Luspatercept

TD is defined as ≥ 3 red blood cells (RBC) units/16 weeks assessed by International Working Group (IWG) 2018.

Percentage of participants who become RBC-transfusion free over any consecutive 12-week period starting in first 24 weeks.

Type, frequency, severity of AEs, relationship of treatment emergent adverse events to luspatercept

Progression to high/very high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (MDS and myelofibrosis \[MF\] only).

Progression to high/very high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (MDS and myelofibrosis \[MF\] only)

Development of other malignancies/pre-malignancies

Development of other malignancies/pre-malignancies

Percentage of participants who are RBC transfusion-free for any 12-week period associated with a concurrent mean hemoglobin (Hgb) increase ≥ 1.5 g/dL compared to baseline. After applying below 14/3-day rule, the baseline Hgb value is defined as the lowest Hgb value from the central, local laboratory, or pre transfusion Hgb from transfusion records that is within 56 days on or prior to the first dose of treatment, or randomization date if participants were not treated. 4/3-day rule: only Hgb values that are at least 14 days after a transfusion may be used unless there is another transfusion within 3 days after the Hgb assessment. If this occurs, that Hgb value will be used despite being \< 14 days after the previous transfusion.

Erythroid Response was defined as red blood cell (RBC) transfusion burden reduction from baseline ≥ 33% with a reduction of at least 2 units during Week 13 - 24 compared to the 12-week interval on or prior to Dose 1 Day 1.

RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during the first 24 weeks of study treatment. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 24 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to or on the cut-off date were counted as non-responders.

of at least 1.0 g/dl

Mean rate of red blood cell transfusion independence (RBC-TI) for at least any consecutive 84 days (≥ 12 consecutive weeks) during weeks 1-24 compared to baseline in non-mutated SF3B1, lower-risk myelodysplastic syndrome patients treated with Luspatercept plus Darbepoetin Alfa

Mean rate of hemoglobin ≥ 1.5 g/dL during weeks 1-24 compared to baseline in non-mutated SF3B1, lower-risk myelodysplastic syndrome patients treated with Luspatercept plus Darbepoetin Alfa.

Adult TD Cohort

Adult NTD Cohort

Adolescent TD and NTD Cohorts

Adolescent TD and NTD Cohorts

Adolescent TD and NTD Cohorts

Determine the recommended dose of luspatercept that is safe and tolerable in pediatric participants with transfusion-dependent B-thalassemia or non-transfusion-dependent β-thalassemia

Maximum serum concentration of drug

Area under the curve

Half-life

Apparent oral clearance

Apparent volume of distribution

Hematologic improvement is defined as the percent of participants meeting HI-E criteria of \>= 1.5 g/dL increase in hemoglobin (Hgb) sustained over any consecutive 56-day period in the absence of red blood cell (RBC) transfusions from Week 1 Day 1 through Week 24. Participants who discontinued from the Treatment Period without achieving HI-E are counted as non-responders.

Erythroid Response is defined as an increase from baseline ≥1.0 g/dL in mean of hemoglobin values over a continuous 12-week interval from Weeks 13 to 24 of treatment in the absence of transfusions. Baseline hemoglobin (Hb) is the average of 2 or more Hb measurements at least 1 week apart within 4 weeks prior to Dose 1.

The number of participants that achieved anemia response as it relates to hemoglobin (Hgb) increase and red blood cell (RBC)-transfusion independence is defined below: Cohorts 1 (anemia only) and 3A: The number of participants achieving ≥ 1.5 g/dL hemoglobin increase from baseline over any consecutive 84-day period without an RBC transfusion from Day 1 up through and including Day 168. Cohorts 2 (RBC-transfusion dependent) and 3B: The number of participants who become RBC-transfusion free over any consecutive 84-day period from Day 1 up through and including Day 168. Baseline value is defined as the last value (including "unscheduled") measured on or before the first dose.

To determine the optimal dose level in terms of both toxicity and efficacy for luspatercept + EPO

To determine, at Week 25, the superiority and efficacy of luspatercept + ESA over luspatecept alone