Review of Myelodysplastic Syndromes Aids Experts in Diagnosing and Treating Patients

Justin Taylor, MD

Myelodysplastic syndrome (MDS) has recently been reclassified by the World Health Organization (WHO) to acknowledge its severity and recognize various mutations observed in patients.

With this major change, some cases of MDS can be classified by molecular mutation, including those with SF3B1 or TP53 mutations or patients with deletion 5q abnormalities. There is also now a category of MDS and acute myeloid leukemia (AML) for patients who have more than 10% bone marrow blasts.

Patients with MDS are at a higher risk of developing AML as they experience a reduction in peripheral blood cells. According to Justin Taylor, MD, the disease is divided into subtypes based on a patient’s risk of developing AML.

As a way to provide clinicians with the knowledge they need when treating patients with AML, Taylor, assistant professor of medicine at the University of Miami, Sylvester Comprehensive Cancer Center, and Mikkael Sekeres, MD, MS, professor of medicine and the chief of the Division of Hematology, Leukemia Section, at the University of Miami Health System and Sylvester Comprehensive Cancer Center in Florida, developed a review, which was published in the Journal of the American Medical Association, to help experts better care for patients based on their MDS risk profiles.

“In this review, we created a figure where we showed how the disease could evolve from something that is a phenomenon of seeing these mutations and one where we don't know who's going to progress to disease, to when we see the disease, maybe a low-risk patient, all the way to the high-risk patients with MDS where maybe it evolves to AML. That's where the field is now in terms of research. [We are] figuring out what dictates those different steps of the disease and maybe how we could prevent progression,” stated Taylor in an interview with Targeted Oncology^TM.

In the interview, Taylor discussed the recent changes that have been seen with this new classification of MDS and how this review article can help make people more aware of the treatment options available.

Targeted Oncology: Can you discuss the classification of MDS and some of recent changes that have been made in the field?

Taylor: Myelodysplastic syndromes are a spectrum of diseases. The classification has evolved over time and the major classification have been from the WHO. The last prior to this year was in 2016. In 2022, we got an updated fifth edition of the WHO classification of MDS. At the same time, separately the International Consensus Classification also put out a new classification for myeloid neoplasms, including MDS. We had 2 different classification systems this year. Both aligned quite well. There were some small differences, but those are being worked out.

The major changes for both, particularly with WHO since we can compare it to the previous 1 which was focused more on genetics, some of the highlights are SF3B1 mutations, which is a splicing factor mutation. That was previously 1 of the provisional diagnosis for MDS based on genetics. Now, MDS with SF3B1 mutations are a fully recognized entity. Then another new one was MDS with biallelic tp53 mutations, meaning more than 1 tp53 mutation or a tp53 mutation with the allelic loss of 17p, which would be the other tp53 gene. Those were the big changes that were made this year. There are now the 2 different classifications and some of us in the MDS community are figuring out how we're going to work with the 2 systems.

Can you discuss the subtypes in which patients with MDS are divided into?

Those classifications do serve as subtypes if you're getting into the nitty gritty of detailed molecular classifications. But for the patients, it doesn't affect their treatment too much whether they're in a certain subcategory or another. For treatment purposes, we classify them based on their risk of transformation to acute myeloid leukemia and risk of death from MDS. Overall, there are 5 risk categories, going from very low-risk to very high-risk. Just for having easier use of these categories, we've mainly broken them down into lower-risk and higher-risk. In the review article that we wrote recently, we focused on those lower-risk groups, which would include the 3 low-risk groups and the intermediate- to high-risk categories of MDS.

Can you discuss your review on the diagnosis and treatment of myelodysplastic syndrome?

The review is in JAMA, the Journal of the American Medical Association. MDS is considered a rare disease with cases [found in] 4 per 100,000 people in the United States. It is on the rare side. This review hopefully will make more people aware of [MDS]. My coauthor, Mikhail Sekeres, MD, has been working in the field of MDS for a long time and I learned a lot from his experience.

The article that we wrote was a review, mainly speaking aboutwhat we know and bringing together other people's work plus these new classifications. We talk a little bit about the path pathobiology and pathophysiology of the disease, how it came to be. Some of the things we're studying now in the lab are clonal hematopoiesis. This is a new phenomenon of healthy individuals that have these mutations seen in the bone marrow that are associated with MDS or AML, yet they have no blood abnormalities, so they don't have a disease. Many of us are studying how clonal hematopoiesis eventually might lead to MDS or AML through acquisition of other mutations, whether it's due to inflammation or infections, etc. There's a lot to learn there.

