MDS Research Expands Treatment Options Across Disease Subsets

The molecular classification of myelodysplastic syndrome (MDS) has opened the door for increasingly effective therapies for patients in this population, particularly approaches that benefit those with historically challenging molecular alterations such as 5q deletions and SF3B1, DNMT3A, ASXL1, and TAT2 mutations, according to Talha Badar, MBBS, MD.

“With the recent advances in MDS, we are now better at prognosticating this disease,” Badar, a hematologist/oncologist in the Departments of Hematology and Oncology (Medical) at Mayo Clinic in Jacksonville, Florida, said in an interview with OncLive^®.

The 2023 FDA approval of luspatercept-aamt (Reblozyl) for the first-line treatment of anemia in adult patients with lower-risk MDS who may require regular red blood cell (RBC) transfusions was based on findings from the phase 3 COMMANDS trial (NCT03682536), in which 58.5%of patients who received luspatercept (n = 178) achieved RBC transfusion independence (TI) of at least 12 weeks with a mean hemoglobin increase of at least 1.5 g/dL within the first 24 weeks vs 31.2% of patients who received the erythropoiesis-stimulating agent (ESA) epoetin alfa (n = 178; P < .0001).1 The benefit with luspatercept was observed regardless of ring sideroblast status.

Furthermore, for patients with heavily transfusion-dependent, non–5q deletion, lower-risk MDS that was relapsed/refractory to ESAs, the phase 2/3 IMerge trial (NCT02598661) demonstrated that 39.8% of those who received imetelstat (n = 118) achieved 8-week transfusion independence vs 15.0% of those who received placebo (n = 60).2 The benefit with imetelstat over placebo was observed across patient subgroups.

In the interview, Badar discussed the evolution of MDS risk stratification, the practice-changing implications of the addition of luspatercept to the treatment paradigm, and how imetelstat increases transfusion independence rates in patients with certain disease driver mutations.

OncLive: How is MDS risk currently classified, and what can be done to improve MDS risk stratification?

Badar: We used to classify MDS based on the Revised International Prognostic Scoring System [IPSS-R], which incorporates cytopenias, cytogenic abnormalities, age of the patient, and so forth. However, we have learned since the evolution of genomic sequencing and [changed] how we use sequencing data for prognosticating hematologic malignancies in acute myeloid leukemia and MDS. Data showed that approximately 50% of patients with MDS with normal karyotype can be upgraded to high-risk disease based on their molecular profile.

With those data, recently, the Molecular IPSS [IPSS-M] was introduced, which has greatly reclassified some of the intermediate-risk patients [as having] high-risk disease and helped us [determine] treatment strategies; when to send patients to transplant; when to [shift] our treatment regimen from symptomatic, supportive care growth factor support regimens to a chemotherapy-based regimen; and when to prep eligible patients for bone marrow transplant, which is still a potential curative strategy for this group of patients. The IPSS-M has helped us prognosticate. However, the downside of this [classification system is that it] is not globally feasible. Because it incorporates molecular data, in some countries it may be associated with a] high financial burden, and it’s difficult to use. Although we have identified ways to better risk stratify patients, we need strategies to implement [these methods] globally [and get them] paid for by [patients’] insurance or government institutions.

What is the significance of the FDA approval of luspatercept in patients with lower-risk MDS with anemia?

Anemia is one of the most common presenting symptoms in patients with MDS. Historically, these patients were treated with ESAs [and achieved] modest responses. These modest responses are suboptimal among those with a high transfusion burden, and the responses are limited for certain weeks and certain months.

Once patients progress on these kinds of therapy, options are limited. The subgroup of patients with a 5q abnormality can be treated with lenalidomide, which is challenging in [those who are] elderly. Otherwise, these patients [are eligible to receive] chemotherapy, such as hypomethylating agents. After that, there are limited treatment options. If patients are eligible, they can go to transplant.

With the approval of luspatercept, we have learned from the randomized [COMMANDS] study from comparing luspatercept with ESAs that [luspatercept elicits responses in this population], irrespective of the presence of ring sideroblasts or SF3B1 mutations, [which are] surrogate markers of MDS with ring sideroblasts. That has improved how we manage MDS with anemia in terms of achieving transfusion independence compared with ESAs, as well as improving hemoglobin levels. More interestingly, what we have also learned with this therapy is that certain groups of patients benefit more than the others, [such as] those with coexistent SF3B1, DNMT3A, ASXL1, and TAT2 mutations. Patients with MDS and splicing factor mutations, such as SSF2 or UTF1 mutations, tend to have a suboptimal response to this agent. However, [luspatercept is a welcome addition to] how we manage MDS with anemia. Luspatercept was initially approved only for patients with MDS with ring sideroblasts who were refractory to ESA-based therapy.

What key outcomes were observed in the IMerge trial of imetelstat in patients with lower-risk MDS?

It is [an] exciting [time for] the oncologist who treats patients with chronic myeloid disorders, such as MDS, when you have 2 phase 3 trials back-to-back that show positive results in this group of patients. One of those trials, IMerge, has shown superior outcomes with imetelstat, a telomerase inhibitor, compared with placebo, in patients who are transfusion dependent with non–deletion 5q, low-risk MDS. It’s a randomized study [that used a] 2:1 randomization. The primary end point of the IMerge trial was 8 weeks of TI. The secondary end point was 24 weeks of TI, as well as TI duration and improvement in hemoglobin.

The study met both its primary and secondary end points. Compared with placebo, 39.8% of patients [who received imetelstat] achieved 8 weeks of TI. The TI duration [with imetelstat] was [longer than that with placebo] at 8 weeks, as well as at 24 weeks.

As we have seen in the COMMANDS trial, [in IMerge, patients with] certain molecular characteristics [were more likely to respond to imetelstat than others. Imetelstat] improved anemia, increased TI duration, and [led to higher rates of] TI achievement. It has also been shown to decrease the allelic burden of certain mutations that drive MDS, such as STAT2, SF3B1, and AXL1, which all favor imetelstat regarding disease modification.

References

1. US FDA approves Bristol Myers Squibb’s Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed January 24, 2024. https://news.bms.com/news/details/2023/U.S.-FDA-Approves-Bristol-Myers-Squibbs-Reblozyl-luspatercept-aamt-as-First-Line-Treatment-of-Anemia-in-Adults-with-Lower-Risk-Myelodysplastic-Syndromes-MDS-Who-May-Require-Transfusions/default.aspx
2. Zeidan AM, Platzbecker U, Santini V, et al. IMerge: results from a phase 3, randomized, double-blind, placebo-controlled study of imetelstat in patients (pts) with heavily transfusion dependent (TD) non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA). J Clin Oncol. 2023;41(suppl 16). doi:10.1200/JCO.2023.41.16_suppl.7004