The Treatment Paradigm for Low-Risk MDS and the Impact of Luspatercept

Low-Risk MDS Treatment Paradigm

Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, and Amer Zeidan, MBBS, MD, of Yale School of Medicine, hosted a panel featuring Christopher Benton, MD, of Rocky Mountain Cancer Centers; Jamile Shammo, MD, of Northwestern Feinberg School of Medicine; and Tiffany Tanaka, MD, of University of California San Diego, for a Clinical Insights series. 

MDS are blood cancers characterized by dysplasia of blast cells, which can result in significant cytopenias. Patients with MDS can progress to acute myeloid leukemia (AML), but mortality is more often related to complications like bone marrow failure, cytopenias, or infections. The doctors discussed the workup and diagnosis process for low-risk MDS, and highlighted the shift in the treatment paradigm brought on by the approval of luspatercept.

How to Diagnose and Stage MDS 

When investigating MDS as the potential source of dysplasia or symptomatic cytopenias in a patient, the first step is ruling out other causes including nutritional deficiencies, autoimmune disorders, or medication side effects. If no other causes are apparent, the workup for MDS involves pathological review, cytogenetic testing, and next-generation sequencing. While these tests are necessary to diagnose and stage patients with MDS, they can also rule out other drivers of dysplasia like CHIP (clonal hematopoiesis of indeterminate potential) or inherited bone marrow disorders.

After a diagnosis of MDS has been confirmed, the current standard staging model is the Molecular International Prognostic Scoring System (IPSS-M). The IPSS-M for MDS uses pathology findings and cytogenetic and molecular profiles to assign a risk score. Risk stratification is the basis for treatment selection. Higher-risk patients may be selected for stem cell transplantation or more aggressive therapies, while the treatment paradigm for low-risk MDS is more focused on quality of life (QoL). 

The Approval of Luspatercept for Low-Risk MDS

Currently, treatment of low-risk MDS seeks to improve QoL by managing anemia symptoms and reducing the need for red blood cell transfusions. For many years, ESAs were the primary treatments for this purpose, but their efficacy varies among MDS subgroups. Novel agents have emerged as alternatives to ESAs, including luspatercept, a first-in-class erythroid maturation agent and the first agent to show superiority in a head-to-head comparison with ESAs. 

Luspatercept was initially approved for patients with ring sideroblast (RS)–positive, lower-risk MDS previously treated with ESA based on the MEDALIST trial. The approval was subsequently expanded to ESA-naïve  patients based on the COMMANDS trial. COMMANDS evaluated luspatercept versus epoetin alfa in ESA–naive, transfusion-dependent, low-risk MDS. The primary end point was red blood cell transfusion independence for at least 12 weeks with a concurrent increase in mean hemoglobin of at least 1.5 g/dL in the first 24 weeks of treatment. Overall, 59% of patients in the luspatercept group versus 31% of those in the epoetin alfa group achieved the primary end point. 

Ongoing follow-up from COMMANDS showed luspatercept yielded long-term transfusion independence and a trend toward improved overall survival. In addition, follow-up analyses and other studies have supported that luspatercept is as or more effective than ESAs across notable patient populations, including both RS–positive and RS–negative subgroups. Notably, ESAs are effective in patients treated with luspatercept, and in practice both agents have been used in combination in the first-line setting. 

Luspatercept Dosing

The doctors all agreed that luspatercept is generally favored over ESAs as first-line therapy for low-risk MDS. Treatment with luspatercept is started at 1 mg/kg subcutaneously every 3 weeks. If patients don’t have a reduction in transfusion requirements after 2 doses, the dose is increased to 1.33 mg/kg for 2 doses, and then to 1.75 mg/kg. In clinical trials, the majority of patients required dose escalations, which the doctors have seen mirrored in their own practices. 

Given the routine need for dose escalations in practice, the active MAXILUS trial investigated starting luspatercept at the full 1.75 mg/kg dose, and has preliminarily reported good responses without excessive toxicity. These data support starting patients at the full dose, although potential label changes will take time, Dr. Zeidan said.

Side Effects of Luspatercept

Luspatercept is generally well tolerated, especially compared with other drugs in MDS like imetelstat or hypomethylating agents, which are more myelosuppressive and require more frequent monitoring and supportive care. The most common side effect of luspatercept is fatigue, although it is typically mild and tends to improve as treatment continues. Persistent fatigue may require discontinuation, but oncologists should rule out secondary causes like iron deficiency anemia or nutritional deficiencies before swapping treatments. 

Hypertension is another commonly reported side effect of luspatercept, and oncologists may need to adjust any other hypertensive medications that patients are on. Less common toxicities include gastrointestinal side effects and muscle or bone pains. Luspatercept should also be held if a patient’s hemoglobin level exceeds 12 g/dL to reduce risk of thrombosis or blood clots, but the doctors all noted they had not seen patients reach those levels in their practice. 

Ultimately, luspatercept and other agents have shifted the treatment paradigm for patients with low-risk MDS. While current treatment is palliative and focused on QoL, the paradigm may continue to shift toward prolonging survival and reducing progression to AML, so long as advancements do not compromise the safety of patients with low-risk MDS.