In this review, we created a figure where we showed how the disease could evolve from something that is a phenomenon of seeing these mutations and one where we don't know who's going to progress to disease, to when we see the disease, maybe a low-risk patient, all the way to the high-risk patients with MDS where maybe it evolves to AML. That's where the field is now in terms of research. [We are] figuring out what dictates those different steps of the disease and maybe how we could prevent progression.

What are the key takeaways from this review?

We reviewed standard treatment we didn't get any into any of the new drugs that might be approved. This was meant to be for a practicing physician, maybe 1 that doesn't see a lot of MDS, to familiarize themselves with the treatment and if they say had a patient with MDS, to generally know how it's treated. Even if they may not be treating MDS, we think patients with MDS should be referred to a hematologist for treatment. This is also written for that hematologist who is treating the patients and spans from low- to high-risk treatment.

Future directions would be some of the new drugs that are coming out down the pike. Those are available at research centers, academic universities, and we highlight in the review that clinical trials are a part of the treatment, they're not just for after these treatments don't work. They can even be incorporated for any patient as part of the first consideration. Maybe they don't opt for a clinical trial, but it could be discussed as an option. Since we do see that there are some drugs that may be approved within the next few months or 18 months, patients could be getting those right now, but only on clinical trials.

What treatment options are currently available for these patients?

With low-risk, we went over that with all the studies that have been done for different treatments for low-risk MDS, none of them have changed the natural history of the disease. All these treatments are more symptomatic treatments and helping the patients to overcome the symptoms and live their life more normally. Each patient may have a different treatment because the disease is heterogeneous and because of how it presents. Most patients have anemia, so low hemoglobin, and they may need blood transfusions of red blood cells. There are agents called erythropoiesis-stimulating agents [ESAs]that can boost the hemoglobin and prevent patients from needing blood transfusions. That's the mainstay of the treatment.

We discussed the different types of ESA’s essays for patients who do not respond to ESAs or stop responding to ESAs. There are also drugs like luspatercept [Reblozyl]. Ultimately, even some low-risk patients have poor outcomes and need other treatments. There are hypomethylating agents that can be used for low-risk patients if they stopped responding to any of these therapies, or for patients who maybe have other adverse events besides anemia, like thrombocytopenia, neutropenia.

Then for high-risk patients, the standard treatment are the hypomethylating agents, either azacitidine [Vidaza] or decitabine [Dacogen] which have been reviewed in studies that led to their FDA approval. Patients with high-risk MDS should be treated fairly. Low-risk patients can sometimes be observed if they're not having any symptoms, and the treatment is just to manage the symptoms. But with high risk MDS, we have good data that treatment can prolong survival. We recommend treating patients right away and not waiting, and to refer patients for metabolic stem cell transplant. That was a bit beyond the scope of our review to talk about everything that's related to hematopoietic stem cell transplant, but that is a mainstay part of the treatment as well and the only curative regimen for MDS.

We refer patients for a hematopoietic stem cell transplant consideration and treat with the hypomethylating agents. After that, there's no standard treatments. That's where some of these clinical trials come into play. Hopefully, we will be getting new drugs approved soon since after hypomethylating agents if the patient does not get a stem cell transplant or they're not a candidate for it, there's no standard treatment for patients. That is a big unmet medical need.

What clinical trials are ongoing in this space?

There are clinical trials looking at agents like venetoclax [Venclexta] and combining that with azacitidine or decitabine to be the standard treatments for someone in the frontline or even for relapsed/refractory patients. Because venetoclax is approved for AML, patients may be able to receive it off-label. Some groups are reporting the outcomes of that treatment.

Some of the other treatments that are being studied are targeted towards specific high-risk subgroups like the tp53 mutated subgroup that we talked about. They tend not to respond very long to the hypomethylating agents and even after stem cell transplant, they may be at higher risk of relapsing. One of the drugs is an immunotherapy type of drug, magrolimab, or an anti-CD47 antibody drug. That works by causing the body's immune system to attack the cancer cells, the MDS cells in this case. That [agent] is being combined with hypomethylating agents. There are a lot of combination studies to see if there is anything we can add to the standard treatments to make outcomes better.

REFERENCES:

Sekeres MA, Taylor J. Diagnosis and treatment of myelodysplastic syndromes: A review. JAMA. 2022;328(9):872-880. doi:10.1001/jama.2022.14578