A Primer on the Management of MDS-Associated Anemia

Evolving classification systems, a complex diagnostic process, and the introduction of new therapeutics are all complicating factors that can impact outcomes for patients with low-risk myelodysplastic syndrome (LR-MDS). In this ECHO, we will 1) emphasize the importance of employing a multidisciplinary approach to assess clinical and pathologic disease characteristics of LR-MDS to improve the diagnosis and treatment selection for patients; 2) discuss erythropoiesis-stimulating agents (ESAs) as treatment for patients with LR-MDS and when to move beyond ESAs; and 3) explore when to incorporate a novel, evidence-based therapeutic option for patients with LR-MDS who are failing or are refractory to ESA treatment.

Diagnosis and Multidisciplinary Management of Lower-Risk Myelodysplastic Syndrome

Many variables must be considered when diagnosing and classifying MDS, creating substantial challenges to optimizing outcomes for patients with LR-MDS-associated anemia. These factors include disease morphology and results from flow cytometry, cytogenetics, and molecular diagnostic studies. Moreover, diagnostic criteria exhibit high rates of interobserver variability. For example, bone marrow morphology may not always be straightforward, with discrepancies in center-to-center interpretations.

Dedicated hematopathologists from high-volume centers can play a major role in determining an accurate LR-MDS diagnosis because they have expertise in analyzing bone marrow aspirations and biopsies which are key to confirming the MDS diagnosis, grading disease severity, and guiding therapeutic decision-making. Thus, a team-based, collaborative clinical approach, reliable morphology interpretation, and the use of cytogenetics and molecular diagnostics are all essential to successfully achieving the most optimal outcome for each patient with MDS.   

The Value of Molecular Diagnostics in LR-MDS

A revised molecular version of the International Prognostic Scoring System for myelodysplastic syndromes (IPSS-M) uses next-generation sequencing assays to risk stratify MDS based on genetic mutations. 

Cytogenetics plays a crucial role in diagnosing, assessing prognosis, and guiding treatment selection for patients with LR-MDS. Nonetheless, even without clear-cut morphology, the presence of certain mutations can establish the diagnosis. As an example, the value of molecular diagnostics can be seen in sideroblastic anemia, previously known as refractory anemia with ring sideroblasts, which is characterized by a mutation on the splicing factor 3B subunit 1 (SF3B1) gene. SF3B1 mutation is a unique entity with both pathology and treatment implications.

Erythropoietin-Stimulating Agents in LR-MDS and Therapeutic Options After Failure

Erythropoietin-stimulating agents are the mainstay of treatment for anemia associated with LR-MDS. However, the response to ESA therapy is variable, not all patients respond to ESA treatment, and patients may become refractory to ESA over time. ESAs are still a reasonable first-line treatment option in patients with LR-MDS who are not heavily transfusion dependent. While there is no specific threshold in hemoglobin level that determines when to initiate ESA therapy, a hemoglobin of 9 g/dL is considered a reasonable cutoff. However, treatment decisions must also incorporate patient symptoms and the relative impact of anemia on the patient’s quality of life.

There are 2 types of ESAs available: epoetin alfa, which is given weekly, and darbepoetin alfa, which is given every other week. There are no major differences in dosing between these 2 agents. ESAs for MDS anemia should typically be dosed between 40,000-60,000 units of erythropoietin and trialed for 6-8 weeks, after which the clinical response can be assessed to determine whether to continue ESA therapy (at the same or increased/decreased dose) or move to an alternative therapeutic option. Unfortunately, patients often continue to receive ESAs despite their persistent and regular need for blood transfusions because it is believed that ESAs are preventing an even greater number of transfusions. It is more likely that the patients are not truly benefiting from ESA treatment and that an alternative therapeutic option should be considered or at least trialed.  

