Blood and Lymph Conditions

Diseases and Abnormalities at or Before Birth

All Conditions

Symptoms and General Pathology

Rare Diseases

Anemia, Sickle Cell

Thalassemia

Anemia

Hemolysis

Anemia, Hemolytic

Anemia, Hemolytic, Congenital

Hematologic Diseases

Hemoglobinopathies

Genetic Diseases, Inborn

Sickle Cell Anemia

Patients with SCD who are chronically transfused (in the U.S. and Brazil)

Patients with thalassemia who are chronically transfused in the U.S.

Patients in U.S. with pediatric oncologic diagnoses with hypo-proliferative bone marrow requiring single unit red blood cell transfusion

Allogenic blood donors in the US (estimated: 10,200) and allogenic blood donors in Brazil (estimated: 2,100) with extended donation genotyping using an investigational hematology array.

Simple RBC transfusion or partial manual exchange

Red Blood Cell (RBC) Transfusion

Eldad A Hod, MD

Brian Custer, PhD, MPH

Red Blood Cell - IMProving trAnsfusions for Chronically Transfused recipients (RBC-IMPACT) is an observational cohort study to assess donor, component, and recipient factors that contribute to RBC efficacy in chronically and episodically transfused patients. The objective of the study is to determine how specific genetic and non-genetic factors in donors and recipients may impact RBC survival after transfusion - in short, what factors on both the donor and recipient side may improve the efficacy of the transfusion.

Sickle cell disease (SCD) and thalassemia are genetic disorders inducing anemia of differing pathophysiology. A primary therapy for preventing certain SCD complications (e.g., stroke) and for thalassemia major is regular red blood cell (RBC) transfusion, coupled with iron chelation to prevent the complications of transfusion-induced iron overload. For patients with pediatric hematology-oncology diagnoses with chemotherapy-induced aplasia, RBC transfusion is also common, but the degree of transfusion-induced iron overload and its implications for these patients is incompletely understood. Because iron-related tissue toxicity is a major cause of morbidity and mortality in regularly transfused patients, developing strategies to minimize iron loading and iron toxicity is a key objective of this proposal (study Aim #2), stemming from the objective to optimize RBC unit characteristics that patients with SCD and thalassemia receive beyond RBC phenotype matching for Rh C, E and K antigens (study Aim #1). The study will enroll patients with SCD, thalassemia or pediatric oncologic diagnoses receiving eligible transfusion at 6 hospital sites in the United States, as well as patients with SCD at 5 hemocenters in Brazil.

Specimens to be stored for future use from enrolled red cell transfusion recipients include whole blood, plasma and serum.

The study will also retain a sample of packed RBCs from the transfused RBC unit, and a retention tube from the donor of that transfused unit (to be used for extended genotyping but not retained in a long-term biorepository).

Red Blood Cell - IMProving trAnsfusions for Chronically Transfused Recipients

Red Blood Cell - IMProving trAnsfusions for Chronically Transfused Recipients (RBC-IMPACT)

De-identified public use datasets will be created and delivered to NHLBI at the end of the study (and end of the REDS-IV-P program) and will be made available indefinitely for future analysis

Recipient oxidative stress pre-transfusion is associated with "RBC survival"

Recipient inflammation pre-transfusion is associated with "RBC survival"

Transfusion reactions are associated with "RBC survival"

Change in hemoglobin A or hemoglobin level per day in between subsequent transfusion episodes, for sickle cell disease and thalassemia cohorts, respectively

For all groups participating, change in serum iron measured from immediately prior to 2 hours post-transfusion

Hemoglobin increment \[defined as Hb/HbA(post-transfusion)visit(i) - Hb/HbA(pre-transfusion)visit(i)\] is associated with "RBC survival"

Includes serum iron, indirect bilirubin, or plasma free hemoglobin

Hepcidin level at time of transfusion is a predictor of change in iron parameters (i.e., transferrin saturation, serum iron) following transfusion

NTBI levels in patients with pediatric oncologic diagnoses with aplasia are elevated at baseline and increase following transfusion

Increased NTBI, serum iron, or transferrin saturation following transfusion is associated with increased risk of clinical adverse effects (i.e., new infections, SCD complications)

National Heart, Lung, and Blood Institute (NHLBI)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Westat

Neoplasms

Myeloproliferative Disorders

Polycythemia Vera

Polycythemia

Primary Myelofibrosis

Thrombocytosis

Thrombocythemia, Essential

Bone Marrow Diseases

Chronic Myeloproliferative Disorders

Essential Thrombocythemia

Hematinics

All Drugs and Chemicals

Luspatercept

Epoetin Alfa

Subjects across each of the cohorts (Cohort 1, Cohort 2, Cohort 3A, and Cohort 3B) will receive luspatercept.

Luspatercept is a recombinant fusion protein consisting of a modified form of the extracellular domain of the human active in receptor type IIB linked to the IgG1 Fc domain. Luspatercept, through a mechanism of action different from erythropoietin, works to correct ineffective erythropoiesis by promoting late-stage maturation of erythroblasts.

