Lower-Risk MDS Treatment Remains an 'Unmet Need'

By Cecilia Brown - Last Updated: March 6, 2023


Myelodysplastic syndromes (MDS) exist on a spectrum of risk, with risk dictated by clinical and molecular features. However, most patients with MDS, even those with lower-risk disease, die from disease-related complications, namely cytopenia.

While cytopenias may be mild upon diagnosis and can be surveilled, they will ultimately require treatment. Anemia is the hallmark of disease and is the most common indication to treat in low-risk MDS (LR-MDS).

Risk Stratification Systems for MDS

Risk stratification is important to prognosticate and understand the disease trajectory. The International Prognostic Scoring System-Revised (IPSS-R) is the most commonly used risk stratification system in MDS but has certain limitations. Researchers also recently developed the IPSS-Molecular, which re-stratified 46% of patients with MDS, upstaging risk for 74% of those patients.

 Clonal Hematopoiesis

Clonal hematopoiesis of indeterminate potential, idiopathic cytopenia of undetermined potential, clonal cytopenia of undetermined significance (CCUS), and MDS may be a spectrum of related syndromes.

While clonal hematopoiesis can increase the risk for hematologic neoplasms, therapy-related myeloid neoplasms, and cardiovascular disease, there are no current recommendations to routinely check for these mutations nor true guidelines on what to do if they are present. However, there is an increasing interest in identifying and following these patients. There is also interest in investigational therapies to change the natural history of clonal hematopoiesis and CCUS.

Response Criteria

In high-risk MDS (HR-MDS), the goal is to prevent progression to acute myeloid leukemia (AML) and improve overall survival (OS). The goal of therapy in LR-MDS is to improve cytopenia(s) and related complications that impact mortality and morbidity. Responses to treatment should be viewed with these goals in mind.

LR-MDS clinical trials frequently use hematologic responses, such as erythroid response, as an endpoint. However, drug approval and the International Working Group (IWG) 2006 response criteria have been mostly based on red blood cell (RBC) transfusion independence. While IWG response criteria is frequently used for MDS clinical trials, they are not ubiquitously used in clinical practice.

Treatment Options for LR-MDS

Many patients with LR-MDS die without progression to AML or HR-MDS. For example, one study showed most patients did not progress beyond LR-MDS, but half of all patients’ mortality was directly related to their disease. Furthermore, those with moderate or severe anemia had significantly worse OS than those with mild anemia or no anemia. Nearly two-thirds of patients in that study did not receive treatment or supportive care at baseline, with around half of those patients having moderate or severe anemia.

Most patients with LR-MDS are anemic and become transfusion dependent, requiring initiation of therapy. Patients rarely require treatment for isolated neutropenia or thrombocytopenia, but co-occurrence of cytopenia may dictate the choice of therapy.

Treatment of Anemia

Erythroid Stimulating Agents

Anemia is the most common cytopenia in patients with MDS. Randomized trials of erythroid stimulating agents (ESA) showed improved response rates, decreased transfusion dependence, and better quality of life compared to placebo in patients with LR-MDS.

However, not all patients with LR-MDS will respond to ESA therapy and identifying those patients early can prevent the use of an ineffective treatment. A validated model based on the pretreatment endogenous serum erythropoietin concentration and RBC transfusion burden distinguished among patients with high, intermediate, or low probabilities of ESA response.


Lenalidomide is the treatment of choice in patients who have transfusion dependent MDS with del5(q). In patients with LR-MDS without del5(q) who are ESA refractory, lenalidomide led to transfusion independence rates of 20% to 30%.

Lenalidomide plus an ESA led to an erythroid response rate of 26% in those with suboptimal responses to lenalidomide monotherapy and ESA refractoriness, with 22% achieving transfusion independence.

A larger confirmatory trial showed combination therapy with lenalidomide plus an ESA led to a higher erythroid response rate and a longer median duration of response than with lenalidomide alone, demonstrating that lenalidomide restores sensitivity to those who are ESA refractory.


The PACE-MDS trial of luspatercept showed hematologic improvement in erythroid responses and transfusion independence in patients with low-or intermediate-1 risk MDS with anemia.

