Key Updates in Lower-Risk MDS

Research plays a pivotal role in the continually evolving treatment landscape for myelodysplastic syndrome [MDS]. In this Precision Medicine Perspectives series titled “Recent Updates in the Management of Lower-Risk Myelodysplastic Syndrome,” Yazan Madanat, MD, an assistant professor at UT Southwestern Medical Center in Dallas, Texas, and the director of the Simmons Comprehensive Cancer Center, discusses highlights from the 2023 ASH [American Society of Hematology] Annual Meeting, focusing particularly on therapies for patients with lower-risk myelodysplastic syndrome.

Targeted Oncology™: What are the current unmet needs in the management of lower-risk MDS?

Yazan Madanat, MD: In lower-risk MDS, lenalidomide has been approved for patients with deletion 5q with really good response rates. However, patients with non–deletion 5q MDS have limited options. Erythropoiesis-stimulating agents [ESA] have been commonly used off-label to mitigate the anemia, which is the most common cytopenia for patients with lower-risk MDS. And luspatercept was approved based on the results of the MEDALIST clinical trial as second-line therapy post–ESA therapy, specifically for patients with MDS with SF3B1 mutation or MDS with ring sideroblasts.

However, in the MEDALIST trial, when we look at patients with heavy transfusion burden, i.e. those needing 6 units of blood in an 8-week period, we note that only 9% of those patients respond to luspatercept. Therefore, patients with non-deletion 5q, and particularly patients with a heavy transfusion burden, are areas of unmet need in MDS management.

Targeted Oncology: What were some takeaways from abstracts looking at imetelstat that were presented at the 2023 ASH [American Society of Hematology] Annual Meeting?

Yazan Madanat, MD: There were a few abstracts looking at imetelstat based on the results of the IMerge phase 3 clinical trial. Imetelstat is an oligonucleotide and a first-in-class telomerase inhibitor that targets cells with high telomerase activity by directly binding to the RNA template of the telomerase enzymes. Imetelstat was studied in the IMerge phase 3 clinical trial specifically in patients with non–deletion 5q MDS who were heavily transfusion-dependent and was compared with placebo in the second-line setting. Those patients were either relapsed/refractory to ESA therapy or ineligible due to a high baseline EPO level. The results of the phase 3 IMerge clinical trial were presented at the 2023 ASCO [American Society of Clinical Oncology] Annual Meeting, and the publication was released in The Lancet in December 2023.

At the 2023 ASH Annual Meeting, an abstract presented by Rami Komrokji, MD, from the Moffitt Cancer Center group looked at the different scoring systems and how imetelstat performed when we used the IPSS-R [Revised International Prognostic Scoring System] or the IPSS-M [Molecular International Prognostic Scoring System], as the original IPSS [International Prognostic Scoring System] was used as the inclusion criteria for the clinical trial.

About 10% of patients with low-risk IPSS were upstaged to moderate-high or high molecular IPSS risk. In patients with intermediate-1 risk IPSS, 22% were upstaged to IPSS-M moderate-high or high risk. The same was seen in the IPSS-R intermediate risk group; about 36% of patients were upstaged to IPSS-M moderate-high, high, or very high risk.

Importantly, the patients who were receiving imetelstat had similar responses across the risk groups, regardless of the IPSS-M or IPSS-R higher risk groups. However, for patients who received placebo, the 24-week transfusion independence rate was 0% for those with higher risk. Imetelstat maintained its efficacy, particularly with longer periods of transfusion independence and for those within the higher-risk IPSS-R or IPSS-M risk groups.

In another abstract looking at imetelstat and specifically focusing on patients with a transfusion independence of longer than 1 year, in the phase 3 clinical trial, 17.8% of patients had long transfusion independence of 1 or more years. In those patients, they noticed that there were some patients with cytogenetic responses, and others with molecular responses as well, possibly indicating a change in the disease biology and a disease modifying capability of imetelstat.

Seven patients in that cohort had abnormal cytogenetics at baseline, and 4 of those 7 achieved a complete cytogenetic response. Two additional patients had a reduction in the cytogenetic abnormal clone. They had 18 patients with SF3B1 mutations at baseline, and they noticed that 72% of those patients had more than or equal to 50% dose reduction in variant allele frequency [VAF]. Seven of those 18 patients had complete elimination of the VAF of their mutation.

These are very encouraging data with more than 1 year transfusion independence, meaning those patients really had 0 red blood cell transfusions. The original median duration of red blood cell transfusions was 6 in an 8-week period, and to go to 0 in a 1-year period is quite impressive. For those patients, the median increase in hemoglobin was also quite dramatic, with a median 5.1-g increase in hemoglobin compared with baseline.

