleeding, and short survival, which in the most aggressive forms of MDS, in the absence of treatment, could be a few months to less than a year. Because the natural history is highly variable, establishing the specific risk status of the patient is important.
Over the years, there have been multiple prognostic scoring systems that were established. One of the first ones that has been used for a long time is the International Prognostic Scoring System: the IPSS. This was described in 1997 in publication in Blood, and it has been the de facto standard of care in terms of prognostication for a long time because it was used not only to counsel patients, but also in terms of enrollment in clinical trials and even approvals for some of their medications by the FDA and other agencies. However, over time, we realized that the IPSS suffers from certain problems. For example, it overestimated the prognostic impact of that blast count and underestimated the prognostic impact of the karyotypic or cytogenetic abnormalities. Because of that and other considerations, a new version of the IPSS was developed, the revised IPSS or IPSS-R. This was published in 2012, and it has gradually become the most commonly used prognostic scoring system. It’s now being used for clinical trials for decision-making. It’s more accurate in terms of predicting the different prognostic groups. There are multiple other prognostic scores that are out there. One of them is WHO [World Health Organization] based prognostic scoring system and The [University of Texas] MD Anderson [Cancer Center] prognostic scoring system.
Ultimately, whichever 1 of those you are using, the bottom line currently is to classify the patients in 1 of 2 big groups: higher risk or lower risk. The reason for that is the course of care is very different. For higher-risk MDS—which would include, in the revised IPSS, very high-risk and high-risk categories—the goals of care revolve around changing the natural history of the disease: trying to cure the patient if possible with a bone marrow transplantation. Lower-risk MDS, which is usually defined by the revised International Prognostic Scoring System as the risk categories of low and very low. In those patients, the quality of life is the focus because, generally, we cannot cure those patients. We generally don’t do a bone marrow transplantation for those patients because the risks of the procedure outweigh the benefit, and the goal is to minimize transfusions to reduce the risk of hospitalizations and infections and such. Then you have 1 group that is the intermediate-risk group within the revised IPSS, and for those patients, there are different ways to treat them. They could be treated as higher risk or lower risk depending on a number of factors we consider, based both on the bloodwork as well as clinical parameters.
In terms of which scoring system to use, people tend to use several scoring systems. All of them have certain caveats along the lines of what we mentioned. One of the bigger caveats of all the current scoring systems is that none of them includes the molecular parameters, which we are understanding more and more that they cannot pick prognosis significantly. For example, having a TP53 mutation—we are recognizing more and more that having those mutations will worsen survival significantly in patients with MDS. However, it’s not part of any of the current prognostic scoring systems. They are going to include that in the molecular-based IPSS or molecular-based revised IPSS. Until that’s available, you have to apply other aspects in your estimation, such as the comorbidities of the patient and what other medical conditions they have, because those are not often included in the prognostic scoring systems. The 1 I tend to use the most is the revised IPSS. In some patients with the revised IPSS, such as an intermediate-risk group, those patients could sometimes have higher risk or lower risk. In those patients, I tend to subcategorize them using the WHO-based scoring system. Sometimes the clinical trials will mandate you to use 1; some of the clinical trials are still using the IPSS. In those situations, we calculate that as 1. Overall, the revised IPSS is the most commonly used 1 in my practice and I suspect in most settings.