Examining Risk Stratification and Novel Treatment Options for Patients With Low and Intermediate-Risk MDS

At the 2024 Great Debates & Updates (GDU) in Hematologic Malignancies meeting in Los Angeles, California, Pinkal Desai, MD, Weill Cornell Medicine, New York, New York, shares expert insight into understanding risk stratification and the range of treatment options available for patients with low- and intermediate-risk myelodysplastic syndrome (MDS).

“It's a very good time to be in this space. Patients have so many options and more trials are ongoing in this setting. There's a lots of other lower-risk targeted therapies coming along,” explained Dr Desai.

Transcript:

Hello, I'm Pinkal Desai. I'm an associate professor of medicine at Weill Cornell Medical College in New York. I'm here at the [Great Debates and Updates] meeting 2024 in [Los Angeles], and I have thoroughly enjoyed the session for the myeloid malignancies and leukemia.

We [have] covered a lot of topics here. I gave a talk on lower-risk [myelodysplastic syndrome] MDS and understanding diagnosis, risk stratification, [and] how to think about improving transfusion requirements in MDS patients. What we covered beginning from a diagnosis, there is a newer classification of MDS with both [World Health Organization] WHO and [Intensive Care Coordination] ICC having slightly different variations of the sub-categories of MDS and diagnosis.

The biggest change I would say is that in general, MDS is now categorized in both classifications as MDS with defining genetic abnormalities that include deletion 5Q, SF3B1, TP53. Then there is the 2^nd  category of morphologically defined MDS, which is to do with dysplasia and the excess blast count, which takes into consideration people who have lower blast count and have MDS-defining—they're more categorized in that genetic defining groups—but they don't have it. It goes into this catch-all MDS group.

The biggest differences between WHO and ICC, I would say, is the definition of TP53 MDS, where WHO doesn't quite classify any allele frequency variations or criteria. In ICC, it's defined as 10% TP53. And ICC has a new category of MDS/AML, which sometimes is confusing to patients, if they have MDS or have AML, but for all practical purposes, I don't think it has changed much in how we manage MDS. We always knew that higher blast count MDS behaves like AML.

We also covered the prognostic tools that we have, [such as the] (Revised International Prognostic Scoring System) IPSS-R, which is based on the degree of cytopenia and cytogenetic groups in MDS as well as the blast count and bone marrow findings does have a classification that is the most used in most clinical trials. But we now have a new IPSS-M—molecular—classification that also incorporates all the other mutations that are present in MDS, and it's able to upstage or downstage about 40% of patients with MDS. It's an important tool in terms of understanding how our patients will do, and whether transplant should be done, and at what point the transplants should be done.

In terms of lower-risk MDS, we talked about several options that are available for our patients. Again, these are not high blast count MDS [cases]. We covered (erythropoiesis-stimulating agents) ESAs, which have been around for a long time. Patients that respond to ESAs are people who have a low (erythropoietin) EPO level, usually less than 500, and who have lesser transfusion requirements. I think that predictive calculator is available and should be deployed in understanding who would respond to these ESAs or not.

We also covered the approval of luspatercept. Luspatercept is approved based on the COMMAND study in all frontline MDS patients, even those who are ESA-naïve because, in people who had an EPO level [of] less than 500, the trial randomized patients to luspatercept versus EPO and there was a significant transfusion independence favoring luspatercept, 64% versus 30%. It's interesting as the ring sideroblast, it's a clear winner and it does a good job and should be used over ESAs in the ring sideroblast category.

For the non-ring sideroblast category, there it seems both are equi-poised in terms of the percentage of response, but on the trial, the duration of response was higher for luspatercept. Sometimes people take that into consideration, but you have both options available for front-line MDS treatment. Luspatercept is obviously based on the MEDALIST trial, already approved for second line setting for the ring sideroblast patients. But now with the COMMAND study, it also has a frontline approval.

We have 2 drugs—ESA and luspatercept—for frontline options. The recent approval of imetelstat is also a new approval in lower risk MDS. Imetelstat treatment was randomized to placebo in the IMerge study and there were 40% transfusion independence compared to about 15% in the placebo arm, [which] led to its approval. It is currently approved for people who have had prior ESAs or some kind of front-line therapy.

There are some cytopenias we see, with grade 3 and 4 cytopenias with imetelstat, but with good dose modification we're able to usually work around that. We tend to use that more in the second-line setting after ESAs or luspatercept because I see lower-risk MDS as sort of a marathon of drugs one after the other to try to get these patients transfusion independent in the long run. And there's no argument that for deletion 5Q, lenalidomide is the standard of care for transfusion-dependent patients.

There is some movement to try to use it in the non-transfusion dependent patients. Those trials are ongoing. There seems to be more time to transfusion-dependence in the lenalidomide arm, but again I think with more follow-up we will determine if we have to wait until transfusion dependence or could be used sooner. Right now, the standard is to use it in people who are transfusion dependent or have started to get transfusion dependent with deletion 5Q. And in some people, after all these drugs are used, lenalidomide does have a 20% response rate in the non [deletion] 5Q group, so that is also an option.

Lastly, I think (hypomethylating agents) HMAs have also been used in lower-risk MDS. I tend to use HMAs last, when all of these drug options are over, but that is also in our armamentarium. When to [begin transplantation with] these patients remains an open question and that's where IPSS molecular risk classification is important because you would consider those people who are sort of the intermediate one but slightly higher risk on the IPSS-M, [that] we could consider transplant in these patients, even in the so-called lower risk when it's upstaged by IPSS molecular.

It's a very good time in this space. Patients have so many options and more trials are ongoing in this setting, with [Interleukin Receptor Associated Kinase-1] (IRAK1) inhibitors. There's a lots of other lower-risk targeted therapies coming along. It will be exciting to see how that pans out.

Source:

Desai P. Advancing Risk Stratification and Symptom Management in Patients with Low- and Intermediate-Risk Myelodysplastic Syndromes. July 27-28, Los Angeles, California.