Treating Low-Risk MDS After the Introduction of Luspatercept 

Treating Low-Risk MDS After the Introduction of Luspatercept 

During a discussion about the treatment of low-risk MDS and the introduction of luspatercept, Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center; Amer Zeidan, MBBS, MD, of Yale School of Medicine; Jamile M. Shammo, MD, of Northwestern Feinberg School of Medicine; Tiffany Tanaka, MD, of University of California San Diego; and Christopher Benton, MD, of Rocky Mountain Cancer Centers, summarized the importance of managing anemia, luspatercept patient selection and dose modifications, and typical sequencing patterns for available therapies in low-risk MDS.

Managing Anemia in MDS

Chronic anemia is a significant driver of morbidity and reduced QoL in patients with low-risk MDS. Historically, ESAs and red blood cell transfusions were the primary treatment options for managing anemia in low-risk MDS, but several novel treatments have been approved in recent years, most notably luspatercept. In addition to luspatercept, other treatment options include lenalidomide, imetelstat, and hypomethylating agents. Incorporating these drugs is highly important to improve QoL and reduce transfusion dependence in low-risk MDS, said Dr. Zeidan. 

Optimizing Patient Selection and Dosing With Luspatercept

The COMMANDS trial showed that luspatercept significantly improved rates of transfusion independence with concurrent hemoglobin increases compared with ESAs for patients with low-risk MDS. Luspatercept was superior to ESAs in the first-line setting in COMMANDS, although the earlier MEDALIST trial showed it is also effective in patients previously treated with ESAs. 

COMMANDS data support that luspatercept has the greatest response rate in ring sideroblast–positive patients. Luspatercept is also favored in patients with serum epoetin concentration above 200 U/L, regardless of ring sideroblast status, as these patients typically have worse responses with ESAs, said Dr. Shammo.  

Luspatercept is administered as a subcutaneous injection once every 3 weeks with weight-based dosing starting at 1 mg/kg. If patients do not show improvements in transfusion burden or hemoglobin after two consecutive doses, the dose can be escalated to 1.33 mg/kg, then to 1.75 mg/kg. The majority of participants in luspatercept trials required dose escalations to improve response, and oncologists should be prepared to escalate dose for most patients in practice. 

Treatment guidelines note that luspatercept doses should be paused if patients reach a hemoglobin of 12 g/dL or higher, although Dr. Tanaka noted she has not seen patients reach this concentration in practice.

Sequencing Luspatercept and Other Therapies in Low-Risk MDS

The doctors agreed luspatercept is a preferred first-line treatment for patients with low-risk MDS. Dr. Benton noted he may still consider epoetin alfa in patients with significant concurrent chronic kidney disease (CKD), as CKD may be the primary driver of anemia rather than MDS. After using luspatercept in the first line, Dr. Benton typically sequences to epoetin alfa, then to imetelstat, and then to low-dose, low-intensity courses of a HMA. However, imetelstat and HMAs are more myelosuppressive than luspatercept and ESAs, which may be a challenge for patients already dependent on transfusions, said Dr. Benton.

In the future, the goals of treatments for low-risk MDS may become more ambitious, shifting from only managing symptoms to prolonging survival, reducing progression to acute myeloid leukemia, and fully resolving anemia. This shift may arise from novel agents, novel combinations, and earlier treatment strategies, Dr. Zeidan said