Dr Garcia-Manero on the Investigation of Luspatercept Dose Levels in Low-Risk MDS

Guillermo Garcia-Manero, MD, professor, chief, Section of Myelodysplastic Syndromes, deputy chair, Translational Research, fellowship program director, Department of Leukemia, Division of Cancer Medicine, chair, faculty senate, The University of Texas MD Anderson Cancer Center, discusses the rationale for evaluating the maximum approved dose level of luspatercept-aamt (Reblozyl) in the phase 3 MAXILUS study (NCT06045689) for patients with low-risk myelodysplastic syndrome (MDS) who require red blood cell (RBC) transfusions.

MAXILUS is enrolling patients who have a documented diagnosis of MDS according to World Health Organization (WHO) classification and meet Revised International Prognostic Scoring System (IPSS-R) classification of very low-, low-, or intermediate-risk disease. Cohorts 1 and 2 will enroll patients who are naive to or have been previously treated with erythropoiesis-stimulating agents, respectively. All patients will receive luspatercept at the maximum approved dose of 1.75 mg/kg. The primary objective of the study is to identify the number of participants who achieve RBC transfusion independence for 8 weeks with a simultaneous mean hemoglobin increase of at least 1 g/dL from week 1 to week 24.

Garcia-Manero states that this study holds importance, given the concerns raised during the initial phase 1/2 trials. When luspatercept was first being evaluated, the FDA expressed concern about the potential for significant increases in hemoglobin levels, which may lead to serious complications such as strokes or other toxicities. These concerns were pertinent in the context of treating patients with early-stage or lower-risk MDS or anemia, where the risk of adverse effects must be weighed against the benefits of treatment; a single death due to treatment-related complications would be unacceptable, Garcia-Manero emphasizes.

To address these concerns, early-phase trials of luspatercept were designed with a cautious approach to dosing. The dosing regimen for luspatercept starts at 1 mg/kg, with the option to escalate to 1.33 mg/kg and then to 1.75 mg/kg if needed. However, data from the phase 3 MEDALIST (NCT02631070) and COMMANDS (NCT03682536) trials have shown that the majority of patients require dose escalation to achieve the desired therapeutic effect. This raises an important question about the appropriateness of the initial 1 mg/kg dose, Garcia-Manero explains. Given the need for many patients to escalate their dose, it is worth considering whether starting at a higher dose might be more effective in maximizing the drug’s benefits from the outset, rather than using a potentially suboptimal dose for several weeks, he adds.

Starting at a higher dose may lead to quicker and more robust responses, but it also comes with the risk of exacerbating the FDA’s initial concerns about hemoglobin levels rising too rapidly. Ultimately, reevaluating the starting dose and dose escalation of luspatercept is critical in optimizing the use of this drug and ensuring that it is both effective and safe for patients, Garcia-Manero concludes.