ESMO Recommendations for the Treatment of Low-Risk Myelodysplastic Syndrome

Low-Risk MDS 

Myelodysplastic syndrome is a disorder of hematopoietic stem cells. This disease prevails in seniors and is characterized by ineffective hematopoiesis leading to cytopenia. A significant risk is the progression to acute myeloid leukemia (AML) in a quarter to a third of all cases. The median age at diagnosis is approximately 70 years; < 10% of patients are younger than 50 years. 

In low-risk MDS, the risk of progression to AML is lower, and approximately half of older patients die from causes other than MDS or AML. The main priority of their treatment is the management of cytopenias, especially predominant anemia, and the improvement of quality of life (QoL). Even in this group, there can be patients with a worse prognosis, associated with the value of the score based on the revised International Prognostic Scoring System (IPSS-R) or with biological characteristics including, for example, somatic mutations. Additionally, there are patients with resistance to 1st line therapy. For these patients, treatments for higher-risk MDS may be beneficial, which is especially true for patients with intermediate IPSS-R. Anemia resulting from the failure of specific therapy often requires repeated red blood cell transfusions, which can potentially lead to iron overload. 

Anemia Therapy 

Chronic red blood cell transfusions can be considered the sole treatment for anemia in patients with low-risk MDS; however, repeated transfusions lead to increased morbidity and do not sufficiently improve QoL. Iron overload may also be detrimental to various organs. Erythropoiesis-stimulating agents (ESAs) do not affect AML progression but are an independent favorable prognostic factor for survival. 

1st Line 

For patients without del(5q), ESAs, i.e., recombinant epoetin (EPO) at a dose of 30,000–80,000 U/week, or darbepoetin (DAR) at a dose of 150–300 μg/week, remain the first-choice treatment for most low-risk MDS, achieving an erythroid response of 40–60%. According to IWG 2006 criteria, low baseline serum EPO levels (<200–500 U/L) and low or no need for red blood cell transfusions are major prognostic factors for response to erythropoiesis-stimulating agents therapy. The effectiveness of ESAs can be enhanced by co-medication with granulocyte colony-stimulating factor (G-CSF). For patients with serum EPO < 200 U/L, epoetin alfa (and its biosimilars) is currently approved in the EU. Response to treatment occurs within 8–12 weeks of therapy, with a median response duration of approximately 20–24 months. 

For patients with del(5q), anemia is associated with a lower response rate and significantly shorter response to ESAs compared to other low-risk MDS variants. 60–65% of patients respond to lenalidomide (LEN) treatment, with a median red blood cell transfusion independence (RBC-TI) of 2–2.5 years. The recommended initial dose of lenalidomide is 10 mg/day for 3 weeks each 4 weeks. Cytogenetic response is achieved in 50–75% of patients.

In contrast, TP53 gene mutation is associated with higher AML progression risk and LEN resistance. Patients with TP53 mutation (during LEN administration) require more intensive monitoring. The most common adverse effects of LEN are neutropenia and thrombocytopenia of grade 3–4, approximately 60% of patients in the first weeks of treatment. 

2nd Line 

For patients without del(5q) after ESAs failure, additional treatment is challenging; most require long-term red blood cell transfusions. Therapeutic options include antithymocyte globulin (ATG), hypomethylating agents (HMA), and LEN, although these are not approved in most countries for this indication. ATG induces erythroid response in 25–40% of patients, with better results in younger individuals (< 65 years). HMA provides RBC-TI response in 20–40% of patients and may also positively impact other cytopenias. LEN achieves RBC-TI response in 25–30% of patients. Combined therapy of LEN + ESA can increase response rate.

Luspatercept blocks Smad2/3 signaling pathways, which slow erythrocyte maturation, enabling their normal maturation. Recent phase II study results demonstrated an erythroid response of 63% and RBC-TI in 38% of patients, with limited toxicity. 

Also, for patients with del(5q), LEN failure is associated with poor prognosis (especially in case of TP53 gene mutation), even when they do not immediately transition to high-risk MDS. These patients are suitable candidates for treatment that has shown a positive impact on survival in high-risk MDS (including HMA and allogeneic hematopoietic stem cell transplantation).

Neutropenia and Thrombocytopenia Therapy 

Low neutrophil levels < 1500/mm³ occur in only 7% of patients with low-risk MDS; neutropenia is rarely associated with life-threatening infections. G-CSF can improve neutropenia in 60–75% of cases and can be combined with anti-infectives. 

Platelet levels < 50,000/mm³ are recorded in approximately 30% of cases. High doses of androgens can positively affect thrombocytopenia in 1/3 of thrombocytopenic patients with low-risk MDS, but the response to treatment is generally transient. 

Therapeutic options include thrombopoietin receptor agonists (TPO-RA), although they are currently not approved in the EU for this indication. Romiplostim, a TPO-RA, at high doses (500–1000 μg/week), showed sufficient response (55% response rate) in a phase II study but led to transient marrow or peripheral blasts in approximately 15% of patients, reversible upon treatment discontinuation. Another phase II study demonstrated the effect of romiplostim on reducing severe bleeding and platelet transfusions. Another TPO-RA, eltrombopag, showed a favorable safety profile, with a 47% response rate to treatment and reduced bleeding events, without observed blast occurrence during administration. 

(lexi) 

Source: Fenaux P., Haase D., Santini V. et al.; ESMO Guidelines Committee. Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2021; 32 (2): 142–156, doi: 10.1016/j.annonc.2020.11.002.