Navigating Frontline Treatment and Disease Progression in Myelodysplastic Syndromes
Key Points
- Risk stratification is significant when selecting frontline therapy for myelodysplastic syndromes (MDS), with molecular and clinical factors helping guide treatment decisions beyond blast percentage alone.
- Earlier treatment of symptomatic anemia may be appropriate in lower-risk MDS, with luspatercept and erythropoiesis-stimulating agents (ESAs) used to improve hemoglobin levels and reduce transfusion dependence.
- Disease progression after luspatercept requires reassessment of treatment strategy, including consideration of hypomethylating agents (HMAs), management of cytopenias, and allogeneic stem cell transplantation for appropriate patients.
The management of MDS continues to evolve as the field advances, with clinicians balancing disease risk, symptom burden, treatment response, and patient-specific factors.
In a clinical discussion as part of the Challenging Cases series on the Oncology Brothers podcast, cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, discussed real-world approaches to treating patients with MDS with Amer Zeidan, MD, of Yale School of Medicine.
The experts delved into two clinical cases that focused on frontline treatment decision-making and management after disease progression.
Risk Stratification and Frontline Treatment in Lower-Risk MDS
In the first case, the doctors explored treatment options for a 74-year-old man with persistent anemia with a hemoglobin level of 8.5 g/dL after transfusion. He had a normal platelet count and an absolute neutrophil count greater than 1500/μL. Bone marrow biopsy demonstrated MDS with 5% blasts, sideroblasts at 8%, and no detection of chromosome 5q deletion. Next-generation sequencing identified an SF3B1-negative profile with no other significant abnormalities, and the erythropoietin (EPO) level was 250 mU/mL. While alternative causes of cytopenia can sometimes mimic MDS, Dr. Zeidan said that the overall clinical and pathologic findings supported the diagnosis in this case.
Risk stratification presented another important consideration. Although the patient’s 5% blast count placed him in an intermediate-risk category by the Revised International Prognostic Scoring System (IPSS-R), with a score of 4, his molecular IPSS score classified him as low risk.
Dr. Zeidan cautioned against making major treatment decisions, including transplant referral, based solely on a single variable such as a 5% blast count. He would approach the patient as having lower-risk MDS primarily characterized by symptomatic anemia and would consider repeating the bone marrow biopsy to confirm the blast percentage.
Treatment goals have also evolved with the availability of new therapies. Historically, Dr. Zeidan used ESAs based on symptom burden because their role was largely palliative. However, he now favors earlier intervention, particularly for patients with clinically meaningful anemia. With therapies such as luspatercept and emerging evidence suggesting potential improvements in longer-term outcomes, he aims not only to achieve transfusion independence, but also to increase hemoglobin levels above 10 g/dL.
Treatment After Luspatercept Progression
The second case involved a 67-year-old woman whose low-risk MDS progressed following treatment with luspatercept. She had an excellent response for 14 months, but then her hemoglobin began to decline. The luspatercept dose was increased from 1 mg/kg to 1.33 mg/kg. At 18 months, her hemoglobin continued to decline despite an additional dose increase. A repeat bone marrow biopsy showed 6% blasts, persistent trilineage dysplasia, and a new cytogenetic finding of trisomy 8. Her EPO level was 620 mU/mL.
HMAs represent an important treatment option in this setting, particularly for patients with higher-risk disease or those who have progressed following earlier therapies, the doctors explained. However, treatment selection should account for expected benefits, tolerability, comorbidities, and the patient’s overall goals of care.
Dr. Zeidan explained that once blasts are more than 5%, patients tend to have worse survival outcomes and could progress to acute myeloid leukemia. In this case, he would have a significant discussion with the patient about allogeneic hematopoietic stem cell transplantation, including its short- and long-term complication risks.
The EPO level is also an important consideration following first-line treatment failure, according to Dr. Zeidan. If the EPO level is less than 200 mU/mL, Dr. Zeidan considers adding ESA in addition to luspatercept or giving ESA alone. However, he bases this on individual cases—Dr. Zeidan does not use ESAs if the EPO level is above 200 mU/mL. With the EPO level of 620 mU/mL, Dr. Zeidan said that this case is more of a bridge to transplant. His main goal would be to reduce blast count and achieve the lowest disease burden before proceeding to transplant.
Dr. Zeidan also discussed management of treatment-related cytopenias. His approach may differ based on disease risk and the severity and type of the cytopenia. In patients with lower-risk MDS who develop neutropenia, granulocyte colony-stimulating factor (G-CSF) may be considered in selected cases. For patients with higher-risk disease, clinicians may be more cautious about G-CSF use and instead consider dose reductions or treatment delays with HMAs to manage cytopenias.
Across both cases, side effect management and communication with patients remain central to effective MDS care. Treatment decisions should be dynamic, with clinicians regularly reassessing blood counts, transfusion requirements, disease status, treatment response, and tolerability. “Lower-risk MDS has seen very nice progress with imetelstat and luspatercept,” Dr. Zeidan said. “I think it’s a very exciting era for lower-risk MDS.”