Updates to MDS Classification Complicate Yet Better Inform Treatment Navigation in MDS

In an interview with OncLive®, Mikkael A. Sekeres, MD, MS, provided insights into recent developments and changes in the management and classification of myelodysplastic syndromes (MDS), as discussed at a recent OncLive State of the Science Summit on hematologic malignancies. This included the complexities and contradictions of current MDS classification systems and risk stratification, the use of International Prognostic Scoring System (IPSS) risk stratification systems to help inform treatment approaches, current recommendations for the use of luspatercept-aamt (Reblozyl), and continued efforts to develop hypomethylating agent (HMA) combinations that provide benefit for patients with MDS.

“[In my presentation], I wanted to demonstrate how complicated it is to make the diagnosis of MDS, and how we’re struggling with classifying it now that we have competing classification systems that have been developed,” Sekeres, who is a 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, stated during the interview. “I also [wanted to show] how we’re starting to use the genetics of these diseases to identify additional therapeutic options for subsets of our patients.”

As chair of the event, Sekeres provided further insights on some of his colleagues’ presentations in another interview.

OncLive: What was the overall importance of discussing developments in MDS at the summit?

Sekeres: This is an exciting time in hematology and there are a lot of new drugs coming out. Some of those are molecularly targeted, and we’re starting to see survival advantages [with these options] in patients who have cancers of the blood and bone marrow. [In this meeting], we took the audience through a few different examples of where we’ve seen these advancements. I started things off with a case discussion about MDS, which was a good model for both MDS and myeloproliferative neoplasms.

What are the current challenges associated with MDS classification, and how should an oncologist navigate the differences between classification systems?

MDS risk stratification is complicated. The World Health Organization [WHO] came out with a revision to how we classify MDS in 2022 [reorganizing MDS categories by histological and genetic covariates]. In the exact same month, the International Consensus Classification [of myeloid neoplasms] came out as well and [their classification criteria] did not exactly line up with the WHO’s. Many of us around the world have contributed data to a big effort to rationalize the classification of MDS.

There was a presentation at the 2023 ASH Annual Meeting evaluating that. What it boiled down to is [that when] first seeing a patient with MDS, getting molecular genetic data about their MDS and then determining if a patient has a TP53, SF3B1, or del5q mutation [is critical]. Then [we need to move] to the morphology of the disease, [evaluating features such as whether] patients have excess blasts or not. [We should] allow that to help us with both classifying these patients and starting to identify [appropriate] therapies.

How have recent updates to MDS risk stratification systems impacted treatment selection in this space, as per the presentation by Namrata Chandhok, MD?

Several abstracts that were presented at the 2023 ASH Annual Meeting looked at these different classification systems and also looked at the IPSS-Molecular [IPSS-M] model to see how accurate it is in predicting outcomes. We start by applying either the IPSS-revised or the IPSS-M stratification systems to determine whether a patient has lower-risk MDS or higher-risk MDS. That helps us [understand] the urgency of treating a patient and what therapies are available. [That can] differ in different countries depending on whether a patient has lower-risk or higher-risk disease.

What are some current or emerging therapeutics of interest within MDS?

Some of the clinical data that has been presented has looked at luspatercept. Luspatercept was initially approved in the United States for [the treatment of anemia in] patients who have ring sideroblasts associated with MDS after they’ve already been exposed to an erythropoiesis stimulating agent [ESA]. That was based on [the phase 3 MEDALIST trial (NCT02631070)] that showed an approximately 40% [red blood cell] transfusion independence rate that lasted for approximately 32 weeks.

We now have updated data from [the phase 3 COMMANDS trial (NCT03682536)], in which luspatercept was compared up front with ESAs in patients with MDS to see what their difference in response rates were. In that study, the response rates were approximately doubled for patients who received luspatercept vs [epoetin alfa], and the duration of response was approaching 2 years [with luspatercept]. An important caveat to that study is that most of those responses occurred, once again, in patients who had ring sideroblasts or the SF3B1 mutation. Most of us in the field are starting to move towards recommending that—if [patients] have [these features] with their MDS, you could start with luspatercept instead of an ESA or use an ESA to start and then switch to luspatercept [if patients progress on that] ESA. For patients who don’t have ring sideroblasts or an SF3B1 mutation, we generally start with ESAs.

Another drug that Dr. Chandhok talked about was the telomerase inhibitor imetelstat. Results from the [phase 2/3 IMerge trial (NCT02598661)] were published recently in Lancet Oncology. In this study, [39.8%] of patients who received imetelstat [were red blood cell] transfusion independent [at 8-weeks] compared with [15.0%] of patients who received placebo. We’re still waiting to see whether this will get approved by the FDA, and we should find out in 2024. If it is [approved], imetelstat would represent another treatment option for patients with lower-risk MDS.

Looking ahead, what ongoing or future research in MDS are you personally involved in or anticipating?

I’ve dedicated a long part of my career to looking at combination therapies in MDS, and we’re still waiting for something to hit. It has been frustrating with a lot of different trials looking at combinations, particularly in higher-risk MDS, that are based on HMA [backbone combinations] vs HMA monotherapy. We’ve learned a lot on this journey to get to this point, but we’ve also seen a lot of trials that have fallen short. We still have 1 [trial] that we’re waiting for results to be reported from this year. That’s a randomized study of patients with higher-risk MDS receiving azacitidine monotherapy or combined with venetoclax [Venclexta]. [There will be] more to come on whether we have a new standard combination therapy to treat higher-risk MDS, or whether we’re going to continue to turn to azacitidine monotherapy as our standard of care.