The results of two major randomized clinical trials for patients with anemia and lower-risk myelodysplastic syndromes (LR-MDS) were presented in 2023.1,2 These results are expanding the treatment armamentarium for this patient population; therefore, it is timely to discuss contemporary issues regarding the management of LR-MDS. In this short review, I discuss how we classify and prognosticate patients with LR-MDS, the incorporation of luspatercept in the front-line treatment of anemia in LR-MDS, emerging data in MDS with deletion 5q (del5q), the development of oral hypomethylating agents (HMAs), and a potential role for hematopoietic stem cell transplantation (HSCT). I also briefly mention some investigational approaches for this disease.
What Is Lower-Risk MDS?
The classification of LR-MDS has changed as better and more modern prognostic classifications have been developed. With the International Prognostic Scoring System (IPSS),3 patients with LR-MDS included those with low- and intermediate-1-risk disease. This definition is more complex when using the IPSS-R4 since its intermediate subgroup includes patients with diverse prognosis. Most clinical trials divide patients into groups of those who have more or less than 3.5 points, thus including patients with very low, low, and some intermediate risk. This concept is being challenged by the recently proposed IPSS-M classification.5 This system incorporates next-generation sequencing results into the IPSS-R system, dividing patients into six different subsets. Using IPSS-M, patients with lower-risk disease are defined as those with very low-, low-, or moderately low-risk disease. Of importance, when comparing IPSS-R with IPSS-M at the individual patient level, prognosis usually worsens once molecular data are added. Therefore, a significant fraction of patients with LR-MDS by IPSS-R could be considered higher-risk (HR)-MDS when using IPSS-M. Some of these patients could be transfusion independent (TI) with no excess blasts but with expected poor prognosis. The question is whether they should be considered candidates for disease-modifying therapy, including HSCT.
Another important development is the identification of patients with clonal hematopoiesis of indeterminate potential/clonal cytopenia of unknown significance (CCUS). A recent classification,6 the clonal hematopoiesis risk score (CHRS), allows for the prognostication of these groups of individuals. Although most individuals with CCUS will never need any therapy, it is possible that those patients with high-risk disease by CHRS could be candidates for some type of intervention. This approach is being explored in clinical trials.
To summarize, the incorporation of molecular data is modifying our definition of LR-MDS.
A 2023 Treatment Approach to Anemia in LR-MDS
Anemia is one of the most common manifestations of LR-MDS. It results in major toxicities for patients and requires significant resources. Anemia in LR-MDS has been traditionally mitigated with erythropoietin-stimulating agents (ESAs). This class of drugs has been the standard for several decades but was never formally studied in the United States in randomized trials. In 2020, luspatercept, a TGF-ß modulator, was shown to be superior against placebo in the second line for patients with refractory anemia with ring sideroblasts.7 These patients are frequently characterized by the presence of mutations in the SF3B1 gene. Based on these results and the mild toxicity profile of this agent, researchers designed the COMMANDS study,1 and those results were recently published.7 In this study, patients with refractory anemia with ring sideroblasts (RS+) and those without (RS−) with LR-MDS requiring transfusion of red cells who had not received prior therapy, including ESAs, were randomized to either luspatercept or darbopoetin alpha. Using an intent-to-treat analysis, the response rate was 58% for luspatercept versus 31% for ESA. In addition, the duration of response was significantly longer in the luspatercept arm. Response was defined as achieving transfusion independence, as well as an increment of hemoglobin of at least 1.5 g/dL.
When looking at different subsets of patients, luspatercept was superior in all subgroups (RS+, low and high transfusion burden, SF3B1 mutated and unmutated, high and low erythropoietin [EPO] levels) except for the RS− subset where the response rate was lower but the duration of response longer with luspatercept. These results have created some controversy. For patients with RS+ disease or an EPO level over 200, the results of luspatercept are clearly superior, but for those patients with RS− disease it could be argued that either an ESA or luspatercept could be considered as a first-line option.
Should We Consider Treatment of TI Patients with LR-MDS?
The standard of care is to restrict any intervention to transfusion-dependent (TD) patients or those with symptomatic anemia. This approach is being challenged by recent data from the SINTRA-REV trial. In this study, patients with TI LR-MDS with del5q were randomized to two years of lenalidomide 5 mg daily versus placebo. Patients treated with low-dose lenalidomide remained TI for a significantly longer period compared with placebo. Over 90% of the patients in the lenalidomide arm achieved a cytogenetic response. Therefore, it is possible that this group of patients could also have longer survival than those in the placebo arm. These data suggest that early intervention is justified in TI patients if we have access to effective, safe agents in specific subsets of patients. Several clinical trials are currently being developed for TI patients.
