Myelodysplastic syndrome (MDS) is a heterogeneous disease characterized by cytopenias and possible progression to acute monocytic leukemia (AML). Some patients with low-risk disease (LR-MDS) and anemia can be treated with supportive therapy alone, which may include red blood cell transfusions, but the goal is to achieve transfusion independence. Treatment with erythropoiesis-stimulating agents (ESAs) is the approved intervention in the United States and Europe. However, only about 30% to 60% of patients will respond, and most will experience a relapse within the first 2 years.¹ High-risk MDS (HR-MDS) has a poor prognosis, with approximately 40% of patients developing AML within 2 years after initial diagnosis.²

Low-Risk MDS

Therapy for LR-MDS is based on the transfusion needs of patients. Chronic anemia not only affects quality of life but can also result in organ damage.³ Repeated transfusions carry the risk of iron overload as well as sensitization leading to hemolysis and loss of venous access. Regular transfusions are also associated with logistical challenges because a clinic visit is necessary.⁴ Frequent transfusions can affect progression-free survival (PFS) in patients with LR-MDS. ESAs are commonly used and result in response rates of 30% to 60%, often of limited duration.^5-7

Patients who do not respond after 8 to 12 weeks of ESA use with or without granulocyte colony-stimulating factor (G‐CSF) are judged to have primary refractory or resistant disease, whereas patients who initially respond but then become resistant are considered to have relapsed.

In a retrospective series with a median follow‐up of 7 years, approximately 50% of patients had refractory disease and 26% relapsed after an initial response.⁸

Current first-line treatment recommendations for lower-risk patients with symptomatic anemia distinguish between patients based on the number of chromosomal anomalies. Patients with del(5q) with or without 1 other cytogenetic abnormality should receive lenalidomide (Revlimid) or an ESA.^9,10

For patients without del(5q) or other abnormalities, guidelines categorize patients regarding the percentage of ring sideroblasts (below or above 15%) and erythropoietin (EPO) level (below or above 500 IU/L).

Luspatercept-aamt (Reblozyl), an erythroid maturation agent, is approved for transfusion-dependent patients in whom ESAs fail or who are not eligible for ESA therapy and have LR-MDS with ring sideroblasts.

Recently presented real-world data¹¹ evaluated treatment patterns in 76 patients with LR-MDS who received luspatercept for 3 months or more and had more than 3 months of follow-up after starting it. All patients started at the approved dose of 1 mg/kg every 3 weeks, and 75% of patients received luspatercept. More than 90% of patients with low transfusion burden achieved transfusion independence (TI) within the first 24 weeks of luspatercept treatment, and patients with moderate transfusion burden saw a decrease in the number of transfusions needed.¹¹

COMMANDS Trial

To decrease the detrimental effects of prolonged transfusion therapy, there is interest in adding luspatercept as an early frontline option.

The phase 3 COMMANDS Trial (NCT03682536) compares the efficacy and safety of luspatercept vs EPO in ESA-naïve, patients with low- to intermediate-risk MDS who are transfusion dependent. Interim results were presented by Della Porta et al at the European Hematology Association 2023 (EHA2023) Hybrid Congress in Frankfurt, Germany, and demonstrated better outcomes with luspatercept compared with epoetin alfa.

Patients (n = 178) with a serum EPO level less than 500 U/L were randomized to luspatercept or epoetin alfa. After a median treatment duration of 41.6 and 27 weeks, respectively, 58.5% of patients who were given luspatercept compared with 31.2% on epoetin alfa reached the primary end point of red blood cell (RBC) TI (RBC-TI) for more than 12 weeks with a concurrent mean hemoglobin increase equal to or greater than 1.5 g/dL during weeks 1 through 24.

The median duration of RBC-TI was also longer with luspatercept (126.6 weeks and 77.0 weeks, respectively), and resulted in a higher probability of achieving clinical benefit, regardless of overall mutational burden and the type of mutation.¹²

Luspatercept was well tolerated, although almost all patients (92.1%) did experience some treatment-emergent adverse events (TEAEs) of any grade, but only a minority (4.5%) discontinued treatment due to TEAEs.