Bristol-Myers Squibb

This is a Phase 2, multicenter, open-label study to evaluate the efficacy and safety of luspatercept in subjects with MPN-associated myelofibrosis and anemia with and without RBC-transfusion dependence. The study is divided into a Screening Period, a Treatment Period (consisting of a Primary Phase, a Day 169 Disease Response Assessment, and an Extension Phase), followed by a Posttreatment Follow-up Period.

Subjects satisfying the eligibility criteria will be assigned to 1 of the following cohorts (which are enrolling in parallel) based on their eligibility:

* Cohort 1 (subjects with anemia only that are not currently receiving RBC transfusions) - Cohort 2: (subjects that are RBC-transfusion dependent)
* Cohort 3A: (subjects on ruxolitinib as part of their standard of care therapy that have anemia only)
* Cohort 3B: (subjects on ruxolitinib as part of their standard of care therapy that are RBC-transfusion dependent) Overall, the study will enroll approximately 100 subjects worldwide.

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

A Phase-2 Study To Determine Efficacy and Safety of Luspatercept in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis and Anemia With or Without Red Blood Cell-Transfusion Dependence

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Apparent volume of distribution of the central compartment

Time to reach the maximum concentration for the first dose (Cmax)

Maximum concentration for the first dose (Cmax) at steady state for the starting dose

Area under the concentration-time curve at the steady state for the starting dose

The ADA status of a participant during treatment is determined based on the longitudinal ADA results as follows:

Negative: All samples (baseline and post-baseline) are negative. Positive to treatment-emergent ADA: At least one post-baseline sample is positive if the baseline sample is negative, or at least one post-baseline sample is positive with a titer ≥ 4-fold of the baseline titer if the baseline sample is positive

Calculated based on average hemoglobin measurements collected during the treatment period.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. The baseline RBC transfusion is defined as average number of RBC units/28 days over the 84 days period immediately prior to the C1D1 date.

The number of participants with a Mean hemoglobin increase of ≥ 1.5 g/dL from baseline over any consecutive 84-day period without an RBC transfusion. 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 all non-missing Hgb records within 28 days on or prior to date of first dose (or date of enrollment if not treated).

Celgene

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 1: Anemia Only

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) 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 3A: Anemia Only (Stable Dose of Ruxolitinib)

Cohort 3B: RBC-Transfusion Dependent (Stable Dose of Ruxolitinib)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Bristol-Myers Squibb Study Director

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

The Number of Participants With Anemia Responses Over Any 84-Day Period During the Primary Treatment Period

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 During the Primary Treatment Period

Duration of Anemia Response

Primary Treatment Period

Entire Treatment Period

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 RBC Units Transfused Per Participant Per 28 Days (Cohorts 2 and 3B Only)

The Number Participants Achieving >=50% RBC Transfusion Burden Reduction From Baseline Over Any 84-Day Period (Cohorts 2 and 3B Only)

Primary Treatment Period (Last Available)

Entire Treatment Period (Last Available)

Primary Treatment Period (Mean)

Entire Treatment Period (Mean)

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)

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)

Day 169

End of Treatment

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.)

Mean Changes in the Functional Assessment of Cancer Therapy - Anemia (FACT-An) Total Scores Over the Study Compared to Baseline

Mean Change in EQ-5D-5L Utility Score Compared to Baseline

Participants with at Least One TEAE

Participants with at Least One Treatment-Related TEAE

Participants with at Least One Serious TEAE

Participants with at Least One Treatment-Related Serious TEAE

Participants with at Least One TEAE Grade >=3

Participants with at Least One Treatment-Related TEAE Grade >=3

Participants with at Least One TEAE Leading to Dose Interruption

Participants with at Least One Treatment-Related TEAE Leading to Dose Interruption

Participants with at Least One TEAE Leading to Dose Reduction

Participants with at Least One Treatment-Related TEAE Leading to Dose Reduction

Participants with at Least One TEAE Leading to Study Drug Withdrawn

Participants with at Least One Treatment-Related TEAE Leading to Study Drug Withdrawn

Participants with at Least One TEAE Leading to Death

Participants with at Least One Treatment-Related TEAE Leading to Death

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

The Number of Participants Treatment-Emergent Adverse Events (TEAE)

All treated participants with available serum concentration measurements

CL/F (L/Day)

V1/F (L)

Ka (Day-1)

T1/2 (Day)

Tmax (Day)

Cmax (µg/mL)

Cmax.ss (µg/mL)

AUCss (Day* µg/mL)

Positive

Negative

The Number of Participants With Antidrug Antibody (ADA) Measurements

Intent-to-treat (ITT) population: All enrolled participants regardless of whether or not the participant received luspatercept. Pre-specified to be collected for Cohorts 1 and 3A only.

Mean Changes in Hemoglobin Over the Study Compared to Baseline in the Absence of RBC Transfusions (Cohorts 1 and 3A)

Intent-to-treat (ITT) population: All enrolled participants regardless of whether or not the participant received luspatercept. Prespecified to be reported for Cohorts 1 and 3A only.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Red Blood Cell - IMProving trAnsfusions for Chronically Transfused Recipients	NCT05255445	Sickle Cell Dis... Thalassemia Pediatric Cance...	Red Blood Cell ...	-	Westat
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	NCT03194542	Primary Myelofi... Anemia	Luspatercept	18 Years -	Celgene

Spots Global Cancer Trial Database for red blood cell (rbc) transfusion