Defining the next steps in myelodysplastic syndromes

Guillermo García-Manero, MD, professor and chief of the Section of Myelodysplastic Syndromes and ad interim chair of the Department of Leukemia at the University of Texas MD Anderson Cancer Center, writes about what is yet to be known regarding both higher-risk and lower-risk myelodysplastic syndromes, detailing the specific gaps that remain in tracking disease progression, refining clinical trial endpoints, and tailoring treatment for each patient group.

Myelodysplastic syndromes (MDS) comprise a highly heterogeneous group of clonal myeloid neoplasms that occur predominantly in older adults and in patients previously exposed to chemotherapy or radiation therapy. During the past several years, we have made meaningful progress in treating anemia associated with lower-risk MDS through agents such as luspatercept and imetelstat, as well as in the development of oral hypomethylating therapy with decitabine/cedazuridine. In contrast, improving survival in higher-risk MDS has remained extraordinarily difficult. This challenge was most recently illustrated by the VERONA trial, in which adding venetoclax to azacitidine improved response measures but did not significantly prolong overall survival.

In contrast, improving survival in higher-risk MDS has remained extraordinarily difficult.

At the same time, emerging results from lower-risk MDS studies raise the possibility that earlier intervention could alter the natural history of the disease. In the COMMANDS trial, luspatercept produced higher and more durable rates of transfusion independence than epoetin alfa. A preplanned secondary analysis also suggested a favorable overall-survival signal. Although these findings do not yet establish disease modification, they challenge us to reconsider both the timing of treatment and the endpoints used in future trials.

Several priorities should guide the next generation of MDS research.

1. Incorporate molecular biology directly into clinical-trial design

Major efforts are underway to improve MDS classification and prognostication through molecular characterization. We now recognize that TP53 is among the most important adverse molecular abnormalities in MDS. At referral centers such as MD Anderson, TP53 mutations may be present in 30% to 40% of patients with higher-risk disease.

Patients with TP53-mutated MDS do not appear to derive the same benefit from certain therapies, including venetoclax-based combinations, as patients with TP53-wild-type disease. Higher-risk MDS should therefore no longer be treated as a single biological entity in phase 3 studies. Trials should incorporate molecular stratification at enrollment, prospectively defined subgroup hypotheses, and therapies selected according to the genetic and biological features of the disease.

Higher-risk MDS should therefore no longer be treated as a single biological entity in phase 3 studies.

2. Determine whether earlier treatment of anemia can modify the disease

In lower-risk MDS, the results achieved through modulation of transforming growth factor–β superfamily signaling with luspatercept are significant. We are learning that earlier use of this agent is associated with very high response rates and prolonged transfusion independence. The critical question is whether these benefits extend beyond the correction of anemia and ultimately alter disease progression or survival.

The next generation of lower-risk MDS trials should evaluate not only hematologic response and transfusion independence but also overall survival, progression-free survival, time to higher-risk MDS or acute myeloid leukemia, quality of life, and cumulative transfusion burden. Translational studies should also investigate whether these agents influence broader signaling pathways, the marrow microenvironment, or immune function.

3. Account for comorbidities and competing causes of mortality

Because most patients with MDS are older and frequently have multiple comorbidities, overall survival is influenced by factors beyond the hematologic disease. We must determine how cardiovascular, pulmonary, renal, inflammatory, and other conditions affect treatment tolerance, response, and survival.

Future studies should incorporate standardized comorbidity assessments and distinguish disease-related mortality from competing causes of death. This will be particularly important when evaluating whether a therapy for lower-risk MDS truly modifies the natural history of the disease.

4. Expand treatment objectives beyond anemia

Most therapeutic development in lower-risk MDS has focused on anemia. Thrombocytopenia, however, remains a major unmet need and can result in bleeding, recurrent platelet transfusions, treatment delays, and substantial impairment in quality of life.

We need therapies specifically directed at improving platelet production and reducing clinically meaningful bleeding. Future trials should incorporate platelet-transfusion independence, bleeding events, and patient-reported outcomes rather than relying exclusively on conventional hematologic-response criteria.

5. Identify the patients who benefit from BCL-2 inhibition

Higher-risk MDS remains the greatest therapeutic challenge. We are now conducting the GLORA-4 trial, which evaluates lisaftoclax plus azacitidine using a design similar to that of VERONA. The central question is no longer simply whether BCL-2 inhibition is active in MDS, as it clearly is in acute myeloid leukemia. Rather, we must identify the biological and clinical subsets of patients with MDS that derive the greatest benefit from this class of therapy.

The field should be more selective when designing large randomized phase 3 doublet studies, particularly those involving BCL-2 inhibitors. Molecular subtype, TP53 status, blast percentage, age, disease risk, biological evidence of BCL-2 dependence, and transplant eligibility should all be considered during trial design. Future studies may require biomarker-enriched or adaptively enriched designs instead of broad all-comer enrollment.

6. Address the impact of stem-cell transplantation on clinical-trial outcomes

Outcomes following allogeneic stem-cell transplantation have improved substantially, with long-term disease control approaching 50% in appropriately selected patients. This progress has important implications for the interpretation of clinical trials in higher-risk MDS.

In a randomized study, patients assigned to the control arm may subsequently undergo transplantation and achieve long-term survival. This can attenuate differences in overall survival between treatment groups, even when the investigational therapy produces deeper or more frequent responses. The VERONA experience illustrates the importance of this issue.

Future trials should stratify patients according to transplant eligibility and intent, prospectively capture transplantation and all subsequent therapies, and define transplantation as an important intercurrent event in the statistical analysis. Overall survival should remain a critical endpoint, but it should be complemented by endpoints such as the rate of successful transition to transplantation, depth of response before transplantation, post-transplant relapse, and transplant-free survival. Both intention-to-treat and prespecified transplant-focused analyses will be required to understand the true contribution of the investigational therapy.

MDS research has reached a pivotal moment. We have effective new therapies for anemia, increasingly sophisticated molecular classification systems, emerging targeted agents, and improving transplantation outcomes. Our principal challenge is to integrate these advances into more biologically precise clinical trials. By selecting the right therapy for the right molecular subset, using endpoints that capture meaningful changes in the disease, and accounting appropriately for comorbidities and transplantation, we can continue to improve outcomes for patients with MDS.