Trial Outcomes & Findings for A Safety and Efficacy Study to Evaluate Luspatercept in Subjects With Myeloproliferative Neoplasm-associated Myelofibrosis Who Have Anemia With and Without Red Blood Cell-transfusion Dependence (NCT NCT03194542)

NCT ID: NCT03194542

Last Updated: 2023-08-24

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

95 participants

Primary outcome timeframe

Any consecutive "rolling" 84-day period from Day 1 through and including Day 168

Results posted on

2023-08-24

Participant Flow

Participant milestones

Participant milestones
Measure	Cohort 1: Anemia Only Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 2: RBC-Transfusion Dependent Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3A: Anemia Only (Stable Dose of Ruxolitinib) Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3B: RBC-Transfusion Dependent (Stable Dose of Ruxolitinib) Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.
Overall Study STARTED	22	21	14	38
Overall Study COMPLETED	0	0	0	0
Overall Study NOT COMPLETED	22	21	14	38

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1: Anemia Only Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 2: RBC-Transfusion Dependent Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3A: Anemia Only (Stable Dose of Ruxolitinib) Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3B: RBC-Transfusion Dependent (Stable Dose of Ruxolitinib) Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.
Overall Study Participant to Receive Bone Marrow Transplant	1	0	0	0
Overall Study Rollover to Long-term follow-up Protocol	1	1	0	5
Overall Study Per Protocol Repeat Blasts of 10%	1	0	1	0
Overall Study Loss of Response	4	2	3	4
Overall Study Physician Decision	0	1	0	0
Overall Study Lack of Efficacy	2	2	2	6
Overall Study Withdrawal by Subject	2	1	5	4
Overall Study Progressive Disease	1	0	1	1
Overall Study Adverse Event	1	2	0	5
Overall Study Death	1	2	0	5
Overall Study Completed the primary treatment phase but did not meet clinical benefit criteria	8	10	2	8

Baseline Characteristics

A Safety and Efficacy Study to Evaluate Luspatercept in Subjects With Myeloproliferative Neoplasm-associated Myelofibrosis Who Have Anemia With and Without Red Blood Cell-transfusion Dependence

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1: Anemia Only n=22 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 2: RBC-Transfusion Dependent n=21 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3A: Anemia Only (Stable Dose of Ruxolitinib) n=14 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3B: RBC-Transfusion Dependent (Stable Dose of Ruxolitinib) n=38 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Total n=95 Participants Total of all reporting groups
Age, Continuous	69 Years STANDARD_DEVIATION 8.87 • n=5 Participants	73.9 Years STANDARD_DEVIATION 5.71 • n=7 Participants	65.4 Years STANDARD_DEVIATION 8.45 • n=5 Participants	71.3 Years STANDARD_DEVIATION 5.80 • n=4 Participants	70.5 Years STANDARD_DEVIATION 7.42 • n=21 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	6 Participants n=7 Participants	7 Participants n=5 Participants	15 Participants n=4 Participants	37 Participants n=21 Participants
Sex: Female, Male Male	13 Participants n=5 Participants	15 Participants n=7 Participants	7 Participants n=5 Participants	23 Participants n=4 Participants	58 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	3 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	16 Participants n=5 Participants	19 Participants n=7 Participants	14 Participants n=5 Participants	32 Participants n=4 Participants	81 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	5 Participants n=4 Participants	11 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants	1 Participants n=4 Participants	7 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants	3 Participants n=21 Participants
Race (NIH/OMB) White	16 Participants n=5 Participants	18 Participants n=7 Participants	10 Participants n=5 Participants	30 Participants n=4 Participants	74 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	5 Participants n=4 Participants	11 Participants n=21 Participants

PRIMARY outcome

Timeframe: Any consecutive "rolling" 84-day period from Day 1 through and including Day 168

Population: Intent-to-treat (ITT) population: All enrolled participants regardless of whether or not the participant received luspatercept.

