Efficacy of Luspatercept in ESA-naive LR-MDS Patients With or Without Ring Sideroblasts Who do Not Require Transfusions

Inclusion Criteria:

• Diagnosis of myelodysplastic syndrome (MDS) according to WHO classification
• Very low-, low-, or intermediate-risk disease MDS with up to 3.5 according to revisedInternational Prognostic Scoring System (IPSS-R)
• Less than 5% blasts in bone marrow
• Peripheral blood white blood cell (WBC) count < 13,000/μL
• sEPO levels ≤ 500 mU/mL
• Non-transfusion dependence (NTD) according to IWG 2018 criteria
• Symptomatic anemia
• Age > 18 years
• Written informed consent

Exclusion Criteria:

• Patient does not accept bone marrow sampling during screening and during treatment
• Patient does not accept regular peripheral blood sampling for screening and duringtreatment.
• Patient does not accept subcutaneous application of LUS every three weeks
• Prior treatment for anemia associated with MDS (i.e. ESA, luspatercept), exceptpreviously treated with G-CSF/granulocyte-macrophage colony-stimulating factor (GM-CSF), both agents must be discontinued at least 4 weeks before registration
• Secondary MDS, i.e. MDS arising as the result of chemical injury or treatment withchemotherapy and/or radiation for other diseases
• Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies,or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding.
• Prior allogeneic or autologous stem cell transplant
• Prior history of AML
• Prior history of malignancies, other than MDS, unless the subject is free of thedisease (including completion of any active or adjuvant treatment for priormalignancy) for ≥ 5 years.
• Major surgery within 8 weeks prior to registration.
• Uncontrolled hypertension, defined as repeated elevations of systolic blood pressure ≥160 mmHg or of diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment
• Platelet count < 30,000/μL (30 × 10^9/L)
• Estimated glomerular filtration rate or creatinine clearance < 40 mL/min
• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) ≥ 3.0 × upper limit of normal (ULN)
• Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≥ 3.0 × ULN
• Total bilirubin ≥ 2.0 × ULN
• Eastern Cooperative Oncology Group (ECOG) performance status > 2
• Stroke, deep venous thrombosis, pulmonary or arterial embolism within 6 months priorto registration
• Myocardial infarction, uncontrolled angina, uncontrolled heart failure, oruncontrolled cardiac arrhythmia within 6 months prior to registration.
• Subjects with a known ejection fraction of ˂ 35%, confirmed by a localechocardiography or multigated acquisition scan (MUGA) performed within 6 months priorto registration, are excluded
• Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoingsigns/symptoms related to the infection without improvement despite appropriateantibiotics, antiviral therapy, and/or other treatment), known human immunodeficiencyvirus (HIV), known evidence of active infectious hepatitis B, and/or known evidence ofactive hepatitis C.
• History of severe allergic or anaphylactic reactions or hypersensitivity torecombinant proteins or excipients in the IMP
• Subject has any significant medical condition, laboratory abnormality, psychiatricillness, or is considered vulnerable by local regulations (e.g., imprisoned orinstitutionalized) that would prevent the subject from participating in the study.
• Subject has any condition, including the presence of laboratory abnormalities, whichplaces the subject at unacceptable risk if he/she participates in the study
• Subject has any condition or concomitant medication that confounds the ability tointerpret data from the study.
• Use of any of the following within five weeks prior to registration are prohibited:Anticancer cytotoxic chemotherapeutic agent or treatment, Corticosteroid, except forsubjects on a stable or decreasing dose for ≥ 1 week prior to inclusion for medicalconditions other than MDS, Iron chelation therapy, except for subjects on a stable ordecreasing dose for at least 8 weeks prior to registration, Other RBC hematopoieticgrowth factors (e.g. interleukin [IL]-3)
• Pregnant or breastfeeding females
• Positive pregnancy test in women of childbearing potential.
• Female subjects of childbearing potential unwilling to use a highly effective methodof contraception for the course of the study through 90 days after the last dose ofstudy medication.
• Male subjects with procreative capacity not willing to use a highly effective methodof contraception, starting with the first dose of study therapy through 90 days afterthe last dose of study therapy.
• Participation in other interventional trials.
• Patients under legal supervision or guardianship.