The most common AEs of any grade were fatigue (14.6%), diarrhea (14.6%), and hypertension (12.9%), most of them mild to moderate and nonserious. There were 4 patients (2.2%) on luspatercept and 5 (2.8%) on epoetin alfa who developed AML, and the overall death rates were similar between arms (18.0% and 18.2%, respectively).¹³ KER-050 Another agent, KER-050, which has shown preclinical activity in ameliorating cytopenias, including anemia, is being evaluated in phase 2 studies in patients with LR-MDS.¹⁴

KER-050

is designed to inhibit select transforming growth-factor–β superfamily ligands activins A and B, growth differentiation factors 8 and 11) and improve the maturation of late-stage hematopoietic precursor cells.¹⁵

Interim safety and tolerability data from 36 patients treated at doses of 3.75 to 5 mg/kg every 4 weeks showed TEAEs in 30.6%, most frequently diarrhea (22%), fatigue (19%), and dyspnea and nausea (17% each). Four patients (11.1%) discontinued treatment due to TEAEs (injection site reaction, cardiac failure, dyspnea, chronic obstructive pulmonary disease exacerbation). The degree of anemia and need for transfusions improved, showing sustained increases in hemoglobin and platelets over 6 months.

High-Risk MDS

Allogeneic transplant is the only curative therapy for HR-MDS but may only be available to a subset of patients based on age, performance status, presence or absence of major comorbid conditions, psychosocial status, patient preference,and availability of a donor.⁹ Cytoreductive therapy—including azacitidine; decitabine, either alone or in combination with cedazuridine; or high-intensity chemotherapy—can be used as bridging therapy. If the patient is not a candidate for transplant, enrollment in a clinical trial or treatment with azacitidine are the preferred options, although decitabine alone or in combination with cedazuridine is also recommended.⁹

Cedazuridine is an orally active cytidine deaminase inhibitor that, when added to decitabine, increases oral bioavailability of the drug.

It was approved for adult patients with MDS with intermediate-or high-risk disease based on the ASTX727-01 trial (NCT02103478) of oral decitabine and cedazuridine (Inqovi) as a combination, and ASTX727-02, a phase 3 study (NCT03306264) to serve as a pharmacokinetic bridge between the oral combination and IV decitabine.^16,17

Decitabine/Cedazuridine Plus Venetoclax

Adding the BCL-2 inhibitor venetoclax (Venclexta)to a hypomethylating agent(HMA) has shown efficacy in the treatment of AML and patients with relapsed or refractory (R/R) MDS.^18,19 At EHA2023,early data from a phase 1/2 open-label, single-institution trial (NCT05600894)of oral decitabine/cedazuridine (ASTX727) in combination with venetoclax in patients with previously untreated MDS or chronic myelomonocytic leukemia (CMML) were presented.²⁰

The median age of the 37 patients was 71 years with a cytogenetic risk according to the Revised International Prognostic Scoring System (IPSS-R)of good, intermediate, and poor in approximately one-third each. The overall response rate was 94.5%, including a complete response(CR) in 35.1%, 29.7% with marrow CR with hematological improvement, and 29.7% marrow CR alone. In addition,53%of patients with cytogenetic abnormalities at diagnosis achieved cytogenetic response.

The median duration of response was 23 months and, after a median follow-up of 9.6 months, the median overall survival (OS) was not reached; the median PFS was 23 months.²⁰

Not unexpectedly for this high-risk population, grade 3 and 4 TEAEs were observed in 92% and 84% of patients, respectively (TABLE).²⁰ Investigators reported that 2 patients died from sepsis and 1 from pneumonia; the 4-week and 8-week mortality rates were 0% and 3%, respectively.

Relapsed/Refractory MDS

There remain limited options available for patients with relapsed MDS that has become ESA refractory. Two presentations at EHA2023 provided an update on the phase 3 IMERGE study (NCT02598661) that evaluates the use of imetelstat, a firstin-class telomerase inhibitor, in heavily transfused patients with non-del(5q) lower-risk MDS.