Outcome measures

Outcome measures
Measure	Cohort 1: Anemia Only n=22 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 2: RBC-Transfusion Dependent n=21 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3A: Anemia Only (Stable Dose of Ruxolitinib) n=14 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3B: RBC-Transfusion Dependent (Stable Dose of Ruxolitinib) n=38 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.
The Number of Participants With Anemia Responses Over Any 84-Day Period During the Primary Treatment Period	3 Participants	2 Participants	2 Participants	10 Participants

SECONDARY outcome

Timeframe: From first dose up to first onset of anemia response (calculated from Day 1 through and including Day 168)

Population: ITT population who achieved anemia response. (Intent-to-treat (ITT) population: All enrolled participants regardless of whether or not the participant received luspatercept.)

Time to anemia response follows the definitions below: Cohorts 1 (anemia only) and 3A: Time between first administration of luspatercept and the first hemoglobin increase of ≥ 1.5 g/dL from baseline that starts a consecutive 84-day period of consecutive increase ≥ 1.5 g/dL without RBC transfusions. Cohorts 2 (RBC-transfusion dependent) and 3B: Time between first administration of luspatercept and the first day of an RBC transfusion-free period of 84 days. Baseline value is defined as the last value (including "unscheduled") measured on or before the first dose.

Outcome measures

Outcome measures
Measure	Cohort 1: Anemia Only n=3 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 2: RBC-Transfusion Dependent n=2 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3A: Anemia Only (Stable Dose of Ruxolitinib) n=2 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3B: RBC-Transfusion Dependent (Stable Dose of Ruxolitinib) n=10 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.
Time to Anemia Response During the Primary Treatment Period	57.3 Days Standard Deviation 14.36	2.0 Days Standard Deviation 0.00	63.5 Days Standard Deviation 30.41	30.7 Days Standard Deviation 27.22

SECONDARY outcome

Timeframe: From first dose through last day of longest response (calculated from Day 1 through end of treatment, up to approximately 232 weeks)

Population: ITT population who achieved anemia response. (Intent-to-treat (ITT) population: All enrolled participants regardless of whether or not the participant received luspatercept.)

The duration of anemia response is defined as the duration of time from first day of longest response to the last day of longest response. Participants who achieved and maintained the anemia response at the time of the analysis are censored at the efficacy cutoff date. For Cohorts 1 and 3A, an anemia responder was defined as a subject with ≥ 1.5 g/dL hemoglobin increase from baseline over any consecutive 84-day period without an RBC transfusion. For Cohorts 2 and 3B, an anemia responder was defined as a subject who becomes RBC transfusion free over any consecutive 84-day period. Baseline value is defined as the last value (including "unscheduled") measured on or before the first dose.

Outcome measures

Outcome measures
Measure	Cohort 1: Anemia Only n=3 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 2: RBC-Transfusion Dependent n=2 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3A: Anemia Only (Stable Dose of Ruxolitinib) n=2 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3B: RBC-Transfusion Dependent (Stable Dose of Ruxolitinib) n=10 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.
Duration of Anemia Response	457.7 Days Standard Deviation 611.20	623.0 Days Standard Deviation 29.70	88.5 Days Standard Deviation 6.36	534.7 Days Standard Deviation 527.67

SECONDARY outcome

Timeframe: From Day 1 through end of treatment (up to approximately 232 weeks).

Population: Intent-to-treat (ITT) population: All enrolled participants regardless of whether or not the participant received luspatercept. Pre-specified to be collected for Cohorts 2 and 3B only.

Frequency of RBC transfusion is defined as the mean number of RBC units transfused per participant every 4 weeks (28 days). The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment.

Outcome measures

Outcome measures
Measure	Cohort 1: Anemia Only n=21 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 2: RBC-Transfusion Dependent n=38 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3A: Anemia Only (Stable Dose of Ruxolitinib) Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3B: RBC-Transfusion Dependent (Stable Dose of Ruxolitinib) Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.
The Number of RBC Units Transfused Per Participant Per 28 Days (Cohorts 2 and 3B Only) Primary Treatment Period	2.76 RBC Units Standard Deviation 1.967	1.49 RBC Units Standard Deviation 1.345	—	—
The Number of RBC Units Transfused Per Participant Per 28 Days (Cohorts 2 and 3B Only) Entire Treatment Period	2.70 RBC Units Standard Deviation 2.040	1.52 RBC Units Standard Deviation 1.365	—	—

SECONDARY outcome

Timeframe: Baseline and from Day 1 through end of treatment (up to approximately 232 weeks).