Is There a Role for HMAs in LR-MDS?
We have access to three HMAs for MDS in the United States, azacitidine, decitabine, and the more recently developed oral agent decitabine/cedazuridine.8 All of these agents are approved for most patients with MDS, including LR-MDS. That said, no prospective, randomized study using these agents has evaluated their role specifically in LR-MDS. A randomized study of CC-486 (oral azacitidine) failed to show improvement in survival in LR-MDS.9 Recent data from the MD Anderson Cancer Center and studies with oral decitabine/cedazuridine that have been presented further support the common use of this class of agents in LR-MDS.10 The development of other oral HMAs, such as ASTX030 or CC-486 could transform the care of these patients.
What About Stem Cell Transplant in LR-MDS?
In general, HSCT is not considered for patients with LR-MDS11 because the early mortality and toxicities associated with HSCT offset any potential survival benefit. This concept could be challenged by the incorporation of the IPSS-M risk score worsening the predicted survival of some patients with LR-MDS, but it needs to be studied in a prospective, systematic fashion. Some of these patients could be considered for HSCT. Other examples include those with HMA failure and potentially those with clonal evolution or poor risk molecular features such as EZH2 or p53 mutations.
What Is Next?
It is of interest that we are witnessing significant progress in LR-MDS instead of HR-MDS, where several combination studies have failed to demonstrate improved outcomes.12 In 2023, in addition to the results of the COMMANDS trial,1 we saw the results of the IMERGE study2 with imetelstat versus placebo in second-line LR-MDS patients with TD anemia. This agent perturbs telomerase activity. The results of this trial are currently being reviewed by the US Food and Drug Administration and may constitute another agent for our patients. In addition, several studies targeting SF3B1, IRAK, or IL-1, among others, are being evaluated in LR-MDS. Finally, we need to study agents targeting thrombocytopenia.
In the table, I propose a potential treatment approach for patients with LR-MDS. Areas of importance include combination studies to further improve results with luspatercept, further studies in TI populations, targeting of HR-CCUS, and better understanding of the role of HSCT in LR-MDS. Perhaps in the future, we will be able to write that the goals of therapy in LR-MDS are prevention of MDS when treating CCUS, or improvement of survival instead of just symptom and cytopenia control.
Guillermo Garcia-Manero, MD, is Chief of the Section of Myelodysplastic Syndromes, Deputy Chair of Translational Research, and a Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center.
- Platzbecker U, Della Porta MG, Santini V, et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Lancet. 2023;402(10399):373-385. doi:10.1016/S0140-6736(23)00874-7
- Zeidan AM. 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). Abstract #7004. Presented at the 2023 ASCO® Annual Meeting; June 2-6, 2023; Chicago, Illinois.
- Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079-2088. PMID: 9058730
- Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454-2465. doi:10.1182/blood-2012-03-420489
- Bernard E, Tuechler H, Greenberg PL, et al. Molecular international prognostic scoring system for myelodysplastic syndromes. NEJM Evid. 2022. doi:10.1056/EVIDoa2200008
- Weeks LD, Niroula A, Neuberg D, et al. Prediction of risk for myeloid malignancy in clonal hematopoiesis. NEJM Evid. 2023. doi:10.1056/evidoa2200310
- Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892
- Garcia-Manero G, Griffiths EA, Steensma DP, et al. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood. 2020;136(6):674-683. doi:10.1182/blood.2019004143
- Garcia-Manero G, Gore SD, Cogle C, et al. Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J Clin Oncol. 2011;29(18):2521-2527. doi:10.1200/JCO.2010.34.4226
- Sasaki K, Jabbour E, Montalban-Bravo G, et al. Low-dose decitabine versus low-dose azacitidine in lower-risk MDS. NEJM Evid. 2022. doi:10.1056/EVIDoa2200034
- DeFilipp Z, Ciurea SO, Cutler C, et al. Hematopoietic cell transplantation in the management of myelodysplastic syndrome: an evidence-based review from the American Society for Transplantation and Cellular Therapy Committee on Practice Guidelines. Transplant Cell Ther. 2023;29(2):71-81. doi:10.1016/j.jtct.2022.11.014
- Garcia-Manero G. Current status of phase 3 clinical trials in high-risk myelodysplastic syndromes: pitfalls and recommendations. Lancet Haematol. 2023. doi:10.1016/S2352-3026(22)00265-4