These findings were validated in the phase III MEDALIST trial, which included patients with low to intermediate-risk MDS with ringed sideroblasts who were receiving frequent transfusions and were refractory or unlikely to respond to ESA. Those who received luspatercept were transfusion independent for eight weeks or longer, compared with 13% of those who received placebo.

Immunosuppressive Therapy

A study of antithymocyte globulin in unselected patients with MDS showed response rates of 30% to 50%. Adding cyclosporine A to antithymocyte globulin may improve responses. Immunosuppressive therapy should be used in selected patients with LR-MDS.

Hypomethylating Agents

In LR-MDS, hypomethylating agents (HMA) should seldom be used as first-line therapy. Other options such as lenalidomide, ESAs, and luspatercept offer hematologic improvement and generally have a better side effect profile. HMA treatment led to a 50% response rate with OS of 32 months in those who lost their response to lenalidomide. Another study showed better hematologic improvement in erythroid responses when lenalidomide was used before HMA versus after HMA.

Treatment of Isolated Thrombocytopenia

While most patients with LR-MDS will present with anemia, many can present with thrombocytopenia. Romiplostim led to a higher rate of platelet response than placebo in a phase II double-blind trial, while a phase I/II trial of eltrombopag showed 54% of patients with LR-MDS achieved platelet transfusion independence.

Treatment of Isolated Neutropenia

Neutropenia is not common in LR-MDS but can be associated with life-threatening infections. Treatment options are limited and continue to remain an unmet need. Granulocyte colony stimulating factor (G-CSF) may be used in certain situations, such as severe life-threatening infections, but long-term use of G-CSF has not shown a survival advantage.

Neutropenia often occurs along with STAT3 mutations. Because of its immune-related pathogenesis, immunosuppressive therapy maybe appropriate in this setting and could be also an option among younger patients and those with hypoplastic MDS.

IDH mutations are enriched in patients with MDS who have severe neutropenia. The IDH1/2 inhibitors ivosidenib and enasidenib had clinical activity in patients with LR-MDS who had ESA failure, with a 50% complete response rate.

Iron Chelation

Iron deposition can result in significant morbidity and mortality. Patients with MDS are at a notable risk for iron overload due to frequent transfusions and ineffective erythropoiesis. Iron chelation therapy should be discussed with patients who have LR-MDS and evidence of iron overload. Treatment should be individualized based on potential risks and benefits.

Allogeneic Hematopoietic Stem Cell Transplant

Allogeneic hematopoietic stem cell transplant (HSCT) remains the only potential for cure in MDS but carries a risk of early morbidity and mortality.

Research suggests delaying HSCT until progression in LR-MDS leads to the maximum survival gain. Allogeneic HSCT should be considered in patients with signs of disease progression, higher risk features, and in profoundly cytopenic patients with no other treatment options.

Novel risk models incorporating a personalized approach and genomic alterations can help identify those who may benefit from HSCT.

Investigational Agents


A phase II/III study of imetelstat in patients with LR-MDS who were heavily transfusion-dependent and ESA refractory showed an eight-week RBC transfusion independence rate of 37%, with a 65% erythroid response rate.


In patients with LR-MDS without del(5q) who were transfusion dependent but had a low transfusion burden, roxadustat led to a 54% erythroid response rate and 38% achieved transfusion independence for at least eight weeks. Because of the tolerable safety profile and improved responses, there is a current ongoing placebo-controlled trial of roxadustat.


Multiple studies of canakinumab as a monotherapy and in combination with other agents for LR-MDS are ongoing.

Other Agents

Multiple other agents are early in development. These include novel agents targeting the activin receptor signaling pathway; an oral dual allosteric inhibitor of CXCR1 and CXCR2, SX-682; a novel IRAK1 and IRAK4 inhibitor, R289; and a splicing factor modulator, RVT-2001.


While treatment of LR-MDS often involves alleviating symptomatic cytopenias, treatment refractory cytopenias can develop, leaving patients without options. Due to this, treatment of LR-MDS remains an unmet need and goals of therapy should extend beyond transfusion independence. Preventing MDS is of interest, with studies planned to target high-risk clonal hematopoiesis and CCUS.

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