Population: Intent-to-treat (ITT) population: All enrolled participants regardless of whether or not the participant received luspatercept. Pre-specified to be collected for Cohorts 2 and 3B only.

The number of participants who reduce their transfusion burden by ≥ 50% from baseline over any consecutive 84-day period. Baseline is defined as average number of RBC units per 28 days over the 84 days period on or prior to the C1D1 date. The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment.

Outcome measures

Outcome measures
Measure	Cohort 1: Anemia Only n=21 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 2: RBC-Transfusion Dependent n=38 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3A: Anemia Only (Stable Dose of Ruxolitinib) Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3B: RBC-Transfusion Dependent (Stable Dose of Ruxolitinib) Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.
The Number Participants Achieving >=50% RBC Transfusion Burden Reduction From Baseline Over Any 84-Day Period (Cohorts 2 and 3B Only) Primary Treatment Period	10 Participants	19 Participants	—	—
The Number Participants Achieving >=50% RBC Transfusion Burden Reduction From Baseline Over Any 84-Day Period (Cohorts 2 and 3B Only) Entire Treatment Period	10 Participants	20 Participants	—	—

SECONDARY outcome

Timeframe: Baseline and from Day 1 through end of treatment (up to approximately 232 weeks)

Population: Intent-to-treat (ITT) population: All enrolled participants regardless of whether or not the participant received luspatercept.

Symptoms response improvement will be assessed using the number of participants who achieve ≥ 50% reduction in fatigue symptoms. Fatigue is 1 out of 10 total symptoms scored on a 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be). The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment. Baseline is defined as the last value on or before the first dose of study drug. Last Available = Last available assessment on or before the end of the treatment period. Mean = Mean value of the weekly assessments over the treatment period.

Outcome measures

Outcome measures
Measure	Cohort 1: Anemia Only n=22 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 2: RBC-Transfusion Dependent n=21 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3A: Anemia Only (Stable Dose of Ruxolitinib) n=14 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3B: RBC-Transfusion Dependent (Stable Dose of Ruxolitinib) n=38 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.
The Number of Participants Who Achieve ≥ 50% Reduction in Fatigue Symptom as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Primary Treatment Period (Last Available)	4 Participants	2 Participants	4 Participants	10 Participants
The Number of Participants Who Achieve ≥ 50% Reduction in Fatigue Symptom as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Entire Treatment Period (Last Available)	4 Participants	1 Participants	4 Participants	7 Participants
The Number of Participants Who Achieve ≥ 50% Reduction in Fatigue Symptom as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Primary Treatment Period (Mean)	5 Participants	1 Participants	3 Participants	5 Participants
The Number of Participants Who Achieve ≥ 50% Reduction in Fatigue Symptom as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Entire Treatment Period (Mean)	4 Participants	0 Participants	3 Participants	5 Participants

SECONDARY outcome

Timeframe: Baseline and from Day 1 through end of treatment (up to approximately 232 weeks)

Population: Intent-to-treat (ITT) population: All enrolled participants regardless of whether or not the participant received luspatercept.

TSS includes 10 items - worst fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers, scored on a 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be). For participants who completed at least six of these 10 items, the MPN-SAF TSS was computed as the average of the observed items multiplied by 10 to achieve a 0-to-100 scale. The MPN-SAF TSS thus had a possible range of 0 to 100. The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment. Baseline is defined as the last value on or before the first dose of study drug. Last Available = Last available assessment on or before the end of the treatment period. Mean = Mean value of the weekly assessments over the treatment period.