One of the true challenges to managing patients with LR-MDS in ESA treatment failure is ascertaining what comes next. Another is determining if the patient is likely to respond to ESA therapy. Fortunately, predicting an ESA response for certain ESA-naïve patients can be simplified. For those patients with an endogenous serum erythropoietin (EPO) >500 U/L and who require >2 transfusions per month, the likelihood of response to ESA treatment is <10%. Thus, for patients in both the failed and refractory categories, it is prudent to consider an alternative therapy to continuing ESA.

Luspatercept is FDA-approved for the treatment of patients with transfusion-dependent LR-MDS with ring sideroblasts who have failed ESA therapy and require 2 or more red blood cell units over the course of 8 weeks.¹ This first-in-class erythroid maturation agent acts on a different stage of erythropoiesis than ESAs (Figure 1). Luspatercept is a recombinant fusion protein that binds to transfusion growth factor (TGF)-β ligands to inhibit SMAD2 and SMAD3 signaling, the inhibition of which results in enhanced terminal erythroid differentiation.¹

Novel Evidence-Based Therapeutics for LR-MDS Without Response to or Refractory to an ESA

The MEDALIST trial was designed to evaluate the safety and efficacy of luspatercept in patients with LR-MDS with ring sideroblastic anemia who were receiving regular red blood cell transfusions and had disease that was refractory to or unlikely to respond to ESAs or who had discontinued ESAs due to an adverse event. The primary endpoint of the study was transfusion independence for 8 weeks or longer during weeks 1 through 24 of the study.² Lustpatercept was administered every 3 weeks by subcutaneous injection at a dose of 1.0 to up to 1.75 mg/kg body weight; injections were continued for 24 weeks.

MEDALIST revealed a significant improvement in rate of transfusion independence in those who received luspatercept as opposed to placebo. Transfusion independence for ≥8 weeks was achieved by 38% of luspatercept recipients, as compared to 13% of participants in the placebo group (Figure 2).²

The key secondary endpoint of this trial was transfusion independence for ≥12 weeks, assessed during study weeks 1 through 24 and 1 through 48. Transfusion independence for ≥12 weeks during weeks 1 through 24 of the study was achieved by 28% of luspatercept participants; 33% achieved transfusion independence ≥12 weeks in weeks 1 through 48. Results in the placebo group were 8% and 12%, respectively (Figure 2).²

In trial weeks 1 through 24, an average increase in hemoglobin of ≥1 g/dL occurred in 35% of patients treated with luspatercept, as compared to only 8% with standard care. In weeks 1 through 48, the average hemoglobin increase of ≥1 g/dL occurred in 41% of patients treated with luspatercept and in 11% who received placebo (Figure 3). These data suggest that in patients with LR-MDS, responses to luspatercept were both durable and provided greater hemoglobin improvement when compared to placebo.²

Notably, response rate was inversely related to the number of red blood cell transfusions received. When evaluated according to baseline transfusion burden, transfusion independence for 8 weeks or longer in the luspatercept group occurred in 80% of patients who had received less than 4 units of red blood cells per 8 weeks, in 37% of those who had been receiving 4 to less than 6 units per 8 weeks, and in 9% of those who had been receiving at least 6 units per 8 weeks (Table1).² These statistics have implications for the value of luspatercept treatment at an earlier stage in MDS treatment. 

Safety was a key secondary endpoint considered in MEDALIST. Fatigue was the most frequently reported adverse effect, followed by diarrhea, asthenia, nausea, dizziness, and back pain (Table 2).²Similar rates of grade 3 or 4 adverse events were observed between luspatercept (42%) and placebo (45%). In total, 31% of patients receiving luspatercept had at least 1 serious adverse event, as compared to 30% in placebo. Thus, luspatercept has a reasonable safety profile and is generally well tolerated, suggesting that safety concerns are unlikely to act as a barrier to the use of luspatercept at an earlier stage in the LR-MDS treatment algorithm. 