Earlier data had shown sustained, continuous TI for 1 year or more in 29% of patients when treated with imetelstat administered as a 2-hour intravenous infusion every 4 weeks at a dose of 7.5 mg/kg.²¹

^{Continuous Transfusion Independence}

Transfusion-dependent patients with nondel(5q) LR-MDS who have relapsed or are primarily refractory to ESAs, and who have not received lenalidomide or HMAs, were randomized to receive imetelstat 7.5 mg/ kg (n = 118) or placebo (n= 60) every 4 weeks. The primary end point of TI after 8 weeks was reached by 39.8% of patients on imetelstat compared with 15% on placebo, and the median TI lasted for 51.6 weeks with imetelstat vs 13.3 weeks with placebo.²²

The most common grade 3/4 TEAEs were thrombocytopenia and neutropenia; all were of short duration, and most (> 80%) resolved to grade 2 or lower within 4 weeks, whereas the rates of grade 3 or higher bleeding and infections were comparable between imetelstat and placebo.²²

Disease-modifying Activity of Imetelstat

The pathogenesis of MDS is characterized by a heterogeneous group of genetic mutations.^23,24 In an analysis of 944 patients with MDS, the authors determined that mutations in TET2, SF3B1, ASXL1, SRSF2, DNMT3A, and RUNX1 occurred in 10% or more cases.²⁴

The mutation SF3B1, an RNA-splicing gene, defines MDS with ring sideroblasts in the presence of 5% or more ring sideroblasts and is seen in over 80% of these patients, and mutations of TET2, important for DNA methylation, is also common in LR-MDS.25,26 The goal of treating patients with LR-MDS is to eradicate these aberrant clones without creating additional toxicity.

Bone marrow samples taken pretreatment and every 24 weeks post treatment with imetelstat were evaluated for cytogenetic response of complete or partial remission.

The blood of patients with a 5% or more variant allele frequency (VAF) at baseline and 1 or more post baseline assessment was assessed every 12 weeks post treatment in between bone marrow samplings.

Approximately 22% of patients in the imetelstat and placebo groups had baseline cytogenetic abnormalities. A cytogenetic response was achieved in a higher proportion (34.6%) of patients in the imetelstat group vs the placebo group (15.4%), and they also demonstrated a higher rate of 50% or more VAF decreases in SF3B1, TET2, DNMT3A, and ASXL1 mutations. Decreases in SF3B1 and TET2 VAF were especially pronounced in patients achieving 8-week or more, 24-week or more, and 1-year or more TI in the imetelstat group, and greater reductions in SF3B1 VAF correlated significantly with hemoglobin increases and longer durations of TI.²⁶

Potential New Targets in MDS

Other important mutations occur in TP53, which is especially common in resistant MDS with a tendency to rapidly progress to AML.²⁷ The inactivation of the tumor suppressor protein TP53 is thought to play a role in decreasing the efficacy of HMAs. The MDM2/ MDMX complex degrades the wild-type p53 protein, and MDMX overexpression was shown to cause the transition of preleukemic stem cells to overt AML in murine models.²⁸

MDMX Expression

Investigators presented data from 340 patients with MDS in different risk categories (4.2%, 25.9%, 23.5%, 22.6%, and 23.8% with IPSS-R very low risk, low risk, intermediate risk, high risk, and very high risk MDS, respectively). MDMX expression was significantly higher in patients with MDS with excess blasts than those without excess blasts. Among 290 patients with unmutated TP53, high expression of MDMX resulted in significantly poorer overall survival and leukemia-free survival (29.1 months vs 91.3 months, and 21.4 months vs 70.3 months), and the rates of primary resistant cells to HMA were significantly higher (59.5% vs 22.7%). The combination of an MDMX inhibitor with an HMA resulted in an additive effect on the killing of THP-1 cells in vitro, possibly adding a therapeutic option.²⁹

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