Roxadustat Combined With Luspatercept Versus Luspatercept Monotherapy in the Treatment of Refractory MDS-RS

Study Overview
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Brief Summary
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In a randomized controlled phase II/III clinical trial, 58% of patients with lower-risk MDS had at least a 50% reduction in red blood cell (RBC) transfusion units every 8 weeks after roxadustat treatment. In a randomized controlled phase III clinical trial, luspatercept significantly improved transfusion dependence in erythropoietin-stimulating agents (ESA)-refractory MDS-RS and improved hemoglobin response and quality of life, compared to placebo. This study aimed to evaluate the efficacy and safety of roxadustat combined with luspatercept versus luspatercept monotherapy in the treatment of refractory MDS-RS.

Detailed Description
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Myelodysplastic neoplasms (MDS) are heterogeneous clonal disorders of stem cells that result in peripheral blood cytopenia and ineffective hematopoiesis, with the potential risk of the development of acute myeloid leukemia (AML). Most patients with myelodysplastic syndromes with ring sideroblasts (MDS-RS) are stratified into lower-risk groups by the revised International Prognostic Scoring System (IPSS). At present, the main therapies for MDS-RS are red blood cell and platelet transfusion, erythropoietin (EPO), androgen, and iron chelation therapy. Roxadustat can up-regulate transferrin receptors to increase iron absorption, up-regulate transferrin to promote iron transport, and down-regulate ferritin levels to indirectly improve iron absorption and transport, promote plasma iron entry into the bone marrow to generate red blood cells and promote the production of EPO in the physiological range. Luspatercept generally promotes advanced erythrocyte maturation by inhibiting the TGF-β/smad2/3 signaling pathway. In a randomized controlled phase II/III clinical trial, 58% of patients with lower-risk MDS had at least a 50% reduction in red blood cell (RBC) transfusion units every 8 weeks after roxadustat treatment. In a randomized controlled phase III clinical trial, luspatercept significantly improved transfusion dependence in erythropoietin-stimulating agents (ESA)-refractory MDS-RS and improved hemoglobin response and quality of life, compared to placebo. The aim of this study was to evaluate the efficacy and safety of roxadustat combined with luspatercept versus luspatercept monotherapy in the treatment of refractory MDS-RS. If it is proved that the combination of the two drugs is better than luspatercept monotherapy, it can quickly improve the anemia of refractory MDS-RS and improve the quality of life.

Official Title
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Roxadustat Combined With Luspatercept Versus Luspatercept Monotherapy in the Treatment of Refractory Myelodysplastic Syndrome With Ring Sideroblasts (MDS-RS): A Prospective Randomized Controlled Study

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Roxadustat
* Drug: Luspatercept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years old. Patients with a definite diagnosis of MDS-RS and stratified as lower-risk according to IPSS-R. After at least 6 weeks of rhEPO treatment, with hemoglobin<100g/L Adequate hepatic functions with alanine transaminase (ALT)/aspartate. transaminase (AST) levels within 2 times of the normal upper limit and total bilirubin levels within 2 times of the normal upper limit. ECOG≤2 with an expected life span of more than 6 months Documented patient consent. Exclusion Criteria: Age <18 years old. Complicated with active or uncontrolled infections. Complicated with other malignancies. Creatinine/transaminase ≥ 2 normal upper limit. Complicated with myelofibrosis. Pregnant or lactating women, or men with recent fertility needs Allergic to luspatercept or excipients Patients with history of polysorbate 80 allergy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: roxadustat and luspatercept<br>Luspatercept (1.0 mg/kg, subcutaneously injection every 3 weeks, adjusted according to blood pattern, up to 1.75mg/kg. Roxadustat (150mgqod) was administered for at least 6 months to evaluate efficacy. Hemoglobin ≥120g/L can be discontinued, and hemoglobin <120g/L can continue to use. Those who are effective will continue to be given the combination therapy until ineffective or intolerant. | Drug: Roxadustat<br>* Roxadustat (150 mgqod)<br>Drug: Luspatercept<br>* Luspatercept (1.0 mg/kg, subcutaneously injection every 3 weeks, adjusted according to blood pattern, up to 1.75mg/kg)<br>|
| Experimental: luspatercept<br>Luspatercept (1.0 mg/kg, subcutaneously injection every 3 weeks, adjusted according to blood pattern, up to 1.75mg/kg. Luspatercept was given for at least 6 months to evaluate the efficacy. Hemoglobin ≥120g/L can be discontinued, and hemoglobin <120g/L can continue to use. Those who are effective will continue to be given the therapy until it is ineffective or intolerant | Drug: Luspatercept<br>* Luspatercept (1.0 mg/kg, subcutaneously injection every 3 weeks, adjusted according to blood pattern, up to 1.75mg/kg)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response rate (ORR) | Proportion of patients who achieved complete response, partial response and hematological response. | 6 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| transfusion indenpendence (TI) | Proportion of patients with transfusion dependence over 8 weeks | 6 month | 
| adverse event rate | Proportion of patients with adverse events | 6 month |