Potential for Multilineage Hematologic Benefit of Luspatercept Treatment

Data from MEDALIST also revealed that luspatercept may have additional benefits beyond the treatment of LR-MDS-associated anemia. A subset of patients enrolled in MEDALIST and who received luspatercept also achieved multilineage hematologic improvement in neutrophils, platelets, and red blood cells. At baseline, neutropenia (<1 x 10⁹/L) was confirmed in 9.8% (15) of patients treated with luspatercept and 13.2% (10) of patients in the placebo arm.³ Analyses showed that 20% (3/15) of participants who received luspatercept and 10% (1/10) of those who received placebo achieved neutrophil hematologic improvement (HI-N) in weeks 1-48 of the study based on the International Working Group 2006 criteria. The average change in neutrophils from baseline was 0.94 x 10⁹/L with luspatercept treatment and 0.04 x 10⁹/L with placebo at trial week 15.³

Furthermore, 5.2% (8) of patients treated with luspatercept and 7.9% (5) who received placebo had baseline thrombocytopenia (<100 x 10⁹/L).³ Of these participants, 62.5% (5/8) who received luspatercept and 33% (2/6) who received placebo achieved platelet hematologic improvement (HI-P) in weeks 1-48. The average increase in platelet count from baseline was 29 x 10⁹/L with luspatercept treatment, as compared with 0.9 x 10⁹/L with placebo after 12 weeks of treatment.³ These data suggest that some patients may achieve benefits from luspatercept beyond the treatment of anemia. Additional information is needed to determine the true hematologic benefit of luspatercept for both neutrophils and platelets.

Luspatercept as a First-Line LR-MDS Treatment Option

The COMMANDS trial is an ongoing phase 3 trial investigating the role of luspatercept as a first-line treatment option for LR-MDS. The main goal of this study is to determine the safety and efficacy of luspatercept versus epoetin alfa for patients with LR-MDS-associated anemia who require red blood cell transfusions and have not received prior ESA therapy.⁴

The primary endpoint of interest in the COMMANDS trial is red blood cell transfusion independence for a duration of 12 weeks within the first 24 weeks of the trial and an average increase in hemoglobin level of ≥1.5 g/dL from baseline. Secondary endpoints of interest include duration of red blood cell transfusion independence, change in hemoglobin level, erythroid hematologic improvement (HI-E) response, and safety (Table 2).⁴ Although the trial has not yet reached completion, the results could be transformative to LR-MDS treatment and may establish a new frontline therapy for LR-MDS-associated anemia.

Conclusions

Key factors needed to overcome the challenge of optimizing outcomes for LR-MDS patients include the use of a collaborative approach to the diagnosis and treatment of LR-MDS, appropriately using ESAs, and understanding when to utilize novel therapeutic options for those who are failing or are refractory to ESA treatment. As shown in MEDALIST, luspatercept offers a unique and tolerable therapeutic approach that can provide meaningful clinical benefit for patients with LR-MDS-associated anemia who do not adequately respond to or tolerate ESA therapy. Soon-to-be emerging data, based on the COMMANDS trial, may well have implications for luspatercept in the first-line setting for patients with LR-MDS.

References

1. REBLOZYL® (luspatercept-aamt). Package insert. Bristol Myers Squibb; 2020. Accessed August 29, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761136orig2lbl.pdf
2. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892
3. Garcia-Manero G, Mufti GJ, Fenaux P, et al. Hematologic improvement-neutrophil and -platelet in the MEDALIST trial: multilineage data from a phase 3, randomized, double-blind, placebo-controlled study of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusions. Blood. 2019;134(Supplement_1):4243. doi:10.1182/blood-2019-123048
4. Della Porta M, Platzbecker U, Santini V, et al. The Commands Trial: a phase 3 study of the efficacy and safety of luspatercept versus epoetin alfa for the treatment of anemia due to IPSS-R very low-, low-, or intermediate-risk MDS in erythropoiesis stimulating agent-naive patients who require RBC transfusions. Blood. 2020;136(Supplement 1):1-2. doi:10.1182/blood-2020-140284