Targeted Oncology: What are some key takeaways from recent data from the COMMANDS trial and long-term outcomes from MEDALIST presented at ASH?

Yazan Madanat, MD: Because the MEDALIST trial was reported back in 2020, there has been quite a long follow-up duration. At this ASH meeting, we saw an additional 26 months of follow-up from the original time the MEDALIST trial was reported. They used an exposure-adjusted incidence rate to look at adverse events because patients who were responding to luspatercept obviously had longer duration of drug exposure, and so that was adjusted to account for any difference in treatment-emergent adverse events.

As of January 2, 2023, 11 patients had remained on luspatercept treatment. The median follow-up time was 39 months for luspatercept, and the median duration of treatment for luspatercept was 50.9 weeks compared with 24 weeks for placebo. They noted that 49% of patients treated with luspatercept had achieved an 8-week transfusion independence during their entire treatment period, and 70% of those patients had 2 or more response periods where they were independent of transfusions for 8 weeks or longer.

If we look at treatment-emergent adverse events leading to permanent treatment discontinuation, the rate was 15% for luspatercept compared with 7.9% for placebo. However, if we look at the actual adverse events, they were quite comparable when we adjust for the duration of treatment for each agent. There were no patients who progressed to higher-risk disease or acute leukemia since the publication in 2022 by Dr Santini.

Another study, the COMMANDS trial, led to the approval of luspatercept in the frontline setting. It randomized patients to receive luspatercept vs erythropoiesis-stimulating agents. The COMMANDS trial was initially presented at the 2023 ASCO Annual Meeting and published on the same day. Based on the results of the COMMANDS study, we will likely see luspatercept more commonly used in the frontline setting, as it became available.

At the ASH meeting, the study led by Esther Natalie Oliva, MD, reported on the patient-reported outcomes from the COMMANDS trial and how those patients did. Using data from the first 24 weeks, they used the EORTC QLQ-C30 [EORTC Core Quality of Life questionnaire] and the FACT-An [Functional Assessment of Cancer Therapy–Anemia] questionnaire. They defined a sustained improvement in quality of life as sustained for at least 42 days through week 25 day 1 of therapy. They noticed that with luspatercept, there was sustained improvement in almost all domains of the EORTC questionnaire compared with placebo, and overall similar treatment tolerability, which was quite impressive for luspatercept to demonstrate an improvement in quality of life, because those patients are heavily transfusion dependent and quality of life is one of the most important measures for the management of lower-risk MDS.

Targeted Oncology: What have we seen regarding novel therapies and alternative targets?

Yazan Madanat, MD: The inflammasome has recently been studied more in lower-risk MDS. Those patients oftentimes have high expression of cytokines, which limits erythropoiesis, so David Sallman, MD, and his group at the Moffitt Cancer Center looked at the combination of canakinumab, an interleukin 1β neutralizing monoclonal antibody, in combination with darbepoetin in patients with lower-risk MDS who have failed prior ESA therapy.

This was a phase 1b early phase trial. It included 9 patients and tested 2 doses of canakinumab, which is given as a subcutaneous injection once every 4 weeks in 2 dose levels, either 150 or 300 mg. They saw some neutropenia, thrombocytopenia, and elevation in liver abnormalities. But the two grade 3 adverse events were deemed unrelated to the study drug, and they determined the phase 2 dose to be 300 mg of canakinumab given once every 4 weeks.

There were no clinical responses in this trial. However, in the phase 2 expansion portion, they will be targeting patients with particularly high expression of interleukin 1β, and those are usually patients with either TET2 mutations or DNMT3A. They will focus on patients with a lower transfusion burden and hope to get some clinical responses.

Targeted Oncology: What are the implications of these data looking toward the future?

Yazan Madanat, MD: We’re seeing more and more advances and hope for patients with lower-risk MDS, where we are moving luspatercept into the frontline setting, seeing improvement in quality of life with luspatercept and no issues with long-term safety signals when we’re using it for years in certain patients. In addition, the use of imetelstat has been quite promising, with a positive phase 3 clinical trial. We hope that this becomes a treatment option for patients with lower-risk MDS in 2024. And then targeting the inflammasome is going to be a novel mechanism. Many drugs are looking at targeting the inflammasome for patients with lower-risk MDS in the hope of restoring hematopoiesis or erythropoiesis for those patients. There is a lot of promise that will be coming in the near future, hopefully.