Outcome measures

Outcome measures
Measure	Cohort 1: Anemia Only n=22 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 2: RBC-Transfusion Dependent n=21 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3A: Anemia Only (Stable Dose of Ruxolitinib) n=14 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3B: RBC-Transfusion Dependent (Stable Dose of Ruxolitinib) n=38 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.
The Number of Participants Who Achieve ≥ 50% Reduction in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Primary Treatment Period (Mean)	2 Participants	2 Participants	3 Participants	6 Participants
The Number of Participants Who Achieve ≥ 50% Reduction in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Entire Treatment Period (Mean)	2 Participants	2 Participants	3 Participants	6 Participants
The Number of Participants Who Achieve ≥ 50% Reduction in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Primary Treatment Period (Last Available)	2 Participants	2 Participants	2 Participants	9 Participants
The Number of Participants Who Achieve ≥ 50% Reduction in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Entire Treatment Period (Last Available)	2 Participants	1 Participants	2 Participants	7 Participants

SECONDARY outcome

Timeframe: Day 169 and End of treatment (up to approximately 232 weeks)

Population: ITT population with available health related quality of life (HRQOL) assessments. (Intent-to-treat (ITT) population: All enrolled participants regardless of whether or not the participant received luspatercept.)

The Functional Assessment of Cancer Therapy - Anemia (FACT-An) questionnaire includes 47 items rating on a 5-point Likert scale from 0 (not at all) to 4 (very much) on five primary subscales: * Physical well-being (sum of 7 items, score range from 0-28) * Social/Family well-being (sum of 7 items, score range from 0-28) * Emotional well-being (sum of 6 items, score range from 0-24) * Functional well-being (sum of 7 items, score range from 0-28) * Anemia-related symptoms (sum of 20 items, score range from 0-80) A total score for the FACT-An can be calculated by summing the five primary subscales with a score range from 0-188. Higher scores representing better quality of life. Baseline is defined as the last value on or before the first dose of study drug.

Outcome measures

Outcome measures
Measure	Cohort 1: Anemia Only n=9 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 2: RBC-Transfusion Dependent n=9 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3A: Anemia Only (Stable Dose of Ruxolitinib) n=8 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3B: RBC-Transfusion Dependent (Stable Dose of Ruxolitinib) n=14 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.
Mean Changes in the Functional Assessment of Cancer Therapy - Anemia (FACT-An) Total Scores Over the Study Compared to Baseline Day 169	-10.4 Score on a scale Standard Deviation 13.23	-15.7 Score on a scale Standard Deviation 14.24	-9.4 Score on a scale Standard Deviation 9.24	5.0 Score on a scale Standard Deviation 21.77
Mean Changes in the Functional Assessment of Cancer Therapy - Anemia (FACT-An) Total Scores Over the Study Compared to Baseline End of Treatment	-15.9 Score on a scale Standard Deviation 18.35	-16.6 Score on a scale Standard Deviation 16.80	-12.6 Score on a scale Standard Deviation 10.03	-14.2 Score on a scale Standard Deviation 21.98

SECONDARY outcome

Timeframe: Day 169 and End of treatment (up to approximately 232 weeks)

Population: Intent-to-treat (ITT) population: All enrolled participants regardless of whether or not the participant received luspatercept.

The European Quality of Life 5D-5L Scale (EQ-5D-5L) assesses general health-related quality of life. Health is defined in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Responses are coded so that a '1' indicates no problem, and '5' indicates the most serious problem. The responses for the 5 dimensions are combined in a 5-digit number. The EQ-5D-5L health utility index for this analysis will be derived using the United Kingdom (UK) value sets based on UK time trade-off (TTO) valuation techniques and will use the Decision Support Unit (DSU) model to cross-walk to the EQ-5D-3L value set from the UK to derive a single index value. The EQ-5D-3L health utility index based on the UK population weights range from -0.594 to 1.0 with higher scores indicating higher health utility.

