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MDS: Driving With the Brakes on, No Longer

By Mehdi Hamadani, MD

Looking at a case of myelodysplastic syndrome (MDS) under a microscope never ceases to amaze me, with its paradox between the excess of blood-forming cells in the marrow and the striking paucity of mature blood cells in the peripheral blood. Erythroid progenitors in a dysplastic marrow are reminiscent of Del Amitri’s hit song, “Driving With the Brakes On.” Proliferating uncontrolled, but an invisible brake seems to prevent their differentiation into mature red blood cells (RBCs). This invisible brake happens to be increased concentrations of transforming growth factor β superfamily ligands, including growth differentiation factor 11 (GDF11), leading to ineffective erythropoiesis in MDS. A new drug, luspatercept, acts as a ligand trap to inhibit negative regulators of late-stage erythropoiesis, including GDF11 and activin B, thereby “releasing” the invisible brakes on RBC production in low-risk MDS.

Alan List, MD

Medalist is a phase III, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of luspatercept in adult patients with transfusion-dependent very low–, low-, or intermediate-risk MDS with ringed sideroblasts (RS). The presenting author Alan F. List, MD, of The Moffitt Cancer Center, Tampa, FL, reported that a total of 229 patients were randomized and treated. The majority (>90%) had previously received erythropoietic agents and harbored the SF3B1 mutation. The primary endpoint of RBC transfusion independence (RBC-TI) for at least eight weeks was achieved in significantly more subjects receiving luspatercept (37.9%) compared with placebo (13.2%). The key secondary endpoint of RBC-TI for at least 12 weeks was achieved by 28.1 percent of luspatercept-treated patients compared with 7.9 percent receiving placebo (p=0.0002). Notably, more patients receiving luspatercept achieved hematologic improvement-erythroid response, based on decrease in transfusion requirements and/or improvement in hemoglobin concentrations. Toxicity profile was favorable.

Is luspatercept a game-changer for transfusion-dependent lower-risk MDS? The abstract introducer David Steensma, MD, of Dana-Farber Cancer Institute in Boston was cautiously optimistic. “If patients have reduction or elimination of transfusions from a therapy that is not particularly toxic or inconvenient (which seems to describe luspatercept), then that can be a genuine benefit,” he said. On generalizability of these results beyond MDS with RS and those without SF3B1 mutation, Dr. Steensma said, “We do not know how effective this drug will be in other MDS subtypes. That is certainly an important thing to look at in other trials, and some are ongoing. The fact that there is a positive randomized β thalassemia study with luspatercept, the Believe Trial, which Dr. Cappellini is presenting at the ASH annual meeting, suggests that the erythropoiesis improvement with luspatercept is not specific to MDS with RS.” He cautioned that no real cost-effective data are available for this likely expensive agent but added, “the injectable nature of the drug may actually be beneficial because it is covered by Medicare part B instead of Medicare part D like an oral agent, so patients won’t have the issue of being unable to afford a copayment.”

There is no doubt that this class of drugs is likely going to play an even greater role in additional marrow maturation disorders such as myelofibrosis and other myeloproliferative neoplasms in coming years.

Dr. Hamadani indicated no relevant conflicts of interest.


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