Outcome measures

Outcome measures
Measure	Cohort 1: Anemia Only n=11 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 2: RBC-Transfusion Dependent n=9 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3A: Anemia Only (Stable Dose of Ruxolitinib) n=8 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3B: RBC-Transfusion Dependent (Stable Dose of Ruxolitinib) n=14 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.
Mean Change in EQ-5D-5L Utility Score Compared to Baseline Day 169	-0.043 Score on a scale Standard Deviation 0.1466	-0.063 Score on a scale Standard Deviation 0.1152	-0.126 Score on a scale Standard Deviation 0.1246	0.005 Score on a scale Standard Deviation 0.1084
Mean Change in EQ-5D-5L Utility Score Compared to Baseline End of Treatment	-0.029 Score on a scale Standard Deviation 0.1029	-0.120 Score on a scale Standard Deviation 0.1740	-0.129 Score on a scale Standard Deviation 0.1812	-0.103 Score on a scale Standard Deviation 0.2055

SECONDARY outcome

Timeframe: From first dose through 42 days after the last dose (up to approximately 238 weeks)

Population: Safety population: All enrolled participants who received at least 1 dose of luspatercept.

TEAE is defined as any AEs that begin or worsen on or after the day of the first dose. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. An SAE is any AE occurring at any dose that: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or constitutes an important medical event. The severity/intensity of AEs will be graded based on the Common Terminology Criteria for Adverse Events (CTCAE, version 4.03) where Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death.

Outcome measures

Outcome measures
Measure	Cohort 1: Anemia Only n=22 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 2: RBC-Transfusion Dependent n=21 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3A: Anemia Only (Stable Dose of Ruxolitinib) n=14 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.	Cohort 3B: RBC-Transfusion Dependent (Stable Dose of Ruxolitinib) n=38 Participants Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant's dose may also be delayed, reduced, or discontinued, depending on the specific criteria.
The Number of Participants Treatment-Emergent Adverse Events (TEAE) Participants with at Least One TEAE	21 Participants	19 Participants	13 Participants	36 Participants
The Number of Participants Treatment-Emergent Adverse Events (TEAE) Participants with at Least One Treatment-Related TEAE	14 Participants	5 Participants	7 Participants	19 Participants
The Number of Participants Treatment-Emergent Adverse Events (TEAE) Participants with at Least One Serious TEAE	8 Participants	8 Participants	4 Participants	17 Participants
The Number of Participants Treatment-Emergent Adverse Events (TEAE) Participants with at Least One Treatment-Related Serious TEAE	1 Participants	0 Participants	0 Participants	2 Participants
The Number of Participants Treatment-Emergent Adverse Events (TEAE) Participants with at Least One TEAE Grade >=3	9 Participants	11 Participants	4 Participants	24 Participants
The Number of Participants Treatment-Emergent Adverse Events (TEAE) Participants with at Least One Treatment-Related TEAE Grade >=3	0 Participants	1 Participants	2 Participants	7 Participants
The Number of Participants Treatment-Emergent Adverse Events (TEAE) Participants with at Least One TEAE Leading to Dose Interruption	2 Participants	2 Participants	3 Participants	12 Participants
The Number of Participants Treatment-Emergent Adverse Events (TEAE) Participants with at Least One Treatment-Related TEAE Leading to Dose Interruption	1 Participants	1 Participants	1 Participants	4 Participants
The Number of Participants Treatment-Emergent Adverse Events (TEAE) Participants with at Least One TEAE Leading to Dose Reduction	1 Participants	0 Participants	2 Participants	2 Participants
The Number of Participants Treatment-Emergent Adverse Events (TEAE) Participants with at Least One Treatment-Related TEAE Leading to Dose Reduction	1 Participants	0 Participants	2 Participants	2 Participants
The Number of Participants Treatment-Emergent Adverse Events (TEAE) Participants with at Least One TEAE Leading to Study Drug Withdrawn	1 Participants	2 Participants	1 Participants	5 Participants
The Number of Participants Treatment-Emergent Adverse Events (TEAE) Participants with at Least One Treatment-Related TEAE Leading to Study Drug Withdrawn	0 Participants	0 Participants	0 Participants	1 Participants
The Number of Participants Treatment-Emergent Adverse Events (TEAE) Participants with at Least One TEAE Leading to Death	1 Participants	2 Participants	0 Participants	5 Participants
The Number of Participants Treatment-Emergent Adverse Events (TEAE) Participants with at Least One Treatment-Related TEAE Leading to Death	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment.